Original Article
Avian Influenza A (H5N1) Infection in Eastern Turkey in 2006
N Engl J Med 2006; 355:2179-2185November 23, 2006
- Abstract
Background
An outbreak of highly pathogenic avian influenza A (H5N1) that had previously been detected throughout Asia, with major economic and health repercussions, extended to eastern Turkey in late December 2005 and early January 2006.
Methods
We documented the epidemiologic, clinical, and radiologic features of all cases of confirmed H5N1 virus infection in patients who were admitted to Yuzuncu Yil University Hospital in Van, Turkey, between December 31, 2005, and January 10, 2006.
Results
H5N1 virus infection was diagnosed in eight patients. The patients were 5 to 15 years of age, and all eight had a history of close contact with diseased or dead chickens. The mean (±SD) time between exposure and the onset of illness was 5.0±1.3 days. All the patients had fever, and seven had clinical and radiologic evidence of pneumonia at presentation; four patients died. Results of enzyme-linked immunosorbent assay and rapid influenza tests were negative in all patients, and the diagnosis was made by means of a polymerase-chain-reaction assay.
Conclusions
H5N1, which causes a spectrum of illnesses in humans, including severe and fatal respiratory disease, can be difficult to diagnose.
Media in This Article
Figure 1
Locations of Cases of H5N1 Infection in Turkey. The white boxes denote places with documented cases of H5N1 virus infection.Figure 2
Diagnostic Testing in the Patients Evaluated.Article Activity
- Article
The first documented case of human infection with the avian influenza A (H5N1) virus occurred in Hong Kong in 1997.1 As of July 26, 2006, a total of 232 H5N1 virus infections in humans had been documented, with a mortality rate of 58% among hospitalized patients.2,3 An outbreak of H5N1 virus had been detected in poultry in eastern Turkey from December 27, 2005, through January 26, 2006. This outbreak in poultry was followed by infection in humans. In contrast to the previously reported cases of H5N1 in southern and eastern Asia,1-4 the human outbreak in Turkey was concentrated in a small geographic area during a short period. H5N1 infection was diagnosed in 12 patients in Turkey and confirmed by the World Health Organization (WHO). Eight of these patients were followed at our hospital in Van. The four other patients, who came from Sanliurfa, Kastamonu, Eskisehir, and Dogubeyazit, were admitted to other health centers and survived without complications (Figure 1Figure 1
Locations of Cases of H5N1 Infection in Turkey. The white boxes denote places with documented cases of H5N1 virus infection.). We report the clinical, epidemiologic, and radiologic features and history of exposure of the eight patients with H5N1 virus infection cared for at our center.Methods
Among patients who were admitted to Yuzuncu Yil University Hospital, Van, Turkey, between December 31, 2005, and January 10, 2006, all those for whom there was a high index of suspicion for H5N1 virus infection were evaluated. Clinical, laboratory, and epidemiologic data were recorded. Nasopharyngeal samples for microbiologic tests were obtained on admission in a standardized fashion and sent to the Refik Saydam Hygiene Institute Laboratory, Ankara. At least two samples were obtained with Dacron-tipped swabs from each patient. The transport medium was 2 ml of minimal essential medium containing 2% fetal-calf serum, 2% antibiotic, and 1% glutamine. A real-time polymerase-chain-reaction (PCR) assay was performed with the RoboGene Bird Flu H5N1 qualitative kit (AJ Roboscreen, Leipzig, Germany),5,6 and the findings were confirmed by the WHO Influenza Reference Laboratory in London. The samples were also tested by means of a rapid influenza test (Quickvue Influenza A+B test, Quidel) and an enzyme-linked immunosorbent assay (ELISA) for influenza A and B (Serion ELISA antigen influenza A and B kits, Institute Virion/Serion).
Results
Patients
A total of 625 patients with suspected H5N1 virus infection were seen at our hospital during the study period. Of these patients, 131 (21%) had a history of contact with poultry and were given prophylactic oseltamivir in our outpatient clinic. One hundred fifty-nine patients (25%) who had both a history of contact with poultry and clinical findings that were compatible with influenza infection were hospitalized. These 290 patients underwent three diagnostic tests for H5N1 infection: the rapid influenza test, ELISA, and real-time PCR. All the samples were found to be negative for the H5N1 virus on the rapid and ELISA tests. The virus was detected in 10 of the patients by means of real-time PCR, and in 8 of these 10 patients, viral infection was confirmed by the WHO laboratory (Figure 2Figure 2
Diagnostic Testing in the Patients Evaluated.).Among the eight patients in whom H5N1 infection was diagnosed, initial test results of nasopharyngeal-swab specimens from four patients were negative. Since these four patients were severely ill, the three tests were repeated with tracheal-aspirate specimens on day 2 of hospitalization, and the real-time PCR test was positive for H5N1. In two patients who died, postmortem real-time PCR tests of lung-tissue samples were also positive for H5N1. The diagnosis was established on the basis of testing of nasopharyngeal-swab specimens in the other four patients. Before H5N1 infection was diagnosed in the eight patients, a total of 8 real-time PCR tests, 12 rapid influenza tests, and 12 ELISA tests were negative.
