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5. The clinical spectrum of human H5N1 infections
At presentation, most cases of human H5N1 infections were characterized by a severe influenza syndrome, clinically indistinguishable from severe human influenza, with symptoms of fever, cough and shortness of breath, and radiological evidence of pneumonia (Chotpitayasunondh et al., 2005, Tran et al., 2004 and Yuen et al., 1998). Abnormalities on chest radiographs at presentation included extensive, usually bilateral infiltration, lobar collapse, focal consolidation, and air bronchograms. Radiological evidence of pulmonary damage could still be observed in surviving patients several months after the illness. Beside respiratory symptoms, a large proportion of patients also complained of gastrointestinal symptoms such as diarrhea, vomiting, and abdominal pain, which are common in children with human influenza, but not in adults. In some cases, diarrhea was the only presenting symptom, preceding other clinical manifestations (Apisarnthanarak et al., 2004 and de Jong et al., 2005). Unlike human infections with H7 or H9 viruses, conjunctivitis was not prominent in H5N1-infected patients. The clinical course of the illness in severe cases was characterized by rapid development of severe bilateral pneumonia necessitating ventilatory support within days after onset. Complications included acute respiratory distress syndrome, renal failure, and multi-organ failure. Evidence that the clinical spectrum of human H5N1 infections is not restricted to pulmonary symptoms was provided by a reported case of possible central nervous system involvement in a Vietnamese boy who presented with diarrhea, followed by coma and death. Influenza H5N1 virus was isolated from throat, rectal, blood, and cerebrospinal fluid specimens, suggesting widely disseminated viral replication (de Jong et al., 2005). His sister had died of a similar illness 2 weeks earlier, but no diagnostic specimens were obtained. Although highly virulent H5N1 viruses have shown neurotropism in mammals such as mice and cats (Keawcharoen et al., 2004, Lipatov et al., 2003 and Tanaka et al., 2003), these cases may be similarly rare as central nervous system manifestations associated with human influenza (Morishima et al., 2002 and Sugaya, 2002). Genetic predisposition of the host to such manifestations may play a role.
Striking routine laboratory results in H5N1-infected patients, especially in severe cases, were an early onset of lymphopenia, with a pronounced inversion of the CD4+/CD8+ ratio, thrombocytopenia and increased levels of serum transaminases (Chotpitayasunondh et al., 2005, Tran et al., 2004 and Yuen et al., 1998). High levels of cytokines and chemokines have been observed in several H5N1-infected patients, suggesting a role of immune-mediated pathology in the pathogenesis of H5N1 infections (Peiris et al., 2004 and To et al., 2001). This was supported by pathological examination in two patients who died during the outbreak in Hong Kong, which showed reactive hemophagocytosis as the most prominent feature (To et al., 2001). Other findings included diffuse alveolar damage with interstitial fibrosis, hepatic central lobular necrosis, acute renal tubular necrosis, and lymphoid depletion. Although the gastrointestinal, hepatic, renal, and hematologic manifestations could suggest wider tissue tropism, there was no evidence of viral replication in organs outside the respiratory tract (To et al., 2001). However, viral replication in the gastrointestinal is strongly suggested by reported virus isolation and detection of positive strand viral RNA from fecal specimens (de Jong et al., 2005 and Uiprasertkul et al., 2005).
While many laboratory-confirmed H5N1 infections were associated with severe, often fatal disease, milder cases have also been reported, especially during the outbreak in Hong Kong (Chan, 2002 and Yuen et al., 1998). An increasing number of milder cases also seemed to occur in Viet Nam, as the outbreak progressed in 2005 (WHO, 2005). While increased clinical awareness and surveillance may account for such observations, progressive adaptation of the virus to humans is the dreaded alternative explanation. The occurrence of mildly symptomatic and asymptomatic infections have also been suggested during the outbreak in Hong Kong by seroepidemiological studies in household members of H5N1-infected patients and health care workers. In these studies, 8 of 217 exposed and 2 of 309 non-exposed healthcare workers were seropositive for H5N1-specific antibodies (Bridges et al., 2002). Seroconversion was documented in two exposed nurses, one of whom reported a respiratory illness 2 days after exposure to an H5N1-infected patient. More importantly than showing the occurrence of asymptomatic infections, these data indicated that nosocomial person-to-person transmission had occurred, albeit limited to a few cases. An additional case of possible human-to-human transmission during the Hong Kong outbreak was suggested by H5N1-seropositivity in a household contact of a patient, who had no history of poultry exposure (Katz et al., 1999). Seroepidemiological studies in health care workers involved in the care of H5N1-infected patients in Thailand and Viet Nam in 2004 have not shown evidence of person-to-person transmission, despite the absence of adequate infection control measures in the Vietnamese cohort at the time of study (Apisarnthanarak et al., 2005, Liem and Lim, 2005 and Schultsz et al., 2005). During the outbreak in Thailand in 2004, extensive epidemiological investigations have suggested person-to-person transmission from a child, who died of presumed H5N1 infection, to her mother who had no history of exposure to poultry and had provided prolonged unprotected nursing care to her daughter (Ungchusak et al., 2005). An aunt of the child may have been infected by the same route since her last exposure to poultry before infection had been 17 days, considerably longer than the estimated incubation period of 2–10 days. There have been several similar family clusters of H5N1 cases in Viet Nam, which have all ignited concerns about the possibility of human-to-human transmission, but most of which could be explained by common exposure to poultry. While there has been no evidence of efficient transmission of influenza H5N1 virus between humans to date, caution and detailed investigations remain warranted in case of any cluster of infections, especially in view of the relatively rapid evolution H5N1 viruses have exhibited in recent years.
