WO2025264860A2

WO2025264860A2 - Methods of treating post-covid airway disease

Info

Publication number: WO2025264860A2
Application number: PCT/US2025/034258
Authority: WO
Inventors: Samir Gautam
Original assignee: Yale University
Current assignee: Yale University
Priority date: 2024-06-18
Filing date: 2025-06-18
Publication date: 2025-12-26
Anticipated expiration: 2026-12-18

Abstract

Airway diseases in patients with Long COVID and other post-viral conditions have been identified, and methods of treating the same are provided. The methods typically include administering a subject in need thereof, an effective amount of an inhibitor to treat the disease or disorder. Some forms of the methods include detecting one or more symptoms of the disease or disorder in the subject before treatment. Also provided are pharmaceutical compositions for use in the methods.

Description

METHODS OF TREATING POST-COVID AIRWAY DISEASE CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No. 63/661,496 filed on June 18, 2024, and U.S. Provisional Application No.63/661,501 filed on June 18, 2024, the contents of each of which is incorporated herein in its entirety. REFERENCE TO THE SEQUENCE LISTING The Sequence Listing submitted as an XML file named “YU8893PCT_ST26.xml,” created on June 17, 2025, and having a size of 78,513 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.834(c)(1). FIELD OF THE INVENTION The disclosed invention is generally in the field of airway diseases and specifically in the area of methods for treating airway hyper-reactivity in Long COVID. BACKGROUND OF THE INVENTION Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), post-acute COVID-19 syndrome, and long-haul COVID, presents a complex and often debilitating array of symptoms that persist for months after the acute phase of COVID-19 has resolved. More than 200 symptoms have been identified with impacts on multiple organ systems, including fatigue, brain fog, shortness of breath, cough, joint pain, and more. At least 65 million individuals worldwide are estimated to have long COVID, with cases increasing daily (Davis et al., Nature Reviews Microbiology, 21, 133–146 (2023)). The condition can affect individuals regardless of the severity of their initial illness. Long COVID not only poses significant challenges to the affected individuals' physical health but also impacts their mental well-being and quality of life. It is known that SARS-CoV-2 infection may trigger new airway disease, but this phenomenon is underrecognized and no effective treatments have been identified. The underlying mechanisms also remain unknown, and scientific research is ongoing to unravel the underlying causes. Currently, the standard of care for this condition is supportive rather than disease-modifying, as it consists of symptom-based treatments and rehabilitation services. Thus, there is a need to develop accurate diagnostic methods and effective therapies for Long COVID. It is an object of the invention to provide methods of using therapeutic agents for treating Long COVID and other post-viral conditions, especially for a subset of patients that have developed airway hyper-reactivity. 45740907.1 1 SUMMARY OF THE INVENTION Methods of treating post-viral airway disease including, but not limited to post-COVID airway disease, as well as methods of treating Long COVID, are provided. The methods typically include administering a subject in need thereof an effective amount of (i) an inhibitor of human thymic stromal lymphopoietin (TSLP); (ii) an inhibitor of the interleukin-4 receptor (IL-4R) signaling pathway, optionally an inhibitor of IL-4R, IL-4, IL-13, or STAT6; (iii) an inhibitor of interleukin-5 (IL-5); (iv) an inhibitor of c-Kit; (v) an inhibitor of Bruton's tyrosine kinase (Btk); (vi) an inhibitor of MRGPRX2; (vii) an inhibitor of Transient Receptor Potential A1 (TRPA1), an inhibitor of TRPV4, and/or an agonist of TRPM8; (viii) an inhibitor of a Protease Receptor, optionally PAR2; (ix) an inhibitor of Interleukin-33 (IL-33); (x) an inhibitor of Chemoattractant Receptor-Homologous Molecule Expressed on Th2 cells (CRTH2); (xi) an inhibitor of Nav1.7; (xii) an inhibitor of Nav1.8; (xiii) an inhibitor of nerve growth factor (NGF); (xiv) an inhibitor of P2X3; (xv) an inhibitor of an eicosanoid, eicosanoid receptor, or an enzyme necessary for synthesis optionally CystLT1, 5-lipoxygenase, and/or PGD2; and/or (xvi) a modulator of the salience network dysfunction optionally wherein the modulator is an NMDAR antagonist, a 5-HT2A agonist, and/or a neurosteroid. In some forms, the subject has been diagnosed with a post-viral airway disease. In some embodiments, the methods include first diagnosing the subject with a post-viral airway disease by detecting one or more symptoms thereof. In some forms, the subject has been diagnosed with Long COVID. In some embodiments, the methods include first diagnosing the subject with Long COVID by detecting one or more symptoms thereof. In some forms, the viral infection preceding or otherwise leading to the airway disease is selected from the group consisting of SARS-CoV-2, other common human coronaviruses (e.g. types 229E, NL63, OC43, HKU1), adenoviruses, human metapneumovirus, influenza virus, parainfluenza virus, respiratory syncytial virus, and rhinoviruses. 45740907.1 2 In some forms, the subject has, and/or the diagnosing includes detection of, a positive result by bronchoprovocation testing. Bronchoprovocation can include exposing the subject’s airway to a respiratory irritant optionally wherein the irritant is a chemical compound, optionally selected from methacholine, mannitol, histamine, or acetaldehyde, or physiologic exposure optionally selected from hyperventilation or exercise. In some forms, the subject has, and/or the diagnosing includes detection of, one or more low type 2 (T2) inflammation biomarkers. Low type 2 (T2) inflammation biomarker(s) can include one or more of blood eosinophils (eos) count less than 300, serum immunoglobulin E (IgE) levels less than 150 and exhaled nitric oxide (FeNO) levels less than 25. In some forms, the subject has, and/or the diagnosing includes detection of, forced expiratory volume in 1 second (FEV1) variability. In some forms, the subject does not have, and/or the diagnosing includes determination of, the absence of asthma. In some forms, the subject is not being treated with, and/or the diagnosing includes determination that the subject is not eligible for treatment with, oral glucocorticoids. In some forms, the subject has, and/or the diagnosis includes detection of, airway hyper- reactivity (AHR) and/or Small Airway Disease (SAD). In some forms, the subject has or had a SARS-CoV-2 infection. In some forms, the subject has, and/or the diagnosis includes detection of, a positive SARS-CoV-2 viral test, optionally wherein the viral test includes one or more of a reverse transcription polymerase chain reaction (RT-PCR) test, antigen test, or serologic (antibody) test. In some forms, the subject had and/or the diagnosis includes detection of, severe acute COVID or mild acute COVID or no COVID symptoms. In some forms, the subject has Small airway disease (PC-SAD), Large/upper airway disease (PC-LAD), Post-COVID Interstitial Lung Disease (PC-ILD), Post-COVID Dysfunctional Breathing (PC-DB), or a combination thereof. For example, the subject can have PC-SAD; PC-LAD; PC-SAD and PC-LAD; PC-SAD, PC-LAD, and PC-DB; PC-SAD and PC- DB; PC-LAD and PC-DB; or each of the foregoing in further combination with PC-ILD. In some forms, the inhibitor is an inhibitory polypeptide such as, but not limited to, an antibody; a small molecule or peptidomimedic, or an inhibitory nucleic acid that targets genomic or expressed nucleic acids (e.g., mRNA) encoding the target molecule, or a vector that encodes an inhibitory nucleic acid. Exemplary inhibitors and pharmaceutical compositions formed therewith are also provided. 45740907.1 3 Additional advantages of the disclosed method will be set forth in part in the description which follows, and in part will be understood from the description, or may be learned by practice of the disclosed method. The advantages of the disclosed method will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed. BRIEF DESCRIPTION OF THE DRAWINGS Figures 1A-1C are images showing the results of a retrospective study of Long COVID patients leading to the identification of previously unappreciated patient subclass referred to here as Post-COVID Airway Disease (PCAD). Fig.1A are images showing diffuse parenchymal lung disease (DPLD) and no DPLD. ** Selected CT images were not of patients in this study, but with representative/illustrative images from individuals in the literature. Fig.1B shows comparison of DPLD and non-DPLD patients across various parameters. Fig.1C shows further clinical characteristics of patients with forced expiratory volume (FEV1) variability. Figure 2 is a diagram showing the design, testing, and results of a trial (n=1) identifying a Long COVID patient with treatment-refractory respiratory symptoms and airway hyper- reactivity (AHR) on pulmonary function testing, who was subsequently treated successfully with Tezepelumab. Notably, improvement was noted not only in terms of small airway symptoms, but also in sinonasal symptoms, vocal cord dysfunction, and cough. Figure 3A is a proposed mechanism depicting the current model of PCAD pathophysiology. The model proposes that SARS-CoV-2 infection leads to prolonged sensitization of airway nociceptors, mast cells, parasympathetic efferents, and smooth muscle cells, which leads to airway hyper-reactivity in response to irritant triggers. Figure 3B is an illustration of a proposed pathophysiology and treatment paradigm for Post-COVID small airway disease (PC-SAD). Figure 3C is an illustration of a proposed pathophysiology and treatment paradigm for Post-COVID large and upper airway disease (PC-LAD). Figure 4 is a flowchart depicting study design in Example 3. Patients were divided into two groups based on the presence or absence of parenchymal abnormalities on chest imaging following acute COVID-19. Figure 5 is a graph showing the relative efficacy of airway disease biologics for PCAD. Retrospective analysis was undertaken on a cohort of patients who were administered biologic therapy for a presumptive diagnosis of asthma by the treating physician, but retrospectively found to meet criteria for PCAD. Their response to different mechanistic classes is shown here. 45740907.1 4 DETAILED DESCRIPTION OF THE INVENTION The disclosed invention may be understood more readily by reference to the following detailed description of particular forms and the Example included therein and to the Figures and their previous and following description. It is to be understood that the disclosed method and compositions are not limited to specific synthetic methods, specific analytical techniques, or to particular reagents unless otherwise specified, and, as such, may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular forms only and is not intended to be limiting. I. DEFINITIONS The term “antibody” is used in the broadest sense unless clearly indicated otherwise. Therefore, an "antibody" can be naturally occurring or man-made such as monoclonal antibodies produced by conventional hybridoma technology. Antibodies include monoclonal and polyclonal antibodies as well as fragments and polymers containing the antigen binding domain and/or one or more complementarity determining regions of these antibodies. As used herein, the term "antibody" refers to any form of antibody or antigen binding fragment or recombinant protein, and specifically covers monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multi-specific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they specifically bind the target antigen. Any specific antibody can be used in the methods and compositions provided herein. Thus, in one form the term "antibody" encompasses a molecule including at least one variable region from a light chain immunoglobulin molecule and at least one variable region from a heavy chain molecule that in combination form a specific binding site for the target antigen. The term “variable region” is intended to distinguish such domain of the immunoglobulin from domains that are broadly shared by antibodies (such as an antibody Fc domain). The variable region includes a “hypervariable region” whose residues are responsible for antigen binding. The hypervariable region includes amino acid residues from a “Complementarity Determining Region” or “CDR” (i.e., typically at approximately residues 24-34 (L1), 50-56 (L2) and 89-97 (L3) in the light chain variable domain and at approximately residues 27-35 (H1), 50-65 (H2) and 95-102 (H3) in the heavy chain variable domain; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)) and/or those residues from a “hypervariable loop” (i.e., residues 26-32 (L1), 50-52 (L2) and 91-96 (L3) in the light chain variable domain and 26-32 (H1), 53-55 (H2) and 96-101 (H3) in the heavy chain variable domain; Chothia, C. et al. (1987) “Canonical Structures For The Hypervariable Regions Of Immunoglobulins,” J. Mol. Biol.196:901-917). “Framework Region” or “FR” residues are those variable domain residues other than the hypervariable region residues as herein defined. 45740907.1 5 The term antibody includes monoclonal antibodies, multi-specific antibodies, human antibodies, humanized antibodies, synthetic antibodies, chimeric antibodies, camelized antibodies (See e.g., Muyldermans et al., 2001, Trends Biochem. Sci.26:230; Nuttall et al., 2000, Cur. Pharm. Biotech.1:253; Reichmann and Muyldermans, 1999, J. Immunol. Meth.231:25; International Publication Nos. WO 94/04678 and WO 94/25591; U.S. Patent No.6,005,079), single-chain Fvs (scFv) (see, e.g., see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol.113, Rosenburg and Moore eds. Springer-Verlag, New York, pp.269-315 (1994)), single chain antibodies, disulfide-linked Fvs (sdFv), intrabodies, and anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id and anti-anti-Id antibodies to antibodies of the invention). In particular, such antibodies include immunoglobulin molecules of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass. An “antibody fragment” or “antigen binding fragment” of an antibody is defined as at least a portion of the variable region of the immunoglobulin molecule that binds to its target, i.e., the antigen binding region (also antigen binding domain). In one form it specifically covers single antibodies and clones thereof and anti- antibody compositions with polyepitopic specificity. The antibody of the present methods and compositions can be monoclonal or polyclonal. An antibody can be in the form of an antigen binding antibody fragment including a Fab fragment, F(ab')2 fragment, a single chain variable region, and the like. Fragments of intact molecules can be generated using methods well known in the art and include enzymatic digestion and recombinant means. Thus, the “fragment” may be a recombinant protein, e.g., a fusion protein. As used herein, any form of the “antigen” can be used to generate an antibody that is specific for the target antigen. Thus, the eliciting antigen may be a single epitope, multiple epitopes, or the entire protein alone or in combination with one or more immunogenicity enhancing agents known in the art. The eliciting antigen may be an isolated full-length protein, a cell surface protein (e.g., immunizing with cells transfected with at least a portion of the antigen), or a soluble protein (e.g., immunizing with only the extracellular domain portion of the protein). The antigen may be produced in a genetically modified cell. The DNA encoding the antigen may genomic or non-genomic (e.g., cDNA) and encodes at least a portion of the extracellular domain. As used herein, the term “portion” refers to the minimal number of amino acids or nucleic acids, as appropriate, to constitute an immunogenic epitope of the antigen of interest. Any genetic vectors suitable for transformation of the cells of interest may be employed, including but not limited to adenoviral vectors, plasmids, and non-viral vectors, such as cationic lipids. In one form, the antibody of the methods and compositions herein specifically bind at least a portion of the extracellular domain of the target antigen of interest. 45740907.1 6 The antibodies or antigen binding fragments thereof provided herein may be conjugated to a “bioactive agent.” As used herein, the term “bioactive agent” refers to any synthetic or naturally occurring compound that binds the antigen and/or enhances or mediates a desired biological effect. In one form, the binding fragments useful in the present invention are biologically active fragments. As used herein, the term “biologically active” refers to an antibody or antibody fragment that is capable of binding the desired the antigenic epitope and directly or indirectly exerting a biologic effect. “Bispecific” antibodies are also useful in the present methods and compositions. As used herein, the term “bispecific antibody” refers to an antibody, typically a monoclonal antibody, having binding specificities for at least two different antigenic epitopes. In one form, the epitopes are from the same antigen. In another form, the epitopes are from two different antigens. Methods for making bispecific antibodies are known in the art. For example, bispecific antibodies can be produced recombinantly using the co-expression of two immunoglobulin heavy chain/light chain pairs. See, e.g., Milstein et al., Nature 305:537-39 (1983). Alternatively, bispecific antibodies can be prepared using chemical linkage. See, e.g., Brennan, et al., Science 229:81 (1985). Bispecific antibodies include bispecific antibody fragments. See, e.g., Hollinger, et al., Proc. Natl. Acad. Sci. U.S.A.90:6444-48 (1993), Gruber, et al., J. Immunol.152:5368 (1994). The monoclonal antibodies herein specifically include “chimeric” antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they specifically bind the target antigen and/or exhibit the desired biological activity (U.S. Pat. No.4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA 81: 6851-6855 (1984)). The term “specifically binds” or “immuno-specifically binds” refers to the binding of an antibody to its cognate antigen, while not significantly binding to other antigens. Preferably, an antibody “specifically binds” to an antigen with an affinity constant (Ka) greater than about 10⁵ mol^–1 (e.g., 10⁶ mol^–1, 10⁷ mol^–1, 10⁸ mol^–1, 10⁹ mol^–1, 10¹⁰ mol^–1, 10¹¹ mol^–1, and 10¹² mol^–1 or more) with that second molecule. The term “monoclonal antibody” or “mAb” refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies within the 45740907.1 7 population are identical except for possible naturally occurring mutations that may be present in a small subset of the antibody molecules. As used herein “bronchoprovocation”, also called bronchial challenge, is a pulmonary function test for small airway disease in which airflow (as measured by FEV1) is measured repeatedly upon exposure to increasing severities of an irritant challenge. Such challenges may include exercise, hyperventilation, or inhaled pharmacologic agents (e.g. mannitol, histamine, acetaldehyde, methacholine). The points relating irritant dose to FEV1 are plotted, and a best-fit curve is fitted (either sigmoidal or exponential) to enable interpolation. The most frequently reported outcome of the test is the PD20; this refers to the interpolated dose of irritant that induces a 20 percent drop in FEV1. Other outcomes may be reported as well. For instance, the concentration of an irritant that induces a 20 percent drop in FEV1 is reported as the PC20. The dose of irritant that induces a 15 percent drop in FEV1 is reported as the PD15. The concentration of an irritant that induces a 15 percent drop in FEV1 is reported as the PC15. The terms “individual” and “subject”, and “patient” are used interchangeably, and refer to vertebrates, typically mammals, including, but not limited to, murines, simians, humans, mammalian farm animals and livestock, mammalian sport animals, and mammalian pets (e.g., horse, pig, rabbit, dog, sheep, goat, non-human primate, cow, cat, guinea pig or rodent). Other animals, particularly those susceptible to viral infections, particularly respiratory viral infections, e.g., fish, birds, reptiles, amphibians, etc. are also contemplated. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. A patient can more specifically refer to a subject afflicted with a disease or disorder. “Treatment” or “treating” means to administer a composition to a subject or a system with an undesired condition (e.g., airway hyper-reactivity). The condition can include one or more symptoms of a disease, pathological state, or disorder. Treatment includes medical management of a subject with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological state, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological state, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological state, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological state, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, 45740907.1 8 pathological state, or disorder. It is understood that treatment, while intended to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder, need not actually result in the cure, amelioration, stabilization or prevention. The effects of treatment can be measured or assessed as described herein and as known in the art as is suitable for the disease, pathological condition, or disorder involved. Such measurements and assessments can be made in qualitative and/or quantitative terms. Thus, for example, characteristics or features of a disease, pathological condition, or disorder and/or symptoms of a disease, pathological condition, or disorder can be reduced to any effect or to any amount. “Prevention” or “preventing” means to administer a composition to a subject or a system at risk for an undesired condition. The condition can include one or more symptoms of a disease, pathological state, or disorder. The condition can also be a predisposition to the disease, pathological state, or disorder. The effect of the administration of the composition to the subject can be the cessation of a particular symptom of a condition, a reduction or prevention of the symptoms of a condition, a reduction in the severity of the condition, the complete ablation of the condition, a stabilization or delay of the development or progression of a particular event or characteristic, or reduction of the chances that a particular event or characteristic will occur. As used herein, the terms “effective amount” or “therapeutically effective amount” means a quantity sufficient to alleviate or ameliorate one or more symptoms of a disorder, disease, or condition being treated, or to otherwise provide a desired pharmacologic and/or physiological effect. Such amelioration only requires a reduction or alteration, not necessarily elimination. The precise quantity will vary according to a variety of factors such as subject- dependent variables (e.g., age, immune system health, weight, etc.), the disease or disorder being treated, as well as the route of administration, and the pharmacokinetics and pharmacodynamics of the agent being administered. The term “dosage regime” refers to drug administration regarding formulation, route of administration, drug dose, dosing interval and treatment duration. The term “pharmaceutically acceptable” or “biocompatible” refers to compositions, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The phrase “pharmaceutically acceptable carrier” refers to pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, solvent or encapsulating material involved in carrying or transporting any subject composition, from one organ, or portion of the body, to another organ, or portion of the body. 45740907.1 9 Each carrier must be acceptable” in the sense of being compatible with the other ingredients of a subject composition and not injurious to the patient. The terms “inhibit” or “reduce” in the context of inhibition, mean to reduce, or decrease in activity and quantity. This can be a complete inhibition or reduction in activity or quantity, or a partial inhibition or reduction. Inhibition or reduction can be compared to a control or to a standard level. Inhibition can be measured as a % value, e.g., from 1% up to 100%, such as 5%, 10, 25, 50, 75, 80, 85, 90, 95, 99, or 100%. For example, compositions including a disclosed inhibitor may inhibit or reduce the activity and/or quantity of one or more disclosed mechanisms, pathways, or symptoms by about 10%, 20%, 30%, 40%, 50%, 75%, 85%, 90%, 95%, or 99% from the activity and/or quantity of the same inhibitor in subjects that did not receive or were not treated with the compositions. In some forms, the inhibition and reduction are compared according to the level of mRNAs, proteins, cells, tissues, and organs. The terms “protein” or “polypeptide” or “peptide” refer to any chain of more than two natural or unnatural amino acids, regardless of post-translational modification (e.g., glycosylation or phosphorylation), constituting all or part of a naturally occurring or non- naturally occurring polypeptide or peptide. As used herein “type 2 (T2) inflammation” refers to a class of immune responses associated with allergic, eosinophilic, and related inflammatory conditions. In general, T2 inflammation involves the activation of immune cells, such as T helper type 2 (Th2) cells, type 2 innate lymphoid cells, mast cells, eosinophils, and/or basophils, and the release of certain cytokines and/or lipid mediators therefrom. Common T2 cytokines include interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-9 (IL-9), interleukin-13 (IL-13), interleukin-33 (IL-33), interleukin-25 (IL-25), and thymic stromal lymphopoietin (TSLP). Common T2 lipid mediators include cysteinyl leukotrienes (e.g. LTC₄, LTD₄, LTE₄), lipoxin A4 (LXA₄), and prostaglandin D2 (PGD2). As discussed in more detail below, a subject can be identified as having T2 inflammation based on the presence or absence of T2 inflammation biomarkers. Common T2 inflammation biomarkers measured in clinical practice include: blood eosinophils counts, sputum and/or bronchoalveolar lavage eosinophil counts, total serum IgE antibody levels, specific anti-allergen IgE levels in the serum (measured via allergen testing), and fractional exhaled nitric oxide (FeNO). Less commonly (primarily in research studies), T2 cytokines and/or lipid mediators such as those listed above may be measured. Disclosed are materials, compositions, and components that can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed method and compositions. