Original Article
Three Indonesian Clusters of H5N1 Virus Infection in 2005
N Engl J Med 2006; 355:2186-2194November 23, 2006
- Abstract
Background
Since 2003, the widespread ongoing epizootic of avian influenza A (H5N1) among poultry and birds has resulted in human H5N1 cases in 10 countries. The first case of H5N1 virus infection in Indonesia was identified in July 2005.
Methods
We investigated three clusters of Indonesian cases with at least two ill persons hospitalized with laboratory evidence of H5N1 virus infection from June through October 2005. Epidemiologic, clinical, and virologic data on these patients were collected and analyzed.
Results
Severe disease occurred among all three clusters, including deaths in two clusters. Mild illness in children was documented in two clusters. The median age of the eight patients was 8.5 years (range, 1 to 38). Four patients required mechanical ventilation, and four of the eight patients (50%) died. In each cluster, patients with H5N1 virus infection were members of the same family, and most lived in the same home. In two clusters, the source of H5N1 virus infection in the index patient was not determined. Virus isolates were available for one patient in each of two clusters, and molecular sequence analyses determined that the isolates were clade 2 H5N1 viruses of avian origin.
Conclusions
In 2005 in Indonesia, clusters of human infection with clade 2 H5N1 viruses included mild, severe, and fatal cases among family members.
Media in This Article
Figure 1
Time Lines for Indonesian Case Clusters of H5N1 Virus Infection. ICU denotes intensive care unit.Table 1
Clinical Data for Patients from Three Indonesian Clusters of H5N1 Virus Infection in 2005.Article Activity
- Article
The avian influenza A (H5N1) epizootic has resulted in sporadic human cases and case clusters. Previously, H5N1 case clustering was observed in cousins in 19971 and in a father and son in 2003.2 H5N1 clustering was described in 2004–2005 but without sufficient information to assess whether human-to-human transmission had occurred.3 Although only one likely instance of limited human-to-human transmission of H5N1 virus was detailed in Thailand in 2004,4 the investigation of case clusters is critically important, since an increase in clusters could suggest greater transmissibility of H5N1 viruses.
Since 2003, H5N1 outbreaks in poultry have occurred throughout Indonesia.5-7 Indonesia's first human H5N1 case was confirmed in July 2005, and three clusters were noted among H5N1 cases through October 2005. In this report, we describe the epidemiologic, clinical, and virologic findings of the three H5N1 case clusters.
Methods
Epidemiologic and Clinical Investigation
After notification of a suspected case of H5N1, the Ministry of Health in Indonesia initiated an investigation with the assistance of public health authorities and the World Health Organization (WHO). Investigators collected nasal and throat swabs, tracheal aspirates (if available), and serum specimens from patients who were suspected of having the disease; all specimens were tested for the presence of H5N1 virus. Laboratory evidence of H5N1 was defined as virus isolation or detection of H5N1 viral RNA by testing of respiratory specimens or serologically by detection of H5N1 neutralizing antibodies. Cases were classified as suspected, probable, or confirmed H5N1 virus infection, according to WHO definitions.8
We collected epidemiologic and clinical data for patients with confirmed H5N1 virus infection and their contacts through interviews and a review of medical records. Contacts of patients with H5N1 infection were followed for illness. Environmental, poultry, and other avian specimens, if available, were tested for H5N1 virus. Clinical, epidemiologic, and laboratory data were analyzed with the use of descriptive statistics. We defined a cluster of H5N1 cases as consisting of at least two persons who had disease with laboratory evidence of H5N1 virus among household members, relatives, or other contacts. This study was part of an ongoing public health investigation of outbreaks of H5N1 virus infection and was determined by the Ministry of Health to be exempt from approval from institutional review boards in Indonesia.
Laboratory Investigation
Indonesian laboratories screened clinical specimens from patients with suspected H5N1 infection for the virus. Respiratory and serum specimens were shipped frozen to WHO H5 Reference Laboratories for H5N1 testing by real-time reverse-transcriptase polymerase chain reaction (RT-PCR), viral culture, molecular sequencing, antiviral resistance testing, microneutralization, and Western blot analyses (see the Supplementary Appendix, available with the full text of this article at www.nejm.org).
Results
Among eight previously healthy patients in three unrelated clusters, there were seven confirmed cases of H5N1 virus infection and one probable case (Figure 1Figure 1
Time Lines for Indonesian Case Clusters of H5N1 Virus Infection. ICU denotes intensive care unit.). The median age of the patients was 8.5 years (range, 1 to 38), and four of the eight patients (50%) died, including two adults and two children.Cluster 1
This cluster included three of five family members living together in a suburb west of Jakarta. Patient 1A, an 8-year-old girl in whom fever, headache, nausea, vomiting, and rhinorrhea developed, was hospitalized with pneumonia 6 days after the onset of symptoms. She was treated with albuterol, fluticasone, ceftriaxone, meropenem, ciprofloxacin, vancomycin, gentamicin, amikacin, linezolid, and mechanical ventilation for respiratory failure, but she died on the 26th day of illness. Serum specimens collected late in her illness showed evidence of acute H5N1 virus infection on microneutralization assay.
Patient 1B was a 1-year-old girl in whom fever developed 1 week after the onset of illness in her sister (Patient 1A). On the ninth day of illness, Patient 1B was hospitalized with fever, rhinorrhea, cough, diarrhea, and vomiting, and she received the diagnosis of pneumonia. She was placed on mechanical ventilation but died on the 12th day of illness. No specimens were available for H5N1 testing.
Patient 1C, who worked as a government auditor, was the 38-year-old father of Patients 1A and 1B. He had close contact with his sick daughters at home and during their hospitalizations. He had onset of fever 3 and 9 days, respectively, after the onset of his daughters' illnesses. On the seventh day of illness, he was hospitalized with pneumonia and was treated with albuterol, budesonide, aminophylline, dexamethasone, meropenem, ceftriaxone, and linezolid. Despite mechanical ventilation, he died on the 11th day of illness. H5N1 virus was isolated from a throat swab collected on day 7.
