HEMOPTYSIS AND EPSTEIN-BARR VIRUS INFECTION

HEMOPTYSIS AND EPSTEIN-BARR VIRUS INFECTION Epstein-Barr virus (EBV) infection causes a wide range of clinical presentations. Although pulmonary manifestations have been described in the literature, severe pulmonary complications of EBV illness are unusual in the immunologically normal host. We present a previously unreported, potentially life-threatening complication associated with EBV. Case presentation. A 12-year-old previously healthy Caucasian boy was admitted to hospital with a 1-day history of hemoptysis associated with pleuritic right-sided chest and shoulder tip pain. He was well until 2 weeks before admission when he developed bilaterally swollen eyelids, which had begun to improve spontaneously. Four days before admission he noted bruising over the dorsum of his left hand and right shin. There was no history of fever or constitutional symptoms, other clinically apparent bleeding, leg pain or swelling or urinary or joint complaints. He had no known contacts with persons with tuberculosis and had not traveled outside the Toronto area. On physical examination he was alert but in marked discomfort with splinting respirations. In a 2-h period 100 ml of bloody sputum had been produced. He was afebrile with a respiratory rate of 22/min and heart rate of 120/min; his transcutaneous oxygen saturation was 96% in room air. He had a 2- by 1.5-cm nontender left anterior cervical lymph node but no other lymphadenopathy and mild, bilateral eyelid swelling. There was dullness to percussion at the right base, with diminished breath sounds and bronchial breathing. There were large ecchymoses on his left hand and right lower extremity. There was no evidence of tonsillopharyngitis, palatal petechiae, generalized lymphadenopathy, hepatosplenomegaly or calf pain or swelling. Initial laboratory investigations revealed a hemoglobin of 112 g/l, platelet count of 89 × 10 9 /l, white blood cell count 14.7 × 10 9 /l (51% neutrophils, 5% band forms, 30% atypical lymphocytes, 6% lymphocytes), erythrocyte sedimentation rate of 30 mm/h and normal serum electrolytes, renal function tests, prothrombin time and partial thromboplastin time. The urinalysis was negative. Initial chest radiograph showed right lower lobe infiltrates with a pleural effusion. He was treated with intravenous cloxacillin, cefotaxime and erythromycin for broad spectrum antibiotic coverage and morphine sulfate because of his severe chest pain. On the night of admission he developed increasing respiratory distress and more frequent episodes of hemoptysis, required 2 liters of oxygen by nasal prongs to maintain a saturation of 93% and was transferred to the critical care unit. Active pulmonary bleeding and progressive anemia developed, requiring ventilatory support as well as packed red blood cell and platelet transfusions. Serial computerized tomographic scans of the chest revealed increasing right and left lower lobe consolidation and effusion; there was no evidence of abnormal vascularity or enlarged lymph nodes. Bronchoscopic evaluation revealed anatomically normal airways with active bleeding from the apical and anteromedial segments of the left upper lobe. Additional laboratory studies revealed 40% atypical lymphocytes. Epstein-Barr serology was conclusive for recent infection: IgM to viral capsid antigen was positive by immunofluorescence (>1:20, normal range <1:10), EBV-viral capsid antigen-IgG (1:1280, normal <1:40) and early antigen (>1:20, normal <1:10) were positive by enzyme-linked immunosorbent assay and Epstein-Barr nuclear antigen was negative (<1:10). A bone marrow aspirate showed normal cellularity, but EBV was present by PCR. On peripheral blood EBV DNA was detected in 1 to 10 cells per 1 000 000 peripheral blood mononuclear cells by semiquantitative PCR, a technique which has been previously described. 1 Bronchoalveolar lavage specimens taken within the first 24 h of admission had no organisms on Gram-stained smear, and cultures were negative. No fungal elements were seen, and fungal species were not grown on culture. Acid-fast bacilli were not seen, and subsequent mycobacterial cultures were negative. Pneumocystis was not seen, cytomegalovirus was not detected by cell culture and Mycoplasma DNA was not found. On nasopharyngeal swabs no viral antigens were detected by immunofluorescence. Those tested included parainfluenza 1, 2 and 3; influenza A and B; respiratory syncytial virus; and adenovirus. No pathogens were isolated on throat swab. Further laboratory studies included elevated lactate dehydrogenase and a reduced CD4+:CD8+ T cell ratio (0.3), with an absolute CD4+ T cell count of 376 cells/μl. A purified protein derivative (5 tuberculin units) test was nonreactive at 72 h. Blood cultures were negative at 7 days. HIV serology was negative, and serum immunoglobulin values were normal. Serology for antinuclear, antiglomerular basement membrane and antinuclear cytoplasmic antibodies were negative. Bleeding time and coagulation function tests were normal, done at 72 h after presentation. Ultrasound of the lower extremities showed no evidence of thrombosis. Subsequently the child developed palpable, bilateral axillary and inguinal lymphadenopathy, mild splenomegaly and an extensive, pruritic maculopapular eruption while receiving a beta-lactam antibiotic. He gradually improved after a 10-day hospitalization while receiving supportive care and was in good health with normal radiographic findings 1 month after his presentation to hospital. Discussion. EBV infection usually presents with fever, exudative pharyngitis, lymphadenopathy, hepatosplenomegaly and atypical lymphocytosis; but most infections are asymptomatic, the spectrum of disease is extremely variable and protean manifestations can occur. 2 Pulmonary involvement including pleural effusion has been documented in the literature. 3 Several large series have reported a 2 to 11% incidence of pulmonary involvement associated with typical presentations of infectious mononucleosis, but pulmonary disease as the presenting problem is rare. 4–6 Lung involvement secondary to EBV infection usually involves clinically insignificant, self-limited interstitial pneumonitis and hilar/mediastinal lymphadenopathy, 7 and symptomatic pulmonary involvement in immunocompetent individuals with EBV is uncommon 8 but can be seen in community-acquired pneumonia in the healthy child. 9, 10 A Medline search of the literature from 1966 until December, 1999, found no reports of hemoptysis as a complication of EBV infection. Necrotizing tracheobronchitis and bronchopneumonia associated with herpes group viruses have been reported, 11 and necrotic ulcerative bronchitis has been observed as the presenting feature of EBV-associated lymphoproliferative disease post-heart-lung transplantation. 12 On bronchoscopy in our patient, however, the airways were normal, with exception of the presence of blood. This child had thrombocytopenia and bruising, both of which occur commonly during viral syndromes. 13 Thrombocytopenia is found in up to 50% of cases of acute EBV infection 14 and may be partly a result of splenic sequestration. 15 There are several reports of severe thrombocytopenia (platelet count, <20 × 10 9 /l), 16, 17 likely related to anti-platelet antibodies. 18 Clinically manifested bleeding may also be caused by changes in vascular integrity or abnormal platelet function. It is likely that this child’s moderate thrombocytopenia and/or reduced platelet function played a role in the pathogenesis of his bleeding from his respiratory tract. He did respond favorably to platelet transfusion. The possibility that EBV was a secondary or copathogen cannot be definitively excluded, but a thorough search for other infectious etiologies was negative. Furthermore investigations for a coagulopathy, pulmonary embolism, malignancy, vasculitis syndrome and an anatomic abnormality were negative. There is clear evidence that this child had recent EBV infection. We speculate that this patient’s hemoptysis and respiratory deterioration thereafter was at least in part a result of EBV infection, although the precise role it played in the pathogenesis is unclear. Acknowledgments. We thank Dr. Upton Allen for his review of the manuscript and helpful suggestions.

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