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while 45740907.1 10 specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a ligand is disclosed and discussed and a number of modifications that can be made to a number of molecules including the ligand are discussed, each and every combination and permutation of ligand and the modifications that are possible are specifically contemplated unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited, each is individually and collectively contemplated. Thus, in this example, each of the combinations A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D. Likewise, any subset or combination of these is also specifically contemplated and disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D. Further, each of the materials, compositions, components, etc. contemplated and disclosed as above can also be specifically and independently included or excluded from any group, subgroup, list, set, etc. of such materials. These concepts apply to all aspects of this application including, but not limited to, steps in methods of making and using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific form or combination of forms of the disclosed methods, and that each such combination is specifically contemplated and should be considered disclosed. All methods described herein can be performed in any suitable order unless otherwise indicated or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the forms and does not pose a limitation on the scope of the forms unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. Use of the term “about” is intended to describe values either above or below the stated value in a range of approx. +/- 10%; in other forms the values can range in value either above or below the stated value in a range of approx. +/- 5%; in other forms the values can range in value 45740907.1 11 either above or below the stated value in a range of approx. +/- 2%; in other forms the values can range in value either above or below the stated value in a range of approx. +/- 1%. The preceding ranges are intended to be made clear by context, and no further limitation is implied. II. METHODS OF TREATMENT Methods of treating a subject in need thereof are provided. A. Subjects to be Treated The subject is typically one that has, is recovering from, or recently recovered from a viral infection, but has the same or different lingering symptoms caused by, or related to, the viral infection. In some forms the subject has post-viral airway disease (PVAD). The viral infection is typically caused by a respiratory virus, such as SARS-CoV-2, other common human coronaviruses (e.g. types 229E, NL63, OC43, HKU1), adenoviruses, human metapneumovirus, influenza virus, parainfluenza virus, respiratory syncytial virus, and rhinoviruses. For example, patients develop new airway hyper-reactivity after influenza infection. (Little et al. Am Rev Resp Dis 118, 295–303 (1978); Laitinen et al. Am Rev Resp Dis 143, 358– 361 (1991)) There is also a connection between early-life respiratory syncytial virus infection and development of airway disease. (Mikhail & Grayson. Annals of Allergy, Asthma and Immunology vol.123, 352–358 (2019)) However, while some guidelines may indicate viral infection as a trigger of exacerbations for pre-existing asthma, they do not recommend a unique therapeutic strategy for such exacerbations. (2024 GINA Main Report - Global Initiative for Asthma - GINA. https://ginasthma.org/2024-report/) Furthermore, they do not define the development of new airway disease after viral infection as a distinct clinical entity. (Romero- Tapia et al. J Clin Med 12, (2023); Lamothe et al. Current Opinion in Pulmonary Medicine vol. 30287–293 (2024)). Thus, although exemplified and tested in the examples below is Post- COVID Airway Disease (PCAD), this clinical phenomena is disclosed as a post-viral airway disease (PVAD) that can be caused by any respiratory virus, including but not limited to those specifically mentioned above. PCAD can be considered a subtype of PVAD. Thus, the pathophysiologic framework and treatment paradigm for PCAD proposed herein can be applied analogously to PVAD, and all of the disclosure herein discussed with respect to PCAD is expressed disclosed for PVAD, including but not limited to, the viruses expressed recited above. In some forms, the subject has Post-COVID Airway Disease (PCAD), typically as part of the larger syndrome of Long COVID affecting multiple organ systems. Thus, methods for treating Long COVID are also provided. Most typically, at least one of the clinical traits is airway hyper-reactivity (AHR). In some forms, the methods include administering a subject in need thereof, e.g., a subject with Long-COVID and optionally PCAD, an effective amount of a therapeutic agent to 45740907.1 12 treat the same. In a particular form, a method for treating Long-COVID and optionally PCAD or treating one or more symptoms associated with a PCAD in a subject in need thereof is provided, the method typically including administering to a subject an effective amount of a pharmaceutical formulation containing one or more of the compounds disclosed herein. Additional patient subclasses are described below. 1. Long COVID In some forms, the subject has Long COVID. Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC) or post-acute COVID-19 syndrome or long-haul COVID, refers to a condition where individuals continue to experience any symptom for weeks or months after the acute phase of COVID-19 illness has resolved. The continuation or development of new symptoms can occur at any time after the initial infection, with symptoms lasting for at least three months with no other explanation (Soriano et al., Lancet Infect Dis 22, e102–e107 (2022)). The CDC estimates that 6% of the US population is affected (Montoy, et al. MMWR Morb Mortal Wkly Rep 72, 859–865 (2023)). Accordingly, expert opinions such as that of the NIH Taskforce on Cardiopulmonary Long COVID generally indicate that it affects at least 10% of the world’s population (Rischard, et al. Chest vol.165978–989, (2024)). Symptoms of Long COVID may be the same or different than symptoms of acute COVID-19, and some symptoms are similar to those of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Symptoms of Long COVID can include: fatigue, feeling tired, weakness, brain fog (problems concentrating or thinking), headaches, tremor, rapid or pounding heartbeat, feeling of skipped heartbeats (palpitations), dizziness upon standing, symptoms that worsen after physical or mental activity (known as post-exertional malaise), gastrointestinal symptoms including stomach pain, diarrhea, and/or constipation, loss of or change in smell and/or taste, thirst (for instance, dry mouth), cough, changes in comfort or capacity for sex and/or desire for sex, chest pain, tightness, or pressure, hearing problems, including hearing loss or ringing in the ears (tinnitus), shortness of breath, muscle and/or joint pain, back pain, sleep apnea, fever, sweats, and/or chills, hair loss, sleep problems, including insomnia, bladder problems, including difficulty urinating or incontinence, vision problems, such as blurry vision, sensitivity to light, floaters, flashing lights, or difficulty reading or focusing eyes, depression, anxiety, swelling of the legs, problems with teeth, foot pain, skin rash, abnormal movements, skin color changes (for instance, skin that is red, white, or purple), or changes in menstrual cycle. Some people may experience only one of these (or other) symptoms, while others may have two or more. Symptoms can vary greatly from one person to the next. COVID-19 can alter the function of multiple organs throughout the body, including the brain, heart, lungs, liver, and kidneys, among others. When this happens, it can increase the risk 45740907.1 13 of the development of new medical conditions, including diabetes, kidney disease, heart conditions, neurological conditions, blood clots, postural orthostatic tachycardia syndrome (POTS), a condition in which the heart beats faster when standing up from a lying down position and can cause lightheadedness and fainting. Multiple studies have demonstrated the existence of overlapping symptom clusters, with one characterized by shortness of breath and cough. An estimated 60% fall within the respiratory cluster (Vos, et al. JAMA 328, 1604–1615 (2022)), and several studies show that dyspnea is one of the most common symptoms, affecting >20% of COVID-19 survivors in a systematic review at a median follow up of 126 days. Of note, upper respiratory symptoms are observed as well, especially anosmia (13%), but also including nasal congestion, and issues related to vocal cord dysfunction such shortness of breath, difficulty inspiring air, throat tightness, wheeze, cough, and hoarseness. Pulmonary Long COVID is a term that has come into common use to describe patients with Long COVID and respiratory symptoms. In some forms, Long COVID is an infection- associated chronic condition (IACC) that occurs after SARS-CoV-2 infection and is present for at least 3 months as a continuous, relapsing and remitting, or progressive disease state that affects one or more organ systems. (Fineberg et al. National Academies Press, 2024). Thus, in some forms, the subject for treatment has one or more symptoms that for at least 3 months. In some forms, the 3-month period need not begin immediately after suspected infection. The 3-month period can occur anytime. The rationale for not specifying that duration be counted from the instigating acute SARS-CoV-2 infection is that studies have shown Long COVID symptoms can appear after a period of seemingly normal health. Furthermore, a diagnosis of Long COVID can include, but does not require, objective confirmation of SARS-CoV-2 infection. This is because of issues concerning COVID-19 test sensitivity, availability, access, and reporting. For those patients without a positive test, health care professionals can use their clinical judgement to decide whether the patients’ clinical picture fits a Long COVID diagnosis. Therefore, development of prolonged respiratory symptoms after even suspected SARS-CoV-2 infection, is sufficient of a diagnosis of Long COVID, when the physician believes an infection was previously present. Herein Pulmonary Long COVID will be used as a general term that subsumes three non- exclusive mechanism-based subtypes of disease as discussed herein: (1) Post-COVID Airway Disease (PCAD), which can be further sub-divided into: - Small airway disease (PC-SAD), with symptoms such as wheezing, dyspnea, and/or chest tightness; testable using bronchoprovocation testing (BPT); and 45740907.1 14 - Large/upper airway disease (PC-LAD), with symptoms such as cough, throat tightness, dyspnea, sensation of choking, dysphonia, dysphagia, throat irritation, throat clearing, globus sensation; testable using cough provocation testing in research settings, but may be diagnosed by a physician using history alone. (2) Post-COVID Interstitial Lung Disease (PC-ILD), which refers to fibrosis and other forms of parenchymal lung disease that arise in patients after suffering severe forms of acute COVID. Patients with PC-ILD serve as the comparator for patients without ILD in a study discussed in the Examples below. Of note, PC-ILD and PCAD (and PC-DB, below) can occur in the same patient. (3) Post-COVID Dysfunctional Breathing (PC-DB), refers to the development or worsening of ‘dysfunctional breathing’ after acute COVID. It is believed to be a neurological disease with signs and symptoms that include frequent sighing and yawning, hyperventilation, and dyspnea during speaking, bending, and recumbency. Thus, for example, in some forms, a subject for treatment according to the instantly disclosed methods has: PC-SAD; PC-LAD; PC-SAD and PC-LAD; PC-SAD, PC-LAD, and PC-DB; PC-SAD and PC-DB; or PC-LAD and PC-DB; each alone or further combination with PC-ILD. In addition, respiratory symptoms of PCAD may present simultaneously with extra- pulmonary symptoms of long COVID – which can be an indication that the airway disease is attributable to Long COVID. Common extra-pulmonary symptoms include brain fog, fatigue, post-exertional malaise, headaches, insomnia, myalgias, parasthesias, anxiety, hair loss, tinnitus, palpitations, heartburn, food intolerances, bowel changes, abdominal pain, etc. as introduced above. 2. Airway Hyper-Reactivity, PCAD, PC-ILD, PC-DB In some forms, the subject to be treated has airway hyper-reactivity. It has been discovered that viral infections, such as SARS-CoV-2 infection can induce syndromes characterized by prolonged airway hyper-reactivity. For example, results presented in the retrospective study below shows that SARS-CoV-2 infection leads to prolonged airway hyper- reactivity. Pathophysiologically, this involves sensitization of airway nociceptors, mast cells, 45740907.1 15 parasympathetic efferents, and smooth muscle cells; together, these events lead to airway hyper- reactivity (AHR) in response to irritant triggers (Fig.3A) in a subset of Long COVID subjects. Thus identified is a subclass of Long COVID, referred to herein as Post-COVID Airway Disease (PCAD). Subjects with one form of PCAD, PC-SAD, are characterized as having Long COVID with prolonged airway hyper-reactivity. Therefore, in some forms, the subject to be treated has PCAD or PVAD. In some forms, the subject has PC-SAD and/or PC-LAD. As above, PCAD can be divided into two clinicopathological subtypes, according to a key anatomical distinction between (i) the small airways (PC-SAD) and (ii) the large airways and vocal cords (aka upper airway, PC-LAD). However, the neurobiological circuit that underpins the pathophysiology of each subtype is very similar (Fig.3B and 3C). In both cases, the initiating insults (noxious stimuli) are similar: inhaled allergens (e.g. pollen, dust), chemical irritants (e.g. fumes from cleaning fluids, perfumes), thermal irritants (e.g. cold air), viral infection, and so on. These act on (i) epithelial cells to elicit release of alarmins such as TSLP, (ii) mast cells to elicit release of secondary mediators (like IL-4), and/or (iii) nociceptors directly. This generates an afferent neural signal that is conducted to key sites within the brainstem and limbic system to trigger protective responses. In the small airways, the response is parasympathetic neuron-mediated bronchoconstriction, which produces symptoms such as dyspnea, wheeze, and chest tightness. In the large and upper airways, the primary protective responses are mucus secretion, laryngospasm, and cough. In healthy individuals, exposure to noxious stimuli leads to a brisk but controlled response that resolves promptly. However, after viral infection, there is sensitization at virtually every node along this pathway. In such patients, which are referred to herein as having PCAD, the same noxious exposure leads to excessive and/or prolonged responses that produce pathology rather than protection. Importantly, excessive and prolonged effector responses can themselves serve as a trigger of nociceptor activation, generating a feed-forward loop that drives chronicity of disease. In small airway (PC-SAD), nociceptive hypersensitivity manifests as a clinical trait called airway hyper-reactivity (AHR). This can be measured in animals and humans using bronchoprovocation testing with chemicals such as methacholine. This is a commonly performed clinical test. Importantly, AHR is also a treatable trait, as it is eminently responsive to Tezepelumab (described below). In the large and upper airway (PC-LAD), nociceptive hypersensitivity manifests as a clinical trait called cough hypersensitivity (CHS). This can be measured in humans using provocation testing with chemicals such as capsaicin and citric acid. However, it is used 45740907.1 16 predominantly in research settings and is not a widely available clinical modality. Similarly to AHR, CHS should be considered a treatable trait. Just as a patient may have comorbid asthma, refractory chronic cough (RCC), and/or vocal cord dysfunction (VCD), a patient with Long COVID may have PC-SAD alone, PC-LAD alone, or both in combination. It is important to note that the pathogenic mediators of the two conditions overlap but are not identical; therefore, treatment strategies are similar but not identical. In summary, there are two anatomically distinct, but functionally similar neural circuits in the airways that mediate protective reflexes upon exposure to noxious stimuli. Viral infection leads to sensitization of these circuits, and consequently, pathological effector responses. These give rise to two distinct forms of airway disease (PC-SAD and PC-LAD), each of which can be quantifiably assessed using provocative testing and treated using drugs that target nociception. The disclosed neurobiological model of Long COVID indicates that the common condition of patients with small airway PCAD is AHR. The new model presented herein is in contrast to a survey of recent high-profile commentaries and consensus statements, (Peluso & Deeks. Cell vol.1875500–5529 (2024); Sariol & Perlman. Science vol.3871039–1040 (2025); Hamlin & Blish. Immunity vol.571195– 1214 (2024); Rischard et al. Chest vol.165978–989 (2024); Antar & Cox. Science translational medicine (2024)), Click or tap here to enter text.which attribute post-COVID lung pathogenesis to processes such as fibrosis, chronic viral infection, immunothrombosis, and persistent type 1 inflammation. To the contrary, the disclosed data and the associated model support the conclusion that Pulmonary Long COVID is predominantly an airway disease, which is mediated by a neurophysiologic pathway with the following key nodes: release of alarmins (e.g., TSLP, IL-33); activation, priming and hyperplasia of mast cells; secondary mediators (e.g., cytokines (e.g. IL-4), eicosanoids, proteases, neurotransmitters and neurotrophins); nociceptor activation; limbic system responses; and activation of an endogenous stimuli/feed-forward loop created by efferent neuron activity. The results in the examples below also report that airway hyper-reactivity in subjects can be characterized in various ways. For example, in some forms, the prolonged airway hyper-reactivity in the subjects is triggered by thymic stromal lymphopoietin (TSLP). Human TSLP, also known as IL-7-like cytokine, is a member of IL-2 cytokine family. TSLP is secreted by epithelial cells of thymus, lung, intestine and skin, and to a lesser extent by fibroblasts, airway smooth muscle cells, endothelial cells, mast cells, monocytes, granulocytes and dendritic cells (DC). TSLP is an alarmin that is released in the airway predominantly by epithelial cells and mast cells after 45740907.1 17 detection of airborne threats. Basic science investigations have demonstrated that TSLP induces many of the core pathophysiologic changes in airway hyper-reactivity including phenotypic switching in nociceptors, hyperplasia and priming of mast cells, and smooth muscle hypertrophy. The target cells of TSLP co-express TSLP receptor (thymic stromal lymphopoietin receptor, TSLPR) and IL-7 receptor α chain (IL-7Rα). TSLPR binds to TSLP with high affinity, thereby allosterically activating TSLP, which in turn recruits IL-7Rα to form TSLP-TSLPR-IL- 7Rα ternary complex that can transmit signals. IL-7Rα binds to TSLP-TSLPR with high affinity but binds to TSLP very weakly. Best studied in the context of type 2 asthma, TSLP contributes to tissue eosinophilia, IgE production, and lymphocyte production of IL4, IL-5, and IL-13. These mechanisms drive airway hyper-reactivity. However, TSLP is also generated in non-T2 inflammatory processes and drives non-T2 inflammatory processes that contribute to airway hyper-reactivity. The retrospective study and clinical trial below collectively illustrate it can play an important role in mediating AHR in patients with a PVAD such as PCAD. In some forms, subjects with a PVAD such as PCAD demonstrate lower type 2 (T2) inflammation biomarkers than those present in reactive in conventional airway diseases such as asthma. For example, in some forms, subjects with a PVAD such as PCAD are characterized by one or more of a blood eosinophils (eos) count less than 300, serum immunoglobulin E (IgE) levels less than 150, and/or exhaled nitric oxide (FeNO) levels less than 25. High T2 biomarkers in subjects with PVAD should not prompt treatment with anti-IL-5 or anti-IgE as recommended in the current asthma algorithm. Furthermore, low T2 biomarkers often dissuade clinicians from considering a diagnosis of asthma; they should not dissuade the clinician from considering the disclosed compositions for treatment of a PVAD such as PCAD. In some forms, subjects with a PVAD such as PCAD demonstrate sensitivity to respiratory irritants. This manifests clinically by symptoms of cough, chest tightness, wheeze, and/or shortness of breath upon exposures to environmental irritants such as hot air, cold air, pollen, dust, perfume, cologne, smoke, cleaning fluids, etc. Sensitivity to respiratory irritants can also be demonstrated objectively through bronchoprovocation testing, also called bronchial challenges, as described above. In some forms, subjects with a PVAD such as PCAD demonstrate positive tests for airway hyper-reactivity elicited by methacholine or mannitol. Another important pathological feature in AHR appears to be the presence of primed chymase-positive mast cells in airway smooth muscle; these have been shown to correlate with airway hyper-reactivity in asthma and COPD (Brightling et al. N Engl J Med 346, 1699–1705 (2002); Ballarin et al.186, 233–239 (2012)). Thus, in some forms, the subject shows evidence 45740907.1 18 of cell accumulation and/or activation, particularly in the airway smooth muscle. Methacholine challenge tests indirectly activate these mast cells and the associated airway smooth muscle to induce bronchospasm. In type 2 airway inflammation, carboxypeptidase 3-positive mast cells also accumulate in the epithelium along with eosinophils. These cell types appear to mediate indirect AHR, which is commonly evaluated using osmotic challenges (e.g. mannitol). Mast cell products such as tryptase and carboxypeptidase are elevated in the serum of patients with Long COVID. (Wechsler et al. Allergy 77, 1288–1291 (2022)) The symptoms of Long COVID overlap strikingly with those in mast cell activation syndrome (Theoharides et al. Annals of Allergy, Asthma and Immunology 126, 217–218 (2021); Weinstock et al. International Journal of Infectious Diseases 112, 217 (2021)). In the aftermath of acute COVID, primed mast cells accumulate in the lung, notably more than after influenza (Motta Junior. et al. Front Immunol 11, 574862 (2020); Budnevsky et al. Respir Res 23, 1–10 (2022); Krysko et al. Front Immunol 13, 968981 (2022); Schaller, T. et al. Allergy 77, 2237–2239 (2022)). High levels of alveolar mast cells are present in the lungs of patients with acute COVID and ARDS. An autopsy study (average of 13-day length of stay (LOS)) also showed higher mast cell progenitor cells (MCPs) and IL-4+ cells compared to influenza (average 5d LOS). An autopsy study in allergy has shown that mast cells drop in early injury, and accumulate late but much higher than in influenza. Importantly, they are tryptase and chymase positive. 3. Asthmatic and Non-Asthmatic As shown in the examples below, PCAD can develop in patients who had been diagnosed with asthma prior to developing Long COVID. Thus, in some forms, the subject has asthma or a history of asthma. In some forms, even where the subject has a history of asthma, if airway symptoms last >3 months despite continuation of therapy on therapy that was previously used to successfully control the asthma, the symptoms can be considered to be due to the PCAD disease process and not asthma. On the other hand, if symptoms are limited to a duration of days-to-weeks and self- resolve or respond to oral corticosteroids, the episode can be considered a conventional asthma exacerbation (also known as flare). In some forms, a subject that has or had asthma also presents with the concurrent onset of extra-pulmonary symptoms and/or new onset or worsened sensitivity to hallmark triggers including chemical irritants and/or new onset or worsened sensitivity to respiratory viral infections. Alternatively, the data presented below also shows that PCAD can develop in patients with no prior airway disease, and in those with childhood asthma that had previously resolved Thus, in some forms, the subjects to be treated according to the disclosed methods are non-asthmatic according to one or more traditional criteria. The results presented in the study 45740907.1 19 below show that subjects determined to have Post-COVID Airway Disease and other PVADs can have multiple features that distinguish the condition from asthma. Subjects with asthma can be diagnosed with bronchodilator testing whereas subjects with PCAD usually show negative results with bronchodilator testing. Thus, in some forms, the subject of the disclosed methods are negative according to bronchodilator testing. Subjects with PCAD also demonstrated markedly lower T2 biomarkers than those typical of asthma. The airway disease in Long COVID often develops in the context of multi-system manifestations, which does not occur in asthma. PCAD is a respiratory manifestation of a broader systemic syndrome. Therefore, in some forms, the subject of the disclosed methods does not have asthma. B. Methods of Detection and Diagnosis Any of the described methods can include one or more steps of identifying a subject to be treated for any of the conditions mentioned herein, including, but not limited to Long COVID, PCAD, and other post-viral airway diseases (PVADs). Thus, some of the treatment methods further including detecting, diagnosing, or otherwise determining that a subject has or is at risk of developing, for example, Long COVID, PCAD, or another PVAD. For example, in some forms, identification of subjects with Long COVID can include having prior evidence of positive SARS-CoV-2 viral test (i.e., reverse transcription polymerase chain reaction [RT-PCR] test or antigen test) or serologic (antibody) test. In some forms, the subjects develop severe acute COVID or mild acute COVID or present no symptoms (e.g., are asymptomatic during acute COVID, but nonetheless develop Long COVID). In some forms, identification of subjects with Long COVID can include diagnosis in the absence of definitive SARS-CoV-2 testing. In this case, the clinician may assess that the patient’s history alone is sufficient to make the diagnosis. Specific clues would include (i) symptoms of a viral infection (e.g. fever, cough, congestion, sore throat, malaise and/or myalgias) preceding onset of Long COVID symptoms; and/or (ii) close contact with an individual with acute COVID preceding onset of Long COVID symptoms. In some forms, selection of the subjects for treatment includes identification of one or more symptoms of the condition, e.g. Long COVID, post-viral airway disease, and/or PCAD. Exemplary symptoms of these conditions are discussed above. Thus, in some forms, the methods include a step of detecting one or more of the symptoms and determining the subject has the condition. In some forms, subjects undergo comprehensive clinical workup including history, physical exam, laboratory testing, imaging, and pulmonary function testing, e.g., with a methacholine challenge to evaluate for airway hyper-reactivity. 45740907.1 20 In some forms the subject has been diagnosed by a doctor. In some forms, the subjects show one or more respiratory symptoms including, but not limited to, breathlessness, cough, chest tightness, throat tightness, hoarseness, lower airway wheeze, upper airway wheeze, stridor, choking sensation, dysphonia, dysphagia, sleep disturbance, sensitivity to respiratory irritants, hyperventilation upon exertion, fatigue, nasal congestion, nasal obstruction, loss of smell, post-nasal drip, throat-clearing. In some forms, the subject can have one or more of the respiratory-related symptoms or test results or exclusions mentioned herein. Having one or more of the respiratory-related symptoms mentioned herein in conjunction with or caused by a viral infection and/or associated with the recovery therefrom indicates that the subject has PVAD. In particular forms, the subject is identified as having PCAD by having Long COVID and one or more of the respiratory-related symptoms mentioned herein. Any of the methods can further include tests detecting the one or more respiratory-related symptoms mentioned elsewhere herein. In some forms, subjects test positive according to a methacholine challenge. Methacholine challenge test (also known as bronchoprovocation test) is performed to evaluate how "reactive" or "responsive" a subject’s airways are. During the test, escalating doses of methacholine, a drug that can cause narrowing of the airways, are inhaled. A breathing test is repeated after each dose of methacholine to measure the degree of narrowing or constriction of the airways. The test typically begins with a very small dose of methacholine and, depending on the subject’s response, the doses will be increased until either the subject experiences 20 percent drop in breathing ability, or reaches a maximum dose with no change in lung function. See, e.g., The American Lung Association website: lung.org/lung-health-diseases/lung-procedures-and- tests/methacholine-challenge-test; Sayeedi and Widrich, “Methacholine Challenge Test,” StatPearls [Internet], Treasure Island (FL): StatPearls Publishing (2024); which are specifically incorporated by reference herein in their entireties. In some forms, subjects demonstrate one or more low levels of type 2 (T2) inflammation biomarkers. Examples of biomarkers include, but are not limited to, blood eosinophil count (eos) less than 300/ul, total serum immunoglobulin E (IgE) levels less than 150 IU/mL, and exhaled nitric oxide (FeNO) levels less than 25 ppb. In some forms, subjects demonstrate sensitivity to bronchoprovocation by respiratory irritants. In some forms, subjects demonstrate FEV1 (forced expiratory volume in 1 second) variability on pulmonary function testing. In some forms, subjects demonstrate negative tests by mannitol challenge. In some forms, subjects do not have, and optionally have never had, asthma. 