Among the eight patients with confirmed H5N1 virus infection, the median age was 10 years (range, 5 to 15), and five of the patients were girls. Seven patients lived in Dogubeyazit and one lived in the city center of Van. Seven of the patients were either related to or lived near at least one of the other patients. Patients 1A, 2A, and 3A were siblings, and Patients 5B and 6B were siblings. Patient 4 was a cousin of Patients 5B and 6B, and the families of Patients 1A, 2A, 3A, 4, and 7 were neighbors (Table 1Table 1
Epidemiologic Characteristics of the Patients.). Because all of these patients shared living space with poultry during the cold winter conditions, they had direct contact with the secretions and feathers of diseased or dead birds.The mean (±SD) time between the last known exposure to ill or dead poultry and the onset of the illness was 5.0±1.3 days (range, 4 to 7), and the mean time between the onset of illness and hospitalization was 6.6±3.2 days (range, 1 to 10). The incubation period was 4 to 7 days, and the interval between the onset of symptoms and hospital admission was more than 1 week in five patients and 1 to 5 days in the other three (Table 1).
Clinical, Radiologic, and Laboratory Findings
All of the patients had fever. Other common symptoms included tachypnea in seven patients (88%), cough in seven patients (88%), sore throat in six patients (75%), myalgia in four patients (50%), bleeding from the gums in three patients (38%), and diarrhea in three patients (38%). Conjunctivitis, headache, and rhinorrhea were also present in one patient each (12%). Seven patients had clinical and radiologic evidence of pneumonia at presentation, and one patient had a milder clinical course, with no pneumonia either on admission or during the follow-up period. The major abnormalities on the chest films were bilateral extensive infiltration, lobar collapse, focal consolidation, and air bronchograms, as well as rapid progression of pneumonia (Figure 3Figure 3
Serial Chest Films for Patient 5B.). No pleural effusions were noted. Among patients with improvement in clinical status, two patients had unilateral consolidation and one patient had bilateral consolidation on the chest film.The results of the laboratory tests performed on admission and the peak abnormal values during hospitalization are shown in Table 2Table 2
Results of Laboratory Tests at Admission and Peak Abnormal Values during Hospitalization.. An increase in aspartate aminotransferase levels was more prominent than an increase in alanine aminotransferase levels. The level of serum lactate dehydrogenase was elevated in seven patients and the level of creatine kinase was elevated in six patients. No pathogenic bacteria were isolated from the cultures of respiratory secretions or blood samples.Treatment and Outcome
Before admission to our facility, seven patients with severe illness received ampicillin and amikacin for 3 to 7 days at the Dogubeyazit Public Hospital. On transfer to our facility, given the rapid course of the disease, vancomycin, imipenem, and amikacin were given to one patient, who had a superimposed bacterial pneumonia. The neuraminidase inhibitor oseltamivir was given to seven patients, and the dose was adjusted according to weight (75 mg twice daily in Patients 2A, 3A, and 5B and 37.5 mg twice daily in Patients 4, 6B, 7, and 8). The antiviral treatment was started on the first day of admission in all patients except Patients 2A and 3A, in whom treatment was started on the second day. Patients 2A, 3A, 5B, and 7 received 0.5 g of intravenous immune globulin per kilogram of body weight on admission for 1 day, and Patient 6B received 0.5 g of intravenous immune globulin per kilogram per day for 4 days.
Mechanical ventilation was required in Patients 1A, 2A, 3A, and 5B during the first 48 to 72 hours of hospitalization. All these patients had a rapid deterioration in gas exchange in spite of mechanical ventilation, and they died on days 2, 4, 6, and 7 of hospitalization, respectively. Alveolar hemorrhage was present in all four patients. Among the patients who recovered, the fever resolved on day 3 to 6 of hospitalization. The case fatality rate was 50%, and the mean interval between the onset of illness and death was 13 days (range, 10 to 15).