The three patients in cluster 1 reported having had no contact with poultry, wild birds, other animals, or any sick persons besides family members before the onset of illness. Family members shared a bed after the onset of illness and before hospitalization. Patient 1C's wife, son, and two housekeepers living in the home remained well. Of the 173 contacts who were followed for 2 weeks (8 household members and neighbors, 143 health care workers, and 22 coworkers), no other ill persons were identified.
Cluster 2
This cluster included two relatives living near south Jakarta. On August 31, fever, rhinorrhea, and cough developed in a 37-year-old woman (Patient 2A). On the seventh day of illness, she was hospitalized with fever, shock, and respiratory failure requiring mechanical ventilation. Methylprednisolone, levofloxacin, and meropenem were administered, and oseltamivir was given on the 10th day of illness. She died 11 days after the onset of illness; H5N1 virus was isolated from tracheal aspirate.
Patient 2B was a 9-year-old boy who lived temporarily with Patient 2A (his aunt) during her illness. Three days after his aunt was hospitalized, he had onset of fever. He was hospitalized on the ninth day of illness, with persistent fever, sore throat, and tachypnea. No supplemental oxygen, antibiotics, or antiviral treatment was administered, and his fever resolved on the 10th day of illness. The presence of H5N1 virus was confirmed by RT-PCR in respiratory specimens obtained on the fourth day of illness.
Patients 2A and 2B did not report having had contact with poultry, wild birds, other animals, or other ill persons, but chickens died nearby, and poultry were slaughtered daily approximately 50 m from the home. In her home garden, Patient 2A used fertilizer containing poultry feces that tested positive for H5N1 by RT-PCR. Of the 132 contacts of Patients 2A and 2B (76 household members and neighbors and 56 health care workers), no other ill persons were identified.
Cluster 3
Three relatives living in the same rural village in southern Sumatra made up the third cluster. In mid-September 2005, backyard chickens started dying in the village. Three days after holding two dead chickens, Patient 3A, a 21-year-old man with a history of smoking cigarettes, had an onset of fever, chills, rhinorrhea, cough, and headache. On the fifth day of illness, he was hospitalized with pneumonia and treated with ceftriaxone. Oseltamivir was started on the seventh day of illness. One week later, his respiratory status worsened, requiring supplemental oxygen, and a pleural effusion was noted on chest radiography. His condition improved, and he was discharged on day 25 of illness. A throat swab that was collected on admission tested positive for H5N1 by RT-PCR. H5N1 virus was isolated from a lung specimen obtained from a chicken close to the home.
Patient 3B, the 5-year-old brother of Patient 3A, had an onset of illness (fever, rhinorrhea, and cough) on the same day as Patient 3A, was hospitalized on the fifth day of illness, recovered without treatment, and was discharged 9 days later. Serologic confirmation of H5N1 virus infection was made more than 3 months later for Patient 3B. Patient 3C was the 4-year-old son of a sister of Patient 3A and Patient 3B. He lived in a separate home and did not have contact with his uncles during their illnesses but moved to their home after they were hospitalized. Patient 3C did not have any known contact with ill persons or with sick or dead poultry, but his mother had handled dead chickens and buried them. On October 4, fever, rhinorrhea, and dry cough developed in Patient 3C, but the fever lasted only 2 days. After a throat specimen tested positive for H5N1 by RT-PCR, he was hospitalized on day 5 and treatment with oseltamivir was started. A chest radiograph on day 7 revealed mild bilateral perihilar and interstitial infiltrates. He remained afebrile, received oseltamivir for 7 days, and was discharged 17 days after the onset of illness. Of the 33 household and neighborhood contacts that were followed for 2 weeks, all others remained well.
Clinical Findings
The median time from the onset of illness to hospitalization was 7 days (range, 5 to 9) (Table 1Table 1
Clinical Data for Patients from Three Indonesian Clusters of H5N1 Virus Infection in 2005.). All patients with fatal disease presented with fever, bilateral pneumonia, and respiratory distress, and three patients presented with leukopenia, lymphopenia, and moderate thrombocytopenia. In all five patients with severe disease, including four who required mechanical ventilation, hypoxemia or hypoxia either was present on admission or developed later, requiring supplemental oxygen. None of the three mild cases required supplemental oxygen. Patients 2B and 3C had normal leukocyte, lymphocyte, and platelet counts on admission and had fever for 2 and 10 days, respectively. Only Patients 2A, 3A, and 3C received treatment with oseltamivir, beginning on illness days 10, 7, and 5, respectively. Six patients received antibiotics to treat possible bacterial coinfection, but no invasive bacterial infections were identified.Of six patients whose serum albumin levels were measured either at or close to their hospital admission, four patients with fatal disease had hypoalbuminemia (albumin range, 2.2 to 3.1 g per deciliter). One patient with severe but nonfatal disease had an albumin level of 2.4 g per deciliter, and one patient with very mild disease had a level of 4.3 g per deciliter. Four patients with severe disease had moderately elevated levels of aspartate aminotransferase and alanine aminotransferase, with levels of aspartate aminotransferase higher than those of alanine aminotransferase, at or shortly after admission, as compared with one patient with mild disease who had normal levels.
H5N1 Testing
H5N1 virus was isolated from a throat swab from Patient 1C on illness day 7 and from a tracheal aspirate from Patient 2A on day 10 (Table 2Table 2
Results of Laboratory Testing for H5N1 Virus Infection from Patients in Three Indonesian Clusters in 2005.). Molecular sequencing of H5N1 viruses isolated from Patient 1C (A/Indonesia/5/2005) and Patient 2A (A/Indonesia/6/2005) indicated that both H5N1 viruses were of the Z genotype. In addition, all eight genes of both H5N1 viruses were of avian origin and were clade 2 viruses, as defined previously.9 Both A/Indonesia/5/2005 and A/Indonesia/6/2005 had M2 gene sequences, indicating susceptibility to adamantanes. Sequencing of the neuraminidase genes and assaying for susceptibility to neuraminidase inhibitors found that both H5N1 viruses were sensitive to such agents. Of the five patients whose disease was confirmed by RT-PCR, the same specimens tested negative by rapid antigen testing. Throat swabs had a higher yield for detection of H5N1 virus by RT-PCR assay and viral isolation than did nasal swabs. A throat swab from Patient 3B was positive on RT-PCR assay on illness day 8, even though the patient had fever for only 2 days and began receiving oseltamivir on day 5.Discussion
Our study documents clusters of clade 2 H5N1 virus infection among Indonesian families. These findings and other reports of clusters among family members and relatives in Hong Kong, Vietnam, Thailand, China, Azerbaijan, and Turkey1-4,10-14 raise questions as to whether genetic or other factors may predispose some persons to H5N1 virus infection or to severe disease. Since the completion of this investigation, additional H5N1 case clusters have been identified in Indonesia, including a large cluster in northern Sumatra in May 2006. WHO recommends close follow-up and oseltamivir chemoprophylaxis for household members and relatives of patients with H5N1 virus infection who had close contact either with the patient with the disease or with sick or dead poultry.15 Prompt antiviral treatment of any associated identified ill persons is also recommended.