45740907.1 21 In some forms, subjects have not been not prescribed treatment with oral glucocorticoids, which are often prescribed for asthma patients with severe symptoms. Any of the methods of detection and diagnosis can include action(s) in one or more of the obtaining patient history, physical examination, laboratory data collection, diagnostic imaging, and/or pulmonary function testing. The one or more actions can be one or more actions outlined below. Detailed History Patient History - Overall disease course: o Understand health baseline before contracting SARS-CoV-2: ^ Antecedent respiratory symptoms? ^ Antecedent respiratory diagnoses? ^ Antecedent respiratory medications? ^ Obtain comprehensive list of all antecedent non-respiratory diagnoses. ^ Obtain comprehensive list of all antecedent non-respiratory medications. o Understand severity of acute COVID-19 course: ^ Hospitalized? Highest oxygen requirement? Intensive care unit admission? Mechanical ventilation? ^ Duration and nature of symptoms? ^ Imaging that reveals parenchymal opacities during or after acute COVID- 19? o Understand post-COVID course: ^ Timing and nature of development of respiratory symptoms (listed below) ^ Timing and nature of development of extra-pulmonary symptoms (listed below) - Specific pulmonary manifestations at presentation: o Dyspnea, wheeze, exercise capacity, cough, sputum production, hemoptysis o Specific airway disease symptomatology: ^ Triggered episodes of coughing, wheezing, chest tightness, dyspnea ^ Nocturnal symptoms ^ Symptomatic response to bronchodilator ^ Symptomatic response to systemic steroids o Allergic triggers: ^ Animals ^ Dust ^ Pollen 45740907.1 22 ^ Mold o Nonallergic triggers: ^ Smoke ^ Perfume or cologne ^ Cleaning fluids ^ Other scented objects such as candles ^ Hot air ^ Cold air ^ Exercise ^ Emotional stress ^ NSAIDs o Course of prior respiratory viral infections: ^ Prolonged cough ^ Prolonged dyspnea ^ Prolonged wheeze ^ Prolonged rhinorrhea ^ Prior mononucleosis o Assessment for vocal cord dysfunction: ^ Change in voice ^ Hoarseness ^ Dysphagia ^ Upper airway wheeze ^ Stridor ^ Throat tightness o Sleep disordered breathing screen: ^ Daytime somnolence ^ Unrefreshing sleep ^ Witnessed apneas ^ Snoring o Other pulmonary questions: ^ Aspiration with food or drink ^ Smoking history - Associated extrapulmonary manifestations: o Atopic dermatitis screen: ^ Dry skin 45740907.1 23 ^ Eczema ^ Hives ^ Keratosis pilaris o Allergic rhinitis screen: ^ Known allergies ^ Loss of smell ^ Nasal congestion ^ Nasal obstruction ^ Post-nasal drip ^ Throat-clearing o Neuropsychiatric screen ^ Anxiety ^ Brain fog ^ Fatigue ^ Exercise intolerance ^ Alcohol use ^ Marijuana use ^ Traumatic experiences / PTSD ^ Headaches • Light/sound intolerance • Unilateral • Throbbing • Associated with nausea • Relieved with sleep • Known triggers o Cardiovasular: ^ Orthostasis ^ Tachycardia ^ Palpitations o Upper GI symptoms (functional dyspepsia/GERD): ^ Heartburn ^ Sore throat ^ Eructation ^ Intolerance of specific foods, e.g. spicy foods, tomatoes, caffeine, alcohol, garlic, onions, cruciferous vegetables, gluten 45740907.1 24 o Lower GI symptoms (IBS): ^ Constipation ^ Diarrhea ^ Abdominal pain ^ Pain relief with defecation ^ Intolerance of specific foods, e.g. spicy foods, tomatoes, caffeine, alcohol, garlic, onions, cruciferous vegetables, gluten o Myalgias (fibromyalgia): ^ Neck pain ^ Back pain ^ Trigger points ^ Worse with stress o Effect of menses on symptoms - Family history: o Asthma o Allergies o Eczema o Depression o Anxiety - Occupational history: o Particular attention to exposures - Drug allergies Physical Examination: - Auscultate lungs for wheeze - Auscultate over trachea for wheeze - Examine nares for bogginess and polyps - Examine skin for dryness, eczematous changes, etc Laboratory Data: - Basic metabolic panel - Complete blood count with differential (especially note absolute eosinophil counts) - Serum respiratory allergen panel - Total serum IgE Diagnostic Imaging: - High-resolution chest CT with inspiratory and expiratory views Pulmonary Function Tests: 45740907.1 25 - Full spirometry - If FEV1 >80%, perform methacholine challenge test - If FEV1 <80%, perform bronchodilator testing - Lung volumes - Diffusion capacity - FeNO C. Therapeutic Agents Therapeutic agents for use in the disclosed methods for treatment of the disclosed subjects are provided. The therapeutic agents are typically administered to a subject in an effective amount to treat the disease or disorder of the subject. The therapeutic agent can be in a pharmaceutical composition. The therapeutic agent is most typically a compound that reduces the biological activity of a target molecule. Thus, compounds for decreasing the bioactivity of target molecules, and formulations formed therewith are provided. In some forms, the compound is an inhibitory polypeptide such as, but not limited to, an antibody; a small molecule or peptidomimedic, or an inhibitory nucleic acid that targets genomic or expressed nucleic acids (e.g., mRNA) encoding the target molecule, or a vector that encodes an inhibitory nucleic acid. The compound can reduce the expression or bioavailability of the target molecule. The inhibition can be competitive, non-competitive, uncompetitive, or product inhibition. Thus, an inhibitor can directly inhibit the target molecule, an inhibitor can inhibit another factor in a pathway that leads to induction, persistence, or amplification of the target molecule’s expression, or a combination thereof. Thus, the therapeutic agents can be and are also referred to herein as inhibitors. In other examples the therapeutic agents are agonists. In some forms, the therapeutic agent is a protein binder that specifically binds to the target molecule, or a ligand or receptor thereof important for activity of the target molecule. In some forms, the protein binder is an antibody. Antibodies include not only intact antibodies, but also antibody fragments and antigen-binding components thereof, and fusion proteins including antigen binding fragments that are capable of immuno-specifically binding to the target molecule (or its counterpart ligand or receipt). The antibodies can be a human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a recombinant antibody, an antigen- binding antibody fragment, a single chain antibody, a monomeric antibody, a diabody, a triabody, a tetrabody, a Fab fragment, an IgD antibody, an IgE antibody, an IgM antibody, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody, or a fragment thereof, and fusion proteins formed therefrom. The antibodies and antigen binding fragments can be monospecific, bispecific, trispecific or multispecific. 45740907.1 26 The inhibitor can be a functional nucleic acid. Functional nucleic acids are nucleic acid molecules that have a specific function, such as binding a target molecule or catalyzing a specific reaction. As discussed in more detail below, functional nucleic acid molecules can be divided into the following non-limiting categories: antisense molecules, siRNA, miRNA, aptamers, ribozymes, triplex forming molecules, RNAi, and external guide sequences. The functional nucleic acid molecules can act as effectors, inhibitors, modulators, and stimulators of a specific activity possessed by a target molecule, or the functional nucleic acid molecules can possess a de novo activity independent of any other molecules. Functional nucleic acid molecules can interact with any macromolecule, such as DNA, RNA, polypeptides, or carbohydrate chains. Thus, functional nucleic acids can interact with the mRNA or the genomic DNA of a target polypeptide or they can interact with the polypeptide itself. Often functional nucleic acids are designed to interact with other nucleic acids based on sequence homology between the target molecule and the functional nucleic acid molecule. In other situations, the specific recognition between the functional nucleic acid molecule and the target molecule is not based on sequence homology between the functional nucleic acid molecule and the target molecule, but rather is based on the formation of tertiary structure that allows specific recognition to take place. Therefore, the compositions can include one or more functional nucleic acids designed to reduce expression of the target molecule’s gene, or a gene product thereof. For example, the functional nucleic acid or polypeptide can be designed to target and reduce or inhibit expression or translation of target molecule’s mRNA; or to reduce or inhibit expression, reduce activity, or increase degradation of target molecule protein. In some forms, the composition includes a vector suitable for in vivo expression of the functional nucleic acid. Examples of functional nucleic acids include, but are not limited to, antisense oligonucleotides, siRNA, shRNA, miRNA, external guide sequences. External guide sequences (EGSs), ribozymes, aptamers, and CRISPR/Cas technology. Molecular targets and exemplary compounds for reducing the biological activity there of are provided. 1. TSLP In some forms, the target molecule is human thymic stromal lymphopoietin (TSLP). TSLP is produced by various cell types, including epithelial cells, and plays a role in promoting inflammation and allergic responses by activating certain immune cells like dendritic cells and T cells. The amino acid and nucleic acid sequences for TSLP are known in the art, see, for example, UniProt accession no. Q969D9 · TSLP_HUMAN, which is specifically incorporated by reference herein in its entirety. 45740907.1 27 In some forms, the TSLP inhibitor is an anti-TSLP antibody. Anti-TSLP inhibitory antibodies are known in the art. See, e.g., U.S. Pat. Nos.7,982,016, 8,163,284, 9,284,372, and 10,287,348; U.S. Patent Publication No. US20240132581A1; International Application No. WO2018191479A1, each of which is specifically incorporated by reference herein in its entirety. Exemplary anti-TSLP antibody sequences include, but are not limited to, Heavy chain variable region: QMQLVESGGGVVQPGRSLRLSCAASGFTFRTYGMHWVRQAPGKGLEWVAVIWYDGSNKHYADSV KGRFTITRDNSKNTLNLQMNSLRAEDTAVYYCARAPQWELVHEAFDIWGQGTMVTVSS (SEQ ID NO:361) A heavy chain CDR1 sequence: TYGMH (SEQ ID NO:145) A heavy chain CDR2 sequence: VIWYDGSNKHYADSVKG (SEQ ID NO:173) A heavy chain CDR3 sequence: APQWELVHEAFDI (SEQ ID NO:212) Light chain variable region: SYVLTQPPSVSVAPGQTARITCGGNNLGSKSVHWYQQKPGQAPVLVVYDDSDRPSWIPERFSGS NSGNTATLTISRGEAGDEADYYCQVWDSSSDHVVFGGGTKLTVL (SEQ ID NO:363) A light chain CDR1 sequence: GGNNLGSKSVH (SEQ ID NO:13) A light chain CDR2 sequence: DDSDRPS (SEQ ID NO:60) A light chain CDR3 sequence: QVWDSSSDHVV (SEQ ID NO:105) For example, in some forms the TSLP inhibitor is an antigen binding protein including: a. a light chain variable domain including: i. a light chain CDR1 sequence including the amino acid sequence set forth in SEQ ID NO:13; ii. a light chain CDR2 sequence including the amino acid sequence set forth in SEQ ID NO:60; iii. a light chain CDR3 sequence including the amino acid sequence set forth in SEQ ID NO:105 and b. a heavy chain variable domain including: i. a heavy chain CDR1 sequence including the amino acid sequence set forth in SEQ ID NO:145; ii. a heavy chain CDR2 sequence including the amino acid sequence set forth in SEQ ID NO:173, and iii. a heavy chain CDR3 sequence including the amino acid sequence set forth in SEQ ID NO:212, optionally wherein the antigen binding protein specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2. In some forms, the antigen binding protein includes either: a. a light chain variable domain selected from the group consisting of: i. a sequence of amino acids at least 80% identical to SEQ ID NO:363; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:362; iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:362; b. a heavy chain variable domain selected from the group consisting of: i. a sequence of amino acids that is at least 80% identical to SEQ ID 45740907.1 28 NO:361; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:360; iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:360; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b). In some forms, the antigen binding protein includes either: a. a light chain variable domain including the amino acid sequence as set for in SEQ ID NO:363; b. a heavy chain variable domain including the amino acid sequence as set forth in SEQ ID NO:361; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b). In some forms, the antigen binding protein includes the light chain variable domain of (a) and the heavy chain variable domain of (b). In some forms, the antigen binding protein binds to TSLP with substantially the same Kd as an antibody including a) a light chain including a light chain variable domain including the amino acid sequence as set for in SEQ ID NO:363 and a lambda light chain constant domain including the amino acid sequence as set forth in SEQ ID NO:369; and b) a heavy chain including a heavy chain variable domain including the amino acid sequence as set forth in SEQ ID NO:361 and an IgG2 heavy constant domain including the amino acid sequence as set forth in SE0 ID NO:365. In some forms, the antigen binding protein inhibits TSLP activity to block osteoprotegerin (OPG) production from primary human dendritic cells with the same IC50 as an antibody including a) a light chain including a light chain variable domain including the amino acid sequence as set for in SEQ ID NO:363 and a lambda light chain constant domain including the amino acid sequence as set forth in SEQ ID NO:369; and b) a heavy chain including a heavy chain variable domain including the amino acid sequence as set forth in SEQ ID NO:361 and an IgG2 heavy constant domain including the amino acid sequence as set forth in SE0 ID NO:365. In some forms, the antigen binding protein is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a recombinant antibody, an antigen-binding antibody fragment, a single chain antibody, a monomeric antibody, a diabody, a triabody, a tetrabody, a Fab fragment, an IgD antibody, an IgE antibody, an IgM antibody, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody. In some forms, the antigen binding protein is a human antibody. In some forms, the TSLP inhibitor is Tezepelumab (TEZSPIRE®). See, e.g., U.S. Pat. Nos.7,982,016, 8,163,284, 9,284,372, and 10,287,348; U.S. Patent Publication No. US20240132581A1; International Application No. WO2018191479A1, each of which is 45740907.1 29 specifically incorporated by reference herein in its entirety. Tezepelumab is a human IgG2λ monoclonal antibody that inhibits the binding of TSLP to the TSLP receptor, suppressing the inflammatory activities mediated by TSLP. Tezepelumab is an FDA approved drug for the treatment of patients with severe asthma. In some forms, Tezepelumab or another anti-TSLP binding protein is administered at a dosage and/or route of administration for Tezepelumab approved for treatment of another indication such as asthma. For example, in some forms, Tezepelumab or another anti-TSLP binding protein is administered at a dosage of 210 mg administered optionally once every 4 weeks. In some forms, Tezepelumab or another anti-TSLP binding protein is administered by subcutaneous injection. Thus, in some forms, the treatment regimen for the disclosed subjects is the same or similar to those with asthma. In other forms, a higher and/or more frequent dose optionally further include a loading dose is used. Non-limiting exemplary treatment regimens include, but are not limited to, 210 mg every 4 weeks; or 420 mg every 4 weeks; or 280 mg every 2 weeks. Other compounds that target TSLP include, but are not limited to, AZD8630 (AstraZeneca), AIO-001 (GSK/Aiolos Bio also known as GSK5784283) in Phase 2b, Ecleralimab/CSJ117 (Novartis), RG7258 (Roche), Verekitug (Upstream Bio), BSI-040502 (Biosion), SAR443765 (Sanofi), HBM9378 (Harbour BioMed), SHR-1905 (Aiolos Bio), CM0326 (Keymed Biosciences), CDX-622 (Celldex Therapeutics), GR-2002 (Genrix Biopharmaceutical), STSA-1201 (Staidson Biopharmaceuticals), 8630A-378 (Sichuan Kelun), AL-3117 (Azcuris), AL-3224 (Azcuris), APG-333 (Apogee), BD-9 (Teva), Bempikibart (Q32 Bio), Bosakitug (Aclaris), BSI-502 (Biosion), CM-326 (Chengdu KeyMed), Crebankitug (Zura), CSJ-117 (Novartis), GB-0895 (Generate), GSK-3191812 (GSK), HBM-9378 (Harbour), HY- 209 (Shaperon), IBI-3002 (Innovent), JKN-24011 (Joincare), Lunsekimig (Sanofi), MG-ZG-122 (Shanghai Mabgeek), PF-07275315 (Pfizer), PX-128 (J&J), Q-1804 (QureBio), SOR-104 (Sorisso), and TAVO-101 (Tavotek). 2. Interleukin-4 receptor Signaling Pathway In some forms, the target molecule is the interleukin-4 receptor (IL-4R) signaling pathway, including, but not limited to, the interleukin-4 receptor (IL-4R). IL-4 and IL-13 are canonical T2 cytokines that play roles in airway disease. They primarily signal through IL-4Rα, leading to STAT6 activation. In some forms, the target is IL-4R. Dimers, e.g., heterodimers, of IL-4R are known. For example, a type 1 IL-4 receptor is a dimeric receptor including an IL-4Rα chain and a γc chain. A type 2 IL-4 receptor is a dimeric receptor including an IL-4Rα chain and an IL-13Rα1 chain. Type 1 IL-4 receptors interact with and are stimulated by IL-4, while type 2 IL-4 receptors 45740907.1 30 interact with and are stimulated by both IL-4 and IL-13. When IL-4 binds to its receptor, it triggers a signaling cascade within the cell, leading to various biological responses, and are implicated in allergic airway inflammation, asthma, autoimmune disorders, and certain cancers. In some forms, the compound is an anti-IL-4R antibody. Examples are known in the art. See, e.g., Corren et al., 2010, Am J Respir Crit Care Med., 181(8):788-796, U.S. Pat. Nos. 7,186,809, 8,945,559, 10,435,473, 9,238,692, 11,059,896, 8,735,095, U.S. Pat. No.7,605,237, U.S. Pat. No.7,608,693, U.S. Pat. No.8,092,804, and U.S. Patent Application Publication No. 2014/0356372, which are specifically incorporated by reference herein in their entireties. In particular forms, the anti-IL-4R is dupilumab (DUPIXENT®), or a bioequivalent thereof, e.g., the antibody referred to and known in the art as AMG317 (see, e.g., Corren et al., 2010, Am J Respir Crit Care Med., 181(8):788-796), or any of the anti-IL-4Rα binding proteins and antibodies as set forth in U.S. Pat. Nos.7,186,809, 8,945,559, 10,435,473, 9,238,692, 11,059,896, 8,735,095, U.S. Pat. No.7,605,237, U.S. Pat. No.7,608,693, U.S. Pat. No. 8,092,804, or U.S. Patent Application Publication No.2014/0356372. In some forms, the anti-IL4 receptor antibody includes a light-chain variable region including the CDRs of the light-chain variable region of the amino acid sequence of SEQ ID NO:10 of U.S. Patent No.7,186,809, or the entire light-chain variable region of SEQ ID NO:10 of U.S. Patent No.7,186,809. In some forms, the anti-IL4 receptor antibody includes a heavy-chain variable region including the CDRs of the heavy-chain variable region of the amino acid sequence of SEQ ID NO:12 of U.S. Patent No.7,186,809, or the entire heavy-chain variable region of SEQ ID NO:12 of U.S. Patent No.7,186,809. In some forms, the anti-IL4 receptor antibody including a light-chain variable region including the amino acid sequence of SEQ ID NO:10 of U.S. Patent No.7,186,809 and a heavy- chain variable region including the amino acid sequence of SEQ ID NO: 12 of U.S. Patent No. 7,186,809. In some forms, the light chain CDR 3 includes the sequence of residues 90-99 of SEQ ID NO:10 of U.S. Patent No.7,186,809, the heavy chain CDR 3 includes the sequence of residues 98-104 of SEQ ID NO:12 of U.S. Patent No.7,186,809, and said antibody binds to the human IL-4 receptor. In some forms, the light chain CDR 1 includes the sequence of residues 24-35 of SEQ ID NO:10 of U.S. Patent No.7,186,809 and the heavy chain CDR 1 includes the sequence of residues 31-35 of SEQ ID NO:12 of U.S. Patent No.7,186,809. 45740907.1 31 In some forms, the light chain CDR 2 includes the sequence of residues 51-57 of SEQ ID NO:10 of U.S. Patent No.7,186,809 and the heavy chain CDR 2 includes the sequence of residues 50-65 of SEQ ID NO:12 of U.S. Patent No.7,186,809. In some forms, the light chain CDR 1 includes the sequence of residues 24-35 of SEQ ID NO:10 of U.S. Patent No.7,186,809, the heavy chain CDR 1 includes the sequence of residues 31-35 of SEQ ID NO:12 of U.S. Patent No.7,186,809, the light chain CDR 2 includes the sequence of residues 51-57 of SEQ ID NO:10 of U.S. Patent No.7,186,809, and the heavy chain CDR 2 includes the sequence of residues 50-65 of SEQ ID NO:12 of U.S. Patent No.7,186,809. In some forms, the light chain variable region includes the sequence of SEQ ID NO:10 of U.S. Patent No.7,186,809. In some forms, the heavy chain variable region includes the sequence of SEQ ID NO:12 of U.S. Patent No.7,186,809. In some forms, the light chain variable region includes the sequence of SEQ ID NO:10 of U.S. Patent No.7,186,809 and the heavy chain variable region includes the sequence of SEQ ID NO:12 of U.S. Patent No.7,186,809. In some forms, the antibody is a monoclonal antibody. In some forms, the antibody is human, partially human, or chimeric. In some forms, the antibody is an IgA antibody, an IgD antibody, an IgE antibody, an IgG antibody, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, an IgG4 antibody, or an IgM antibody. In some forms, the fragment includes the sequence of residues 90-99 of SEQ ID NO:10 of U.S. Patent No.7,186,809, the sequence of residues 98-104 of SEQ ID NO:12 of U.S. Patent No.7,186,809, and binds to human IL-4 receptor. In some forms, the fragment further includes an Fc domain or a leucine zipper. In some forms, the fragment includes a Fab fragment or a F(ab')2 fragment. In some forms, the fragment is part of a single chain antibody (scFv). In some forms, dupilumab or another anti-IL-4R binding protein is administered at a dosage and/or route of administration for dupilumab approved for treatment of another indication. For example, in some forms, the dupilumab or other anti-IL-4R binding protein is administered at an initial dose of 600 mg (e.g., two 300 mg injections in different injection sites), followed by 300 mg given every other week. In some forms, the dupilumab or other anti-IL-4R binding protein is administered by subcutaneous injection. The results presented below show the efficacy of IL-4Rα blockade in the disclosed methods using dupilumab. 45740907.1 32 Other compounds that can be used to target the IL-4/IL-13/IL-4R/STAT6 pathway include, but are not limited to, IL-4 (and IL-13) Dom-0910 (GSK), QAX-576 + VAK-694 (Novartis), romilkimab (Sanofi) IL-4R AER-001 (Bayer), AK-139 (Akeso), manfidokimab (Akeso), APG-808 (Apogee), AVE- 0309 (Sanofi), BA-2101 (Luye), BC-005 (Guilin), eblasakimab (Aslan), elarekibep (AstraZeneca), MEDI-2405 (AstraZeneca), MEDI-9314 (AstraZeneca), GB-12 (Kexing), Genrix (GR-1802), GSK-2434735 (GSK), IBI-3002 (Innovent, also targets TSLP), LQ-036 (Shanghai Novamab), MDNA-413 (Medicenna), MG-010 (Mabgeek), NM26-2198 (Kaken), pascolizumab (Abbott), PF-07264660 (Pfizer, also targets IL-33), PF-07275315 (Pfizer, also targets TSLP), PM-1017 (BioNTech), PM-1268 (BioNTech), POL-201 (Seasun), QX-005N (Qyuns), Rademikibart (Connect), RC-1416 (Nanjing), SHR-1819 (Jiangsu), SSGJ-611 (3SBio), stapokibart (Chengdu), TMC-260 (Mitsubishi), TQH-2722 (Sino), ZW-1528 (Zymeworks), ZW- 1572 (Zymeworks) STAT6 AS-1810722 (Astellas), KP-723 (J&J), KT-621 (Kymera), PM-43I (Atrapos) 3. Interleukin-5 In some forms, the target molecule is interleukin-5 (IL-5). IL-5 plays a role in a number of different diseases such as asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, uncontrolled eosinophilic asthma, eosinophilic asthma, sub-eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis (EGPA), hypereosinophilic syndrome (HES), nasal polyposis (NP), bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, moderate atopic dermatitis and severe atopic dermatitis and chronic rhinosinusitis with nasal polyps (CRSwNP), Inflammatory bowel disease (IBD), and allergic bronchopulmonary aspergillosis (ABPA). These serious diseases affect hundreds of millions of people worldwide. In some forms, the compound is an anti-IL-5 antibody. Examples are known in the art. In particular forms the antibody is benralizumab, or a bioequivalent thereof. Benralizumab (MEDI-563) is a humanized monoclonal antibody (mAb) that binds to the alpha chain of the interleukin-5 receptor alpha (IL-5Ra), which is expressed on eosinophils and basophils. It induces apoptosis of these cells via antibody-dependent cell cytotoxicity. Information regarding benralizumab (or fragments thereof) for use in the methods provided herein can be found in e.g., U.S. Patent No.9,441,037 and U.S. Patent Application 45740907.1 33 Publication No. US 2010/0291073 A1, the disclosures of which are incorporated herein by reference herein in their entireties. Benralizumab and antigen-binding fragments thereof for use in the methods provided herein can include a heavy chain and a light chain or a heavy chain variable region and a light chain variable region. In a further aspect, benralizumab or an antigen- binding fragment thereof for use in the methods provided herein includes any one of the amino acid sequences of SEQ ID NOs: 1-4 of U.S. Patent No.9,441,037. In a specific aspect, benralizumab or an antigen-binding fragment thereof for use in the methods provided herein include a light chain variable region including the amino acid sequence of SEQ ID NO:1 and a heavy chain variable region including the amino acid sequence of SEQ ID NO:3. In a specific aspect, benralizumab or an antigen-binding fragment thereof for use in the methods provided herein including a light chain including the amino acid sequence of SEQ ID NO: 2 and heavy chain including the amino acid sequence of SEQ ID NO:4. In a specific aspect, benralizumab or an antigen-binding fragment thereof for use in the methods provided herein including a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region including the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 7-9 of U.S. Patent No.9,441,037, and wherein the light chain variable region includes the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 10-12 of U.S. Patent No.9,441,037. Those of ordinary skill in the art would easily be able to identify Chothia-defined, Abm-defined or other CDRs. In a specific aspect, benralizumab or an antigen-binding fragment thereof for use in the methods provided herein include the variable heavy chain and variable light chain CDR sequences of the KM1259 antibody as disclosed in U.S. Pat. No.6,018,032, which is herein incorporated by reference in its entirety. In some forms, benralizumab or another anti-IL-5 binding protein is administered at a dosage and/or route of administration for benralizumab approved for treatment of another indication such as asthma. For example, in some forms, the benralizumab or other anti-IL-5 binding protein is administered at dose of 30 mg. In some forms, the benralizumab or other anti- IL-4R binding protein is administered by subcutaneous injection. Other compounds that target IL-5 include, but are not limited to, Mepolizumab (GSK) and Reslizumab (Teva). 