Case 1 -

Fatal Influenza B infection Sherif R. Zaki Centers for Disease Control and Prevention Atlanta GA

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Clinical History: A previously healthy 4 year old female from New York had a two day history of abdominal pain and vomiting. She was not seen by a medical provider. The parents last saw the child alive on the early morning of March 1, 2004 but found her dead in bed later that morning. No information on travel history or other significant exposure could be obtained. Case 1 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 1 - Slide 2 Click to view with ImageScope Click to view with a Web-Based Viewer Case 1 - Figure 1 Sections of the bronchi and trachea show focal denudation of epithelium, and submuscosal edema, congestion, and abundant inflammatory cell infiltrates comprised of lymphocytes, macrophages, and occasional eosinophils. Abundant detached epithelium admixed with necrotic debris and inflammatory exudates are present in the lumens of these airways. Case 1 - Figure 2 Sections of the bronchi and trachea show focal denudation of epithelium, and submuscosal edema, congestion, and abundant inflammatory cell infiltrates comprised of lymphocytes, macrophages, and occasional eosinophils. Abundant detached epithelium admixed with necrotic debris and inflammatory exudates are present in the lumens of these airways. Case 1 - Figure 3 The lungs show congestion, multifocal peribronchiolar and perivascular inflammatory cells infiltrates, and mixed intraalveolar collections of inflammatory cells. Case 1 - Figure 4 The heart shows focal mild lymphocytic myocarditis. Case 1 - Figure 5 Abundant immunohistochemical (IHC) staining of influenza B antigens was observed in the nuclei and cytoplasm of respiratory epithelial cells lining the trachea, bronchi, and bronchioles, and in the detached necrotic debris within the lumens of these airways. Description: Sections of the bronchi and trachea show focal denudation of epithelium, and submuscosal edema, congestion, and abundant inflammatory cell infiltrates comprised of lymphocytes, macrophages, and occasional eosinophils. Abundant detached epithelium admixed with necrotic debris and inflammatory exudates are present in the lumens of these airways. The lungs show congestion, multifocal peribronchiolar and perivascular inflammatory cells infiltrates, and mixed intraalveolar collections of inflammatory cells. Abundant immunohistochemical (IHC) staining of influenza B antigens was observed in the nuclei and cytoplasm of respiratory epithelial cells lining the trachea, bronchi, and bronchioles, and in the detached necrotic debris within the lumens of these airways. Diagnosis: Fatal Influenza B infection Discussion: Influenzaviruses belong to the Orthomyxoviridae family which consists of 4 genera that include the two important influenza viruses types A and B associated with significant human disease. [1, 2] Influenza A viruses are further classified into subtypes based on the antigenicity of their hemagglutinin (HA) and neuraminidase ( NA ) surface glycoproteins. Only one type of HA and one type of NA are recognized for influenza B. Influenza A occurs in both pandemic and interpandemic forms. Fortunately, pandemics, defined as worldwide outbreaks of severe disease, occur infrequently. Interpandemic influenza, although less extensive in its impact, occurs virtually every year. The epidemiological pattern of influenza in humans is related to two types of antigenic variation of its envelope glycoproteins, namely antigenic drift and antigenic shift. During antigenic drift, new strains related to those circulating in previous epidemics evolve by accumulation of point mutations in the surface glycoproteins. This enables the virus to evade the immune system leading to repeated outbreaks during interpandemic years. Antigenic shift occurs with the emergence of a "new" potentially pandemic, influenza A virus that possesses a novel HA alone or in combination with a novel NA. Influenza viruses are spread person-to-person primarily through the coughing and sneezing of infected persons. The typical incubation period for influenza is 1 to 4 days, with an average of 2 days. Adults can be infectious from the day before symptoms begin through approximately 5 days after illness onset. Children can be infectious for > 10 days, and young children can shed virus for several days before their illness onset. Severely immunocompromised persons can shed virus for weeks or months. Uncomplicated influenza illness is characterized by the abrupt onset of constitutional and respiratory signs and symptoms (e.g., fever, myalgia, headache, malaise, nonproductive cough, sore throat, and rhinitis). Among children, otitis media, nausea, and vomiting are also commonly reported with influenza illness. Respiratory illness caused by influenza is difficult to distinguish from illnesses caused by other respiratory pathogens on the basis of symptoms alone. Influenza typically resolves after 3 to 7 days in most patients, although cough and malaise can persist for >2 weeks. Among certain persons, influenza can exacerbate underlying medical conditions (e.g., pulmonary or cardiac disease), lead to secondary bacterial pneumonia or primary influenza viral pneumonia, or occur as part of a