We identified three pediatric patients with clinically mild disease in two clusters. This finding is consistent with data from 1997, when most pediatric patients with H5N1 virus infection in Hong Kong had relatively mild disease.16,17 Another study identified mild and asymptomatic H5N1 virus infection in two adult health care workers in 1997.18 Identification of three mild H5N1 cases in this study and one case in Turkey (as reported by Oner et al.12 elsewhere in this issue of the Journal) has implications for surveillance, since most H5N1 case findings have focused on patients who were hospitalized with severe pneumonia.
We were not able to determine the source of H5N1 virus infection for the index patients in two clusters, and transmission through contact with environmentally contaminated material remains a possibility. In the first cluster, a caged bird with H5N1 virus infection near the home suggested the possibility of environmental contamination with H5N1 virus, although no virus was detected around the residence. The index patient in the second cluster could have acquired infection through contact with fertilizer containing H5N1-contaminated poultry feces. The presence of a poultry-slaughtering operation approximately 50 m from the home and dead chickens in the neighborhood also suggests that H5N1 environmental contamination could have been a source.
Limited person-to-person H5N1 transmission could not be excluded in two clusters among patients who had no known contact with poultry or other animals. Although Patient 1B was not tested, her clinical characteristics and evidence that her sister (Patient 1A) and her father had acute H5N1 virus infection all strongly suggest she also had H5N1 virus infection. Both Patient 1B and her father had close contact with Patient 1A before their illnesses. Similarly, the only identified exposure for Patient 2B was close contact with his aunt (Patient 2A) during her illness. Limited, nonsustained H5N1 virus transmission from Patient 1A to her sister and father, from Patient 1B to her father, and from Patient 2A to her nephew remain possible explanations given the epidemiologic investigation.
As compared with nasal swabs, throat specimens provided the highest yield for the detection of H5N1 virus. Rapid antigen testing did not detect any H5N1 cases, which is consistent with data reported for clade 1 infections19 and supports guidance against using such tests for the detection of H5N1 virus.20
Few Indonesian patients with clade 2 H5N1 virus infection in these clusters had diarrhea, unlike patients with clade 1 H5N1 virus infection.19,21,22 Most patients with H5N1 virus infection had hypoalbuminemia at or close to the time of hospital admission, which has not been reported previously. Whether this finding is related to viral, renal, hepatic, gastrointestinal, iatrogenic, or other factors is unknown. The effects of corticosteroid therapy or late oseltamivir treatment could not be determined. Both H5N1 clade 2 viral isolates were sensitive to adamantanes and neuraminidase inhibitors, although adamantanes are not recommended by the WHO owing to a high frequency of H5N1 viruses that are resistant to amantadine and rimantadine.15 Resistance to oseltamivir has been reported in patients with clade 1 H5N1 virus infection.13,14 A recent study showed a correlation between a high H5N1 viral load and hypercytokinemia, and the investigators concluded that early antiviral treatment is needed to suppress viral replication and to prevent the overwhelming inflammatory response implicated in H5N1 pathogenesis.23 Therefore, much more research is needed to define optimal treatment for patients with H5N1 virus infection.
Our findings of a wide range of clinical features and outcomes associated with clade 2 H5N1 virus infection in Indonesia highlight the importance of careful clinical examination, laboratory diagnosis, and sequential monitoring of all patients with suspected H5N1 virus infection and their close contacts. Further research is needed to understand the role of mild cases in the epidemiology of this disease and whether genetic, behavioral, immunologic, and environmental factors may contribute to case clustering of H5N1 virus infection.
All authors report receiving financial support from their respective institutions. No potential conflict of interest relevant to this article was reported.
The views expressed in this article are those of the authors and do not reflect the official policy or position of the Indonesian National Institute of Health Research and Development and Directorate General of Disease Control and Environmental Health (Ministry of Health), the U.S. Department of Defense, the U.S. Department of the Navy, or the Centers for Disease Control and Prevention (CDC).
We thank our many colleagues at the Directorate General of Disease Control and Environmental Health and the National Institute of Health Research and Development, Ministry of Health, Jakarta; the provincial, district, and subdistrict health offices; the health care providers at Indonesian hospitals who cared for patients with H5N1 virus infection; the U.S. Naval Medical Research Unit 2; the WHO in Indonesia; Hong Kong University; Hong Kong Government Virus Unit; and the CDC, for their contributions to our epidemiologic, clinical, virologic, and immunologic investigations.
Source Information
From the Directorate General of Disease Control and Environmental Health (I.N.K., H.W., Y., W.H., W.P., H.S., C.S.) and the National Institute of Health Research and Development (E.R.S., E.T., B.H., D.Y., S.H.), Ministry of Health, Jakarta; the Infectious Disease Hospital Rumah Sakit Penyakit Infeksi Sulianti Saroso, North Jakarta (S.S., S.G.); the U.S. Naval Medical Research Unit 2, Jakarta (P.J.B., A.J., H.K., S.D.P.); and the World Health Organization, Jakarta (G.S., M.S.) — all in Indonesia; the University of Hong Kong (K.H.C., L.L.M.P., Y.G., M.P.) and the Department of Health (W.L.) — both in Hong Kong; and the Centers for Disease Control and Prevention, Atlanta (A.K., S.L., R.D., J.K., N.C., T.M.U.).