4. c-Kit In some forms, the target molecule is c-Kit. KIT (or c-Kit) is a type III receptor tyrosine kinase encoded by the c-kit gene. KIT comprises five extracellular immunoglobulin (Ig)-like domains, a single transmembrane region, an inhibitory cytoplasmic juxtamembrane domain, and a split cytoplasmic kinase domain separated by a kinase insert segment (see, e.g., Yarden et al., Nature, 1986, 323:226-232; Ullrich and Schlessinger, Cell, 1990, 61:203-212; Clifford et al., J. 45740907.1 34 Biol. Chem., 2003, 278:31461-31464). The human c-kit gene encoding the KIT receptor has been cloned as described by Yarden et al., EMBO J., 1987, 6:3341-3351. KIT is also known as CD117 or stem cell factor receptor (“SCFR”), because it is the receptor for the stem cell factor (“SCF”) ligand (also known as Steel Factor or Kit Ligand). SCF ligand binding to the first three extracellular Ig-like domains of KIT induces receptor dimerization, and thereby activates intrinsic tyrosine kinase activity through the phosphorylation of specific tyrosine residues in the juxtamembrane and kinase domains (see, e.g., Weiss and Schlessinger, Cell, 1998, 94:277-280; Clifford et al., J. Biol. Chem., 2003, 278:31461-31464). Members of the Stat, Src, ERK, and AKT signaling pathways have been shown to be downstream signal transducers of KIT signaling. The fourth (D4) and fifth (D5) extracellular Ig-like domains of KIT are believed to mediate receptor dimerization (see, e.g., International Patent Application Publication No. WO 2008/153926; Yuzawa et al., Cell, 2007, 130:323-334). In some forms, the compound is an anti-c-Kit antibody. Examples are known in the art. In particular forms the antibody is Barzolvolimab. Barzolvolimab (CDX-0159) is a clinical stage humanized anti-KIT IgG1 monoclonal antibody that was developed by Celldex Therapeutics, see, e.g., U.S. Patent No.10,781,267 and National Center for Biotechnology Information. “PubChem Substance Record for SID 442878641, barzolvolimab, Source: IUPHAR/BPS Guide to PHARMACOLOGY” PubChem, pubchem.ncbi.nlm.nih.gov/substance/442878641, each of which are specifically incorporated by reference herein in their entities. In some forms, the anti-c-Kit binding protein includes (i) a light chain variable region (“VL”) including the CDRs or the entire light chain variable region of the amino acid sequence of SEQ ID NO: 12 of U.S. Patent No.10,781,267, and (ii) a heavy chain variable region (“VH”) comprising the amino acid sequence including the CDRs or the entire light chain variable region of the amino acid sequence of SEQ ID NO:11 of U.S. Patent No.10,781,267. In some forms, the anti-c-Kit binding proteins includes: (i) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 19, 20, and 21 of U.S. Patent No.10,781,267, respectively; and a VH comprising the amino acid sequence of SEQ ID NO: 2 of U.S. Patent No.10,781,267; (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID Nos: 19, 20, and 21 of U.S. Patent No.10,781,267, respectively; and a VH comprising the amino acid sequence of SEQ ID NO: 3 of U.S. Patent No.10,781,267; (iii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 19, 20, and 21 of U.S. Patent No.10,781,267, respectively; and a VH comprising the amino acid sequence of SEQ ID NO: 4 of U.S. Patent No.10,781,267; 45740907.1 35 (iv) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 19, 20, and 21 of U.S. Patent No.10,781,267, respectively; and a VH comprising the amino acid sequence of SEQ ID NO: 5 of U.S. Patent No.10,781,267; (v) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 19, 20, and 21 of U.S. Patent No.10,781,267, respectively; and a VH comprising the amino acid sequence of SEQ ID NO: 6 of U.S. Patent No.10,781,267; (vi) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID Nos: 59, 60, and 61 of U.S. Patent No.10,781,267, respectively; and a VH comprising the amino acid sequence of SEQ ID NO: 2 of U.S. Patent No.10,781,267; (vii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 59, 60, and 61 of U.S. Patent No.10,781,267, respectively; and a VH comprising the amino acid sequence of SEQ ID NO: 3 of U.S. Patent No.10,781,267; (viii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 59, 60, and 61 of U.S. Patent No.10,781,267, respectively; and a VH comprising the amino acid sequence of SEQ ID NO: 4 of U.S. Patent No.10,781,267; (ix) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 59, 60, and 61 of U.S. Patent No.10,781,267, respectively; and a VH comprising the amino acid sequence of SEQ ID NO: 5 of U.S. Patent No.10,781,267; (x) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 59, 60, and 61 of U.S. Patent No.10,781,267, respectively; and a VH comprising the amino acid sequence of SEQ ID NO: 6 of U.S. Patent No.10,781,267; (xi) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID Nos: 66, 67, and 68 of U.S. Patent No.10,781,267, respectively; and a VH comprising the amino acid sequence of SEQ ID NO: 2 of U.S. Patent No.10,781,267; (xii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 66, 67, and 68 of U.S. Patent No.10,781,267, respectively; and a VH comprising the amino acid sequence of SEQ ID NO: 3 of U.S. Patent No.10,781,267; (xiii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 66, 67, and 68 of U.S. Patent No.10,781,267, respectively; and a VH comprising the amino acid sequence of SEQ ID NO: 4 of U.S. Patent No.10,781,267; (xiv) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 66, 67, and 68 of U.S. Patent No.10,781,267, respectively; and a VH comprising the amino acid sequence of SEQ ID NO: 5 of U.S. Patent No.10,781,267; 45740907.1 36 (xv) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID Nos: 66, 67, and 68 of U.S. Patent No.10,781,267, respectively; and a VH comprising the amino acid sequence of SEQ ID NO: 6 of U.S. Patent No.10,781,267; (xvi) a VL comprising the amino acid sequence of SEQ ID NO: 7 of U.S. Patent No. 10,781,267, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 16, 17, and 18 of U.S. Patent No.10,781,267, respectively; (xvii) a VL comprising the amino acid sequence of SEQ ID NO: 8 of U.S. Patent No. 10,781,267, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 16, 17, and 18 of U.S. Patent No.10,781,267, respectively; (xviii) a VL comprising the amino acid sequence of SEQ ID NO: 9 of U.S. Patent No. 10,781,267, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 16, 17, and 18 of U.S. Patent No.10,781,267, respectively; (xix) a VL comprising the amino acid sequence of SEQ ID NO: 10 of U.S. Patent No. 10,781,267, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 16, 17, and 18 of U.S. Patent No.10,781,267, respectively; (xx) a VL comprising the amino acid sequence of SEQ ID NO: 7 of U.S. Patent No. 10,781,267, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 56, 57, and 58 of U.S. Patent No.10,781,267, respectively; (xxi) a VL comprising the amino acid sequence of SEQ ID NO: 8 of U.S. Patent No. 10,781,267, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 56, 57, and 58 of U.S. Patent No.10,781,267, respectively; (xxii) a VL comprising the amino acid sequence of SEQ ID NO: 9 of U.S. Patent No. 10,781,267, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID Nos: 56, 57, and 58 of U.S. Patent No.10,781,267, respectively; (xxiii) a VL comprising the amino acid sequence of SEQ ID NO: 10 of U.S. Patent No. 10,781,267, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 56, 57, and 58 of U.S. Patent No.10,781,267, respectively; 45740907.1 37 (xxiv) a VL comprising the amino acid sequence of SEQ ID NO: 7 of U.S. Patent No. 10,781,267, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID Nos: 56, 62, and 63 of U.S. Patent No.10,781,267, respectively; (xxv) a VL comprising the amino acid sequence of SEQ ID NO: 8 of U.S. Patent No. 10,781,267, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 56, 62, and 63 of U.S. Patent No.10,781,267, respectively; (xxvi) a VL comprising the amino acid sequence of SEQ ID NO: 9 of U.S. Patent No. 10,781,267, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 56, 62, and 63 of U.S. Patent No.10,781,267, respectively; (xxvii) a VL comprising the amino acid sequence of SEQ ID NO: 10 of U.S. Patent No. 10,781,267, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 56, 62, and 63 of U.S. Patent No.10,781,267, respectively; (xxviii) a VL comprising the amino acid sequence of SEQ ID NO: 7 of U.S. Patent No. 10,781,267, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 64, 65, and 58 of U.S. Patent No.10,781,267, respectively; (xxix) a VL comprising the amino acid sequence of SEQ ID NO: 8 of U.S. Patent No. 10,781,267, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 64, 65, and 58 of U.S. Patent No.10,781,267, respectively; (xxx) a VL comprising the amino acid sequence of SEQ ID NO: 9 of U.S. Patent No. 10,781,267, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 64, 65, and 58 of U.S. Patent No.10,781,267, respectively; (xxxi) a VL comprising the amino acid sequence of SEQ ID NO: 10 of U.S. Patent No. 10,781,267, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 64, 65, and 58 of U.S. Patent No.10,781,267, respectively; (xxxii) a VL comprising the amino acid sequence of SEQ ID NO: 7 of U.S. Patent No. 10,781,267, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the 45740907.1 38 amino acid sequences of SEQ ID NOs: 70, 71, and 72 of U.S. Patent No.10,781,267, respectively; (xxxiii) a VL comprising the amino acid sequence of SEQ ID NO: 8 of U.S. Patent No. 10,781,267, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 70, 71, and 72 of U.S. Patent No.10,781,267, respectively; or (xxxiv) a VL comprising the amino acid sequence of SEQ ID NO: 9 of U.S. Patent No. 10,781,267, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 70, 71, and 72 of U.S. Patent No.10,781,267, respectively. In some forms, the anti-c-Kit binding protein is CDX-0159. CDX-0159 is a variant of CDX-0158 (a.k.a. KTN0158 [PMID:27815356]) that was re-engineered to improve its safety profile and increase its serum half-life. CDX-0158 was originally designed for potential to treat GIST and other KIT-dependent tumours. This original version of the antibody inhibits mutant and wild type KIT phosphorylation, reduces mast cell degranulation and mast cell numbers, and shrinks tumours in a preclinical canine model of spontaneous mast cell tumour development. In some forms, the c-Kit inhibitor is masitinib (AB1010). The compound specifically blocks tyrosine kinases that are essential for the function of certain immune cells, including macrophages, microglia, and mast cells. Masitinib blocks microglia proliferation and activation, and mast cell-mediated degranulation, the release of cytotoxic substances that might further damage the motor nerves. Examples are known in the art. See, e.g., Dubreuil et al., PLoS One. 2009; 4(9): e7258., Hahn et al., J Vet Intern Med.2008 Nov-Dec;22(6):1301-9., U.S. pat. No. 8,492,545, PCT application Nos. WO2008098949A2, WO03004007, WO03004006, WO03003006, WO03003004, WO03002114, WO03002109, WO03002108, WO03002107, WO 03002106, WO03002105, WO03039550, WO03035050, WO03035049, WO030720090, WO03072106, WO04076693 and WO2005016323 which are specifically incorporated by reference herein in their entireties. In some forms, the c-Kit inhibitor is a chemical equivalent of masitinib or any of the inhibitors having general structural formula as set forth in U.S. pat. No. 8,492,545, PCT application Nos. WO2008098949A2, WO03004007, WO03004006, WO03003006, WO03003004, WO03002114, WO03002109, WO03002108, WO03002107, WO 03002106, WO03002105, WO03039550, WO03035050, WO03035049, WO030720090, WO03072106, WO04076693 and WO2005016323. Other compounds that targets c-Kit include, but are not limited to, CDX-0159 (Celldex), Imatinib (Novartis), Sunitinib (Pfizer), Regorafenib (Bayer), Midostaurin (Novartis), Ripretinib (Deciphera), Avapritinib (Blueprint Medicines), Sorafenib (Bayer), Axitinib (Pfizer), 45740907.1 39 Cabozantinib (Exelixis), Dasastinib (BMS), Nilotinib (Novartis), Pazopanib (Novartis), Tivozanib (Aveo Oncology), Briquilimab (Jasper), and Lirentelimab (Allakos). 5. BTK In some forms, the target molecule is Bruton's tyrosine kinase (Btk). Btk is a member of the Tec family of non-receptor tyrosine kinases, is a key signaling enzyme expressed in all hematopoietic cells types except T lymphocytes and natural killer cells. Btk plays a role in a number of other hematopoetic cell signaling pathways, e.g., Toll like receptor (TLR) and cytokine receptor-mediated TNF-α production in macrophages, IgE receptor (FcepsilonRI) signaling in mast cells, inhibition of Fas/APO-1 apoptotic signaling in B-lineage lymphoid cells, and collagen-stimulated platelet aggregation. See, e.g., C. A. Jeffries, et al., (2003), Journal of Biological Chemistry 278:26258-26264; N. J. Horwood, et al., (2003), The Journal of Experimental Medicine 197:1603-1611; Iwaki et al. (2005), Journal of Biological Chemistry 280(48):40261-40270; Vassilev et al. (1999), Journal of Biological Chemistry 274(3):1646- 1656, and Quek et al. (1998), Current Biology 8(20):1137-1140. In some forms, the compound is a Btk inhibitor. Examples are known in art. See, e.g., U.S. Pat. Nos.7,514,444, 8,008,309, 8,476,284, 8,497,277, 8,563,563, 8,697,711, 8,703,780, 8,735,403, 8,754,090, 8,754,091, 8,952,015, 8,957,079, 8,999,999, 9,125,889, 9,181,257, 9,296,753, 9,540,382, 9,713,617, 9,725,455, 9,795,604, 9,801,881, 9,801,883, 10,004,746, 10,016,435, 10,106,548, 10,125,140, 10,294,231, 10,294,232, 10,463,668, 10,478,439, 10,695,350, 10,751,342, 10,961,251, and 11,672,803, which are specifically incorporated by reference herein in their entireties. In particular forms, the Btk inhibitor is ibrutinib (IMBRUVICA®), or a chemical equivalent thereof or any of the inhibitors having general structural formula as set forth in U.S. Pat. Nos.7,514,444, 8,008,309, 8,476,284, 8,497,277, 8,563,563, 8,697,711, 8,703,780, 8,735,403, 8,754,090, 8,754,091, 8,952,015, 8,957,079, 8,999,999, 9,125,889, 9,181,257, 9,296,753, 9,540,382, 9,713,617, 9,725,455, 9,795,604, 9,801,881, 9,801,883, 10,004,746, 10,016,435, 10,106,548, 10,125,140, 10,294,231, 10,294,232, 10,463,668, 10,478,439, 10,695,350, 10,751,342, 10,961,251, and 11,672,803. In some forms, the Btk inhibitor is fenebrutinib. Fenebrutinib is an orally available inhibitor of Bruton's tyrosine kinase (BTK) with potential antineoplastic activity. Upon administration, fenebrutinib inhibits the activity of BTK and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents both B-cell activation and BTK- mediated activation of downstream survival pathways, which leads to the inhibition of the growth of malignant B-cells that overexpress BTK. BTK, a member of the Src-related BTK/Tec family of cytoplasmic tyrosine kinases, is overexpressed in B-cell malignancies; it plays an important role in B-lymphocyte development, activation, signaling, proliferation and survival. 45740907.1 40 Examples are known in the art. See, e.g., Crawford et al., J Med Chem.2018 Mar 22;61(6):2227-2245., Erickson et al., J Pharmacol Exp Ther.2017 Jan;360(1):226-238., Reiff et al., Blood.2018 Sep 6;132(10):1039-1049, U.S. Pat. No.11,478,474, U.S. Patent Application Publication Nos. US 20240132508 A1, US 11969418 B2, PCT publication Nos. WO2022266285A1, WO2022261138A1, WO2022233801A1, WO2021216814A1, WO2021202825A1, WO2021164735A1, which are specifically incorporated by reference herein in their entireties. In some forms, the Btk inhibitor is a chemical equivalent fenebrutinib or any of the inhibitors having general structural formula as set forth in U.S. Pat. No.11,478,474, U.S. Patent Application Publication Nos. US 20240132508 A1, US 11969418 B2, PCT publication Nos. WO2022266285A1, WO2022261138A1, WO2022233801A1, WO2021216814A1, WO2021202825A1, WO2021164735A1. Other compounds that target BTK include, but are not limited to, Acalabrutinib (AstraZeneca), Zanubrutinib (BeiGene), Evobrutinib (Merck), Tolebrutinib (Sanofi), Orelabrutinib (InnoCare), Remibrutinib (Novartis), Tirabrutinib Ono/Gilead), Rilzabrutinib (Sanofi), and Branebrutinib (BMS). 6. MRGPRX2 In some forms, the target molecule is MRGPRX2, also referred to as “MRGX2,” or “MGRG3,” and refers to a member of the MRGPR family that is expressed on mast cells and capable of mediating IgE-independent activation (e.g., mast cell degranulation) in response to ligand binding. An exemplary human MRGPRX2 amino acid sequence is set forth in Uniprot Q96LB1. MRGPRX2 and its ortholog receptors mediate disorders including pseudo-allergic reactions including pseudo-allergic drug reactions, chronic itch (e.g., pruritus), inflammation disorders, pain disorders, skin disorders, wound healing, cardiovascular disease, and lung inflammation/COPD. In one form, both mrgprb2 and MRGPRX2 expression is largely restricted to mast cells. Upon activation of MRGPRX2, mast cells release a cascade of substances including histamine, tryptase, chymase, chemokines, and cytokines. In some forms, the MRGPRX2 inhibitor is EP262. EP262 is an effective and highly specific small molecule antagonist capable of inhibiting the activation of MRGPRX2. Its mechanism of action is independent of IgE. In some forms, MRGPRX2 inhibitors are compounds having a general structural formula as set forth in Wollam, et al., (2023, February), Journal of Allergy and Clinical Immunology, 151(2)., or U.S. Patent Application Publication Nos. US11970452B2, US 11952346 B2, US 11667636 B2, US 11919864 B2, US20200370051A1, US 11976057 B2, each of which are specifically incorporated by reference herein in their entireties. 45740907.1 41 Other compounds that target MRGPRX2 include, but are not limited to, EVO756 (Evommune) and KRP-M223 (Novartis). 7. TRPA1, TRPV4, TRPM8 In some forms, the target molecule is TRPA1 which is a non-cation selective channel that belongs to the Transient Receptor Potential (TRP) superfamily. TRPA1 was first identified from cultured lung fibroblasts (Jaquemar et al., 1999), and further studies indicated that TRPAI was highly expressed in sensory neurons of the dorsal root, trigeminal and nodose ganglia. In sensory neurons, TRPA1 expression is most prevalent in small diameter neurons where it colocalizes with markers of peptidergic nociceptors such as TRPV1, calcitonin gene-related peptide (CGRP) and substance P (Kaneko et al., 2013). Moreover, TRPA1 has been identified in the small intestine, colon, pancreas, skeletal muscle, heart, brain, and T and B-lymphocytes (Stokes et al., 2006). TRPA1 is activated by a variety of noxious stimuli, including cold temperatures and pungent natural compounds (e.g., mustard, cinnamon and garlic). TRPA1 is also activated by environmental irritants, including isocyanates and heavy metals produced during the manufacturing of polymers, fertilizers and pesticides. Vehicle exhaust, burning vegetation and electrophilic tear gases used as incapacitating agents, are potent activators of TRPA1. TRPA1 antagonists or inhibitors could also have applications in defense against such agents. In some forms, the TRPA1 inhibitor is LY3526318. LY3526318 is known to reduce the cinnamaldehyde-induced vasodilation in both rats and humans, confirming its TRPA1 engagement in vivo (Bamps et al., Clin Pharmacol Ther.2023 Nov;114(5):1093-1103). In some forms, TRPA1 inhibitors are compounds having a general structural formula as set forth in Chen & Terrett, Expert Opinion on Therapeutic Patents., 2020, 30(9), 643–657, Skerratt, Progress in Medicinal Chemistry, 2017, Volume 56, 81-115, Preti et al., Pharm. Pat. Anal., (2015) 4 (2), 75-94, Bioorg. Med. Chem. Lett.2012, 22, 5485, Bioorg. Med. Chem. Lett. 2010, 20, 276, Bioorg. Med. Chem. Lett 2012, 22, 797, Med. Chem. Comm.2012, 3, 187, Bamps et al., Clin Pharmacol Ther.2023 Nov;114(5):1093-1103 or U.S. Patent Application Publication Nos. US 11891403 B2, US 11884681 B2, US 11858921 B2, US 11661430 B2 US 11661427 B2, US 11464720 B2 or international Patent Application Publication Nos. WO2017060488A1, WO2013103155, WO2012050512, WO 2011043954, WO2009089082, WO2009089083, WO2010141805, EP2520566, WO2013108857 WO2014049047, WO2007073505, WO2009002933, WO2009118596, WO2009144548, WO2009158719, WO2010004390, WO2010036821 , WO2010075353, WO2010109287, WO2010109328, WO2010109329, WO2010109334, WO2010125469, WO2010132838, WO2010138879, WO2011114184, WO2011132017, WO2012176105, WO2012085662, WO2013023102, 45740907.1 42 WO2007073505, WO2009147079, WO2007098252 or WO2012152940, each of which are specifically incorporated by reference herein in their entireties. Other compounds that target TRPA1 include, but are not limited to, GDC-0334 (Genentech), GRC-17536 (Glenmark), LY3526318 (Eli Lilly), CB-189625 (Merck), ODM-108 (Orion), HC-030031 (Orion), AMG-0902 (Amgen), A-967079 (Abbott), HX-100 (Hydra), and BAY-390 (Evotec). In other forms, the target molecule is additionally or alternatively TRPM4 and/or TRPM8. Inhibitors of TRPM4 include, but are not limited to, GSK2798745 (GSK) and ABS-0871 (Actio). TRPM8, in contrast to the targets above, represents an inhibitor of airway reflexes. Agonists at this receptor are disclosed for use in the methods provided herein and include, but are not limited to, AR-15512 (Alcon), AX-8 (Axalbion), and IVW-1001 (IVIEW). 8. Protease Receptors In addition to TRP channels and MRGPRs, protease receptors, particularly PAR2, is an important class of irritant receptor. This in some forms, the target is a protease-activated receptor such as PAR2. Protease-activated receptors (PARs) are a family of G protein-coupled receptors that are activated by proteolytic cleavage of their extracellular domain. This cleavage exposes a tethered ligand, which then binds to and activates the receptor, initiating intracellular signaling pathways. For example, PAR2, also known as Protease-activated receptor 2, is a protein that functions as a G protein-coupled receptor and is involved in various physiological and pathological processes including inflammation, pain, and potentially cancer development. Its expression is found in various tissues and cell types. It is activated by proteases like trypsin, and its activation triggers intracellular signaling cascades. PAR2 plays a role in. Exemplary compounds that target PAR2 include, but are not limited to, MEDI0618 (AstraZeneca), TEV-‘192 (Teva), and OA-235i (Oasis). 9. IL-33 In some forms, the target molecule is Interleukin-33 (IL-33). IL-33 is also known as IL-1 F11, is a member of the IL-1 family of cytokines. IL- 33 is a 270 amino acid protein having two domains: a homeodomain and a cytokine (IL-1 like) domain. The homeodomain contains a nuclear localization signal (NLS). IL-33 is known to exist in different forms; a reduced form (redlL-33) and an oxidised form (oxlL-33). Previous studies have shown that the reduced form is rapidly oxidised under physiological conditions to form at least one disulphide bond in the oxidised form, and that the two forms likely have different binding patterns and effects. 45740907.1 43 In some forms, the compound is an anti-IL-33 antibody. Examples are known in the art. In particular forms, the antibody is tozorakimab, or a bioequivalent thereof. Tozorakimab (MEDI-3506) which is a human IgGl mAb that binds to human IL- 33. Tozorakimab binds full length and mature forms of human IL-33 with exceptionally high affinity and prevents IL-33 binding to soluble (sST2) and membrane-bound forms of ST2 (also known as IL-1RL1) receptor. Information regarding tozorakimab (or bioequivalents thereof or fragments thereof) for use in the methods provided herein can be found in e.g., international patent application Nos. WO2024038186A1 or WO2024042212A1 or WO2023180503A1, the disclosures of which are incorporated herein by reference in their entireties. Tozorakimab and antigen-binding fragments thereof for use in the methods provided herein can include a heavy chain and a light chain or a heavy chain variable region and a light chain variable region. In a further aspect, tozorakimab or an antigen-binding fragment thereof for use in the methods provided herein includes any one of the amino acid sequences of SEQ ID NOs: 1-6 of international patent application No. WO2024038186A1. In a specific aspect, tozorakimab or an antigen-binding fragment thereof for use in the methods provided herein include a heavy chain variable region comprising a VHCDR1 having the sequence of SEQ ID NO: 1, a VHCDR2 having the sequence of SEQ ID NO: 2, and a VHCDR3 having the sequence of SEQ ID NO: 3; and a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO: 4, a VLCDR2 having the sequence of SEQ ID NO: 5, and a VLCDR3 having the sequence of SEQ ID NO: 6 of the international patent application No. WO2024038186A1. In some forms, tozorakimab or another anti-IL-33 binding protein is administered to the subject in a dose of 250 to 350 mg. Other compounds that target IL-33 include, but are not limited to, Itepekimab (Sanofi/Regeneron), Astegolimab (Genentech/Roche), and Etokimab (AnaptysBio), Tozorakimab (AstraZeneca), Itepekimab (Sanofi/Regeneron), CAN-10 (Cantargia), GSK- 3862995B (GSK), PF-07264660 (Pfizer), and TQC-2938 (Sino). 10. CRTH2 In some forms, the target molecule is CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells), also known as DP2, GPR44, and CD292. CRTH2 is a G protein-coupled receptor expressed on Th2 cells, eosinophils, and ILC2s. It plays well- established roles in airway disease and type 2 inflammation. CRTH2 serves as the receptor for prostaglandin D2 (PGD2), which is an eicosanoid, a class of chemical mediator synthesized by cells in response to local tissue damage, normal stimuli or hormonal stimuli or via cellular activation pathways. Eicosanoids bind to specific cell surface receptors on a wide variety of 45740907.1 44 tissues throughout the body and mediate various effects in these tissues. PGD2 is known to be produced by mast cells, macrophages and Th2 lymphocytes and has been detected in high concentrations in the airways of asthmatic patients challenged with antigen (Murray et al, (1986), N. Engl. I. Med.315: 800-804). Instillation of PGD into airways can provoke many features of the asthmatic response including bronchoconstriction (Hardy et al, (1984) N. Engl. I. Med.311: 209-213; Sampson et al, (1997) Thorax 52: 513-518) and eosinophil accumulation (Emery et al, (1989) J. Appl Physiol.67: 959-962). In some forms, the CRTH2 inhibitor is fevipiprant. Fevipiprant also known as NVP- QAW039 or QAW-039, and by the chemical name 2-[2-methyl-1-[4-(methylsulfonyl)-2- (trifluoromethyl)benzyl]-1H-pyrrolo[2,3- b]pyridin-3-yl] acetic acid is a type of a prostaglandin D2 receptor (DP2/CRTh2) inhibitor that can promote the integrity of airway epithelia. In some forms, CRTH2 inhibitors are compounds having general structural formula as set forth in U.S. Patent Nos.7,666, 878, 8,455, 645, or 8,791,256 or International Patent Application Publication Nos. WO2005123731A2, WO2005121141A1, WO2005040112A1, or EP1505061A1 which are specifically incorporated by reference herein in their entireties. Other compounds that target CRTH2 include, but are not limited to, Timapiprant (Chiesi), AZD1981 (AstraZeneca), ARRY-502 (Array), BI-671800 (Boeringer Ingelheim), MK- 1029 (Merck), Setipiprant (J&J), and Vedupiprant (Amgen). 11. Nav1.7 and Nav1.8 In some forms, the targets are Nav1.7 and Nav1.8. The NaVs form a subfamily of the voltage-gated ion channel super-family and has 9 isoforms, designated Nav1.1-Nav1.9. The tissue localizations of the nine isoforms vary. Navs 1.7 and 1.8 are primarily localized to the peripheral nervous system. The functional behaviors of the nine isoforms are similar but distinct in the specifics of their voltage-dependent and kinetic behavior (Catterall, et al., Pharmacol. Rev. 57 (4), p.397 (2005). Nav1.8 channels were identified as likely targets for analgesia (Akopian et al., Nature, 1996.379(6562): p.257-62). Since then, Nav1.8 has been shown to be a carrier of the sodium current that maintains action potential firing in small dorsal root ganglia (DRG) neurons (Blair, et al., J. Neurosci., 2002.22(23): p.10277-90). Nav1.8 is involved in spontaneous firing in damaged neurons, like those that drive neuropathic pain (Roza, et al., J. Physiol., 2003.550(Pt 3): p.921-6; Jarvis, M. F., et al., A-803467, Proc. Natl. Acad. Sci. USA, 2007.104(20): p.8520-5; Joshi, S. K., et al., Pain, 2006.123(1-2): pp.75-82; Lai, J., et al.). In some forms, the Nav1.8 inhibitor is Suzetrigine (VX-548). Suzetrigine is selective Nav1.8 pain signal inhibitor that is highly selective for Nav1.8 relative to other Nav channels. In some forms, Nav1.8 inhibitors are compounds having general structural formula as set forth in Jones et al., N Engl J Med.2023 Aug 3;389(5):393-405 or U.S. Patent No 11,834,441 or the 45740907.1 45 International Patent Application Publication Nos. WO2021113627A1, WO-2022256708-A1, WO-2022256676-A1 or WO-2022256660-A1, which are specifically incorporated by reference herein in their entireties. In some forms, the Nav1.7 inhibitor is AZD-3161. AZD-3161 is a blocker of Nav1.7 channel. In some forms, Nav1.7 inhibitors are compounds having general structural formula as set forth in Bagal et al., 2015 Nov-Dec; 9(6): 360–366, US Patent Application Publication Nos. US11221329B2, US2018328915A1, US2019359662A1, US10662229B2 or International Patent Application Publication Nos. WO2015036734A1, WO-2017075222-A1, which are specifically incorporated by reference herein in their entireties. Other compounds that target Nav1.7 include, but are not limited to, Vixotrigine (Biogen), Ralfinamide (Newron), CC-8464 (Channel), DWP-17061 (iN Therapeutics), DSP-3905 (Sumitono), PF-05089771, RG-6029 (Xenon), BIIB-095 (Biogen), and ST-2427 (Siteone). Other compounds that target Nav1.8 include, but are not limited to, JMKX-000623 (Orion), LTG-305 (Latigo), VX-973 (Vertex), HBW-004285 (Hyperway), STC-004 (Siteone), HRS-4800 (Jiangsu), and 14C-VX-993 (Vertex). Other compounds that target both Nav1.7 and Nav1.8 include, but are not limited to, ANP-230 (Sumitono), Kindolor (Lohocla). 12. NGF In some forms, the targets are nerve growth factor (NGF). NGF was the first neurotrophin to be identified, and its role in the development and survival of both peripheral and central neurons has been well characterized. NGF has been shown to be an important survival and maintenance factor in the development of peripheral sympathetic and embryonic sensory neurons and of basal forebrain cholinergic neurons (Smeyne et al., Nature 368:246-249 (1994); Crowley et al., Cell 76:1001 - 1011 (1994)). NGF upregulates expression of neuropeptides in sensory neurons (Lindsay and Harmer, Nature 337:362-3640989)) and its activity is mediated through two different membrane-bound receptors. The TrkA tyrosine kinase receptor mediates high affinity binding and the p75 receptor, which is structurally related to other members of the tumor necrosis factor receptor family, mediates low affinity binding (Chao et al., Science 232:518-521 (1986)). In some forms, the NGF inhibitor is MEDI7352. MEDI7352 is a bispecific monoclonal antibody that specifically binds to NGF and TNF-α, thus blocking their effects. In some forms, NGF antibodies or inhibitors are as set forth in U.S Patent Application Publication Nos. US9315573B2 or International Patent Application Publication Nos. WO2005019266A2, AU2020203115A1, EP2340849A1, AU2018201858B2, AU2014203316B2, 45740907.1 46 AU2014217561B2, WO2014/125374, PCT/IB2014/000692 or CA2722378C which are specifically incorporated by reference herein in their entireties. Other compounds that target NGF include, but are not limited to, Tanezumab (Eli Lilly/Pfizer), Fasinumab (Teva/Regeneron), MEDI7352 (AstraZeneca), Fulranumab (J&J). 13. P2X3 In some forms, the target is P2X3. Compounds that can be used to target P2X3 include Camlipixant (GSK), Gefapixant (Merck), AZ-004 (AstraZeneca), and Eliapixant (Bayer). 