Downloaded from http://journals.tums.ac.ir/ on Saturday, November 24, 2012 Clinical Problem-Solving Iran J Pediatr Dec 2011; Vol 21 (No 4), Pp: 557-562 Pleuritic Chest Pain; Where Should We Search for? Behdad Gharib*1, MD; Vahid Ziaee1,2,3, MD; Mohammad-Hassan Moradinejad1,2, MD; Sara Esmaeili1, MD . . . Children’s Medical Center, Pediatrics Center of Excellence, Tehran, )ran Departments of Pediatrics, Tehran University of Medical Sciences, Tehran, )ran Growth and Development Research Center, Tehran University of Medical Sciences, Tehran, )ran Received: Aug 06, 2010; Final Revision: Jan 20, 2011; Accepted: Feb 16, 2011 Abstract Pleuritic pain is not an unusual problem in children. Other concomitant symptoms should be considered for diagnostic approach in a child with pleuritic chest pain. )n this report we discuss chest pain in a -year-old child with regard to other signs and symptoms. Finally, we found a rare life-threatening complication of juvenile systemic lupus erythematosus JSLE in our patient. Iranian Journal of Pediatrics, Volume 21(Number 4), December 2011, Pages: 557-562 Key Words: Systemic Lupus Erythematosus; Chest Pain; Macrophage Activating Syndrome Introduction Pleuritic pain is not an unusual problem in children. Other concomitant symptoms should be considered for diagnostic approach in a child with pleuritic chest pain. )n this report we discuss chest pain in a -year-old child with regard to other signs and symptoms. Case presentation This six-year old boy was presented to the emergency department of Children's Medical Center, Tehran, with dyspnea and pleuritic chest pain. The symptoms had begun two months ago and gradually aggravated for the past two weeks. The patient awoke by chest pain at night. (e preferred to remain in up-right position. Pleuritic chest pain has a broad differential diagnosis. Pain is exaggerated by deep breathing, coughing, and straining. Some of the differential diagnoses of chest pain in the pediatric patient are pneumonia, pleurisy, pneumothorax, pericarditis, endocarditis, costochondritis (tietze syndrome), herpes zoster (cutaneous), angina (familial hypercholesterolemia, anomalous coronary artery), epidemic pleurodynia, trauma and rib fracture, lesions of the dorsal root ganglia, tumors of the spinal cord, and gallbladder disease. Gastrointestinal diseases like peptic ulcer, esophagitis (gastroesophageal reflux, infectious, pill), cholecystitis, perihepatitis (Fitz-Hugh-Curtis syndrome), esophageal foreign body and spasm are less common causes of chest pain in children. The chronicity of the symptom indicates that a systemic chronic problem could be the main cause. * Corresponding Author; Address: Division of rheumatology, Children’s Medical Center, No 62, Dr Gharib St, Keshavarz Blvd, Tehran, Iran E-mail: behdad_gharib@yahoo.co.uk © by Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, All rights reserved. 558 Pleuritic Chest Pain in Children; B Gharib, et al Downloaded from http://journals.tums.ac.ir/ on Saturday, November 24, 2012 Cardiac diseases like pericarditis, endocarditis, mitral valve prolapse, and arrhythmias are among the ''must not miss'' diagnoses and should be ruled out. However chest pain is not a usual presentation of cardiac diseases in childhood. (e had short stature and a cachectic appearance. (eart beat was /min, respiratory rate /min, blood pressure / , temperature °C, body weight kg and height cm. Both weight and height were under the 3rd percentile. The low growth indicators suggesed a chronic disease involved. The medical history was notable for days of hospitalization at years of age, because of a history of months fever and bad appetite. (e had received antibiotics during hospitalization and one month after discharge. The medical files were not available, but his mother had been told that her son was treated for typhoid. Six months after getting discharged from the hospital, the patient again developed fever and general asthenia, and his mother noted that since then he continuously felt weak, had low growth rate, and developed fever occasionally. One year ago