Address reprint requests to Dr. Uyeki at the Influenza Division, Mail Stop A-32, Centers for Disease Control and Prevention, Atlanta, GA 30333, or at tuyeki@cdc.gov.
- References
References
1
Isolation of avian influenza A(H5N1) viruses from humans -- Hong Kong, May-December 1997. MMWR Morb Mortal Wkly Rep 1997;46:1204-1207
Medline2
Peiris JS ,Yu WC ,Leung CW , et al. Re-emergence of fatal human influenza A subtype H5N1 disease. Lancet 2004;363:617-619
CrossRef | Web of Science | Medline3
Olsen SJ ,Ungchusak K ,Sovann L , et al. Family clustering of avian influenza A (H5N1). Emerg Infect Dis 2005;11:1799-1801
Web of Science | Medline4
Ungchusak K ,Auewarakul P ,Dowell SF , et al. Probable person-to-person transmission of avian influenza A (H5N1). N Engl J Med 2005;352:333-340
Full Text | Web of Science | Medline5
Office International des Epizooties. Highly pathogenic avian influenza in Indonesia. Jakarta, Indonesia: Department of Agriculture, February 6, 2004. (Accessed October 30, 2006, at ftp://ftp.oie.int/infos_san_archives/eng/2004/en_040206v17n06.pdf.)
6
Avian influenza — situation in Indonesia — update 32. Geneva: World Health Organization, September 29, 2005. (Accessed October 30, 2006, at http://www.who.int/csr/don/2005_09_29/en/index.html.)
7
Smith GJD ,Naipospos TSP ,Nguyen TD , et al. Evolution and adaptation of H5N1 influenza virus in avian and human hosts in Indonesia and Vietnam. Virology 2006;350:258-268
CrossRef | Web of Science | Medline8
WHO case definitions for human infections with influenza A (H5N1) virus. Geneva: World Health Organization, August 29, 2006. (Accessed October 30, 2006, at http://www.who.int/csr/disease/avian_influenza/guidelines/case_definition2006_08_29/en/index.html.)
9
World Health Organization Global Influenza Program Surveillance Network
Web of Science | Medline10
Yu H ,Shu Y ,Hu S , et al. The first confirmed human case of avian influenza A (H5N1) in Mainland China. Lancet 2006;367:84-84
CrossRef | Web of Science | Medline11
Human avian influenza in Azerbaijan, February-March 2006. Wkly Epidemiol Rec 2006;81:183-188
Medline12
Oner AF ,Bay A ,Arslan S , et al. Avian influenza A (H5N1) infection in eastern Turkey in 2006. N Engl J Med 2006;355:2179-2185
Full Text | Web of Science | Medline13
Le QM ,Kiso M ,Someya K , et al. Avian flu: isolation of drug-resistant H5N1 virus. Nature 2005;437:1108-1108[Erratum, Nature 2005;438:754.]
CrossRef | Web of Science | Medline14
de Jong MD ,Tran TT ,Truong HK , et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med 2005;353:2667-2672
Full Text | Web of Science | Medline15
WHO rapid advice guidelines on pharmacological management of humans infected with avian influenza A (H5N1) virus. Geneva: World Health Organization, 2006. (Accessed October 30, 2006, at http://www.who.int/csr/disease/avian_influenza/guidelines/pharmamanagement/en/index.html.)
16
Chan PK . Outbreak of avian influenza A(H5N1) virus infection in Hong Kong in 1997. Clin Infect Dis 2002;34:Suppl 2:S58-S64
CrossRef | Web of Science | Medline17
Yuen KY ,Chan PK ,Peiris M , et al. Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus. Lancet 1998;351:467-471
CrossRef | Web of Science | Medline18
Buxton Bridges C ,Katz JM ,Seto WH , et al. Risk of influenza A (H5N1) infection among health care workers exposed to patients with influenza A (H5N1), Hong Kong. J Infect Dis 2000;181:344-348
CrossRef | Web of Science | Medline19
The Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5
Full Text | Web of Science | Medline20
WHO recommendations on the use of rapid testing for influenza diagnosis. Geneva: World Health Organization, July 2005. (Accessed October 30, 2006, at http://www.who.int/csr/disease/avian_influenza/guidelines/RapidTestInfluenza_web.pdf.)