14. Cysteinyl leukotrienes Mast cells generate cysteinyl leukotrienes (which signals through CysLT1 and requires 5- lipoxygenase for synthesis). Montelukast is a generic leukotriene inhibitor that has been tested for Long COVID based on the putative role of mast cells in disease pathogenesis (NCT04695704, NCT06597682). CRTH2 inhibitors were well-studied in the context of asthma, but ultimately abandoned when they failed in Phase 3. It is herein contemplated that treatment with cysLT inhibitors alone or in combination with CRTH2 and could be effective for Long COVID. Thus, in some forms, the disclosed method includes treatment with a drug that targets CystLT1, 5-lipoxyenase, and/or CRTH2 (above). Exemplary drugs include, but are not limited to, CystLT1 Montelukast (Merck, generic), Zafirlukast (AstraZeneca), and Pranlukast (ONO). 5-lipoxygenase Zileuton (Abbott). 15. Salience network dysfunction Another important aspect of the disclosed pathophysiologic framework relates to salience network dysfunction. The salience network functions as a gating system to license protective airway responses. As such, changes in salience network sensitivity contribute to exaggerated and/or prolonged cough and bronchospasm. The fronto-corticolimbic network, which includes structures such as the mPFC and sgACC, serves as an inhibitor of the salience network and, as shown in depression, represents an important target for neuroplastogens like ketamine. Thus, it is believed that ketamine improves PCAD by suppressing salience network processing, at least in part through actions at the fronto-corticolimbic network. Additionaly, neuroplastogens like ketamine may improve PCAD through effects at the CTSC, which is a key element of the salience network. 45740907.1 47 Drugs that can treat salience network dysfunction include, but are not limited to, rapid- acting antidepressants (RAADs). In one example, shown in the experiments below, ketamine has proven highly effective in the clinic. Dosing is an important element of the response to neuroplastogens; in general, higher doses that achieve psychedelic effects are generally associated with stronger clinical improvements (Romeo et al. Neurosci Biobehav Rev. May:172:106086 (2025)). As such, higher doses are recommended for effective treatment of PCAD. Other RAADs are also provided. RAADs can be divided into neurosteroids and neuroplastogens. In turn, neuroplastogens can be subdivided into NMDAR antagonists and 5- HT2A agonists (classic psychedelics). Neurosteroids may be particularly effective for patients with PCAD who experience menstrual-related fluctuations in symptoms (a common clinical finding in the patients of the studies reported below). Thus, in addition to ketamine, exemplary RAADs for use in the disclosed methods, listed by subcategory include, but are not limited to, NMDAR antagonists Esketamine (J&J), Acamprosate (Merck), ADS-5002 (Supernus), ALKS-7119 (Alkermes), ALTO-202 (Alto), AmiKet (Immune Pharma), Aptiganel (Paion), Arketamine, ASP-0777 (Astellas), AV-101 (Vistagen), AZD-4282 (AstraZeneca), AZD-8108 (AstraZeneca), Besonprodil (Pfizer), BI-1569912 (Boehringer), Dextromethorphan, Dextromethorphan- bupropion (Auvelity, Axsome), BIO-176 (Switch), Budipine (Takeda), CGP-40116 (Novartis), CGX-1007 (Cognetix), CNS-5161 (Paion), Delucemine (Takeda), Dimiracetam (GSK), Dizocilpine (Merck), DLX-7 (Delix), ED-1529 (Nxera), Eliprodil (Sanofi), EVT-101 (J&J), GM-1020 (Gilgamesh), GV-196771 (GSK), GV-48816 (GSK), Ifenprodil (Algernon), Indantadol (Chiesi), Lanicemine (Biohaven), Memantine, MP-101 (Novaremed), NBI-1070770 (Neurocrine), Neramexane (Merz), Nezavist (Lohocla), Norketamine (J&J), NP-10679 (Seyltx), NYX02925 (Aptinyx), Onfasprodil (Novartis), Perzinfotel (Pfizer), Rislenemdaz (Avalo), SNA- 1 (SyneuRx), Traxoprodil (Pfizer), Rapastinel (Abbvie), and Ibogaine (Atai). 5-HT2A agonists LSD, Psilocybin, DMT, 5-MeO-DMT, Ayahuasca, Mescaline, DOI, MDMA, Methylone, ACP-204 (Acadia), Altanserin (J&J), BETR-001 (Entheogen), Eplivanserin (Sanofi), GM-2505 (Gilgamesh), MSP-1014 (Otsuka), and RE-104 (Reunion). Neurosteroids Brexanolone (Sage), Zuranolone (Sage), Ganaxolone (Marinus), Sepranolone (Relmada), LYT-300 (Lyndra), and PRAX-114 (Praxis). 45740907.1 48 D. Formulations The disclosed compounds can be formulated in a pharmaceutical composition. Pharmaceutical compositions can be for administration by parenteral (intramuscular, intraperitoneal, intravenous (IV) or subcutaneous injection), enteral, transdermal (either passively or using iontophoresis or electroporation), or transmucosal (nasal, pulmonary, vaginal, rectal, or sublingual) routes of administration or using bioerodible inserts and can be formulated in dosage forms appropriate for each route of administration. The compositions can be administered systemically. Drugs can be formulated for immediate release, extended release, or modified release. A delayed release dosage form is one that releases a drug (or drugs) at a time other than promptly after administration. An extended release dosage form is one that allows at least a twofold reduction in dosing frequency as compared to that drug presented as a conventional dosage form (e.g. as a solution or prompt drug-releasing, conventional solid dosage form). A modified release dosage form is one for which the drug release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as solutions, ointments, or promptly dissolving dosage forms. Delayed release and extended-release dosage forms and their combinations are types of modified release dosage forms. Formulations are typically prepared using a pharmaceutically acceptable “carrier” composed of materials that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions. The “carrier” is all components present in the pharmaceutical formulation other than the active ingredient or ingredients. The term “carrier” includes, but is not limited to, diluents, binders, lubricants, disintegrators, fillers, and coating compositions. “Carrier” also includes all components of the coating composition which may include plasticizers, pigments, colorants, stabilizing agents, and glidants. The delayed release dosage formulations may be prepared as described in references such as “Pharmaceutical dosage form tablets”, eds. Liberman et al. (New York, Marcel Dekker, Inc., 1989), “Remington – The science and practice of pharmacy”, 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, and “Pharmaceutical dosage forms and drug delivery systems”, 6^th Edition, Ansel et.al., (Media, PA: Williams and Wilkins, 1995) which provides information on carriers, materials, equipment and process for preparing tablets and capsules and delayed release dosage forms of tablets, capsules, and granules. 45740907.1 49 The compound can be administered to a subject with or without the aid of a delivery vehicle. Appropriate delivery vehicles for the compounds are known in the art and can be selected to suit the particular active agent. For example, in some forms, the active agent(s) is incorporated into or encapsulated by, or bound to, a nanoparticle, microparticle, micelle, synthetic lipoprotein particle, or carbon nanotube. For example, the compositions can be incorporated into a vehicle such as polymeric particles which provide controlled release of the active agent(s). In some forms, release of the drug(s) is controlled by diffusion of the active agent(s) out of the particles and/or degradation of the polymeric particles by hydrolysis and/or enzymatic degradation. Suitable polymers include ethylcellulose and other natural or synthetic cellulose derivatives. Polymers which are slowly soluble and form a gel in an aqueous environment, such as hydroxypropyl methylcellulose or polyethylene oxide, may also be suitable as materials for drug containing particles or particles. Other polymers include, but are not limited to, polyanhydrides, poly (ester anhydrides), polyhydroxy acids, such as polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), poly-3-hydroxybut rate (PHB) and copolymers thereof, poly-4-hydroxybutyrate (P4HB) and copolymers thereof, polycaprolactone and copolymers thereof, and combinations thereof. In some forms, both agents are incorporated into the same particles and are formulated for release at different times and/or over different time periods. For example, in some forms, one of the agents is released entirely from the particles before release of the second agent begins. In other forms, release of the first agent begins followed by release of the second agent before the all of the first agent is released. In still other forms, both agents are released at the same time over the same period of time or over different periods of time. 1. Formulations for Parenteral Administration Compounds and pharmaceutical compositions thereof can be administered in an aqueous solution, by parenteral injection. The formulation may also be in the form of a suspension or emulsion. In general, pharmaceutical compositions are provided including effective amounts of the active agent(s) and optionally include pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers. Such compositions include diluents sterile water, buffered saline of various buffer content (e.g., Tris-HCl, acetate, phosphate), pH and ionic strength; and optionally, additives such as detergents and solubilizing agents (e.g., TWEEN® 20, TWEEN® 80 also referred to as POLYSORBATE® 20 or 80), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), and preservatives (e.g., Thimerosol, benzyl alcohol) and bulking substances (e.g., lactose, mannitol). Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and 45740907.1 50 injectable organic esters such as ethyl oleate. The formulations may be lyophilized and redissolved/resuspended immediately before use. The formulation may be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. 2. Oral Immediate Release Formulations Suitable oral dosage forms include tablets, capsules, solutions, suspensions, syrups, and lozenges. Tablets can be made using compression or molding techniques well known in the art. Gelatin or non-gelatin capsules can be prepared as hard or soft capsule shells, which can encapsulate liquid, solid, and semi-solid fill materials, using techniques well known in the art. Examples of suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins that are commercially available under the trade name Eudragit^® (Roth Pharma, Westerstadt, Germany), Zein, shellac, and polysaccharides. Additionally, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilization agents, pore formers and surfactants. Optional pharmaceutically acceptable excipients present in the drug-containing tablets, beads, granules or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants. Diluents, also termed "fillers," are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powder sugar. Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms. Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydorxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone. 45740907.1 51 Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil. Disintegrants are used to facilitate dosage form disintegration or "breakup" after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross-linked polymers, such as cross- linked PVP (Polyplasdone XL from GAF Chemical Corp). Stabilizers are used to inhibit or retard drug decomposition reactions which include, by way of example, oxidative reactions. Surfactants may be anionic, cationic, amphoteric or nonionic surface-active agents. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, POLOXAMER^® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl-beta-alanine, sodium N-lauryl-beta- iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine. If desired, the tablets, beads granules or particles may also contain minor amount of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, and preservatives. 3. Extended-release dosage forms The extended-release formulations are generally prepared as diffusion or osmotic systems, for example, as described in “Remington – The science and practice of pharmacy” (20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000). A diffusion system typically consists of two types of devices, reservoir and matrix, and is well known and described in the art. 45740907.1 52 The matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form. The three major types of materials used in the preparation of matrix devices are insoluble plastics, hydrophilic polymers, and fatty compounds. Plastic matrices include, but not limited to, methyl acrylate-methyl methacrylate, polyvinyl chloride, and polyethylene. Hydrophilic polymers include, but are not limited to, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and carbopol 934, polyethylene oxides. Fatty compounds include, but are not limited to, various waxes such as carnauba wax and glyceryl tristearate. Alternatively, extended-release formulations can be prepared using osmotic systems or by applying a semi-permeable coating to the dosage form. In the latter case, the desired drug release profile can be achieved by combining low permeable and high permeable coating materials in suitable proportion. The devices with different drug release mechanisms described above could be combined in a final dosage form having single or multiple units. Examples of multiple units include multilayer tablets, capsules containing tablets, beads, granules, etc. An immediate release portion can be added to the extended-release system by means of either applying an immediate release layer on top of the extended-release core using coating or compression process or in a multiple unit system such as a capsule containing extended and immediate release beads. Extended-release tablets containing hydrophilic polymers are prepared by techniques commonly known in the art such as direct compression, wet granulation, or dry granulation processes. Their formulations usually incorporate polymers, diluents, binders, and lubricants as well as the active pharmaceutical ingredient. The usual diluents include inert powdered substances such as any of many different kinds of starch, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include substances such as starch, gelatin and sugars such as lactose, fructose, and glucose. Natural and synthetic gums, including acacia, alginates, methylcellulose, and polyvinylpyrrolidine can also be used. Polyethylene glycol, hydrophilic polymers, ethylcellulose and waxes can also serve as binders. A lubricant is necessary in a tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. 45740907.1 53 Extended-release tablets containing wax materials are generally prepared using methods known in the art such as a direct blend method, a congealing method, and an aqueous dispersion method. In a congealing method, the drug is mixed with a wax material and either spray- congealed or congealed and screened and processed. 4. Delayed-release dosage forms Delayed-release formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in the acid environment of the stomach, and soluble in the neutral environment of small intestines. The delayed-release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material. The drug-containing composition may be, e.g., a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule. Preferred coating materials include bioerodible, gradually hydrolyzable, gradually water-soluble, and/or enzymatically degradable polymers, and may be conventional "enteric" polymers. Enteric polymers, as will be appreciated by those skilled in the art, become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly in the colon. Suitable coating materials for effecting delayed release include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, and other methacrylic resins that are commercially available under the tradename EUDRAGIT^®. (Rohm Pharma; Westerstadt, Germany), including EUDRAGIT^®. L30D-55 and L100-55 (soluble at pH 5.5 and above), EUDRAGIT^®. L-100 (soluble at pH 6.0 and above), EUDRAGIT^®. S (soluble at pH 7.0 and above, as a result of a higher degree of esterification), and EUDRAGITS^®. NE, RL and RS (water-insoluble polymers having different degrees of permeability and expandability); vinyl polymers and copolymers such as polyvinyl pyrrolidone, vinyl acetate, vinylacetate phthalate, vinylacetate crotonic acid copolymer, and ethylene-vinyl acetate copolymer; enzymatically degradable polymers such as azo polymers, pectin, chitosan, amylose and guar gum; zein and shellac. Combinations of different coating materials may also be used. Multi-layer coatings using different polymers may also be applied. 45740907.1 54 The preferred coating weights for particular coating materials may be readily determined by those skilled in the art by evaluating individual release profiles for tablets, beads and granules prepared with different quantities of various coating materials. It is the combination of materials, method and form of application that produce the desired release characteristics, which one can determine only from the clinical studies. The coating composition may include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents, glidants, etc. A plasticizer is normally present to reduce the fragility of the coating, and will generally represent about 10 wt. % to 50 wt. % relative to the dry weight of the polymer. Examples of typical plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil and acetylated monoglycerides. A stabilizing agent is preferably used to stabilize particles in the dispersion. Typical stabilizing agents are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce sticking effects during film formation and drying, and will generally represent approximately 25 wt. % to 100 wt. % of the polymer weight in the coating solution. One effective glidant is talc. Other glidants such as magnesium stearate and glycerol monostearates may also be used. Pigments such as titanium dioxide may also be used. Small quantities of an anti-foaming agent, such as a silicone (e.g., simethicone), may also be added to the coating composition. Methods of manufacturing As will be appreciated by those skilled in the art and as described in the pertinent texts and literature, a number of methods are available for preparing drug-containing tablets, beads, granules or particles that provide a variety of drug release profiles. Such methods include, but are not limited to, the following: coating a drug or drug-containing composition with an appropriate coating material, typically although not necessarily incorporating a polymeric material, increasing drug particle size, placing the drug within a matrix, and forming complexes of the drug with a suitable complexing agent. The delayed release dosage units may be coated with the delayed release polymer coating using conventional techniques, e.g., using a conventional coating pan, an airless spray technique, fluidized bed coating equipment (with or without a Wurster insert). For detailed information concerning materials, equipment and processes for preparing tablets and delayed release dosage forms, see Pharmaceutical Dosage Forms: Tablets, eds. Lieberman et al. (New York: Marcel Dekker, Inc., 1989), and Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 6.sup.th Ed. (Media, PA: Williams & Wilkins, 1995). 45740907.1 55 A preferred method for preparing extended-release tablets is by compressing a drug- containing blend, e.g., blend of granules, prepared using a direct blend, wet-granulation, or dry- granulation process. Extended-release tablets may also be molded rather than compressed, starting with a moist material containing a suitable water-soluble lubricant. However, tablets are preferably manufactured using compression rather than molding. A preferred method for forming extended-release drug-containing blend is to mix drug particles directly with one or more excipients such as diluents (or fillers), binders, disintegrants, lubricants, glidants, and colorants. As an alternative to direct blending, a drug-containing blend may be prepared by using wet-granulation or dry-granulation processes. Beads containing the active agent may also be prepared by any one of a number of conventional techniques, typically starting from a fluid dispersion. For example, a typical method for preparing drug-containing beads involves dispersing or dissolving the active agent in a coating suspension or solution containing pharmaceutical excipients such as polyvinylpyrrolidone, methylcellulose, talc, metallic stearates, silicone dioxide, plasticizers or the like. The admixture is used to coat a bead core such as a sugar sphere (or so-called "non-pareil") having a size of approximately 60 to 20 mesh. An alternative procedure for preparing drug beads is by blending drug with one or more pharmaceutically acceptable excipients, such as microcrystalline cellulose, lactose, cellulose, polyvinyl pyrrolidone, talc, magnesium stearate, a disintegrant, etc., extruding the blend, spheronizing the extrudate, drying and optionally coating to form the immediate release beads. 5. Formulations for Mucosal and Pulmonary Administration Active agent(s) and compositions thereof can be formulated for pulmonary or mucosal administration. The administration can include delivery of the composition to the lungs, nasal, oral (sublingual, buccal), vaginal, or rectal mucosa. In a particular form, the composition is formulated for and delivered to the subject sublingually. In one form, the compounds are formulated for pulmonary delivery, such as intranasal administration or oral inhalation. The respiratory tract is the structure involved in the exchange of gases between the atmosphere and the blood stream. The lungs are branching structures ultimately ending with the alveoli where the exchange of gases occurs. The alveolar surface area is the largest in the respiratory system and is where drug absorption occurs. The alveoli are covered by a thin epithelium without cilia or a mucus blanket and secrete surfactant phospholipids. The respiratory tract encompasses the upper airways, including the oropharynx and larynx, followed by the lower airways, which include the trachea followed by bifurcations into the bronchi and bronchioli. The upper and lower airways are called the conducting airways. The terminal bronchioli then divide into respiratory bronchiole, which then lead to the ultimate 45740907.1 56 respiratory zone, the alveoli, or deep lung. The deep lung, or alveoli, is the primary target of inhaled therapeutic aerosols for systemic drug delivery. Pulmonary administration of therapeutic compositions composed of low molecular weight drugs has been observed, for example, beta-androgenic antagonists to treat asthma. Other therapeutic agents that are active in the lungs have been administered systemically and targeted via pulmonary absorption. Nasal delivery is considered to be a promising technique for administration of therapeutics for the following reasons: the nose has a large surface area available for drug absorption due to the coverage of the epithelial surface by numerous microvilli, the subepithelial layer is highly vascularized, the venous blood from the nose passes directly into the systemic circulation and therefore avoids the loss of drug by first-pass metabolism in the liver, it offers lower doses, more rapid attainment of therapeutic blood levels, quicker onset of pharmacological activity, fewer side effects, high total blood flow per cm³, porous endothelial basement membrane, and it is easily accessible. The term aerosol as used herein refers to any preparation of a fine mist of particles, which can be in solution or a suspension, whether or not it is produced using a propellant. Aerosols can be produced using standard techniques, such as ultrasonication or high-pressure treatment. Carriers for pulmonary formulations can be divided into those for dry powder formulations and for administration as solutions. Aerosols for the delivery of therapeutic agents to the respiratory tract are known in the art. For administration via the upper respiratory tract, the formulation can be formulated into a solution, e.g., water or isotonic saline, buffered or un- buffered, or as a suspension, for intranasal administration as drops or as a spray. Preferably, such solutions or suspensions are isotonic relative to nasal secretions and of about the same pH, ranging e.g., from about pH 4.0 to about pH 7.4 or, from pH 6.0 to pH 7.0. Buffers should be physiologically compatible and include, simply by way of example, phosphate buffers. For example, a representative nasal decongestant is described as being buffered to a pH of about 6.2. One skilled in the art can readily determine a suitable saline content and pH for an innocuous aqueous solution for nasal and/or upper respiratory administration. Preferably, the aqueous solution is water, physiologically acceptable aqueous solutions containing salts and/or buffers, such as phosphate buffered saline (PBS), or any other aqueous solution acceptable for administration to an animal or human. Such solutions are well known to a person skilled in the art and include, but are not limited to, distilled water, de-ionized water, pure or ultrapure water, saline, phosphate-buffered saline (PBS). Other suitable aqueous vehicles include, but are not limited to, Ringer's solution and isotonic sodium chloride. Aqueous suspensions may include suspending agents such as cellulose derivatives, sodium alginate, 45740907.1 57 polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate. In another form, solvents that are low toxicity organic (i.e. nonaqueous) class 3 residual solvents, such as ethanol, acetone, ethyl acetate, tetrahydrofuran, ethyl ether, and propanol may be used for the formulations. The solvent is selected based on its ability to readily aerosolize the formulation. The solvent should not detrimentally react with the compounds. An appropriate solvent should be used that dissolves the compounds or forms a suspension of the compounds. The solvent should be sufficiently volatile to enable formation of an aerosol of the solution or suspension. Additional solvents or aerosolizing agents, such as freons, can be added as desired to increase the volatility of the solution or suspension. In one form, compositions may contain minor amounts of polymers, surfactants, or other excipients well known to those of the art. In this context, “minor amounts” means no excipients are present that might affect or mediate uptake of the compounds in the lungs and that the excipients that are present are present in amount that do not adversely affect uptake of compounds in the lungs. Dry lipid powders can be directly dispersed in ethanol because of their hydrophobic character. For lipids stored in organic solvents such as chloroform, the desired quantity of solution is placed in a vial, and the chloroform is evaporated under a stream of nitrogen to form a dry thin film on the surface of a glass vial. The film swells easily when reconstituted with ethanol. To fully disperse the lipid molecules in the organic solvent, the suspension is sonicated. Nonaqueous suspensions of lipids can also be prepared in absolute ethanol using a reusable PARI LC Jet+ nebulizer (PARI Respiratory Equipment, Monterey, CA). Dry powder formulations (“DPFs”) with large particle size have improved flowability characteristics, such as less aggregation, easier aerosolization, and potentially less phagocytosis. Dry powder aerosols for inhalation therapy are generally produced with mean diameters primarily in the range of less than 5 microns, although a preferred range is between one and ten microns in aerodynamic diameter. Large “carrier” particles (containing no drug) have been co- delivered with therapeutic aerosols to aid in achieving efficient aerosolization among other possible benefits. Polymeric particles may be prepared using single and double emulsion solvent evaporation, spray drying, solvent extraction, solvent evaporation, phase separation, simple and complex coacervation, interfacial polymerization, and other methods well known to those of ordinary skill in the art. Particles may be made using methods for making microspheres or microcapsules known in the art. The preferred methods of manufacture are by spray drying and 45740907.1 58 freeze drying, which entails using a solution containing the surfactant, spraying to form droplets of the desired size, and removing the solvent. The particles may be fabricated with the appropriate material, surface roughness, diameter and tap density for localized delivery to selected regions of the respiratory tract such as the deep lung or upper airways. For example, higher density or larger particles may be used for upper airway delivery. Similarly, a mixture of different sized particles, provided with the same or different active agents may be administered to target different regions of the lung in one administration. 