the patient contracted pneumonia and was hospitalized for treatment. (e also had an intermittent fever which according to his mother lasts for a few years. As his mother told, he has not received vaccination since four years of age. The main reason of his past hospitalization is not known. However, we had to check for typhoid, but it should be considered that another underlying chronic febrile disease involvement was probable. He developed dyspnea, which progressed gradually. Now in physical examination we searched for signs and symptoms of a chronic disease and specific organ involvement. At admission, the patient was in apparent respiratory distress, which worsened on supine position and he preferred to remain in semi-sitting position. Chest x-ray and ECG were normal. Conjunctivae were pale, and auscultation of heart and lung was normal. On abdominal examination, a generalized tenderness interfered with the examination process. Right wrist and heap joints were tender. (e had no symptoms of clubbing, edema or cyanosis. The mother reported of a generalized bone pain, weight loss, nocturnal sweating and fever during the last three months. (is father also had a three years history of night-fever and cough without any medical evaluation. The symptoms of pale conjunctivae, weight loss, night sweating and fever, indicate the chronic pattern of the illness. Iran is an endemic area for tuberculosis, so it also had to be considered, especially with the positive suspicious family history. Because of bone pain, malignancies should be among the list of differential diagnoses. Cardiopulmonary causes had to be ruled out, because of pleuritic chest pain and orthopnea. Echocardiography performed soon after his admission, revealed mild pericardial effusion. The pericardial effusion could justify the chest pain and the respiratory symptoms. Infectious, rheumatologic and maybe malignant causes of serositis are among the possible diagnoses, which could be the reason for other signs and symptoms of the patient. The first blood-work tests showed the following results normal values in parentheses : Complete blood count: WBC /μl Neutr %, Lymph %, Mono %, Eosin % , RBC . , /μl, (b . g/dl, MCV . fl, MC( . pg, Plt /μl, ESR mm/h. Blood glucose mg/dl, Creatinine . mg/dl . - . , Blood urea nitrogen mg/dl - , C-reactive protein mg/l < . A bactech blood culture was negative for bacterial growth. The most important findings were the very high level of ESR, and low hemoglobin level. Again we searched for infectious, rheumatologic and malignant causes. However, malignancies were less probable as the ill condition of the patient started four years ago and malignancies would have caused much more problems during this period of time. Because of fever and elevated ESR, the patient was admitted to the )nfectious Disease Ward. The following tests were completed and respective results obtained. Negative PPD test, bone marrow aspiration with normal cellularity and negative for Ziehl-Neelson staining, and negative culture results for typhoid. Iran J Pediatr; Vol 21(No 4); Dec 2011 559 Downloaded from http://journals.tums.ac.ir/ on Saturday, November 24, 2012 Radionucleotide scan showed some hyperactivity in the right hip and ankle. Wright, Coombs Wright, and Widal tests, as well as blood and urine cultures were also negative. These results indicate a low probability of infectious and malignant diseases, so rheumatologic diseases had to be taken into account and evaluated. More laboratory tests were performed with suspicion to malignancies, rheumatologic, autoimmunity and immunodeficiency. Anti nucleotide antibody ANA was positive [ neg < . , pos > . ]. The complete blood count series obtained for seven days showed no significant changes. Amylase, lipase, uric acid, cholesterol, triglycerides, calcium, phosphorous, liver function tests, lactate dehydrogenase, total protein and albumin were normal. Positive ANA, justified more tests and examinations for rheumatologic diseases to be done. The presence of serositic arthritis and a positive ANA made the rheumatologic diseases, especially