21
Tran TH ,Nguyen TL ,Nguyen TD , et al. Avian influenza A (H5N1) in 10 patients in Vietnam. N Engl J Med 2004;350:1179-1188
Full Text | Web of Science | Medline22
Chotpitayasunondh T ,Ungchusak K ,Hanshaoworakul W , et al. Human disease from influenza A (H5N1), Thailand, 2004. Emerg Infect Dis 2005;11:201-209
Web of Science | Medline23
de Jong MD ,Simmons CP ,Thanh TT , et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med 2006;12:1203-1207
CrossRef | Web of Science | Medline
- Citing Articles (84)
Citing Articles
1
T. Y. Aditama, G. Samaan, R. Kusriastuti, W. H. Purba, Misriyah, H. Santoso, A. Bratasena, A. Maruf, E. Sariwati, V. Setiawaty, A. R. Cook, M. S. Clements, K. Lokuge, P. M. Kelly, I. N. Kandun. (2011) Risk Factors for Cluster Outbreaks of Avian Influenza A H5N1 Infection, Indonesia. Clinical Infectious Diseases 53:12, 1237-1244
CrossRef2
Li-Mei Chen, Ola Blixt, James Stevens, Aleksandr S. Lipatov, Charles T. Davis, Brian E. Collins, Nancy J. Cox, James C. Paulson, Ruben O. Donis. (2011) In vitro evolution of H5N1 avian influenza virus toward human-type receptor specificity. Virology
CrossRef3
EM Sorrell, EJA Schrauwen, M Linster, M De Graaf, S Herfst, RAM Fouchier. (2011) Predicting ‘airborne’ influenza viruses: (trans-) mission impossible?. Current Opinion in Virology
CrossRef4
Gina Samaan, Anita Gultom, Risa Indriani, Kamalini Lokuge, Paul M. Kelly. (2011) Critical control points for avian influenza A H5N1 in live bird markets in low resource settings. Preventive Veterinary Medicine 100:1, 71-78
CrossRef5
Vincent C.C. Cheng, Jasper F.W. Chan, X. Wen, W.L. Wu, T.L. Que, H. Chen, K.H. Chan, K.Y. Yuen. (2011) Infection of immunocompromised patients by avian H9N2 influenza A virus. Journal of Infection 62:5, 394-399
CrossRef6
Taronna R. Maines, Li-Mei Chen, Jessica A. Belser, Neal Van Hoeven, Elizabeth Smith, Ruben O. Donis, Terrence M. Tumpey, Jacqueline M. Katz. (2011) Multiple genes contribute to the virulent phenotype observed in ferrets of an H5N1 influenza virus isolated from Thailand in 2004. Virology 413:2, 226-230
CrossRef7
Erik De Clercq. (2011) The next ten stories on antiviral drug discovery (part E): advents, advances, and adventures. Medicinal Research Reviews 31:1, 118-160
CrossRef8
Jason E McDermott, Harish Shankaran, Amie J Eisfeld, Sarah E Belisle, Gabriele Neuman, Chengjun Li, Shannon McWeeney, Carol Sabourin, Yoshihiro Kawaoka, Michael G Katze, Katrina M Waters. (2011) Conserved host response to highly pathogenic avian influenza virus infection in human cell culture, mouse and macaque model systems. BMC Systems Biology 5:1, 190
CrossRef9
Jessica A. Belser, Taronna R. Maines, Terrence M. Tumpey, Jacqueline M. Katz. (2010) Influenza A virus transmission: contributing factors and clinical implications. Expert Reviews in Molecular Medicine 12,
CrossRef10
P. HORBY, H. SUDOYO, V. VIPRAKASIT, A. FOX, P. Q. THAI, H. YU, S. DAVILA, M. HIBBERD, S. J. DUNSTAN, Y. MONTEERARAT, J. J. FARRAR, S. MARZUKI, N. T. HIEN. (2010) What is the evidence of a role for host genetics in susceptibility to influenza A/H5N1?. Epidemiology and Infection 138:11, 1550-1558
CrossRef11
Arunee Thitithanyanont, Anneke Engering, Monkol Uiprasertkul, Peeraya Ekchariyawat, Suwimon Wiboon-ut, Romchat Kraivong, Amporn Limsalakpetch, Utaiwan Kum-Arb, Kosol Yongvanitchit, Noppadol Sa-Ard-Iam, Pimprapa Rukyen, Rangsini Mahanonda, Kamon Kawkitinarong, Prasert Auewarakul, Pongsak Utaisincharoen, Stitaya Sirisinha, Carl J. Mason, Mark M. Fukuda, Sathit Pichyangkul. (2010) Antiviral immune responses in H5N1-infected human lung tissue and possible mechanisms underlying the hyperproduction of interferon-inducible protein IP-10. Biochemical and Biophysical Research Communications 398:4, 752-758
CrossRef12
I. N. Kandun, G. Samaan, S. Harun, W. H. Purba, E. Sariwati, C. Septiawati, M. Silitonga, N. P. I. Dharmayanti, P. M. Kelly, T. Wandra. (2010) Chicken Faeces Garden Fertilizer: Possible Source of Human Avian Influenza H5N1 Infection. Zoonoses and Public Health 57:4, 285-290
CrossRef13
P. Rabinowitz, M. Perdue, E. Mumford. (2010) Contact Variables for Exposure to Avian Influenza H5N1 Virus at the Human-Animal Interface. Zoonoses and Public Health 57:4, 227-238
CrossRef14
Najwa Khuri-Bulos, John V. Williams, Asem A. Shehabi, Samir Faouri, Ehsan Al Jundi, Omar Abushariah, Qingxia Chen, S. Asad Ali, Sten Vermund, Natasha B. Halasa. (2010) Burden of respiratory syncytial virus in hospitalized infants and young children in Amman, Jordan. Scandinavian Journal of Infectious Diseases 42:5, 368-374
CrossRef15
Syed Asad Ali, John V. Williams, Qingxia Chen, Sameer Faori, Assem Shehabi, Eshan Al Jundi, Najwa Khuri-Bulos, Natasha Halasa. (2010) Human metapneumovirus in hospitalized children in Amman, Jordan. Journal of Medical Virology 82:6, 1012-1016
CrossRef16
J. R. Smith. (2010) Oseltamivir in human avian influenza infection. Journal of Antimicrobial Chemotherapy 65:Supplement 2, ii25-ii33
CrossRef17
James R. Smith, Robert E. Ariano, Stephen Toovey. (2010) The use of antiviral agents for the management of severe influenza. Critical Care Medicine 38, e43-e51