6. Topical and Transdermal Formulations Transdermal formulations may also be prepared. These will typically be gels, ointments, lotions, sprays, or patches, all of which can be prepared using standard technology. Transdermal formulations can include penetration enhancers. A “gel” is a colloid in which the dispersed phase has combined with the continuous phase to produce a semisolid material, such as jelly. An “oil” is a composition containing at least 95% wt of a lipophilic substance. Examples of lipophilic substances include but are not limited to naturally occurring and synthetic oils, fats, fatty acids, lecithins, triglycerides and combinations thereof. A “continuous phase” refers to the liquid in which solids are suspended or droplets of another liquid are dispersed, and is sometimes called the external phase. This also refers to the fluid phase of a colloid within which solid or fluid particles are distributed. If the continuous phase is water (or another hydrophilic solvent), water-soluble or hydrophilic drugs will dissolve in the continuous phase (as opposed to being dispersed). In a multiphase formulation (e.g., an emulsion), the discreet phase is suspended or dispersed in the continuous phase. An “emulsion” is a composition containing a mixture of non-miscible components homogenously blended together. In particular forms, the non-miscible components include a lipophilic component and an aqueous component. An emulsion is a preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. Preferred excipients include surfactants, especially non-ionic surfactants; emulsifying agents, especially emulsifying waxes; and liquid non-volatile non-aqueous materials, particularly glycols such as propylene glycol. The oil phase may contain 45740907.1 59 other oily pharmaceutically approved excipients. For example, materials such as hydroxylated castor oil or sesame oil may be used in the oil phase as surfactants or emulsifiers. “Emollients” are an externally applied agent that softens or soothes skin and are generally known in the art and listed in compendia, such as the “Handbook of Pharmaceutical Excipients”, 4^th Ed., Pharmaceutical Press, 2003. These include, without limitation, almond oil, castor oil, ceratonia extract, cetostearoyl alcohol, cetyl alcohol, cetyl esters wax, cholesterol, cottonseed oil, cyclomethicone, ethylene glycol palmitostearate, glycerin, glycerin monostearate, glyceryl monooleate, isopropyl myristate, isopropyl palmitate, lanolin, lecithin, light mineral oil, medium-chain triglycerides, mineral oil and lanolin alcohols, petrolatum, petrolatum and lanolin alcohols, soybean oil, starch, stearyl alcohol, sunflower oil, xylitol and combinations thereof. In one form, the emollients are ethylhexylstearate and ethylhexyl palmitate. “Surfactants” are surface-active agents that lower surface tension and thereby increase the emulsifying, foaming, dispersing, spreading and wetting properties of a product. Suitable non-ionic surfactants include emulsifying wax, glyceryl monooleate, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polysorbate, sorbitan esters, benzyl alcohol, benzyl benzoate, cyclodextrins, glycerin monostearate, poloxamer, povidone and combinations thereof. In one form, the non-ionic surfactant is stearyl alcohol. “Emulsifiers” are surface active substances which promote the suspension of one liquid in another and promote the formation of a stable mixture, or emulsion, of oil and water. Common emulsifiers are: metallic soaps, certain animal and vegetable oils, and various polar compounds. Suitable emulsifiers include acacia, anionic emulsifying wax, calcium stearate, carbomers, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, ethylene glycol palmitostearate, glycerin monostearate, glyceryl monooleate, hydroxpropyl cellulose, hypromellose, lanolin, hydrous, lanolin alcohols, lecithin, medium-chain triglycerides, methylcellulose, mineral oil and lanolin alcohols, monobasic sodium phosphate, monoethanolamine, nonionic emulsifying wax, oleic acid, poloxamer, poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, propylene glycol alginate, self-emulsifying glyceryl monostearate, sodium citrate dehydrate, sodium lauryl sulfate, sorbitan esters, stearic acid, sunflower oil, tragacanth, triethanolamine, xanthan gum and combinations thereof. In one form, the emulsifier is glycerol stearate. A “lotion” is a low- to medium-viscosity liquid formulation. A lotion can contain finely powdered substances that are in soluble in the dispersion medium through the use of suspending agents and dispersing agents. Alternatively, lotions can have as the dispersed phase liquid substances that are immiscible with the vehicle and are usually dispersed by means of 45740907.1 60 emulsifying agents or other suitable stabilizers. In one form, the lotion is in the form of an emulsion having a viscosity of between 100 and 1000 centistokes. The fluidity of lotions permits rapid and uniform application over a wide surface area. Lotions are typically intended to dry on the skin leaving a thin coat of their medicinal components on the skin’s surface. A “cream” is a viscous liquid or semi-solid emulsion of either the “oil-in-water” or “water-in-oil type”. Creams may contain emulsifying agents and/or other stabilizing agents. In one form, the formulation is in the form of a cream having a viscosity of greater than 1000 centistokes, typically in the range of 20,000-50,000 centistokes. Creams are often time preferred over ointments as they are generally easier to spread and easier to remove. An emulsion is a preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. The oil phase may consist at least in part of a propellant, such as an HFA propellant. Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. Preferred excipients include surfactants, especially non-ionic surfactants; emulsifying agents, especially emulsifying waxes; and liquid non-volatile non-aqueous materials, particularly glycols such as propylene glycol. The oil phase may contain other oily pharmaceutically approved excipients. For example, materials such as hydroxylated castor oil or sesame oil may be used in the oil phase as surfactants or emulsifiers. A sub-set of emulsions are the self-emulsifying systems. These drug delivery systems are typically capsules (hard shell or soft shell) composed of the drug dispersed or dissolved in a mixture of surfactant(s) and lipophillic liquids such as oils or other water immiscible liquids. When the capsule is exposed to an aqueous environment and the outer gelatin shell dissolves, contact between the aqueous medium and the capsule contents instantly generates very small emulsion droplets. These typically are in the size range of micelles or nanoparticles. No mixing force is required to generate the emulsion as is typically the case in emulsion formulation processes. The basic difference between a cream and a lotion is the viscosity, which is dependent on the amount/use of various oils and the percentage of water used to prepare the formulations. Creams are typically thicker than lotions, may have various uses and often one uses more varied oils/butters, depending upon the desired effect upon the skin. In a cream formulation, the water- 45740907.1 61 base percentage is about 60-75 % and the oil-base is about 20-30 % of the total, with the other percentages being the emulsifier agent, preservatives and additives for a total of 100 %. An “ointment” is a semisolid preparation containing an ointment base and optionally one or more active agents. Examples of suitable ointment bases include hydrocarbon bases (e.g., petrolatum, white petrolatum, yellow ointment, and mineral oil); absorption bases (hydrophilic petrolatum, anhydrous lanolin, lanolin, and cold cream); water-removable bases (e.g., hydrophilic ointment), and water-soluble bases (e.g., polyethylene glycol ointments). Pastes typically differ from ointments in that they contain a larger percentage of solids. Pastes are typically more absorptive and less greasy that ointments prepared with the same components. A “gel” is a semisolid system containing dispersions of small or large molecules in a liquid vehicle that is rendered semisolid by the action of a thickening agent or polymeric material dissolved or suspended in the liquid vehicle. The liquid may include a lipophilic component, an aqueous component or both. Some emulsions may be gels or otherwise include a gel component. Some gels, however, are not emulsions because they do not contain a homogenized blend of immiscible components. Suitable gelling agents include, but are not limited to, modified celluloses, such as hydroxypropyl cellulose and hydroxyethyl cellulose; Carbopol homopolymers and copolymers; and combinations thereof. Suitable solvents in the liquid vehicle include, but are not limited to, diglycol monoethyl ether; alklene glycols, such as propylene glycol; dimethyl isosorbide; alcohols, such as isopropyl alcohol and ethanol. The solvents are typically selected for their ability to dissolve the drug. Other additives, which improve the skin feel and/or emolliency of the formulation, may also be incorporated. Examples of such additives include, but are not limited, isopropyl myristate, ethyl acetate, C12-C15 alkyl benzoates, mineral oil, squalane, cyclomethicone, capric/caprylic triglycerides, and combinations thereof. Foams consist of an emulsion in combination with a gaseous propellant. The gaseous propellant consists primarily of hydrofluoroalkanes (HFAs). Suitable propellants include HFAs such as 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), but mixtures and admixtures of these and other HFAs that are currently approved or may become approved for medical use are suitable. The propellants preferably are not hydrocarbon propellant gases which can produce flammable or explosive vapors during spraying. Furthermore, the compositions preferably contain no volatile alcohols, which can produce flammable or explosive vapors during use. Buffers are used to control pH of a composition. Preferably, the buffers buffer the composition from a pH of about 4 to a pH of about 7.5, more preferably from a pH of about 4 to 45740907.1 62 a pH of about 7, and most preferably from a pH of about 5 to a pH of about 7. In a preferred form, the buffer is triethanolamine. Preservatives can be used to prevent the growth of fungi and microorganisms. Suitable antifungal and antimicrobial agents include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, and thimerosal. Additional agents that can be added to the formulation include penetration enhancers. In some forms, the penetration enhancer increases the solubility of the drug, improves transdermal delivery of the drug across the skin, in particular across the stratum corneum, or a combination thereof. Some penetration enhancers cause dermal irritation, dermal toxicity and dermal allergies. However, the more commonly used ones include urea, (carbonyldiamide), imidurea, N, N-diethylformamide, N-methyl-2-pyrrolidone, 1-dodecal-azacyclopheptane-2-one, calcium thioglycate, 2-pyrrolidone, N,N-diethyl-m-toluamide, oleic acid and its ester derivatives, such as methyl, ethyl, propyl, isopropyl, butyl, vinyl and glycerylmonooleate, sorbitan esters, such as sorbitan monolaurate and sorbitan monooleate, other fatty acid esters such as isopropyl laurate, isopropyl myristate, isopropyl palmitate, diisopropyl adipate, propylene glycol monolaurate, propylene glycol monooleatea and non-ionic detergents such as BRIJ^® 76 (stearyl poly(10 oxyethylene ether), BRIJ^® 78 (stearyl poly(20)oxyethylene ether), BRIJ^® 96 (oleyl poly(10)oxyethylene ether), and BRIJ^® 721 (stearyl poly (21) oxyethylene ether) (ICI Americas Inc. Corp.). Chemical penetrations and methods of increasing transdermal drug delivery are described in Inayat, et al., Tropical Journal of Pharmaceutical Research, 8(2):173-179 (2009) and Fox, et al., Molecules, 16:10507-10540 (2011). In some forms, the penetration enhancer is, or includes, an alcohol such ethanol, or others disclosed herein or known in the art. Delivery of drugs by the transdermal route has been known for many years. Advantages of a transdermal drug delivery compared to other types of medication delivery such as oral, intravenous, intramuscular, etc., include avoidance of hepatic first pass metabolism, ability to discontinue administration by removal of the system, the ability to control drug delivery for a longer time than the usual gastrointestinal transit of oral dosage form, and the ability to modify the properties of the biological barrier to absorption. Controlled release transdermal devices rely for their effect on delivery of a known flux of drug to the skin for a prolonged period of time, generally a day, several days, or a week. Two mechanisms are used to regulate the drug flux: either the drug is contained within a drug reservoir, which is separated from the skin of the wearer by a synthetic membrane, through which the drug diffuses; or the drug is held dissolved or suspended in a polymer matrix, through 45740907.1 63 which the drug diffuses to the skin. Devices incorporating a reservoir will deliver a steady drug flux across the membrane as long as excess undissolved drug remains in the reservoir; matrix or monolithic devices are typically characterized by a falling drug flux with time, as the matrix layers closer to the skin are depleted of drug. Usually, reservoir patches include a porous membrane covering the reservoir of medication which can control release, while heat melting thin layers of medication embedded in the polymer matrix (e.g., the adhesive layer), can control release of drug from matrix or monolithic devices. Accordingly, the active agent can be released from a patch in a controlled fashion without necessarily being in a controlled release formulation. Patches can include a liner which protects the patch during storage and is removed prior to use; drug or drug solution in direct contact with release liner; adhesive which serves to adhere the components of the patch together along with adhering the patch to the skin; one or more membranes, which can separate other layers, control the release of the drug from the reservoir and multi-layer patches, etc., and backing which protects the patch from the outer environment. Common types of transdermal patches include, but are not limited to, single-layer drug- in-adhesive patches, wherein the adhesive layer contains the drug and serves to adhere the various layers of the patch together, along with the entire system to the skin, but is also responsible for the releasing of the drug; multi-layer drug-in-adhesive, wherein which is similar to a single-layer drug-in-adhesive patch, but contains multiple layers, for example, a layer for immediate release of the drug and another layer for control release of drug from the reservoir; reservoir patches wherein the drug layer is a liquid compartment containing a drug solution or suspension separated by the adhesive layer; matrix patches, wherein a drug layer of a semisolid matrix containing a drug solution or suspension which is surrounded and partially overlaid by the adhesive layer; and vapor patches, wherein an adhesive layer not only serves to adhere the various layers together but also to release vapor. Methods for making transdermal patches are described in U.S. Patent Nos.6,461,644, 6,676,961, 5,985,311, and 5,948,433. E. Dosage Units and Methods of Administration A treatment regimen can include one or multiple administrations of the compositions including an effective amount of one or more of the compounds for achieving a desired physiological change, including administering to an animal, such as a mammal, especially a human being, an effective amount of the compositions to treat the disease or symptom thereof, or to produce the physiological change. The effective amount or therapeutically effective amount of a pharmaceutical compositions can be a dosage sufficient to treat, inhibit, or alleviate one or more symptoms of a disease or disorder or to otherwise provide a desired pharmacologic and/or physiologic effect, 45740907.1 64 for example, reducing, inhibiting, or reversing one or more of the underlying pathophysiological mechanisms underlying a disease or disorder, such as PCAD, or any of the other symptoms and conditions mentioned herein, each alone or in any combination. In preferred forms, the desired physiological change could include improvement in one or more symptoms of a disease or condition treated herein, such as improvement in breathing and exercise capacity or improved sensitivity to irritants or drop in albuterol use or improved vocal cord function or reduction in cough in the subject. In some forms, when administrating the pharmaceutical composition, the amount administered can be expressed as the amount effective to achieve a desired effect in the recipient. The effective amount of the pharmaceutical composition will vary based on the active agent and from subject to subject, depending on the species, age, weight and general condition of the subject, the severity of the disorder being treated, and its mode of administration. Thus, it is not possible to specify an exact amount for every pharmaceutical composition. However, an appropriate amount can be determined by one of ordinary skill in the art using only routine experimentation given the teachings herein. For example, effective dosages and schedules for administering the pharmaceutical composition can be determined empirically. In some forms, the dosage ranges for the administration of the composition are those large enough to resolve mucosal hyper-reactivity throughout the respiratory tract. Preferably, the dosage is not so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the age, condition, and sex of the patient, route of administration, whether other drugs are included in the regimen, and the type, stage, and location of the disease to be treated. The dosage can be adjusted by the individual physician in the event of any counter-indications. It will also be appreciated that the effective dosage of the composition can increase or decrease over the course of a particular treatment. Changes in dosage can result and become apparent from the results of diagnostic assays. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the subject or patient. Persons of ordinary skill can determine optimum dosages, dosing methodologies and repetition rates. Optimum dosages can vary depending on the relative potency of individual pharmaceutical compositions, and can generally be estimated based on EC50s found to be effective in in vitro and in vivo animal models. 45740907.1 65 In some forms, the dosage of a compound known for use in another medical treatment(s), is administered in the same dosage and/or according to the same regimen as for the treatment of the other medical treatment(s). In cases of a solid dosage form, examples of daily dosages of the compounds described herein which can be used are an effective amount within the dosage range of about 0.001 mg to about 2 mg per kilogram of body weight, about 0.001 mg to about 5 mg per kilogram of body weight, about 0.001 mg to about 10 mg per kilogram of body weight, about 0.001 mg to about 20 mg per kilogram of body weight, about 0.001 mg to about 50 mg per kilogram of body weight, about 0.001 mg to about 100 mg per kilogram of body weight, about 0.001 mg to about 200 mg per kilogram of body weight, or about 0.001 mg to about 300 mg per kilogram of body weight. When administered orally or by inhalation, examples of daily dosages are an effective amount within the dosage range of about 0.1 mg to about 10 mg, or about 0.1 mg to about 20 mg, or about 0.1 mg to about 30 mg, or about 0.1 mg to about 40 mg, or about 0.1 mg to about 50 mg, or about 0.1 mg to about 60 mg, or about 0.1 mg to about 70 mg, or about 0.1 mg to about 80 mg, or about 0.1 mg to about 90 mg, or about 0.1 mg to about 100 mg, or about 0.1 mg to about 200 mg, or about 0.1 mg to about 300 mg, or about 0.1 mg to about 400 mg, or about 0.1 mg to about 500 mg, or about 0.1 mg to about 600 mg, or about 0.1 mg to about 700 mg, or about 0.1 mg to about 800 mg, or about 0.1 mg to about 900 mg, or about 0.1 mg to about 1 g, or about 20 mg to 300 mg, or about 20 mg to 500 mg, or about 20 mg to 700 mg, or about 20 mg to 1000 mg, or about 50 mg to 1500 mg, or about 50 mg to 2000 mg. Exemplary fixed daily doses include about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 12 mg, about 15 mg, about 18 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1500 mg, or about 2000 mg, independently of body weight. However, it is understood that pediatric patients may require smaller dosages, and depending on the severity of the disease and condition of the patient, dosages may vary. When formulated as a liquid, the concentration of the compounds described herein may be about 0.01 mg/ml to about 0.1 mg/ml or about 0.1 mg/ml to about 1 mg/ml, but can also be about 1 mg/ml to about 10 mg/ml or about 10 mg/ml to about 100 mg/ml. The liquid formulation could be a solution or a suspension. When formulated as a solid, for example as a tablet or as a powder for inhalation, the concentration, expressed as the weight of a compound divided by total weight, will typically be about 0.01% to about 0.1%, about 0.1% to about 1%, about 1% to about 45740907.1 66 10%, about 10% to about 20%, about 20% to about 40%, about 40% to about 60%, about 60% to about 80%, or about 80% to about 100%. In some forms, administration of the composition will be given as a long-term treatment regimen whereby pharmacokinetic steady state conditions will be reached. For example, some forms, antibodies are packaged in a hermetically sealed container, such as an ampoule or sachette, indicating the quantity of antibody. In some forms, the antibodies are supplied as a dry sterilized lyophilized powder or water free concentrate in a hermetically sealed container and can be reconstituted, e.g., with water or saline to the appropriate concentration for administration to a subject. For example, antibodies can be supplied as a dry sterile lyophilized powder in a hermetically sealed container at a unit dosage of at least 5 mg, more preferably at least 10 mg, at least 15 mg, at least 25 mg, at least 35 mg, at least 45 mg, at least 50 mg, or at least 75 mg. The lyophilized antibodies can be stored at between 2 and 8°C in their original container and the antibodies can be administered within 12 hours, preferably within 6 hours, within 5 hours, within 3 hours, or within 1 hour after being reconstituted. In an alternative form, antibodies can be supplied in liquid form in a hermetically sealed container indicating the quantity and concentration of the antibody, fusion protein, or conjugated molecule. Preferably, the liquid form of the antibodies are supplied in a hermetically sealed container at least 1 mg/ml, more preferably at least 2.5 mg/ml, at least 5 mg/ml, at least 8 mg/ml, at least 10 mg/ml, at least 15 mg/ml, at least 25 mg/ml, at least 50 mg/ml, at least 100 mg/ml, at least 150 mg/ml, at least 200 mg/ml of the antibodies. For antibodies, the dosage administered to a patient is typically 0.01 mg/kg to 100 mg/kg of the patient’s body weight. Preferably, the dosage administered to a patient is between 0.01 mg/kg and 20 mg/kg, 0.01 mg/kg and 10 mg/kg, 0.01 mg/kg and 5 mg/kg, 0.01 and 2 mg/kg, 0.01 and 1 mg/kg, 0.01 mg/kg and 0.75 mg/kg, 0.01 mg/kg and 0.5 mg/kg, 0.01 mg/kg to 0.25 mg/kg, 0.01 to 0.15 mg/kg, 0.01 to 0.10 mg/kg, 0.01 to 0.05 mg/kg, or 0.01 to 0.025 mg/kg of the patient’s body weight. In particular, the invention contemplates that the dosage administered to a patient is 0.2 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 6 mg/kg or 10 mg/kg. A dose as low as 0.01 mg/kg may show appreciable pharmacodynamic effects. Dose levels of 0.10 – 1 mg/kg are predicted to be most appropriate. Higher doses (e.g., 1-30 mg/kg) are also contemplated. Generally, human antibodies have a longer half-life within the human body than antibodies from other species due to the immune response to the foreign polypeptides. Thus, lower dosages of human antibodies and less frequent administration is often possible. Further, the dosage and frequency of administration of antibodies may be reduced by enhancing uptake and tissue penetration of the antibodies by modifications such as, for example, lipidation. 45740907.1 67 Injections and infusion of the disclosed compositions can be repeated as often and as many times as the patient can tolerate until the desired response is achieved. Thus, antibodies can also be administered once or multiple times at these dosages. The optimal dosage and treatment regime for a particular patient can be determined by one skilled in the art of medicine by monitoring the patient for signs of disease and adjusting the treatment accordingly. In some forms, the unit dosage is in a unit dosage form for intravenous injection. In some forms, the unit dosage is in a unit dosage form for oral administration. In some forms, the unit dosage is in a unit dosage form for inhalation. In some forms, the unit dosage is in a unit dosage form for subcutaneous injection. Treatment can be continued for an amount of time sufficient to achieve one or more desired therapeutic goals. The timing of the administration of the composition will also depend on the formulation and/or route of administration used. The compound may be administered once daily, but may also be administered two, three or four times daily, or every other day, or once or twice per week. For example, the subject can be administered one or more treatments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours, days, weeks, or months apart. In some forms, the compositions are formulated for extended release. For example, the formulation can be suitable for administration once daily or less. In some forms, the composition is only administered to the subject once every 24-48 hours. Treatment can be continued for a desired period of time, and the progression of treatment can be monitored e.g., using any means known for monitoring the airway hyper-reactivity. In some forms, administration is carried out every day of treatment, or every week, or every fraction of a week. In some forms, treatment regimens are carried out over the course of up to two, three, four or five days, weeks, or months, or for up to 6 months, or for more than 6 months, for example, up to one year, two years, three years, or up to five years. The efficacy of administration of a particular dose of the pharmaceutical compositions can be determined by evaluating the aspects of the medical history, signs, symptoms, and objective laboratory tests that are known to be useful in evaluating the status of a subject in need for the treatment of a disease or condition discussed herein. These signs, symptoms, and objective laboratory tests will vary, depending upon the particular disease or condition being treated or prevented, as will be known to any clinician who treats such patients or a researcher conducting experimentation in this field. For example, if, based on a comparison with an appropriate control group and/or knowledge of the normal progression of the disease in the general population or the particular individual: (1) a subject’s physical condition is shown to be improved such as exercise capacity, or improved sensitivity for airway irritants (2) the 45740907.1 68 progression of the disease or condition is shown to be stabilized, or slowed, or reversed, or (3) the need for other medications for treating the disease or condition is lessened or obviated, then a particular treatment regimen will be considered efficacious. In a particular form, an effective amount (in one example 210 mg), is injected subcutaneously every 4 weeks. Such administrations may be given in the clinic or by pre-filled auto-injector device at home after training on the technique. No dose adjustments are required in patients with hepatic or renal impairment. Exemplary dosages and treatment regimens are discussed in the working Examples, and any such dosages and treatment regimens are be utilized in part or in whole to treat the subjects disclosed herein. The disclosed invention can be further understood by the following numbered paragraphs: 1. A method of treating Long COVID including administering a subject in need thereof an effective amount of an inhibitor of (i) human thymic stromal lymphopoietin (TSLP); (ii) interleukin-4 receptor (IL-4R); (iii) interleukin-5 (IL-5); (iv) c-Kit; (v) Bruton's tyrosine kinase (Btk); (vi) MRGPRX2; (vii) Transient Receptor Potential A1 (TRPA1); (viii) Interleukin-33 (IL-33); (ix) prostaglandin D2 (PGD2); (x) Nav1.7; (xi) Nav1.8; or (xii) nerve growth factor (NGF) and/or tumor necrosis factor (TNF). 2. The method of paragraph 1, wherein the subject has been diagnosed with Long COVID. 3. The method of paragraph 1, further including first diagnosing the subject with Long COVID by detecting one or more symptoms thereof. 