Discussion
We describe the epidemiologic, clinical, and laboratory features of H5N1 virus infection that developed in eight patients during a short period in Turkey. As in previous reports of H5N1 infection7-11 (but unlike the eight patients with H5N1 infection described by Kandun and colleagues in this issue of the Journal 12), all of our patients were school-age children with a history of exposure to chickens. They were from a small geographic area, and seven of them were from four families. Many of these patients' siblings and parents also had contact with diseased poultry in the home but remained healthy, suggesting that the intensity and duration of contact with infected birds may be important in transmission.
An important observation in this case series is that the results of initial diagnostic testing for H5N1, including real-time PCR assays of nasopharyngeal swabs, were negative in many of the patients. As in the cases reported by Kandun and colleagues, the rapid influenza antigen test did not detect H5N1 infection in our patients. We were able to diagnose H5N1 infection in these patients because of a high index of suspicion during a known epidemic of this infection in poultry and because all the patients were seen at a regional referral center, were from a small geographic area, and had similar clinical presentations. Thus, testing was repeated. Because of the difficulties in detecting H5N1 infection, repeated testing from nasopharyngeal swabs or deep tracheal-aspiration samples in patients who are strongly suspected of having H5N1 infection should be performed even if tests of initial nasopharyngeal swabs are negative. Our experience suggests that ELISA and rapid influenza tests have limited value in diagnosing H5N1 infection and that real-time PCR should be performed.
The clinical manifestations of H5N1 virus infection in humans range from asymptomatic infection or a mild upper respiratory tract illness, to severe pneumonia and multiorgan failure.1,9 Most of our patients had a severe influenza syndrome and radiologic evidence of pneumonia at presentation. In our series, fever was a major symptom, and most of our patients had pneumonia on admission. Although diarrhea was a more prominent symptom among the Vietnamese patients described in a previous report, only three of eight children in our series presented with this symptom.9 The most striking hematologic findings were marked leukopenia, lymphopenia, and thrombocytopenia. Elevated aspartate aminotransferase, lactate dehydrogenase, and creatine kinase levels were found in most of the children. To our knowledge, elevated levels of lactate dehydrogenase and creatine kinase in patients with H5N1 infection have not been reported previously.
Neuraminidase inhibitors such as oseltamivir and zanamivir are effective in the treatment of influenza when given early in the course of infection (e.g., during the first 48 hours).13,14 Unfortunately, our patients presented later in the course of illness, and it is difficult to assess the effect of this type of medication on the outcome because of the delay in administration of the drug. However, 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. We do not know the clade of the infecting H5N1 strain (or strains) in this series, nor do we know whether antiviral resistance mutations were present or absent.
Measures taken by the local authorities to control this epidemic were primarily performed by the regional disease control center in Ankara. The hunting of all poultry species and poultry sales in open markets were prohibited throughout Turkey. Under this program, 2 million poultry were culled and destroyed, and their owners were compensated. To date no further human cases of H5N1 virus infection have been identified in Turkey.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Faculty of Medicine, Yuzuncu Yil University, Van (A.F.O., A.B., S.A., H.A., H.A.S., Y.C., S.E., I.D., B.K., H.K.); Refik Saydam Hygiene Institute, Ankara (N.Y.); and the Faculty of Medicine, Hacettepe University, Ankara (M.C.) — all in Turkey.
Address reprint requests to Dr. Oner at Arastirma hst. Cocuk hst.srv. Van, Turkey, or at afo59@yahoo.com.
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Kandun, I. Nyoman, Wibisono, Hariadi, Sedyaningsih, Endang R., Yusharmen, Hadisoedarsuno, Widarso, Purba, Wilfried, Santoso, Hari, Septiawati, Chita, Tresnaningsih, Erna, Heriyanto, Bambang, Yuwono, Djoko, Harun, Syahrial, Soeroso, Santoso, Giriputra, Sardikin, Blair, Patrick J., Jeremijenko, Andrew, Kosasih, Herman, Putnam, Shannon D., Samaan, Gina, Silitonga, Marlinggom, Chan, K.H., Poon, Leo L.M., Lim, Wilina, Klimov, Alexander, Lindstrom, Stephen, Guan, Yi, Donis, Ruben, Katz, Jacqueline, Cox, Nancy, Peiris, Malik, Uyeki, Timothy M., . (2006) Three Indonesian Clusters of H5N1 Virus Infection in 2005. New England Journal of Medicine 355:21, 2186-2194
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