SLE to be the first in the list of the Criterion Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Renal disorder Neurologic disorder Hematologic disorder Immunologic disorder Antinuclear antibody differential diagnosis. Systemic-onset juvenile rheumatoid arthritis could also be a possible cause. Some more tests, especially anti-dsDNA, and RF were needed. Antinuclear Antibodies (ANAs) can be positive in systemic lupus erythematosus, druginduced lupus, juvenile arthritis, juvenile dermatomyositis, vasculitis syndromes, scleraderma, infectious mononucleosis, chronic active hepatitis and hyperextensibility. The latest CBC: WBC Neut %, Lymph %, Mono . %, Eos , Baso . % , RBC . , (b g/dl, MCV . , MC( . , Platelets . Results of the new tests are as follow: AntiCCP . μ/ml within normal range, neg < . ,C mg/ml ,C mg/dl , Anti-dsDNA )U/ml neg < , pos > , RF ++++, ASO Todd units up to Todd units . On the criteria for lupus, diagnosis of SLE was made Table and treatment with prednisolone tablets mg/kg/day and hydroxychloroquine mg/kg/day initiated. A few days later, the patient’s condition improved gradually and the fever subsided. Table 1: Criteria for Systemic Lupus Erythematosus Definition Fixed erythema, flat or raised on the malar areas sparing the nasolabial folds Erythematous raised patches in the company of adherent keratotic scaling and follicular plugging Rash as a result of unusual reaction to sunlight Oral or nasopharyngeal ulceration, usually painless, observed by a physician Non-erosive arthritis in two or more peripheral joints, tenderness, swelling, or effusion Pleuritis: history of pleuritic pain or rub proved by a physician , pleural effusion Pericarditis: ECG, rub, pericardial effusion Persistent proteinuria > . g/day or > plus + + + Cellular casts: red blood cell, hemoglobin, granular, tubular, or mixed Seizures: in the absence of drugs that can be the cause or metabolic impairments e.g., uremia, ketoacidosis, electrolyte imbalance Psychosis: in the absence of drugs that can be the cause or metabolic impairments e.g., uremia, ketoacidosis, electrolyte imbalance (emolytic anemia, with reticulocytosis, or Leukopenia: < , /mm two or more occasions or Lymphopenia: < , /mm two or more occasions or Thrombocytopenia: < , /mm Anti-DNA antibody abnormal titer or Anti-Smith: Antibody to Smith nuclear antigen or Positive Antiphospholipid antibodies An abnormal titer in the absence of drugs recognized to be associated with drug-induced lupus syndrome Our patient + + + + Downloaded from http://journals.tums.ac.ir/ on Saturday, November 24, 2012 560 Pleuritic Chest Pain in Children; B Gharib, et al The diagnosis of lupus is established by combination of clinical and laboratory manifestations. The company of 4 (serositis, arthritis, abnormal titer of anti-DNA antibody, antinuclear antibody) of 11 criteria serially or simultaneously strongly suggests the diagnosis. Patients who are suspect to have lupus, but show fewer than 4 criteria should receive proper medical treatment. A positive ANA test is not necessary for diagnosis; absence of ANA in lupus is very rare. Hypocomplementemia is not diagnostic, and very low levels or absence of total hemolytic complement suggests the likelihood of complement component insufficiency. The treatment for SLE should be started. Having different pictures, lupus must be among the differential diagnoses of many problems, from fevers of unknown origin to arthralgias, anemia, and nephritis. The differential diagnosis depends on the presenting manifestation and affected organ and includes systemic-onset juvenile rheumatoid arthritis, acute poststreptococcal glomerulonephritis, acute rheumatic fever, infective endocarditis, leukemia, immune thrombocytopenic purpura, and idiopathic hemolytic anemia. Sometimes the early presentation is atypical such as parotitis, abdominal pain, transverse myelitis, ordizziness. Lupus should also be considered in patients with multiorgan involvement, especially in the presence of hematologic or urinalysis problems. Clinical manifestations of SLE include constitutional