This week in the New England Journal of Medicine (NEJM), Oner and colleagues describe the epidemiologic, clinical, and radiologic features of an outbreak of highly pathogenic avian influenza (H5N1) in eastern Turkey between December 31, 2005 and January 10, 2006 [1]. The World Health Organization confirmed infection with H5N1 virus in a total of 12 patients, 8 of whom were treated at the same hospital, Yuzuncu Yil University Hospital in Van, Turkey. The human outbreak followed a poultry outbreak in the same area.

Patients
During the study period, 625 patients with suspected H5N1 virus infection were evaluated at the hospital in Van. Of these, 290 had a history of contact with potentially infected poultry; 159 also had clinical findings consistent with influenza infection. All of the 131 patients with a history of contact with potentially infected poultry but no clinical symptoms were given oseltamivir prophylaxis. The 159 patients who had symptoms of influenza infection were hospitalized. H5N1 infection was eventually confirmed in 8 patients.

The median age was 10 years, with a range of 5 to 15 years. Oseltamivir was given to 7 patients beginning on the first or second day of admission. Five patients also received intravenous immunoglobulin. Mechanical ventilation was required in 4 patients, all of whom eventually died. 

Clinical Findings

Diagnostic Tests and Results
All 290 patients who had a history of contact with potentially infected poultry underwent diagnostic testing for H5N1 virus infection. Sampling of the nasopharynx with a dacron-tipped swab was performed at least twice in each patient. Three laboratory detection methods were undertaken: Real-time polymerase-chain-reaction (PCR) assay, a rapid influenza test, and an enzyme-linked immunosorbent assay (ELISA) for influenza A and B. PCR assays were performed by a reference laboratory in Ankara, and the findings were confirmed by the WHO Influenza Reference Laboratory in London.

The rapid influenza and ELISA tests were negative in all patients. H5N1 virus was detected by PCR in 10 patients, and results were confirmed for 8 by the WHO laboratory. Remarkably, 4 of those 8 confirmed patients had negative results with the initial nasopharyngeal swab. However, because those 4 were severely ill, PCR with tracheal aspirate was performed on day 2 of hospitalization and yielded positive results.

Conclusions
H5N1 infection in humans is a spectrum illness, with clinical manifestations ranging from an asymptomatic infection or mild upper respiratory tract illness, to severe pneumonia, with respiratory and multiorgan failure. All confirmed patients had fever, and most had a respiratory illness, but only a few had diarrhea, which was a prominent finding in the series of patients from Vietnam [2].

Although it is not possible to assess the efficacy of oseltamivir from this small study, the authors noted that “the interval between the onset of illness and hospitalization – and thus, the time to treatment with oseltamivir – tended to be shorter among the patients who survived than among those who died.”

Infection with H5N1 influenza virus is difficult to diagnose with standard laboratory diagnostic tests and even PCR assay of a nasopharyngeal swab specimen was negative in many of the patients who were subsequently found to be infected. Thus, diagnosis required repeated testing, done as a result of a high index of suspicion in the setting of a known outbreak in poultry in the geographic area. A better diagnostic test is urgently needed if public health measures, such as isolation of potentially infected and symptomatic persons, observation of potentially infected persons, and administration of antiviral prophylaxis or treatment, are to be implemented efficiently.

Author’s Note: The clinical findings and diagnostic challenges discussed in this article are consistent with those reported in the article by Kandun and colleagues [3] in the same issue of the NEJM, describing the three human clusters of H5N1 virus infection in Indonesia in 2005. Also in this issue, Webster and Govorkova write about the evolution and spread of H5N1 influenza, and discuss some of the challenges in controlling the virus in poultry despite strategies such as quarantine, culling of infected poultry, and vaccination of uninfected ones[4].

References
[1] Oner AF, Bay A, Arslan S, et al. Avian influenza A (H5N1) infection in eastern Turkey in 2006. N Engl J Med 2006;355:2179-85. Accessed on November 28, 2006 at http://content.nejm.org/cgi/content/full/355/21/2179.

[2] Tran TH, Nguyen TL, Nguyen TD, et al. Avian influenza A (H5N1) in 10 patients in Vietnam. N Engl J Med 2004;350:1179-88.

[3] Kandun N, Wibisono H, Sedyaningsih ER, et al. Three Indonesian clusters of H5N1 virus infection in 2005. N Engl J Med 2006;355:2186-94. Accessed on November 28, 2006 at http://content.nejm.org/cgi/content/full/355/21/2186.

[4] Webster RG and Govorkova EA. H5N1 influenza – continuing evolution and spread. N Engl J Med 2006;355:2174-77. Accessed on November 28, 2006 at http://content.nejm.org/cgi/content/full/355/21/2174.