Case 2 -

Adenovirus Pneumonia Ricardo V. Lloyd and Arie Perry

Clinical History This 60-year-old woman presented with a low-grade fever and cough. Chest x-ray showed a patchy infiltrate. She died with organizing diffuse alveolar damage. The section is from the right upper lobe. Gross Description The lungs were beefy, red, and firm with areas of hemorrhage. Case 2 - Figure 1 Case 2 - Figure 2 Case 2 - Figure 3 Microscopic Description The histologic sections showed patchy, acute bronchopneumonia with organization, diffuse alveolar damage with necrotizing bronchitis and bronchiolitis. Enlarged pneumocytes with viral inclusions were present. In situ hybridization was positive for adenovirus and negative for CMV. Discussion Adenovirus is a double-stranded virus from the Adenoviridae family which causes infections of upper and lower respiratory tract, conjunctivitis, and diarrhea. There are over 40 viral serotypes of adenovirus, although certain subgroups are more likely involved in certain patient populations such as serotypes 4, 7, 21. Adenovirus infections of the respiratory tract are usually clinically indolent and self-limited. Adenovirus pneumonia with a necrotizing bronchitis and bronchiolitis is relatively uncommon in healthy individuals, but may be seen in immunocompromised patients, pediatric patients, and military recruits. The incidence of adenovirus pneumonia is highest in bone marrow transplantation recipients, intermediate in liver transplantation recipients, and lowest in renal transplantation recipients. Once pneumonia develops, the infection tends to disseminate, and the mortality is 60 to 80 percent. In some cases, in situ hybridization may be helpful to distinguish between adenovirus and cytomegalovirus infections. Adenovirus infects the upper and lower respiratory tract, conjunctiva, and gastrointestinal tract. Enteric adenoviruses which can be distinguished from adenoviruses that cause respiratory disease by their failure to grow easily in culture is one of the second leading causes of diarrhea among infants. Although most cases of ADV pneumonia are nonlethal infections resulting in complete resolution of chronic pulmonary diseases including bronchiectasis, bronchiolitis obliterans and interstitial fibrosis, some cases can be fatal with disseminated infections in other organs [7, 8, 9, 10] . The mortality with ADV pneumonia can range from 15% in immunocompetent patients to over 60% in immunocompromised individuals [8]. The highest mortality among post-transplant patients is associated with bone marrow transplants and the lowest with renal transplant patients [8, 11] . In a series of 2889 adult bone marrow transplant patients, there was an overall mortality of 26%. Patients with pneumonia and disseminated disease had mortality rates of 73% and 61%, respectively. Risk factors for dissemination included receipt of an allogenic transplant, presence of graft-vs-host disease, and receipt of concurrent immunosuppressive therapy. Antiviral therapy (ribavirin) was not helpful in the 12 patients treated with this drug [11]. The histologic diagnosis of ADV pneumonia is characterized by viral inclusions including the Cowdy type A and basophilic smudgy inclusions. The smudgy inclusions are probably derived from the Cowdy type A inclusions [12]. These inclusions may mimic CMV inclusions, so immunohistochemistry and in situ hybridization can be helpful in making this distinction. Early detection of ADV infection is often difficult, and culture results can be problematic because of the slow growth and identification of the virus. Occasionally, adenovirus outbreaks of self-limited types occur in young adults, especially in basic military training. During the 1950's and 1960's, up to 10% of recruits were infected with adenovirus, and these pathogens (serotype 4 and 7) were responsible for up to 90% of pneumonia hospitalizations. Military recruits started receiving enteric-coated vaccines in 1971. In 1996, the sole manufacturer stopped producing adenoviral vaccines, and outbreaks redeveloped. Since 1999, approximately 10-12% of all recruits have become ill with adenovirus infections in basic training similar to the pre-vaccine era. Recently, two recruits had fatal infections probably the first ones since the vaccines became unavailable [13]. References Ohori NP, Michaels MG, Jaffe R, Williams P, Yousem SA: Adenovirus pneumonia in lung transplant recipient. Hum Pathol 26:1073-1079, 1995 Hierholzer JC: Adenovirus in the immunocompromised host. Clin Microbiol Rev 5:262-274, 1992 Zarraga AL, Kerns FT, Kitchen LW: Adenovirus pneumonia with severe sequelae in an immunocompetent adult. Clin Infect Dis 15:712-713, 1992 Shields AF, Hackman RC, Fife H, et al.: Adenovirus infections in patients undergoing bone marrow transplantation. New England J Med 312:529-543, 1985 Michaels MG, Green M, Wall ER, et al.: Adenovirus infection in pediatric liver transplant recipients. J Infect Dis 165:170-174, 1992 Becroft DMO: Bronchiolitis obliterans, bronchiectasis, and other sequelae of adenovirus type 21 infection in young children. J Clin Pathol 24:72-82, 1971 Zahradnik JM, Spencer MJ, Porter DD: Adenovirus infection in the immunocompromised paitent. Am J Med 68:724-732, 1980 Hierholzer JC: Adenoviruses in the immunocompromised host. Clin Microbiol Rev 5:262-274, 1992 Dudding BA, Wagner SC, Zeller JA, et al: Fatal pneumonia associated with adenovirus type 7 in three military trainees. N Engl J Med 286:1289-1292, 1972 Lehtomaki K, Julkunen I, Sandelin K, et al: Rapid diagnosis of respiratory adenovirus infections in young adult men. J Clin Microbiol 24:108-111, 1986 La Rosa AM, Champlin RE, Mirza N, Gajeuski J, et al. Adenovirus infections in adult recipients of blood and bone marrow transplants. Clinical Infectious Diseases 32:871-876, 2001 Craighead JE: Cytopathology of adenovirus types 7 and 12 in human respiratory epithelium. Lab Invest 22:553-557, 1970 Morbidity and Mortality Weekly Report. Two fatal cases of adenovirus-related illnesses in previously healthy young adults. 50:553-555, 2001 Shayan K, Sanders F, Roberts F, Cautz E. Adenovirus enterocolitis in pediatric patients following bone marrow transplantation: report of 2 cases and review of the literature. Arch Pathol Lab Med 127:1615-1618, 2003. Table 1. Adenovirus Infection in Adults with Blood and Marrow Transplants Diagnosis Cases Percentage Asymptomatic viruria 9 10 URT infection 20 24 Enteritis 18 21 Hemorrhagic cystitis 10 12 Pneumonia 15 18 Disseminated disease 13 15 La Rosa et al. Clinical Infectious Diseases 32:871-876, 2001.