symptoms (fatigue, prolonged fever, anorexia, lymphadenopathy, weight loss), musculoskeletal (arthralgias, arthritis) cardiovascular, pulmonary (pulmonary hemorrhage, pleuritic pain), skin, renal, hematologic, neurologic (seizures, psychosis, stroke, cerebral venous thrombosis, pseudotumor cerebri, aseptic meningitis, chorea, global cognitive deficits, mood disorders, transverse myelitis, and peripheral neuritis (mononeuritis multiplex). The Whit Blood Cell Neutrophils Lymphocytes Hemoglobin Platelet On the sixth day of treatment our patient’s condition suddenly deteriorated. (e was found in apparent respiratory distress, high fever, dyspnea and having an enlarged liver span. (e was then transferred to P)CU, and cotrimoxazole, ceftazidim, and stress dose of hydrocortisone was initiated. CBC showed decrease in WBC, (gb and Platelets. The trend of CBC tests in P)CU is seen in Table . Other blood work test results in P)CU were as follow: Ferritin ng/ml , Fibrinogen mg/dl , Cholesterol mg/dl , Triglycerides mg/dl , Adenosine deaminase u/l - , Calcium mg/dl, Na meq/l , AST u/l up to , ALT u/l up to , C-reactive protein mg/dl neg < , ESR mm/h, reticulocytes . %, C mg/dl ,C mg/dl - , C( u , )gG mg/dl , Lactate dehydrogenase )U/L . Other tests such as creatine phosphokinase, serum )gA and )gM, BUN, creatinine, blood glucose and serum potassium were in normal range. After respiratory distress as the first presenting manifestation, we evaluated our patient for pulmonary and cardio-vascular involvement, which may occur in the course of SLE. He developed fever again while receiving immunosuppressive medications and empirical antibiotics for opportunistic infections started. The acute deterioration of the patient's condition during treatment of SLE, is suggestive of macrophage activation syndrome (MAS). The diagnosis is supported by acute leucopenia, high liver function tests, hepatomegaly, and high ferritin level. This diagnosis was suggested by clinical presentation and confirmed by bone marrow biopsy. In the most cases of MAS, bone marrow demonstrates hemophagocytosis. Urgent treatment Table 2: Trend of CBC tests in the patient in P)CU 1st day . % . % . mg/dl The 3rd day . % . % . The 5th day . The 7th day % . % . The 8th day . % . % . Downloaded from http://journals.tums.ac.ir/ on Saturday, November 24, 2012 Iran J Pediatr; Vol 21(No 4); Dec 2011 with intravenous pulse of methyl-prednisolone, cyclosporine, and sometimes, etanercept, are generally effective. Administration of IVIG, is useful in infections and MAS syndrome and was highly recommended in our immunodefficient patient. Performing a CXR, echocardiography, and bone marrow aspiration would help doctors in deciding appropriately. Having MAS in mind, which is an occasionally fatal condition, may save the patient. MAS may not have its typical manifestation at the beginning, but if it progresses, it would be more difficult to manage. )ntravenous immunoglobulin )V)G mg/kg was administered. A chest x-ray showed the possibility of atypical bronchopneumonia and patchy bilateral paracardiac opacities. The size of the heart was at the upper normal limit. Echocardiography revealed no pericardial effusions, no vegetation, no Limbman-Sacks lesion, good systolic and diastolic function, and an ejection fraction of %. Cardiac enzyme test results: CK-MB-Mass . ng/ml - . , CPK u/l , Troponin T . ng/ml < . neg , Troponin ) . ng/ml < . neg , NT-PRO BNP pg/ml . A new bone marrow aspiration showed: (ypocellular marrow without any specific diagnosis. As no significant improvement was observed, a three-day pulse-therapy with methylprednisolone mg/kg/day was prescribed and cyclosporine A added to the regimen. Because of severe neutropenia, Granulocyte Colony Stimulating Factor GCSF was initiated on the fifth day of admission to )CU. Packed cells were also transfused several times. The level of serum B-type natriuretic peptide (BNP), raised in response to abnormal ventricular wall tension, heart failure, systolic dysfunction, volume overload and cardiomyopathy. Measurement of BNP (elevated in heart disease), can