CrossRef18
Michael J. Loeffelholz. (2010) Avian Influenza A H5N1 Virus. Clinics in Laboratory Medicine 30:1, 1-20
CrossRef19
Nurettin Erben, Elif Doyuk Kartal, Saygin Nayman Alpat, Ilhan Ozgunes, Gaye Usluer. (2010) A case of pneumonia following human infection with avian influenza a (H5N1). Central European Journal of Medicine 5:1, 59-61
CrossRef20
Suryaprakash Sambhara, Gregory A. Poland. (2010) H5N1 Avian Influenza: Preventive and Therapeutic Strategies Against a Pandemic. Annual Review of Medicine 61:1, 187-198
CrossRef21
Burke A. Cunha, Uzma Syed, Nardeen Mickail, Stephanie Strollo. (2010) Rapid clinical diagnosis in fatal swine influenza (H1N1) pneumonia in an adult with negative rapid influenza diagnostic tests (RIDTs): Diagnostic swine influenza triad. Heart & Lung: The Journal of Acute and Critical Care 39:1, 78-86
CrossRef22
A. Nicoll, A. Ammon, A. Amato, B. Ciancio, P. Zucs, I. Devaux, F. Plata, A. Mazick, K. Mølbak, T. Asikainen, P. Kramarz. (2010) Experience and lessons from surveillance and studies of the 2009 pandemic in Europe. Public Health 124:1, 14-23
CrossRef23
Gabriele Neumann, Hualan Chen, George F Gao, Yuelong Shu, Yoshihiro Kawaoka. (2010) H5N1 influenza viruses: outbreaks and biological properties. Cell Research 20:1, 51-61
CrossRef24
Arthur C. Stoops, Katie A. Barbara, Mochamad Indrawan, Ima N. Ibrahim, Wicaksana B. Petrus, Susan Wijaya, Arik Farzeli, Ungke Antonjaya, Lim W. Sin, N. Hidayatullah, Ige Kristanto, A.M. Tampubolon, S. Purnama, Adam Supriatna, Timothy H. Burgess, Maya Williams, Shannon D. Putnam, Steve Tobias, Patrick J. Blair. (2009) H5N1 Surveillance in Migratory Birds in Java, Indonesia. Vector-Borne and Zoonotic Diseases 9:6, 695-702
CrossRef25
Lyna Zhang, Jacqueline M. Katz, Marta Gwinn, Nicole F. Dowling, Muin J. Khoury. (2009) Systems-based candidate genes for human response to influenza infection. Infection, Genetics and Evolution 9:6, 1148-1157
CrossRef26
Robert G. Wallace. (2009) Breeding Influenza: The Political Virology of Offshore Farming. Antipode 41:5, 916-951
CrossRef27
Janette Taylor, Kenneth McPhie, Julian Druce, Chris Birch, Dominic E. Dwyer. (2009) Evaluation of twenty rapid antigen tests for the detection of human influenza A H5N1, H3N2, H1N1, and B viruses. Journal of Medical Virology 81:11, 1918-1922
CrossRef28
Scott Santibañez, Anthony E. Fiore, Toby L. Merlin, Stephen Redd. (2009) A Primer on Strategies for Prevention and Control of Seasonal and Pandemic Influenza. American Journal of Public Health 99:S2, S216-S224
CrossRef29
Isabella Alberini, Elena Del Tordello, Alba Fasolo, Nigel J. Temperton, Grazia Galli, Chiara Gentile, Emanuele Montomoli, Anne K. Hilbert, Angelika Banzhoff, Giuseppe Del Giudice, John J. Donnelly, Rino Rappuoli, Barbara Capecchi. (2009) Pseudoparticle neutralization is a reliable assay to measure immunity and cross-reactivity to H5N1 influenza viruses. Vaccine 27:43, 5998-6003
CrossRef30
Terrence M. Tumpey, Jessica A. Belser. (2009) Resurrected Pandemic Influenza Viruses*. Annual Review of Microbiology 63:1, 79-98
CrossRef31
Frances Childre, Joyce Hood, Lisa LaCoe. (2009) The Roles of the Occupational Health Nurse and Infection Control in Managing a Novel H1N1 Surge— Lessons From the Front Line. AAOHN Journal 57:9, 355-358
CrossRef32
Edward C. Holmes. (2009) RNA virus genomics: a world of possibilities. Journal of Clinical Investigation 119:9, 2488-2495
CrossRef33
Marguerite Pappaioanou. (2009) Highly pathogenic H5N1 avian influenza virus: Cause of the next pandemic?. Comparative Immunology, Microbiology and Infectious Diseases 32:4, 287-300
CrossRef34
Gerald Choon-Huat Koh, Nugroho Abikusno, Cheong Seng Kwing, Wong Teck Yee, Rina Kusumaratna, Meena Sundram, Kelvin Koh, Chia Sin Eng, David Koh. (2009) Avian influenza and South Jakarta primary healthcare workers: a controlled mixed-method study. Tropical Medicine & International Health 14:7, 817-829
CrossRef35
Sawyin Oh, Paul Selleck, Nigel J. Temperton, Paul K.S. Chan, Barbara Capecchi, Jim Manavis, Geoff Higgins, Christopher J. Burrell, Tuckweng Kok. (2009) Neutralizing monoclonal antibodies to different clades of Influenza A H5N1 viruses. Journal of Virological Methods 157:2, 161-167
CrossRef36
Di Liu, XiaoLing Liu, JingHua Yan, Wen-Jun Liu, George Fu Gao. (2009) Interspecies transmission and host restriction of avian H5N1 influenza virus. Science in China Series C: Life Sciences 52:5, 428-438
CrossRef37
CuiLin Xu, LiBo Dong, Li Xin, Yu Lan, YongKun Chen, LiMei Yang, YueLong Shu. (2009) Human avian influenza A (H5N1) virus infection in China. Science in China Series C: Life Sciences 52:5, 407-411
CrossRef38
Katherine A. Poehling, H. Keipp Talbot, John V. Williams, Yuwei Zhu, John Lott, Lori Patterson, Kathryn M. Edwards, Marie R. Griffin. (2009) Impact of a school-based influenza immunization program on disease burden: Comparison of two Tennessee counties. Vaccine 27:20, 2695-2700
CrossRef39
N. Van Hoeven, C. Pappas, J. A. Belser, T. R. Maines, H. Zeng, A. Garcia-Sastre, R. Sasisekharan, J. M. Katz, T. M. Tumpey. (2009) Human HA and polymerase subunit PB2 proteins confer transmission of an avian influenza virus through the air. Proceedings of the National Academy of Sciences 106:9, 3366-3371
