DISPATCHES Human Infection with Avian Influenza

Human infection with avian influenza (H5N1) virus raises concern for the possibility of a pandemic. We report 20 cases, which ranged from asymptomatic to fatal, in Pakistan in 2007. These cases indicate human-to-human-to-human transmission of this virus, and the number of cases may be higher than realized.

Signs and symptoms were mainly those of a febrile infl uenza-like illness ( Table 2), although 1 patient with a laboratory-confi rmed case was asymptomatic (microneutralization titer 320, Western blot positive, throat swab positive for H5 by reverse transcription-PCR); this case-patient was also described in a previous epidemiologic investigation (2). Gastrointestinal signs and symptoms were not prominent, and neurologic signs were not reported.
The fi rst 8 cases constituted a cluster ( Figure 2). The index case-patient (patient 1) had culled infl uenza (H5N1) virus-infected poultry. After becoming febrile (38°C) while in Abbottabad, he traveled by public transportation to his family home in Peshawar. His illness progressed and on November 5, 2007, he was admitted to Khyber Teaching Hospital, where the diagnosis of infl uenza (H5N1) infection was made. Infection appeared to spread initially from household family contacts (patients 2-6) to medical staff (patient 7, who had positive PCR but negative microneutralization test results) and to a frequent visitor to the intensive care unit (patient 8).
As previously noted (2), the extended period from the time persons were exposed to the index case-patient, during which family members became ill, points to humanto-human-to-human transmission; patient 2 probably accounted for intermediary or second-generation infection. The chain of infection illustrated in Figure 2 suggests that further human-to-human-to-human transmission might have occurred and suggests nosocomial transmission. Of note, patient 6 (a cousin of the index case-patient) had a microneutralization titer of 80 but a negative Western blot result. Although 4 contacts of patient 6 exhibited no signs or symptoms of infl uenza, they did have positive H5 microneutralization titers ranging from 80 to 160.
No evidence epidemiologically links the remaining 12 patients to the 8 patients in the cluster; each of the 12 either had direct contact with infl uenza (H5N1) virusinfected poultry or was near healthy or diseased poultry before symptom onset. Three patients worked on poultry farms: 1 had taken a sample from an infl uenza (H5N1) virus-infected chicken, 1 was directly involved in culling, and 1 was indirectly exposed to live poultry. Eight patients had negative test results for infl uenza (H5N1) virus, and 3 had positive results from the National Institute of Health Islamabad but negative confi rmatory-testing results from WHO; 1 patient died before samples could be taken. Different laboratories reported confl icting results with respect to confi rmation of infection, possibly because of the diffi culties of complying with specimen-handling Excessive sputum production 0/1 (0) 0/4 (0) 2/6 (33) Rhinorrhea/nasal discharge 1/2 (50) 1/4 (25) 1/5 (20) Unexplained respiratory illness with cough, shortness of breath, or difficulty breathing  Table 2.

Conclusions
The preponderance of male patients is probably explained by sociocultural factors; the index case-patient was a poultry culler, a male-dominated task, and shared accommodation with male family members. Health careseeking behavior may also account for this fi nding.
The human-to-human transmission from the index casepatient to at least some household contacts seems clear, and the extended period over which these contacts became ill supports subsequent human-to-human transmission. Figure  2 supports the conclusion that patient 2 initiated a chain of infection in which further human-to-human transmission to patients 7 and 8 occurred. Possible nosocomial transmission is of concern because full implementation of isolation procedures in resource-poor settings may be problematic.
Although virologically supported probable humanto-human transmission of infl uenza (H5N1) virus has been documented, it has been thought to occur only with prolonged and close contact (4). Household clustering and the diffi culty of establishing exact virus exposures have encumbered efforts to investigate possible humanto-human transmission (5). Modeling has (6) suggested human-to-human transmission in Indonesia, but the utility of statistical modeling unsupported by fi eld data has been questioned (7).
Although the index case-patient traveled by public transportation from Abbottabad, where he acquired his infection, no infections were reported for anyone other than household contacts, who were all related and exposed at his family home at Peshawar. In contrast, patients 2 and 6 might have spread infection through less intimate contact, which raises 2 questions. Might some persons shed virus more effi ciently than others, possibly in greater quantity? And what role might host factors play in susceptibility to infl uenza (H5N1) virus infection and disease? A degree of virus adaptation to humans might also have occurred, although absence of sustained community transmission argues against this possibility.
Of concern is the 4:1 ratio of likely/possible to laboratory-confi rmed cases, suggesting that offi cial tallies understate true incidence of infection. Factors that may contribute to undercounting are the diffi culty of obtaining virologic confi rmation or of storing and transporting samples in resource-poor settings and reluctance by relatives to consent to autopsy. Another reason to believe that less fulminant cases may go unreported is the occurrence in Pakistan, and elsewhere, of clinically mild and asymptomatic cases (5,(8)(9)(10)(11)(12)(13)(14), indicating that infl uenza (H5N1) virus may cause a spectrum of illness. The demonstration during the 1997 Hong Kong outbreak of infl uenza (H5N1) with seroconversion in apparently asymptomatic health care workers and social contacts suggests human-to-human transmission, although in Hanoi, no transmission to health care workers was detected (8,13,15). Also contributing to underreporting are the predominant clinical signs of undifferentiated infl uenza-like illness observed in Pakistan and elsewhere, which, unless clinical deterioration occurred, would be unremarkable in many tropical settings. Although the survival rate was greater for patients who received oseltamivir, the small number of patients and the inclusion of those with mild and asymptomatic illness prevent meaningful statistical comparison.
Several features of the outbreak are unusual or give cause for concern: human-to-human-to-human transmission, possible nosocomial transmission, occurrence of mild and asymptomatic cases, and diffi culties of establishing laboratory confi rmation of likely and possible cases (which also prevented genotypic matching of specimens from primary and putative secondary cases). Taken together, these features suggest that current surveillance might undercount the extent of human infection with infl uenza (H5N1) virus and that human-to-human transmission might possibly be associated with less severe disease. . He was hospitalized on November 5 and transferred to an intensive care unit the next day. His cousin cared for him and became patient 6; his attending doctor became patient 7. On November 23, patient 3 was hospitalized and on November 28 was transferred to an intensive care unit; during this time, patient 8 frequently visited his wife in the same intensive care unit.