help distinguish cardiac from pulmonary causes of pulmonary edema. A BNP >500pg/mL suggests heart problems, <100pg/mL suggests lung disease. The level of ESR, creatine phosphokinase, lactate dehydrogenase, and BNP may be elevated in acute or chronic myocarditis[1]. We expect that treatment with immunosuppressives along with antibiotics and supportive care, may cause the presenting critical 561 condition to subside and also improve heart condition involved in the process of background disease. Receiving medication for opportunistic infections, MAS and supportive care, the patient's respiratory distress and general condition improved gradually and he was transferred to Rheumatology Ward and after weeks he was discharged with an appropriate regimen for SLE. )n long time follow up the disease went into reemission and treatment was reduced gradually. A flare up of the disease after . years forced to increase the drugs which could be decreased again after remission. After years follow up, the disease is in remission and he is on low dose prednisolone mg/daily and hydroxychlroquine mg/daily . Commentary The patient initially came to the emergency room with mild respiratory distress, pleuritic chest pain and other signs and symptoms that indicate a chronic disease. The initial evaluation revealed diminished growth pattern, bone pain, night sweating and fever, pleuritic dyspnea, high ESR and serositis, which have a long list of differential diagnosis cardiopulmonary, infectious, rheumatologic and malignancies , but the chronic pattern of the illness made the malignancies less probable. The infectious causes were ruled out by laboratory tests, and soon after, the rheumatologic causes were taken into consideration. MAS is a potentially fatal complication of childhood systemic inflammatory diseases [ , ]. )t can be one of the causes of secondary hemophagocytic lymphohistiocytosis (L( [ , ]. (igh ferritin level is one of the diagnostic criteria for (L( [ ]. This syndrome is characterized by excessive activation of T lymphocytes and macrophages and massive production of cytokines[ ]. The clinical presentation of MAS includes persistent high fever, pancytopenia, hepatosplenomegaly, hepatic dysfunction, encephalopathy and coagulation abnormalities[ , ]. MAS can occur as a complication of rheumatic diseases or triggered by an infection or by a Downloaded from http://journals.tums.ac.ir/ on Saturday, November 24, 2012 562 Pleuritic Chest Pain in Children; B Gharib, et al change in treatment regimen [ , , ]. There are few case reports, that describe MAS as the first manifestation of rheumatic and also Kawasaki disease [ ]. Abnormal immune system reaction and regulation that leads to the lack of control of an exaggerated immune response is one of the mechanisms suggested for MAS [ ]. The diagnostic criteria for MAS that complicates systemic juvenile idiopathic arthritis s-J)A , include decreased platelet count, elevated aspartate aminotransferase, decreased white blood cells, hypofibrinogenemia, central nervous system impairment, hemorrhages, hepatomegaly and histologic evidence of macrophage hemophagocytosis in bone marrow aspirates [ ]. MAS is seen most commonly in s-J)A[ ]. )t is also diagnosed in systemic lupus erythematous [ , ]. )n our patient, MAS happened during the treatment of SLE, and it should always be kept in mind, if the condition of a rheumatologic patient deteriorates acutely without any obvious reason rapid initiation of the treatment is very important and critical. References . . Bernstein D. Cardiac therapeutics. )n: Kliegman RB, Behrman RE, Stanton BF, et al eds . Nelson th ed. Philadelphia, Textbook of Pediatrics, Saunders. ; Pp: - . Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child ; : - . . . . . . . . Grom AA. Natural killer cell dysfunction: a common pathway in systemic-onset juvenile rheumatoid arthritis, macrophage activation syndrome, and hemophagocytic lymphohistiocytosis? Arthritis Rheum ; : - . Ravelli A. Macrophage activation syndrome. Curr Opin Rheumatol ; : - . 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