4. A method of treating a post-viral airway disease including administering a subject in need thereof an effective amount of an inhibitor of (i) human thymic stromal lymphopoietin (TSLP); (ii) interleukin-4 receptor (IL-4R); (iii) interleukin-5 (IL-5); 45740907.1 69 (iv) c-Kit; (v) Bruton's tyrosine kinase (Btk); (vi) MRGPRX2; (vii) Transient Receptor Potential A1 (TRPA1); (viii) Interleukin-33 (IL-33); (ix) prostaglandin D2 (PGD2); (x) Nav1.7; (xi) Nav1.8; or (xii) nerve growth factor (NGF) and/or tumor necrosis factor (TNF). 5. The method of paragraph 4, wherein the subject has been diagnosed with the post- viral airway disease. 6. The method of paragraph 4, further including first diagnosing the subject with the post-viral airway disease by detecting one or more symptoms thereof. 7. The method of any one of paragraphs 4-6, wherein the viral infection preceding or otherwise leading to the airway disease is selected from the group consisting of SARS-CoV-2, other common human coronaviruses (e.g. types 229E, NL63, OC43, HKU1), adenoviruses, human metapneumovirus, influenza virus, parainfluenza virus, respiratory syncytial virus, and rhinoviruses. 8. A method of treating post-COVID airways disease (PCAD) including administering a subject in need thereof an effective amount of an inhibitor of (i) human thymic stromal lymphopoietin (TSLP); (ii) interleukin-4 receptor (IL-4R); (iii) interleukin-5 (IL-5); (iv) c-Kit; (v) Bruton's tyrosine kinase (Btk); (vi) MRGPRX2; (vii) Transient Receptor Potential A1 (TRPA1); (viii) Interleukin-33 (IL-33); (ix) prostaglandin D2 (PGD2); (x) Nav1.7; (xi) Nav1.8; or (xii) nerve growth factor (NGF) and/or tumor necrosis factor (TNF). 9. The method of paragraph 8, wherein the subject has been diagnosed with PCAD. 10. The method of paragraph 8, further including first diagnosing the subject with the post-viral airway disease by detecting one or more symptoms thereof. 45740907.1 70 11. The method of any one of paragraphs 1-10, wherein the subject has, and/or the diagnosing include detection of, a positive result by bronchoprovocation testing. 12. The method of paragraph 11, wherein bronchoprovocation includes exposing the subject’s airway to a respiratory irritant optionally wherein the irritant is a chemical compound, optionally selected from methacholine, mannitol, histamine, or acetaldehyde, or physiologic exposure optionally selected from hyperventilation or exercise. 13. The method of any one of paragraphs 1-11, wherein the subject has, and/or the diagnosing includes detection of, one or more low type 2 (T2) inflammation biomarkers. 14. The method of paragraph 14, wherein low type 2 (T2) inflammation biomarker(s) includes one or more of blood eosinophils (eos) count less than 300, serum immunoglobulin E (IgE) levels less than 150 and exhaled nitric oxide (FeNO) levels less than 25. 15. The method of any one of paragraphs 1-14, wherein the subject has, and/or the diagnosing includes detection of, forced expiratory volume in 1 second (FEV1) variability. 16. The method of any one of paragraphs 1-15, wherein the subject has, and/or the diagnosing includes detection of, a negative mannitol test. 17. The method of any one of paragraphs 1-16, wherein the subject does not have, and/or the diagnosing includes determination of, the absence of asthma. 18. The method of any one of paragraphs 1-17, wherein the subject is not being treated with, and/or the diagnosing includes determination that the subject is not eligible for treatment with, oral glucocorticoids. 19. The method of any one of paragraphs 1-18, wherein the subject has, and/or the diagnosis includes detection of, airway hyper-reactivity (AHR) and/or Small Airway Disease (SAD). 20. The method of any one of paragraphs 1-19, wherein the subject has or had a SARS-CoV-2 infection. 21. The method of any one of paragraphs 1-20, wherein the subject has, and/or the diagnosis includes detection of, a positive SARS-CoV-2 viral test, optionally wherein the viral test includes one or more of a reverse transcription polymerase chain reaction (RT-PCR) test, antigen test, or serologic (antibody) test. 22. The method of any one of paragraphs 1-21, wherein the subject had and/or the diagnosis includes detection of, severe acute COVID or mild acute COVID or no COVID symptoms. 23. The method of any one of paragraphs 1-22, wherein the inhibitor is an inhibitory polypeptide such as, but not limited to, an antibody; a small molecule or peptidomimedic, or an 45740907.1 71 inhibitory nucleic acid that targets genomic or expressed nucleic acids (e.g., mRNA) encoding the target molecule, or a vector that encodes an inhibitory nucleic acid. 24. The method of any one of paragraphs 1-23 including (i), wherein the inhibitor is an anti-TSLP antibody. 25. The method of paragraph 24, wherein the anti-TSLP antibody includes heavy and light chain variable regions including the heavy and light chain variable region CDRs of tezepelumab. 26. The method of paragraph 25, wherein the anti-TSLP antibody is tezepelumab. 27. The method of any one of paragraphs 1-23 including (ii), wherein the inhibitor is an anti-IL-4R antibody. 28. The method of paragraph 27, wherein the anti-IL-4R antibody includes heavy and light chain variable regions including the heavy and light chain variable region CDRs of dupilumab. 29. The method of paragraph 28, wherein the anti-IL-4R antibody is dupilumab. 30. The method of any one of paragraphs 1-23 including (iii), wherein the inhibitor is an anti-IL-5 antibody. 31. The method of paragraph 30, wherein the anti-IL-5 antibody includes heavy and light chain variable regions including the heavy and light chain variable region CDRs of benralizumab. 32. The method of paragraph 31, wherein the anti-IL-5 antibody is benralizumab. 33. The method of any one of paragraphs 1-23 including (iv), wherein the inhibitor is an anti-c-Kit antibody. 34. The method of paragraph 33, wherein the anti-c-Kit antibody includes heavy and light chain variable regions including the heavy and light chain variable region CDRs of barzolvolimab. 35. The method of paragraph 34, wherein the anti-c-Kit antibody is barzolvolimab. 36. The method of any one of paragraphs 1-23 including (iv), wherein the inhibitor is a small molecule. 37. The method of paragraph 36, wherein the small molecule is masitinib or a derivative thereof. 38. The method of paragraph 37, wherein the small molecule is masitinib. 39. The method of any one of paragraphs 1-23 including (v), wherein the inhibitor is a small molecule. 40. The method of paragraph 39, wherein the small molecule is ibrutinib or a derivative thereof. 45740907.1 72 41. The method of paragraph 40, wherein the small molecule is ibrutinib. 42. The method of paragraph 39, wherein the small molecule is fenebrutinib or a derivative thereof. 43. The method of paragraph 42, wherein the small molecule is fenebrutinib. 44. The method of any one of paragraphs 1-23 including (vi), wherein the inhibitor is a small molecule. 45. The method of paragraph 44, wherein the small molecule is EP262 or a derivative thereof. 46. The method of paragraph 45, wherein the small molecule is EP262. 47. The method of any one of paragraphs 1-23 including (vii), wherein the inhibitor is a small molecule. 48. The method of paragraph 47, wherein the small molecule is LY3526318 or a derivative thereof. 49. The method of paragraph 48, wherein the small molecule is LY3526318. 50. The method of any one of paragraphs 1-23 including (viii), wherein the inhibitor is an anti-IL-33 antibody. 51. The method of paragraph 50, wherein the anti-IL-33 antibody includes heavy and light chain variable regions including the heavy and light chain variable region CDRs of tozorakimab. 52. The method of paragraph 51, wherein the anti-IL-33 antibody is tozorakimab. 53. The method of any one of paragraphs 1-23 including (ix), wherein the inhibitor is a small molecule. 54. The method of paragraph 53, wherein the small molecule is fevipiprant or a derivative thereof. 55. The method of paragraph 54, wherein the small molecule is fevipiprant. 56. The method of any one of paragraphs 1-23 including (x), wherein the inhibitor is a small molecule. 57. The method of paragraph 56, wherein the small molecule is AZD-3161 or a derivative thereof. 58. The method of paragraph 57, wherein the small molecule is AZD-3161. 59. The method of any one of paragraphs 1-23 including (xi), wherein the inhibitor is a small molecule. 60. The method of paragraph 59, wherein the small molecule is Suzetrigine or a derivative thereof. 61. The method of paragraph 60, wherein the small molecule is Suzetrigine. 45740907.1 73 62. The method of any one of paragraphs 1-23 including (xii), wherein the inhibitor is an bispecific anti-NGF/TNF antibody. 63. The method of paragraph 62, wherein the bispecific anti-NGF/TNF antibody includes heavy and light chain variable regions including the heavy and light chain variable region CDRs of MEDI7352. 64. The method of paragraph 63, wherein the bispecific anti-NGF/TNF antibody is MEDI7352. 65. A pharmaceutical composition suitable for use in the method of any one of paragraphs 1-64. Examples Example 1: Identification of patient subclass for Post-COVID Airway Disease Methods To investigate whether small airway disease contributes to respiratory symptoms in patients with Long COVID, a retrospective cohort study was performed on 2000+ patients seen in the Pulmonary Long COVID clinic at Yale. In a sub-analysis, 58 patients were examined who underwent comprehensive clinical workup including history, physical exam, laboratory testing, imaging and pulmonary function testing with bronchoprovocation testing to evaluate for airway hyper-reactivity. First, patients were delineated into two groups based on the presence of diffuse parenchymal lung disease (DPLD) on imaging nearest to the time of evaluation Pulmonary Long COVID clinic. Results Of the 58 patients, 7 had DPLD and 51 had no DPLD (Fig.1A-1B). Compared to those without DPLD, patients with DPLD were older, more obese, and more likely to be male – all risk factors for severe acute COVID. It was found they had been hospitalized for acute COVID at a higher rate than those without DPLD. In contrast, those without DPLD tended to be younger women with milder acute COVID. They also showed a surprisingly high frequency of small airway disease as indicated by FEV1 variability on pulmonary function testing (67%). Even more striking was the observation that more than half (51%) showed airway hyper-reactivity on bronchoprovocation testing. Closer examination of the patients led to the identification of a new subclass of disease in Long COVID subjects referred to hereafter as Post-COVID Airway Disease (PCAD). The study revealed multiple additional features that distinguished the condition from asthma. First, despite persistent symptoms, no patients were considered appropriate candidates by pulmonary specialists for treatment with oral glucocorticoids – the cornerstone of therapy for asthma exacerbations. Second, patients with PCAD demonstrate markedly lower T2 biomarkers than 45740907.1 74 those with asthma, including blood eosinophils (eos), serum immunoglobulin E (IgE), and exhaled nitric oxide (FeNO) (FIG.1C). Third, the airway disease in Long COVID develops in the context of multi-system manifestations, which does not occur in asthma. Therefore, PCAD should be seen as respiratory manifestation of a broader systemic syndrome. Other conclusions from the study include, overall, small airways disease is common in patients with Long COVID. PCAD is a distinct disease process from asthma. A test for PCAD is methacholine challenge. Thus, methacholine-elicited airway hyper-reactivity – a known correlate of disease activity in chronic airway conditions like asthma – is one of the first treatable traits identified in Long COVID. This advance stands in contrast to Long COVID research to date, which has identified a number of interesting observations such as alterations in clotting factors and complement activation, but no direct links between these phenomena and a clinical manifestation of Long COVID. As such, these prior observations cannot be considered bona fide mechanisms of disease. Example 2: AHR-directed therapy for treatment of Long COVID A Long-COVID patient with treatment-refractory respiratory symptoms caused by airway hyper-reactivity (AHR) was tested and subsequently initiated therapy with monoclonal antibody, Tezepelumab. Within weeks, the patient’s small airway disease symptoms essentially resolved (FIG.2). Subsequent bronchoprovocation testing demonstrated normalization of airway hyper-reactivity after Tezepelumab therapy. Interestingly, the patient’s nasal symptoms, vocal cord sensitivity, and cough also markedly improved. These results indicate the broad efficacy of Tezepelumab on mechanisms that underlie mucosal hyper-reactivity throughout the respiratory tract. Example 3: A Subset of Patients with Pulmonary Long COVID Shows Airway Hyper- Reactivity A follow-up retrospective cohort study was performed to build upon the findings in Example 1, with refined inclusion criteria that specified that all patients had undergone bronchoprovocation testing for unexplained respiratory symptoms and a documented SARS- CoV-2 infection. In this study, 48 patients seen at the Yale Pulmonary Long COVID clinic were analyzed. Having been referred to Long COVID clinic, they met stringent clinical standards for the diagnosis of Long COVID. Patients were divided into two subgroups based on the presence (PC-ILD) or absence of parenchymal abnormalities on chest imaging following acute COVID (Figure 4). Of note, p-values throughout are nominal. 45740907.1 75 As shown in Table 1, the subgroup with PC-ILD was male-predominant, more likely to have been hospitalized for acute COVID, and linked to vascular risk factors such as diabetes and hypertension. The subgroup without ILD was female-predominant and demonstrated neuropsychiatric comorbidities (e.g. migraines and mental health disorders). Table 2 shows that ~50% patients with PC-ILD demonstrated coincident small airway disease, as indicated on CT scan and/or bronchoprovocation testing (BPT). In comparison, the Table 1. Demographic features, acute COVID course, and pre-morbid diseases Total (n=48) No ILD (n=35) ILD p-value 81 11 45 15 31 71 31 01 45 79 33 43 43 11 01 09 07 28 51 28 03 04 09 the patient selection criteria for the study (requiring BPT) likely biased to those with negative bronchodilator responses (BDR), it is notable that the vast majority had negative BDR testing. Taken together, these data show that BPT is an important diagnostic test for identifying PCAD in patients with Long COVID. 45740907.1 76 Table 2. Laboratory, radiographic, and pulmonary function test results Total (n=48) No ILD ILD (n=13) p-value 12 26 32 24 51 68 90 25 01 02 03 95 38 21 ), Tabl of positive T2 biomarkers in PCAD and reveals the high frequency of new onset airway disease – as opposed to worsening of an existing condition. Table 3. Pulmonary function and lab testing in patients with airway hyper-reactivity 5) 5 0 2 1 1 1 .6 .5 457409 . 77 diagnosis of Long Average FeNO 18.1 18.1 18.2 COVID Average eosinophils >300 7% 4% 20% % % % % % Exa PCAD Based on the new pathophysiologic framework of PCAD presented herein, the evidence of AHR in patients with PCAD, and the efficacy of Tezepelumab for improving AHR, PCAD patients were treated with Tezepelumab, regardless of T2 biomarkers that may prompt use of other airway biologics. A cohort of 8 patients were treated with Tezepelumab during this time. Of these 8 patients, 7 have shown a positive response to therapy. Notably, the lone non- responder showed no small airway PCAD symptoms, indicating that Tezepelumab may be less appropriate for PCAD with exclusively large/upper airway disease features (PC-LAD). However, in the 7 responders, all had large/upper airway PCAD as well, and cough uniformly improved. See Table 4. Table 4. Efficacy of anti-TSLP therapy in patients with PCAD A e Sex I E Eosino hil FeNO BDR BPT S m tom Res onse to thera 45740907.1 78 55 F Low High Low - SAD and Yes, robust. ACA score 9 ^ 17. LAD To better understand Tezepelumab in the context of treatment of PCAD, a retrospective analysis was performed on a cohort of 137 patients who were (i) presumptively diagnosed with asthma by the treating physician, (ii) treated with biologics, and (iii) retrospectively found to meet criteria for PCAD (development of airway symptoms after SARS-CoV-2 infection lasting >3 months). Their response to drugs targeting TSLP, IL-4R, IL-5, and IgE, respectively, are shown in Figure 5. Determination of clinical response was based on the treating clinician’s judgement; continuation of therapy due to perceived efficacy was considered a positive response; stopping the medication or changing to another agent was considered a failure, excepting cases where cessation of biologic was due to adverse effects. Some patients were stable on biologics prior to acute COVID and switched to different agents due to sustained loss of disease control after infection; these instances were also deemed treatment failures. Of note, patients in this study were not separated into small and large/upper airway subtypes of PCAD. The majority of patients had pre-morbid asthma. Tezepelumab showed >95% efficacy for PCAD. In contrast, T2-targeted therapies such as anti-IL-5 and anti-IgE biologics showed <40% efficacy. These success rates were approximately half of their reported efficacies for asthma. See, Table 5. Table 5: Comparison of different treatments for PCAD Tezepelumab Dupilumab Benralizumab Mepolizumab Omalizumab Ref B – Wechsler et al. Lancet Respir Med 10, 11–25 (2022) Ref C – Harrison et al. Lancet Respir Med 9, 260–274 (2021) Ref D – Khurana et al. Clin Ther 41, 2041-2056.e5 (2019) 45740907.1 79 Ref E – Snelder et al. Allergy Asthma Clin Immunol 13, 34 (2017) Dupilumab showed an intermediate efficacy of 58%. This was below its usual efficacy for asthma, but superior to anti-IL-5 and anti-IgE therapy. Taken together, these findings indicate that dupilumab is effective for a subset of patients with PCAD. Future analyses will be necessary to define this subset and identify biomarkers that may predict response to therapy. A large number of patients comprised asthmatics who were previously controlled on T2- targeted therapies such as inhaled corticosteroids, montelukast, and/or biologics against IL-5 or IgE, but then persistently lost control after SARS-CoV-2 infection. This finding supports the conclusion that the biology of PCAD involves non-T2 mechanisms and is therefore qualitatively different from that of asthma. Importantly, clinicians often failed to recognize that the new or worsened airway disease in their patients had been triggered by SARS-CoV-2, and therefore represented a manifestation of Long COVID. This under-recognition of Long COVID (and, here characterized as PCAD) led to the use of less effective treatments in this cohort. More broadly, missed diagnoses of PCAD lead prolonged symptoms, decreased quality of life, and disability in large numbers of patients with this condition. Example 6: Ketamine Therapy Shows Efficacy for Patients with Cough and Dysfunctional Breathing in Patients with Pulmonary Long COVID To determine the role of the salience network in the pathophysiology of Long COVID, several patients were prescribed ketamine therapy for treatment of large/upper airway PCAD. Treatment regimens were intravenous or intramuscular (both have similar bioavailability) and are defined as follows: low-dose (<0.5 mg/kg/dose) and high-dose (>0.5mg/kg/dose). It was believed that the latter may be more effective, but certain patients preferred the lower dose due to concern of neuropsychiatric side effects. The recommended dosing schedule includes an induction phase with 4-6 treatments within the span of 2-3 weeks and then a maintenance phase with doses every 4-12 weeks for a total of a year. The therapeutic effect on cough was found to be rapid (usually within 24 hours of treatment) and persistent (lasting for months, at least), see Table 6. The one patient who experienced recurrence of symptoms notably stopped ketamine therapy after the induction phase, and utilized a low-dose regimen. Rapid effects on symptoms of dysfunctional breathing were noted as well. At the time of the data presented in the Table 6 below, all patients had undergone an “induction phase” with 4-6 treatments within 2-3 weeks. Dosing varied with all getting more than 0.5 mg/kh/dose except one. All but the discontinued subject had entered “maintenance phase”, were least 3 months into therapy. One subject’s treatment was approaching a full year. 45740907.1 80 Table 6. Effect of ketamine therapy on symptoms of cough and dysfunctional breathing in a series of patients with Pulmonary Long COVID r ) A larger clinical trial to further test the efficacy of Tezepelumab on Long COVID subjects with AHR, a measurable and treatable trait in PCAD, has been designed. Baseline data - Demographics: age, sex, race, ethnicity - Comorbidities: asthma, allergic rhinitis, POTS, CFS, GERD, IBS, anxiety, migraines - Medications - Acute COVID history: timing, severity - Respiratory symptoms: dyspnea, irritant sensitivity, exercise capacity, cough, VCD, sinonasal symptoms - Extra-pulmonary Long COVID symptoms: - Laboratory findings: blood eosinophils, IgE, respiratory allergen test, iron studies, urinalysis - Imaging findings: high-resolution CT scan - Pulmonary function testing: spirometry with bronchodilator test, FeNO, volumes, DLCO, methacholine testing for AHR, mannitol testing, capsaicin challenge for cough sensitivity Inclusion criterion - Evidence of prior COVID infection - Positive methacholine challenge Exclusion criteria - Baseline FEV1<80% (unsafe to do methacholine challenge test) - Receipt of asthma biologics 45740907.1 81 - Oral corticosteroids Primary outcomes - Increase in methacholine PC20 (continuous variable) and normalization of methacholine PC20 (dichotomous variable) Secondary outcomes - Small airways disease: spirometry with bronchodilator responsiveness - Cough: scores, capsaicin sensitivity - Sinonasal symptoms: SNOT-22 score (patient-reported outcome measure) +/- Sniffin’ Sticks (objective olfactory test) - Exercise capacity: 6-minute walk test, daily steps per watch accelerometer, hand grip - Fatigue: fatigue severity score (FSS), multidimensional fatigue inventory (MFI), and DePaul Symptom Questionnaire (DSQ) Translational studies / additional endpoints (pre- and post-treatment) - Bronchoscopy with BAL, brush, and biopsy o BAL: PGD2, cysLT, histamine, tryptase, TSLP, neuropeptides, proteomics. o Brush for scRNAseq: epithelial cells, mast cells, eosinophils o Tissue histopathology: mast cells (number and location), neurons, eosinophils - Blood o Serum tryptase, TSLP Pre-specified subgroup analyses - T2 high vs T2 low patients Important features of this trial - Rational approach (based on pathophysiology and clinical data) - Outcome is an easily quantifiable biomarker of disease (airway hyper-reactivity) - Directly to phase 2B (guided by numerous early phase Tezepelumab trials) - Small size (60 patients may be sufficient) - Speed (can recruit quickly from large pool of patients) Example 8: Clinical Trial Design II A. Overview - This Example provides a general plan for phase 2, randomized, double-blind, placebo- controlled clinical trials to evaluate the efficacy and safety of medications for patients with PC-SAD. Co-primary outcomes will include improvement in AHR (measured by methacholine challenge) and CHS (measured by capsaicin challenge). These provocation studies will evaluate for PC-SAD and PC-LAD, respectively. Numerous secondary endpoints will be assessed related to PC-SAD (e.g. dyspnea scales), PC-LAD (e.g. cough 45740907.1 82 monitoring and laryngospasm), and sinonasal symptoms (an exploratory analysis based on the known effect of many airway disease drugs on chronic rhinosinusitis, which is common in Long COVID). B. Study Design and Objectives - Patient Population Definition o The planned phase 2 trial will enroll 60-200 patients meeting specific PCAD diagnostic criteria: ^ Adults aged 18-75 years ^ Confirmed PC-SAD diagnosis • Here, documented SARS-CoV-2 testing will be required prior to respiratory symptom onset • >3 months of respiratory symptoms such as cough, dyspnea, wheeze, chest tightness, etc. ^ FEV1 ≥80% predicted (preserved baseline lung function) ^ Positive methacholine challenge (PD20 ≤400 μg) o Exclusion criteria ^ Chronic oral corticosteroid use at baseline ^ Prior receipt of biologics for airway disease ^ Active smoking and/or >10 pack years of smoking history ^ Presence of PC-ILD ^ Significant other underlying lung disease such as bronchiectasis, COPD, ILD, etc ^ In one version of the trial, some of the subjects will have pre-morbid asthma. In another version of the trial, none of the subjects will have pre- morbid asthma. - Treatment Regimens and Dosing o The study design will evaluate patients over 24 weeks: ^ Placebo (20-50 patients) ^ 1-3 treatment arms (20-50 patients each) • For example, when the treatment is Tezepelumab, then the following dosages will be used. These dosing regimens are borrowed from established asthma and COPD trials to ensure feasibility and regulatory acceptance. The intensive dosing regimen is from a phase 2 trial and is intended to address the frequent complaint in PCAD patients that the efficacy of 45740907.1 83 Tezepelumab wanes toward the end of the standard 4-week dosing interval. o 210 mg every 4 weeks (asthma dosing) o 420 mg every 4 weeks (COPD dosing) o 280 mg every 2 weeks (intensive dosing) - Endpoints o Co-Primary Efficacy Endpoints ^ The PC-SAD primary endpoint will be an improvement from baseline to week 24 in AHR using PD20 methacholine challenge, calculated as log₂ doubling dose differences between treatment and placebo groups. Additional dichotomous analysis will examine PD20 normalization rates (>400 μg) as a clinically meaningful binary outcome complementing the continuous primary analysis ^ The PC-LAD primary endpoint will be an improvement from baseline to week 24 in cough reflex sensitivity measured using capsaicin delivered via a dosimeter-controlled nebulizer. Increasing concentrations will be administered until the subject elicits two (C2) or five (C5) coughs, which will be recorded as the thresholds for cough reflex sensitivity. The change in capsaicin C5 from baseline will be reported. o Secondary analyses ^ Patient-Reported Outcome Measures: Symptom-Specific Assessment Tools • Asthma Control Assessment (ACA): Standardized tool evaluating respiratory symptom control, rescue medication use, and activity limitations • Leicester Cough Questionnaire: Disease-specific quality of life instrument measuring the impact of chronic cough across physical, psychological, and social domains • Cough Severity Diary: Daily patient-reported assessment of cough frequency, intensity, and impact on daily activities • SNOT-22 (Sinonasal Outcome Test-22): Validated 22-item questionnaire assessing sinonasal symptoms including nasal obstruction, rhinorrhea, facial pain, and olfactory dysfunction 45740907.1 84 • Fatigue Severity Scale (FSS): Nine-item validated instrument assessing fatigue impact on daily functioning, with excellent reliability (Cronbach's α = 0.96) in respiratory disease populations • Visual Analog Scales: 100mm scales for overall symptom severity, breathing difficulty, and quality of life impact ^ Objective Physiological Monitoring Using Continuous Digital Health Monitoring • VitaloJAK Cough Monitoring: 24-hour ambulatory cough frequency recording using validated acoustic analysis technology to provide objective cough rate quantification • Smartwatch Activity Monitoring: Continuous assessment of daily step counts, physical activity levels, sleep quality metrics, and heart rate variability patterns • Sleep Pattern Analysis: Overnight monitoring of sleep duration, efficiency, and fragmentation patterns associated with respiratory symptoms ^ Pulmonary Function Assessment • Spirometry with Bronchodilator Response: Pre- and post- bronchodilator FEV1, FVC, and FEV1/FVC ratio measurements • Fractional Exhaled Nitric Oxide (FeNO): Standardized measurement of airway inflammation ^ Systemic Inflammatory Markers • Complete Blood Count with Differential: Including absolute eosinophil counts • Total and Specific IgE: Comprehensive respiratory allergen panel • Serum Cytokine Analysis: Multiplex assessment including TSLP, IL-33, IL-25, IL-4, IL-5, IL-13, IL-9, TNF-alpha, and IFN-gamma levels • Serum Tryptase Levels: Mast cell activation marker ^ Airway-Specific Biomarkers • Sputum Cytokine Profiling: Induced sputum analysis for TSLP, IL-33, IL-25, IL-4, IL-5, IL-13, IL-9, TNF-alpha, and IFN-gamma levels 45740907.1 85 • Sputum Cellular Analysis: Differential cell counting including eosinophils, neutrophils, macrophages, and lymphocytes • Sputum Tryptase Measurement: Local mast cell activation assessment in the airway compartment ^ Advanced Tissue-Based Analyses • Endobronchial Biopsy Analysis: Quantitative assessment of tissue architecture and cellular infiltration patterns o Mast cell enumeration and phenotypic