co-infection with other viral or bacterial pathogens. Young children with influenza infection can have initial symptoms that mimic bacterial sepsis. More than 20% of children hospitalized with influenza can have febrile seizures. Influenza has also been associated with encephalopathy, transverse myelitis, Reye syndrome, myositis, myocarditis, and pericarditis. Influenza-related deaths can result from pneumonia or from exacerbations of cardiopulmonary conditions and other chronic diseases. The histopathologic features of non-fatal and fatal influenza have been well described and include necrotizing bronchitis, thrombosis, interstitial inflammation, hemorrhage, hyaline membrane formation and intra-alveolar edema. [3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14] The pathology is more prominent in larger bronchi and inflammation may vary in intensity in individual patients. Viral inclusions cannot be identified by light microscopy. Secondary bacterial infections with organisms such as Streptococcus pneumoniae , group A streptococcus ( GAS ), Staphylococcus aureus, and Haemophilus influenzae may occur as a complication in about 50-75% of fatal cases and make it difficult to recognize the pathologic changes associated with the primary viral infection. [12, 15, 16] The histopathologic features in other organs may include myocarditis, cerebral edema, rhabdomyolysis and hemophagocytosis. Immunohistochemistry (IHC) and in situ hybridization ( ISH ) assays demonstrate that viral antigens and nucleic acids are usually sparse and are primarily seen in the bronchioepithelial cells of larger bronchioles . [11, 12, 14] Antigens are more readily identified in patients who die within 3-4 days of onset of illness. The diagnosis of influenza, suspected by history and clinical manifestations, can also be supported histopathologically. However, because of the absence of any characteristic viral inclusions and because the overall pathologic features of influenza may resemble other viral, rickettsial, and certain bacterial infections, an unequivocal diagnosis can be made only by laboratory tests such as viral culture, direct fluorescent antibody and rapid antigen assays, serology and IHC. [12, 17, 18] References: Wright PF, Webster, R.G. Orthomyxoviruses. In: Knipe DM, Howley, P.M., ed. Fields Virology. 4th ed. Philadelphia: Lippincott Williams and Wilkins; 2001:1533-79. Cox NJ, Kawaoka, Y. Orthomyxoviruses: Influenza. In: Mahy BWJ, Collier, L., ed. Topley and Wilson's microbiology and microbial infections. London: Arnold; 1998:385-433. Hers JFP. Changes in the respiratory mucosa resulting from infection with influenza virus. B J Pathol Bacteriol 1957;73:565-8. Hers JF, Masurel N, Mulder J. Bacteriology and histopathology of the respiratory tract and lungs in fatal Asian influenza. Lancet 1958;2(7057):1141-3. Martin CM, Kunin CM, Gottlieb LS, Barnes MW, Liu C, Finland M. Asian influenza A in Boston, 1957-1958. I. Observations in thirty-two influenza-associated fatal cases. AMA Arch Intern Med 1959;103(4):515-31. Martin CM, Kunin CM, Gottlieb LS, Finland M. Asian influenza A in Boston, 1957-1958. II. Severe staphylococcal pneumonia complicating influenza. AMA Arch Intern Med 1959;103(4):532-42. Noble RL, Lillington GA, Kempson RL. Fatal diffuse influenzal pneumonia: premortem diagnosis by lung biopsy. Chest 1973;63(4):644-6. Oseasohn R, Adelson L, Kaji M. Clinicopathologic study of thirty-three fatal cases of Asian influenza. N Engl J Med 1959;260(11):509-18. Yeldandi AV, Colby TV. Pathologic features of lung biopsy specimens from influenza pneumonia cases. Hum Pathol 1994;25(1):47-53. Walsh JJ, Dietlein LF, Low FN, Burch GE, Mogabgab WJ. Bronchotracheal response in human influenza. Type A, Asian strain, as studied by light and electron microscopic examination of bronchoscopic biopsies. Arch Intern Med 1961;108:376-88. Nolte KB, Alakija P, Oty G, et al. Influenza A virus infection complicated by fatal myocarditis. Am J Forensic Med Pathol 2000;21(4):375-9. Guarner J, Paddock, C.D., Shieh, W.J., Packard, M.M., Patel, M., Montague, J.L., Uyeki, T.M., Klimov, A., Bhat, N., Balish, A., Lindstrom, S., Zaki, S.R. Histopathologic and immunohistochemical features of fatal influenza virus infections in children during the 2003-2004 season. Clin Infect Dis 2006; 15;43(2):132-40. Ungchusak K, Auewarakul P, Dowell SF, et al. Probable person-to-person transmission of avian influenza A (H5N1). N Engl J Med 2005;352(4):333-40. Guarner J, Shieh WJ, Dawson J, et al. Immunohistochemical and in situ hybridization studies of influenza A virus infection in human lungs. Am J Clin Pathol 2000;114(2):227-33. Mulder J, Hers, J.F.Ph. Influenza. Groningen: Wolters-Noordhoff; 1972. Bhat N, Wright JG, Broder KR, et al. Influenza-associated deaths among children in the United States, 2003-2004. N Engl J Med 2005;353(24):2559-67. Uyeki TM. Influenza diagnosis and treatment in children: a review of studies on clinically useful tests and antiviral treatment for influenza. Pediatr Infect Dis J 2003;22(2):164-77. Ruest A, Michaud S, Deslandes S, Frost EH. Comparison of the Directigen flu A+B test, the QuickVue influenza test, and clinical case definition to viral culture and reverse transcription-PCR for rapid diagnosis of influenza virus infection. J Clin Microbiol 2003;41(8):3487-93.