CrossRef40
H. Keipp Talbot, Katherine A. Poehling, John V. Williams, Yuwei Zhu, Qingxia Chen, Paul McNabb, Kathryn M. Edwards, Marie R. Griffin. (2009) Influenza in older adults: Impact of vaccination of school children. Vaccine 27:13, 1923-1927
CrossRef41
M. Khanna, P. Kumar, K. Choudhary, B. Kumar, V. K. Vijayan. (2008) Emerging influenza virus: A global threat. Journal of Biosciences 33:4, 475-482
CrossRef42
Menno D. de Jong. (2008) H5N1 Transmission and Disease. The Pediatric Infectious Disease Journal 27:Supplement, S54-S56
CrossRef43
Mary Hoelscher, Shivaprakash Gangappa, Weimin Zhong, Lakshmi Jayashankar, Suryaprakash Sambhara. (2008) Vaccines against epidemic and pandemic influenza. Expert Opinion on Drug Delivery 5:10, 1139-1157
CrossRef44
Maria D. Van Kerkhove, Sowath Ly, Davun Holl, Javier Guitian, Punam Mangtani, Azra C. Ghani, Sirenda Vong. (2008) Frequency and patterns of contact with domestic poultry and potential risk of H5N1 transmission to humans living in rural Cambodia. Influenza and Other Respiratory Viruses 2:5, 155-163
CrossRef45
Joyshri Sarangi, Chloe Sellwood, Jonathan S. Nguyen-Van-Tam. (2008) Responding to bird influenza: Past, present and future. Travel Medicine and Infectious Disease 6:4, 190-194
CrossRef46
Peggy A. Lalor, Richard J. Webby, Jane Morrow, Denis Rusalov, David C. Kaslow, Alain Rolland, Larry R. Smith. (2008) Plasmid DNA–Based Vaccines Protect Mice and Ferrets against Lethal Challenge with A/Vietnam/1203/04 (H5N1) Influenza Virus. The Journal of Infectious Diseases 197:12, 1643-1652
CrossRef47
J. A. Belser, O. Blixt, L.-M. Chen, C. Pappas, T. R. Maines, N. Van Hoeven, R. Donis, J. Busch, R. McBride, J. C. Paulson, J. M. Katz, T. M. Tumpey. (2008) Contemporary North American influenza H7 viruses possess human receptor specificity: Implications for virus transmissibility. Proceedings of the National Academy of Sciences 105:21, 7558-7563
CrossRef48
Christine Korteweg, Jiang Gu. (2008) Pathology, Molecular Biology, and Pathogenesis of Avian Influenza A (H5N1) Infection in Humans. The American Journal of Pathology 172:5, 1155-1170
CrossRef49
Anucha Apisarnthanarak, Piphob Phattanakeitchai, David K. Warren, Victoria J. Fraser. (2008) Impact of Knowledge and Positive Attitudes About Avian Influenza (H5N1 Virus Infection) on Infection Control and Influenza Vaccination Practices of Thai Healthcare Workers. Infection Control and Hospital Epidemiology 29:5, 472-474
CrossRef50
Rungrueng Kitphati, Anucha Apisarnthanarak, Malinee Chittaganpitch, Pranee Tawatsupha, Wattana Auwanit, Pilaipan Puthavathana, Prasert Auewarakul, Mongkol Uiprasertkul, Linda M. Mundy, Pathom Sawanpanyalert. (2008) A Nationally Coordinated Laboratory System for Human Avian Influenza A (H5N1) in Thailand: Program Design, Analysis, and Evaluation. Clinical Infectious Diseases 46:9, 1394-1400
CrossRef51
Joan L. Robinson, Bonita E. Lee, Sushma Kothapalli, William R. Craig, Julie D. Fox. (2008) Use of Throat Swab or Saliva Specimens for Detection of Respiratory Viruses in Children. Clinical Infectious Diseases 46:7, e61-e64
CrossRef52
Andrea Gambotto, Simon M Barratt-Boyes, Menno D de Jong, Gabriele Neumann, Yoshihiro Kawaoka. (2008) Human infection with highly pathogenic H5N1 influenza virus. The Lancet 371:9622, 1464-1475
CrossRef53
Prasert Auewarakul, Arunee Thitithanyanont, Anucha Apisarnthanarak, Pokrath Hansasuta, Porntippa Lekcharoensuk, Pilaipan Puthvathana. (2008) Bangkok International Conference on Avian Influenza 2008. Expert Review of Vaccines 7:3, 293-298
CrossRef54
Nguyen Tran Hien, Jeremy Farrar, Peter Horby. (2008) Person-to-person transmission of influenza A (H5N1). The Lancet 371:9622, 1392-1394
CrossRef55
Hua Wang, Zijian Feng, Yuelong Shu, Hongjie Yu, Lei Zhou, Rongqiang Zu, Yang Huai, Jie Dong, Changjun Bao, Leying Wen, Hong Wang, Peng Yang, Wei Zhao, Libo Dong, Minghao Zhou, Qiaohong Liao, Haitao Yang, Min Wang, Xiaojun Lu, Zhiyang Shi, Wei Wang, Ling Gu, Fengcai Zhu, Qun Li, Weidong Yin, Weizhong Yang, Dexin Li, Timothy M Uyeki, Yu Wang. (2008) Probable limited person-to-person transmission of highly pathogenic avian influenza A (H5N1) virus in China. The Lancet 371:9622, 1427-1434
CrossRef56
Arnold S. Monto, Richard J. Whitley. (2008) Seasonal and Pandemic Influenza: A 2007 Update on Challenges and Solutions. Clinical Infectious Diseases 46:7, 1024-1031
CrossRef57
Timothy M. UYEKI. (2008) Global epidemiology of human infections with highly pathogenic avian influenza A (H5N1) viruses. Respirology 13:s1, S2-S9
CrossRef58
David S.-C. HUI. (2008) Review of clinical symptoms and spectrum in humans with influenza A/H5N1 infection. Respirology 13:s1, S10-S13
CrossRef59
Marie-Anne Rameix-Welti, Sylvie van der Werf, Nadia Naffakh. (2008) Sensitivity of H5N1 influenza viruses to oseltamivir: an update. Future Virology 3:2, 157-165
CrossRef60
John M. NICHOLLS, J.S. Malik PEIRIS. (2008) Avian influenza: Update on pathogenesis and laboratory diagnosis. Respirology 13:s1, S14-S18
CrossRef61