characterization (tryptase-positive, chymase-positive subtypes) o Airway nerve density measurement and neuropeptide expression analysis o Eosinophil infiltration quantification with activation status assessment o Pulmonary neuroendocrine cell (PNEC) identification • Single-Cell RNA Sequencing o Bronchoscopic Brush Collection: Standardized sampling technique for comprehensive cellular characterization o scRNAseq Analysis: Following validated methodology for large-scale transcriptomic profiling of airway epithelial cells and immune cells ^ Laryngeal Function Assessment - Vocal Cord Evaluation • Laryngoscopy Procedures: Pre- and post-treatment assessment of vocal cord structure and function • Paradoxical Vocal Cord Dysfunction Testing: Evaluation of inappropriate vocal cord adduction during inspiration • Laryngospasm Provocation Assessment: Standardized testing for laryngeal hyper-responsiveness and treatment response - Clinical Outcome Measures o Intervals ^ Baseline: All testing modalities ^ 12 weeks: Repeat all noninvasive testing modalities. This specifically excludes bronchoscopy and laryngoscopy. ^ 24 weeks: Repeat all testing modalities - Biomarker Stratification Analyses o Pre-Specified Subgroup Evaluations 45740907.1 86 ^ Eosinophil-Stratified Analysis: Treatment response comparison in patients with ≥150 vs <150 cells/μL ^ FeNO-Stratified Analysis: Efficacy assessment in patients with ≥25 vs <25 ppb fractional exhaled nitric oxide ^ Combined Biomarker Analysis: Response patterns in patients with high vs low type 2 inflammatory burden - Safety and Tolerability Endpoints o Comprehensive Safety Assessment ^ Treatment-Emergent Adverse Events: Systematic collection and analysis of all adverse events with relationship assessment ^ Serious Adverse Events: Detailed evaluation of events requiring hospitalization or prolonged medical care ^ Injection Site Reactions: Local tolerability assessment including erythema, swelling, and pain ^ Laboratory Safety Parameters: Monitoring of hepatic function, renal function, and hematologic parameters Example 9: Clinical Trial Design III A. Overview - This Example provides a general plan for phase 2, randomized, double-blind, placebo- controlled clinical trials to evaluate the efficacy and safety of medications for patients with PC-LAD. Co-primary outcomes will include improvement in AHR (measured by methacholine challenge) and CHS (measured by capsaicin challenge). These provocation studies will evaluate for PC-SAD and PC-LAD, respectively. Numerous secondary endpoints will be assessed related to PC-SAD (e.g. dyspnea scales), PC-LAD (e.g. cough monitoring and laryngospasm), and sinonasal symptoms (an exploratory analysis based on the known effect of many airway disease drugs on chronic rhinosinusitis, which is common in Long COVID). B. Study Design and Objectives - Patient Population Definition o The planned phase 2 trial will enroll 60-200 patients meeting specific PCAD diagnostic criteria: ^ Adults aged 18-75 years ^ Confirmed PC-LAD diagnosis • Documented SARS-CoV-2 testing prior to respiratory symptom onset 45740907.1 87 • >3 months of respiratory symptoms, which must include chronic cough o Exclusion criteria ^ Active smoking and/or >10 pack years of smoking history ^ Significant other underlying lung disease such as bronchiectasis, COPD, ILD, etc - Treatment Regimens and Dosing o The study design evaluates patients over 24 weeks: ^ Placebo (20-50 patients) ^ 1-3 treatment arms (20-50 patients each) • For example, when the treatment is ketamine, then the following intramuscular treatment schedules may be used: o 0.2 mg/kg/dose for 4 doses within a two week span, spaced by at least two days each (low-dose induction only) o 0.6 mg/kg/dose for 4 doses within a two week span, spaced by at least two days each (high-dose induction only) o 0.6 mg/kg/dose for 4 doses within a two week span, spaced by at least two days each, followed by monthly doses for 6 months (high-dose induction and maintenance) - Endpoints o Co-Primary Efficacy Endpoints ^ The PC-SAD primary endpoint will be an improvement from baseline to week 24 in AHR using PD20 methacholine challenge, calculated as log₂ doubling dose differences between treatment and placebo groups. Additional dichotomous analysis will examine PD20 normalization rates (>400 μg) as a clinically meaningful binary outcome complementing the continuous primary analysis ^ The PC-LAD primary endpoint will be an improvement from baseline to week 24 in cough reflex sensitivity measured using capsaicin delivered via a dosimeter-controlled nebulizer. Increasing concentrations will be administered until the subject elicits two (C2) or five (C5) coughs, which will be recorded as the thresholds for cough reflex sensitivity. The change in capsaicin C5 from baseline will be reported. o Secondary analyses 45740907.1 88 ^ Patient-Reported Outcome Measures: Symptom-Specific Assessment Tools • Asthma Control Assessment (ACA): Standardized tool evaluating respiratory symptom control, rescue medication use, and activity limitations • Leicester Cough Questionnaire: Disease-specific quality of life instrument measuring the impact of chronic cough across physical, psychological, and social domains • Cough Severity Diary: Daily patient-reported assessment of cough frequency, intensity, and impact on daily activities • SNOT-22 (Sinonasal Outcome Test-22): Validated 22-item questionnaire assessing sinonasal symptoms including nasal obstruction, rhinorrhea, facial pain, and olfactory dysfunction • Fatigue Severity Scale (FSS): Nine-item validated instrument assessing fatigue impact on daily functioning, with excellent reliability (Cronbach's α = 0.96) in respiratory disease populations • Visual Analog Scales: 100mm scales for overall symptom severity, breathing difficulty, and quality of life impact ^ Objective Physiological Monitoring Using Continuous Digital Health Monitoring • VitaloJAK Cough Monitoring: 24-hour ambulatory cough frequency recording using validated acoustic analysis technology to provide objective cough rate quantification • Smartwatch Activity Monitoring: Continuous assessment of daily step counts, physical activity levels, sleep quality metrics, and heart rate variability patterns • Sleep Pattern Analysis: Overnight monitoring of sleep duration, efficiency, and fragmentation patterns associated with respiratory symptoms ^ Pulmonary Function Assessment • Spirometry with Bronchodilator Response: Pre- and post- bronchodilator FEV1, FVC, and FEV1/FVC ratio measurements • Fractional Exhaled Nitric Oxide (FeNO): Standardized measurement of airway inflammation ^ Systemic Inflammatory Markers 45740907.1 89 • Complete Blood Count with Differential: Including absolute eosinophil counts • Total and Specific IgE: Comprehensive respiratory allergen panel • Serum Cytokine Analysis: Multiplex assessment including TSLP, IL-33, IL-25, IL-4, IL-5, IL-13, IL-9, TNF-alpha, and IFN-gamma levels • Serum Tryptase Levels: Mast cell activation marker ^ Airway-Specific Biomarkers • Sputum Cytokine Profiling: Induced sputum analysis for TSLP, IL-33, IL-25, IL-4, IL-5, IL-13, IL-9, TNF-alpha, and IFN-gamma levels • Sputum Cellular Analysis: Differential cell counting including eosinophils, neutrophils, macrophages, and lymphocytes • Sputum Tryptase Measurement: Local mast cell activation assessment in the airway compartment ^ Advanced Tissue-Based Analyses • Endobronchial Biopsy Analysis: Quantitative assessment of tissue architecture and cellular infiltration patterns o Mast cell enumeration and phenotypic characterization (tryptase-positive, chymase-positive subtypes) o Airway nerve density measurement and neuropeptide expression analysis o Eosinophil infiltration quantification with activation status assessment o Pulmonary neuroendocrine cell (PNEC) identification • Single-Cell RNA Sequencing o Bronchoscopic Brush Collection: Standardized sampling technique for comprehensive cellular characterization o scRNAseq Analysis: Following validated methodology for large-scale transcriptomic profiling of airway epithelial cells and immune cells ^ Laryngeal Function Assessment - Vocal Cord Evaluation • Laryngoscopy Procedures: Pre- and post-treatment assessment of vocal cord structure and function 45740907.1 90 • Paradoxical Vocal Cord Dysfunction Testing: Evaluation of inappropriate vocal cord adduction during inspiration • Laryngospasm Provocation Assessment: Standardized testing for laryngeal hyper-responsiveness and treatment response - Clinical Outcome Measures o Intervals ^ Baseline: All testing modalities ^ 12 weeks: Repeat all noninvasive testing modalities. This specifically excludes bronchoscopy and laryngoscopy. ^ 24 weeks: Repeat all testing modalities - Biomarker Stratification Analyses o Pre-Specified Subgroup Evaluations ^ Eosinophil-Stratified Analysis: Treatment response comparison in patients with ≥150 vs <150 cells/μL ^ FeNO-Stratified Analysis: Efficacy assessment in patients with ≥25 vs <25 ppb fractional exhaled nitric oxide ^ Combined Biomarker Analysis: Response patterns in patients with high vs low type 2 inflammatory burden - Safety and Tolerability Endpoints o Comprehensive Safety Assessment ^ Treatment-Emergent Adverse Events: Systematic collection and analysis of all adverse events with relationship assessment ^ Serious Adverse Events: Detailed evaluation of events requiring hospitalization or prolonged medical care ^ Injection Site Reactions: Local tolerability assessment including erythema, swelling, and pain ^ Laboratory Safety Parameters: Monitoring of hepatic function, renal function, and hematologic parameters Example 10: Design of Mouse Model and Study Designs Related Thereto The clinical data presented herein has informed a number of important conclusions, including that AHR is a defining pathophysiological (and treatable) trait in PC-SAD, and which has informed the development of further tests. In mouse studies of airway disease, AHR is one of the most commonly-studied outcomes. Thus, AHR represents an attractive preclinical correlate – a measurable clinical biomarker that has been validated as a surrogate for disease severity in humans, and a 45740907.1 91 quantitative biomarker that is easily measurable in mice. Furthermore, SARS-CoV-2 infection in mice leads to AHR. (Halfmann et al. Nature 603, 687–692 (2022)) Thus, it is believed a murine model be used to screen drug candidates for efficacy in PCAD: Mice will be administered a sublethal dose of a SARS-CoV-2 strain capable of infection in wild type mice, e.g. B.1.1.529, the Omicron variant (10⁴-10⁶ PFU, delivered in a 50 µl saline bolus via oropharyngeal aspiration). (Halfmann et al. Nature 603, 687–692 (2022)) Medications under investigation will be administered at pharmacokinetically appropriate dosing schedules throughout 0-10 days post-infection (dpi). AHR will be assessed via methacholine challenge at baseline, at 2 dpi, 5 dpi, and 10 dpi. (Halfmann et al. Nature 603, 687–692 (2022)) Long COVID is known to be more common in patients with pre-existing asthma, and those with mental health disorders such as depression. (Tsampasian, V. et al. JAMA Intern Med 183, (2023); Subramanian et al. Nat Med 28, 1706–1714 (2022)). Thus, to better recapitulate the pathophysiology of PCAD, some groups of mice will be pre-exposed to the following conditions to accentuate development of PCAD-associated AHR: * Early-life stress (prior to 4 weeks) through maternal separation, forced swimming, or frequent handling, which has been directly demonstrated to worsen asthma pathology in rodent models. (Kruschinski et al. 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Publications cited herein and the materials for which they are cited are specifically incorporated by reference. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific forms of the method and compositions described herein. Such equivalents are intended to be encompassed by the following claims. 45740907.1 98

Claims

CLAIMS I claim: 1. A method of treating Long COVID comprising administering a subject in need thereof an effective amount of (i) an inhibitor of human thymic stromal lymphopoietin (TSLP); (ii) an inhibitor of the interleukin-4 receptor (IL-4R) signaling pathway, optionally an inhibitor of IL-4R, IL-4, IL-13, or STAT6; (iii) an inhibitor of interleukin-5 (IL-5); (iv) an inhibitor of c-Kit; (v) an inhibitor of Bruton's tyrosine kinase (Btk); (vi) an inhibitor of MRGPRX2; (vii) an inhibitor of Transient Receptor Potential A1 (TRPA1), an inhibitor of TRPV4, and/or an agonist of TRPM8; (viii) an inhibitor of a Protease Receptor, optionally PAR2; (ix) an inhibitor of Interleukin-33 (IL-33); (x) an inhibitor of Chemoattractant Receptor-Homologous Molecule Expressed on Th2 cells (CRTH2); (xi) an inhibitor of Nav1.7; (xii) an inhibitor of Nav1.8; (xiii) an inhibitor of nerve growth factor (NGF); (xiv) an inhibitor of P2X3; (xv) an inhibitor of an eicosanoid, eicosanoid receptor, or an enzyme necessary for synthesis optionally CystLT1, 5-lipoxygenase, and/or PGD2; and/or (xvi) a modulator of the salience network dysfunction optionally wherein the modulator is an NMDAR antagonist, a 5-HT2A agonist, and/or a neurosteroid. 2. The method of claim 1, wherein the subject has been diagnosed with Long COVID. 3. The method of claim 1, further comprising first diagnosing the subject with Long COVID by detecting one or more symptoms thereof. 4. A method of treating a post-viral airway disease comprising administering a subject in need thereof an effective amount of an inhibitor of (i) an inhibitor of human thymic stromal lymphopoietin (TSLP); (ii) an inhibitor of the interleukin-4 receptor (IL-4R) signaling pathway, optionally an inhibitor of IL-4R, IL-4, IL-13, or STAT6; (iii) an inhibitor of interleukin-5 (IL-5); 45740907.1 99 (iv) an inhibitor of c-Kit; (v) an inhibitor of Bruton's tyrosine kinase (Btk); (vi) an inhibitor of MRGPRX2; (vii) an inhibitor of Transient Receptor Potential A1 (TRPA1), an inhibitor of TRPV4, and/or an agonist of TRPM8; (viii) an inhibitor of a Protease Receptor, optionally PAR2; (ix) an inhibitor of Interleukin-33 (IL-33); (x) an inhibitor of Chemoattractant Receptor-Homologous Molecule Expressed on Th2 cells (CRTH2); (xi) an inhibitor of Nav1.7; (xii) an inhibitor of Nav1.8; (xiii) an inhibitor of nerve growth factor (NGF); (xiv) an inhibitor of P2X3; (xv) an inhibitor of an eicosanoid, eicosanoid receptor, or an enzyme necessary for synthesis optionally CystLT1, 5-lipoxygenase, and/or PGD2; and/or (xvi) a modulator of the salience network dysfunction optionally wherein the modulator is an NMDAR antagonist, a 5-HT2A agonist, and/or a neurosteroid. 5. The method of claim 4, wherein the subject has been diagnosed with the post-viral airway disease. 6. The method of claim 4, further comprising first diagnosing the subject with the post-viral airway disease by detecting one or more symptoms thereof. 7. The method of any one of claims 4-6, wherein the viral infection preceding or otherwise leading to the airway disease is selected from the group consisting of SARS-CoV-2, other common human coronaviruses optionally 229E, NL63, OC43, or HKU1, adenoviruses, human metapneumovirus, influenza virus, parainfluenza virus, respiratory syncytial virus, and rhinoviruses. 8. A method of treating post-COVID airways disease (PCAD) comprising administering a subject in need thereof an effective amount of an inhibitor of (i) an inhibitor of human thymic stromal lymphopoietin (TSLP); (ii) an inhibitor of the interleukin-4 receptor (IL-4R) signaling pathway, optionally an inhibitor of IL-4R, IL-4, IL-13, or STAT6; (iii) an inhibitor of interleukin-5 (IL-5); (iv) an inhibitor of c-Kit; (v) an inhibitor of Bruton's tyrosine kinase (Btk); 45740907.1 100 (vi) an inhibitor of MRGPRX2; (vii) an inhibitor of Transient Receptor Potential A1 (TRPA1), an inhibitor of TRPV4, and/or an agonist of TRPM8; (viii) an inhibitor of a Protease Receptor, optionally PAR2; (ix) an inhibitor of Interleukin-33 (IL-33); (x) an inhibitor of Chemoattractant Receptor-Homologous Molecule Expressed on Th2 cells (CRTH2); (xi) an inhibitor of Nav1.7; (xii) an inhibitor of Nav1.8; (xiii) an inhibitor of nerve growth factor (NGF); (xiv) an inhibitor of P2X3; (xv) an inhibitor of an eicosanoid, eicosanoid receptor, or an enzyme necessary for synthesis optionally CystLT1, 5-lipoxygenase, and/or PGD2; and/or (xvi) a modulator of the salience network dysfunction optionally wherein the modulator is an NMDAR antagonist, a 5-HT2A agonist, and/or a neurosteroid. 9. The method of claim 8, wherein the subject has been diagnosed with PCAD. 10. The method of claim 8, further comprising first diagnosing the subject with the post-viral airway disease by detecting one or more symptoms thereof. 11. The method of any one of claims 1-10, wherein the subject has, and/or the diagnosing comprise detection of, a positive result by bronchoprovocation testing. 12. The method of claims 11, wherein bronchoprovocation includes exposing the subject’s airway to a respiratory irritant optionally wherein the irritant is a chemical compound, optionally selected from methacholine, mannitol, histamine, or acetaldehyde, or physiologic exposure optionally selected from hyperventilation or exercise. 13. The method of any one of claims 1-11, wherein the subject has, and/or the diagnosing comprises detection of, one or more low type 2 (T2) inflammation biomarkers. 14. The method of claims 13, wherein low type 2 (T2) inflammation biomarker(s) comprises one or more of blood eosinophils (eos) count less than 300, serum immunoglobulin E (IgE) levels less than 150 and exhaled nitric oxide (FeNO) levels less than 25. 15. The method of any one of claims 1-14, wherein the subject has, and/or the diagnosing comprises detection of, forced expiratory volume in 1 second (FEV1) variability. 16. The method of any one of claims 1-15, wherein the subject does not have, and/or the diagnosing comprises determination of, the absence of asthma. 45740907.1 101

17. The method of any one of claims 1-16, wherein the subject is not being treated with, and/or the diagnosing comprises determination that the subject is not eligible for treatment with, oral glucocorticoids. 18. The method of any one of claims 1-17, wherein the subject has, and/or the diagnosis includes detection of, airway hyperactivity (AHR) and/or Small Airway Disease (SAD). 19. The method of any one of claims 1-18, wherein the subject has or had a SARS-CoV-2 infection. 20. The method of any one of claims 1-19, wherein (a) the subject has, and/or the diagnosis includes detection of, a positive SARS-CoV-2 viral test, optionally wherein the viral test comprises one or more of a reverse transcription polymerase chain reaction (RT-PCR) test, antigen test, or serologic (antibody) test, or (b) the subject is suspected of having had a SARS- CoV-2 infection, but does not have a positive viral test. 21. The method of any one of claims 1-20, wherein the subject has developed airway disease in the context of extra-pulmonary symptoms and/or a new sensitivity to respiratory irritants optionally selected from hot air, cold air, pollen, dust, perfume, cologne, smoke, or cleaning fluids. 22. The method of any one of claims 1-21, wherein the subject had and/or the diagnosis includes detection of, severe acute COVID or mild acute COVID or no COVID symptoms. 23. The method of any one of claims 1-22, wherein the subject has Small airway disease (PC-SAD), Large/upper airway disease (PC-LAD), Post-COVID Interstitial Lung Disease (PC- ILD), Post-COVID Dysfunctional Breathing (PC-DB), or a combination thereof. 24. The method of any one of claims 1-23, wherein the subject has PC-SAD; PC-LAD; PC- SAD and PC-LAD; PC-SAD, PC-LAD, and PC-DB; PC-SAD and PC-DB; PC-LAD and PC- DB; or each of the foregoing in further combination with PC-ILD. 25. The method of any one of claims 1-24, wherein the inhibitor is an inhibitory polypeptide such as, but not limited to, an antibody; a small molecule or peptidomimedic, or an inhibitory nucleic acid that targets genomic or expressed nucleic acids (e.g., mRNA) encoding the target molecule, or a vector that encodes an inhibitory nucleic acid. 26. The method of any one of claims 1-25 comprising (i), wherein the inhibitor is an anti- TSLP antibody. 27. The method of claim 26, wherein the anti-TSLP antibody comprises heavy and light chain variable regions comprising the heavy and light chain variable region CDRs of tezepelumab. 28. The method of claim 27, wherein the anti-TSLP antibody is tezepelumab. 45740907.1 102

29. The method of any one of claims 1-2, wherein (i) is selected from the group consisting of AZD8630, AIO-001, Ecleralimab/CSJ117, RG7258, Verekitug, BSI-040502, SAR443765, HBM9378, SHR-1905, CM0326, CDX-622, GR-2002, STSA-1201, 8630A-378, AL-3117, AL- 3224, APG-333, BD-9, Bempikibart, Bosakitug, BSI-502, CM-326, Crebankitug, CSJ-117, GB- 0895, GSK-3191812, HBM-9378, HY-209, IBI-3002, JKN-24011, Lunsekimig, MG-ZG-122, PF-07275315, PX-128, Q-1804, SOR-104, TAVO-101, and derivatives thereof. 30. The method of any one of claims 1-25 comprising (ii), wherein the inhibitor is an anti-IL- 4R antibody. 31. The method of claim 30, wherein the anti-IL-4R antibody comprises heavy and light chain variable regions comprising the heavy and light chain variable region CDRs of dupilumab. 32. The method of claim 31, wherein the anti-IL-4R antibody is dupilumab. 33. The method of any one of claims 1-25 comprising (ii), wherein the inhibitor is selected from the group consisting of Dom-0910, QAX-576 + VAK-694, romilkimab, AER-001, AK- 139, manfidokimab, APG-808, AVE-0309, BA-2101, BC-005, eblasakimab, elarekibep, MEDI- 2405, MEDI-9314, GB-12, Genrix, GSK-2434735, IBI-3002, LQ-036, MDNA-413, MG-010, NM26-2198, pascolizumab, PF-07264660, PF-07275315, PM-1017, PM-1268, POL-201, QX- 005N, Rademikibart, RC-1416, SHR-1819, SSGJ-611, stapokibart, TMC-260, TQH-2722, ZW- 1528, ZW-1572, AS-1810722, KP-723, KT-621, PM-43I, and derivatives thereof. 34. The method of any one of claims 1-25 comprising (iii), wherein the inhibitor is an anti- IL-5 antibody. 35. The method of claim 34, wherein the anti-IL-5 antibody comprises heavy and light chain variable regions comprising the heavy and light chain variable region CDRs of benralizumab. 36. The method of claim 35, wherein the anti-IL-5 antibody is benralizumab. 37. The method of any one of claims 1-25 comprising (iii), wherein the inhibitor is selected from the group consisting of Mepolizumab and Reslizumab, and derivatives thereof. 39. The method of any one of claims 1-25 comprising (iv), wherein the inhibitor is an anti-c- Kit antibody. 40. The method of claim 39, wherein the anti-c-Kit antibody comprises heavy and light chain variable regions comprising the heavy and light chain variable region CDRs of barzolvolimab. 41. The method of claim 40, wherein the anti-c-Kit antibody is barzolvolimab. 42. The method of any one of claims 1-25 comprising (iv), wherein the inhibitor is a small molecule. 43. The method of claim 42, wherein the small molecule is masitinib or a derivative thereof. 45740907.1 103

44. The method of any one of claims 1-25, wherein the inhibitor is selected from the group consisting of CDX-0159, Imatinib, Sunitinib, Regorafenib, Midostaurin, Ripretinib, Avapritinib, Sorafenib, Axitinib, Cabozantinib, Dadastinib, Nilotinib, Pazopanib, Tivozanib, Briquilimab, Lirentelimab, and derivatives thereof. 45. The method of any one of claims 1-25 comprising (v), wherein the inhibitor is a small molecule. 46. The method of claim 45, wherein the small molecule is ibrutinib or a derivative thereof. 47. The method of claim 45, wherein the small molecule is fenebrutinib or a derivative thereof. 48. The method of any one of claims 1-25 comprising (v), wherein the inhibitor is selected from the group consisting of Acalabrutinib, Zanubrutinib, Evobrutinib, Tolebrutinib, Orelabrutinib, Remibrutinib, Tirabrutinib, Rilzabrutinib, Branebrutinib, or a derivative thereof. 49. The method of any one of claims 1-25 comprising (vi), wherein the inhibitor is a small molecule. 50. The method of claim 49, wherein the small molecule is EP262 or a derivative thereof. 51. The method of any one of claims 1-25 comprising (vi) wherein the inhibitor is selected from the group consisting of EVO756, KRP-M223, and derivatives thereof. 52. The method of any one of claims 1-24 comprising (vii), wherein the modulator is a small molecule. 53. The method of claim 52, wherein the small molecule is LY3526318 or a derivative thereof. 54. The method of any one of claims 1-24 comprising (vii), wherein the modulator is selected from the group consisting of GDC-0334, GRC-17536, LY3526318, CB-189625, ODM- 108, HC-030031, AMG-0902, A-967079, HX-100, BAY-390, GSK2798745, ABS-0871, AR- 15512, AX-8, IVW-1001, and derivatives thereof. 55. The method of any one of claims 1-25 comprising (viii), wherein the modulator is a small molecule. 56. The method of any one of claims 1-25 comprising (viii), wherein the inhibitor is a small molecule. 57. The method of any one of claims 1-25 comprising (viii), wherein the inhibitor is selected from the group consisting of MEDI0618, TEV-‘192, OA-235i, and derivatives thereof. 58. The method of any one of claims 1-25 comprising (ix), wherein the inhibitor is an anti- IL-33 antibody. 45740907.1 104

59. The method of claim 58, wherein the anti-IL-33 antibody comprises heavy and light chain variable regions comprising the heavy and light chain variable region CDRs of tozorakimab. 60. The method of claim 59, wherein the anti-IL-33 antibody is tozorakimab. 61. The method of any one of claims 1-25 comprising (ix) wherein the inhibitor is selected from the group consisting of Itepekimab, Astegolimab, and Etokimab, Tozorakimab, Itepekimab, CAN-10, GSK-3862995B, PF-07264660, TQC-2938, and derivatives thereof. 62. The method of any one of claims 1-25 comprising (x), wherein the inhibitor is a small molecule. 63. The method of claim 62, wherein the small molecule is fevipiprant or a derivative thereof. 64. The method of any one of claims 1-25 comprising (x), wherein the inhibitor is Timapiprant, AZD1981, ARRY-502, BI-671800, MK-1029, Setipiprant, Vedupiprant, and derivatives thereof or a derivative thereof. 65. The method of any one of claims 1-25 comprising (xi), wherein the inhibitor is a small molecule. 66. The method of claim 65, wherein the small molecule is AZD-3161 or a derivative thereof. 67. The method of any one of claims 1-25, comprising (xi), wherein the inhibitor is selected from the group consisting of Vixotrigine, Ralfinamide, CC-8464, DWP-17061, DSP-3905, PF- 05089771, RG-6029, BIIB-095, ST-2427, ANP-230, Kindolor, and derivatives thereof. 68. The method of any one of claims 1-25 comprising (xii), wherein the inhibitor is a small molecule. 69. The method of claim 68, wherein the small molecule is Suzetrigine or a derivative thereof. 70. The method of any one of claims 1-25, comprising (xii), wherein the inhibitor is selected from the group consisting of JMKX-000623, LTG-305, VX-973, HBW-004285, STC-004, HRS- 4800, 14C-VX-993, ANP-230, Kindolor, and derivatives thereof. 71. The method of any one of claims 1-25 comprising (xiii), wherein the inhibitor is an anti- NGF antibody. 72. The method of claim 71, wherein the anti-NGF antibody comprises heavy and light chain variable regions comprising the heavy and light chain variable region CDRs of MEDI7352. 73. The method of claim 72, wherein the anti-NGF antibody is MEDI7352. 45740907.1 105

74. The method of any one of claims 1-25 comprising (xiii), wherein the inhibitor is selected from group consisting of Tanezumab, Fasinumab, MEDI7352, Fulranumab, and derivatives thereof. 75. The method of any one of claims 1-25 comprising (xiv), wherein the inhibitor is selected from the group consisting of Camlipixant, Gefapixant, AZ-004, Eliapixant (Bayer) and derivatives thereof. 76. The method of any one of claims 1-25 comprising (xv), wherein the inhibitor is selected from the group consisting of Montelukast, Zafirlukast, Pranlukast, Zileuton, and derivatives thereof. 77. The method of any one of claims 1-25 comprising (xvi), wherein the inhibitor is selected from the group consisting of Ketamine, Esketamine, Acamprosate, ADS-5002, ALKS-7119, ALTO-202, AmiKet, Aptiganel, Arketamine, ASP-0777, AV-101, AZD-4282, AZD-8108, Besonprodil, BI-1569912, Dextromethorphan, Dextromethorphan-bupropion, BIO-176, Budipine, CGP-40116, CGX-1007, CNS-5161, Delucemine, Dimiracetam, Dizocilpine, DLX-7, ED-1529, Eliprodil, EVT-101, GM-1020, GV-196771, GV-48816, Ifenprodil, Indantadol, Lanicemine, Memantine, MP-101, NBI-1070770, Neramexane, Nezavist, Norketamine, NP- 10679, NYX02925, Onfasprodil, Perzinfotel, Rislenemdaz, SNA-1, Traxoprodil, Rapastinel, Ibogaine, LSD, Psilocybin, DMT, 5-MeO-DMT, Ayahuasca, Mescaline, DOI, MDMA, Methylone, ACP-204, Altanserin, BETR-001, Eplivanserin, GM-2505, MSP-1014, RE-104, Brexanolone, Zuranolone, Ganaxolone, Sepranolone, LYT-300, and PRAX-114. 78. A pharmaceutical composition for use in the method of any one of claims 1-77. 45740907.1 106