David S.C. HUI. (2008) Influenza A/H5N1 infection: Other treatment options and issues. Respirology 13:s1, S22-S26
CrossRef62
M. Gottfredsson, B. V. Halldorsson, S. Jonsson, M. Kristjansson, K. Kristjansson, K. G. Kristinsson, A. Love, T. Blondal, C. Viboud, S. Thorvaldsson, A. Helgason, J. R. Gulcher, K. Stefansson, I. Jonsdottir. (2008) From the Cover: Lessons from the past: Familial aggregation analysis of fatal pandemic influenza (Spanish flu) in Iceland in 1918. Proceedings of the National Academy of Sciences 105:4, 1303-1308
CrossRef63
Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus. (2008) Update on Avian Influenza A (H5N1) Virus Infection in Humans. New England Journal of Medicine 358:3, 261-273
Full Text64
A. Kumar. (2008) Three Indonesian Clusters of H5N1 Virus Infection in 2005. Yearbook of Critical Care Medicine 2008, 144-145
CrossRef65
M A Hoelscher, L Jayashankar, S Garg, V Veguilla, X Lu, N Singh, J M Katz, S K Mittal, S Sambhara. (2007) New Pre-pandemic Influenza Vaccines: An Egg- and Adjuvant-independent Human Adenoviral Vector Strategy Induces Long-lasting Protective Immune Responses in Mice. Clinical Pharmacology & Therapeutics 82:6, 665-671
CrossRef66
G C Gray, W S Baker. (2007) The Importance of Including Swine and Poultry Workers in Influenza Vaccination Programs. Clinical Pharmacology & Therapeutics 82:6, 638-641
CrossRef67
Jessica A. Belser, Xiuhua Lu, Kristy J. Szretter, Xiaoping Jin, Laura M. Aschenbrenner, Alice Lee, Stephen Hawley, Do Hyong Kim, Michael P. Malakhov, Mang Yu, Fang Fang, Jacqueline M. Katz. (2007) DAS181, A Novel Sialidase Fusion Protein, Protects Mice from Lethal Avian Influenza H5N1 Virus Infection. The Journal of Infectious Diseases 196:10, 1493-1499
CrossRef68
A. Apisarnthanarak, D. K. Warren, V. J. Fraser. (2007) Issues Relevant to the Adoption and Modification of Hospital Infection-Control Recommendations for Avian Influenza (H5N1 Infection) in Developing Countries. Clinical Infectious Diseases 45:10, 1338-1342
CrossRef69
Gary T. Brice, Steven J. Drews, Donald E. Low. (2007) Respiratory virus panels for global surveillance of emerging infectious diseases. Journal of Clinical Virology 40, S58-S60
CrossRef70
X.-F. Wan, G. Chen, F. Luo, M. Emch, R. Donis. (2007) A quantitative genotype algorithm reflecting H5N1 Avian influenza niches. Bioinformatics 23:18, 2368-2375
CrossRef71
X. Chen, G.J.D. Smith, B. Zhou, C. Qiu, W.L. Wu, Y. Li, P. Lu, L. Duan, S. Liu, J. Yuan, G. Yang, H. Wang, J. Cheng, H. Jiang, J.S.M. Peiris, H. Chen, K.Y. Yuen, N. Zhong, Y. Guan. (2007) Avian influenza A (H5N1) infection in a patient in China, 2006. Influenza and Other Respiratory Viruses 1:5-6, 207-213
CrossRef72
Jindrich Cinatl, Martin Michaelis, Hans W. Doerr. (2007) The threat of avian influenza a (H5N1): part II: Clues to pathogenicity and pathology. Medical Microbiology and Immunology 196:4, 191-201
CrossRef73
Jindrich Cinatl, Martin Michaelis, Hans W. Doerr. (2007) The threat of avian influenza A (H5N1). Part I: epidemiologic concerns and virulence determinants. Medical Microbiology and Immunology 196:4, 181-190
CrossRef74
Suryaprakash Sambhara, Carolyn B Bridges, Gregory A Poland. (2007) H5N1 vaccine hits the target, but not the bull's eye. The Lancet Infectious Diseases 7:8, 503-505
CrossRef75
(2007) Expert consultation on diagnosis of H5N1 avian influenza infections in humans. Influenza and Other Respiratory Viruses 1:4, 131-138
CrossRef76
Philippe Buchy, Sek Mardy, Sirenda Vong, Tetsuya Toyoda, Jean-Thierry Aubin, Megge Miller, Sok Touch, Ly Sovann, Jean-Baptiste Dufourcq, Beat Richner, Phan Van Tu, Nguyen Thi Kim Tien, Wilina Lim, J.S. Malik Peiris, Sylvie Van der Werf. (2007) Influenza A/H5N1 virus infection in humans in Cambodia. Journal of Clinical Virology 39:3, 164-168
CrossRef77
Jonathan S. Nguyen-Van-Tam, Chloe Sellwood. (2007) Avian influenza and the threat of the next human pandemic. Journal of Hospital Infection 65, 10-13
CrossRef78
Gabriele A. Landolt, Christopher W. Olsen. (2007) Up to new tricks – A review of cross-species transmission of influenza A viruses. Animal Health Research Reviews 8:01, 1
CrossRef79
Gregory C. Gray, Darrell W. Trampel, James A. Roth. (2007) Pandemic influenza planning: Shouldn’t swine and poultry workers be included?. Vaccine 25:22, 4376-4381
CrossRef80
(2007) Human H5N1 Influenza. New England Journal of Medicine 356:13, 1375-1377
Full Text81
Lars R. Haaheim. (2007) Vaccines for an influenza pandemic: scientific and political challenges. Influenza and Other Respiratory Viruses 1:2, 55-60
CrossRef82
D.R. Snydman. (2007) Three Indonesian Clusters of H5N1 Virus Infection in 2005. Yearbook of Medicine 2007, 55-56
CrossRef83
Oner, Ahmet Faik, Bay, Ali, Arslan, Sukru, Akdeniz, Hayrettin, Sahin, Huseyin Avni, Cesur, Yasar, Epcacan, Serdar, Yilmaz, Neziha, Deger, Ibrahim, Kizilyildiz, Baran, Karsen, Hasan, Ceyhan, Mehmet, . (2006) Avian Influenza A (H5N1) Infection in Eastern Turkey in 2006. New England Journal of Medicine 355:21, 2179-2185
Full Text84
Webster, Robert G., Govorkova, Elena A., . (2006) H5N1 Influenza — Continuing Evolution and Spread. New England Journal of Medicine 355:21, 2174-2177
Full Text
- Letters
