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Avian Influenza A (H5N1) Penyebaran Pada Manusia

The Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5 N Engl J Med 2005; 353:1374-1385September 29, 2005

ABSTRACT Avian influenza A (H5N1), or highly pathogenic avian influenza (HPAI), has become the worlds attention because of possibility of global pandemic. This review describes the features of human infection, pathogenesis, transmission, and clinical management of avian influenza A (H5N1). Key word : H5N1, avian influenza, pathogenesis.

PENDAHULUAN
The H5N1 HPAI virus (A/Whooper Swan/Mongolia/244/05 [H5N1]; Mongolia/05) used in this study was obtained from the Southeast Poultry Research Laboratory (SEPRL), Agricultural Research Service (ARS), US Department of Agriculture (USDA), Athens, Georgia, USA. This virus was originally isolated from a dead whooper swan (Cygnus cygnus) in Mongolia during a 2005 outbreak of H5N1 HPAI virus in waterfowl (OIE Disease Information, 2005; Brown et al., 2006). The Mongolia/05 strain is in the Goose/Guandong/96 lineage and, phylogenetically, is included in clade 2 (World Health Organization Global Influenza Program Surveillance Network, 2005). Mongolia/05 was selected for use in this study because it is representative of the H5N1 HPAI viruses that have been reported from wild birds in Asia, Europe, and Africa (Brown et al., 2006).

Dalam beberapa tahun terakhir ini perhatian dunia kesehatan terpusat kepada semakin merebaknya penularan avian influenza A (H5N1). Meningkatnya kasus infeksi H5N1 yang menyebabkan kematian pada manusia sangat dihawatirkan dapat berkembang menjadi wabah pandemi yang berbahaya bagi umat manusia di muka bumi ini. Sejak lebih dari satu abad yang lalu, beberapa subtipe dari virus influenza A telah menghantui manusia. Berbagai variasi mutasi subtipe virus influenza A yang menyerang manusia dan telah menyebabkan pandemi sehingga tidak mengherankan jika kewaspadaan global terhadap wabah pandemi flu burung mendapatkan perhatian yang serius. Diawali pada tahun 1918 dunia dikejutkan oleh wabah pandemi yang disebabkan virus influenza, yang telah membunuh lebih dari 40.000 orang, dimana subtipe yang mewabah saat itu adalah virus H1N1 yang dikenal dengan Spanish Flu. Tahun 1957 kembali dunia dilanda wabah global yang disebabkan oleh kerabat dekat virus yang bermutasi menjadi H2N2 atau yang dikenal dengan Asian Flu yang telah merenggut 100.000 jiwa meninggal. Pada tahun 1968, virus flu kembali menyebabkan wabah pandemi dengan merubah dirinya menjadi H3N2. Mutan virus yang dikenal dengan Hongkong Flu ini telah menyebabkan 700.00 orang meninggal dunia. Saat ini dunia kembali dikagetkan dengan merebaknya avian influenza H5N1 yang pertama kali menyerang dan menewaskan 6 orang penduduk Hongkong pada tahun 1997 dari 18 orang yang terinfeksi (Horimoto T, Kawaoka Y. 2001).

Tahun 2003 sebanyak 83 orang terinfeksi dengan subtipe virus lainnya yaitu H7N7, dan H9N2. Tahun 2004, subtipe H5N1 dan H7N2 telah menginfeksi puluhan penduduk Vietman, Thailand, dan Kanada. Virus H5N1 lebih patogen daripada subtype lainnya sehingga disebut dengan Highly Pathogenic H5N1 Avian Influenza (HPAI). Sampai dengan akhir bulan Agustus 2006, telah dilaporkan sebanyak 241 kasus infeksi dan 141 diantaranya telah meninggal dunia. Dalam Tabel 1, terlihat bahwa telah terjadi kecenderungan yang meningkat baik angka kesakitan ataupun angka kematian manusia yang terkena nfeksi virus H5N1. Sejak tahun 2003 telah terjadi penyebaran yang semakin luas dari HPAI-H5N1 ke beberapa negara lain, dengan angka kematian yang cukup tinggi (WHO, 2006). Berdasarkan hasil kajian secara genomik, dikenal beberapa subtipe dari avian influenza, namun demikian selama 6 tahun terakhir hanya subtipe H5, H7 dan H9 yang diketahui mampu menyebar dari unggas ke manusia (Liu J.,et.al. 2005). Selama tahun 2003-2004 telah teridentifikasi dua jenis genotipe baru dari HPAI yang telah menyebabkan wabah di Thailand, Cambodia, Vietnam, Laos, Korea, Japan, China dan Malaysia. Virus HPAIH5N1 yang diisolasi dari beberapa korban yang meninggal di Vietnam menunjukkan bahwa virus tersebut patotelah resisten terhadap amantadine dan rimantadine (Horimoto & Kawaoka, 2005).

PATOGENESIS Mutasi genetik virus avian influenza seringkali terjadi sesuai dengan kondisi dan lingkungan replikasinya. Mutasi gen ini tidak saja untuk mempertahankan diri akan tetapi juga dapat meningkatkan sifat patogenisitasnya Penelitian terhadap virus H5N1 yang diisolasi dari pasien yang terinfeksi pada tahun 1997, menunjukkan bahwa mutasi genetik pada posisi 627 dari gen PB2 yang mengkode ekspresi polymesase basic protein (Glu627Lys) telah menghasilkan highly cleavable hemagglutinin glycoprotein yang merupakan faktor virulensi yang dapat meningkatkan aktivitas replikasi virus H5N1 dalam sel hospesnya (Hatta M, et. al. 2001). Disamping itu adanya substitusi pada nonstructural protein (Asp92Glu), menyebabkan H5N1 resisten terhadap interferon dan tumor necrosis factor (TNF-) secara invitro (Seo SH, et.al. 2002). Infeksi virus H5N1 dimulai ketika virus memasuki sel hospes setelah terjadi penempelan spikes virion dengan reseptor spesifik yang ada di permukaan sel hospesnya. Virion akan menyusup ke sitoplasma sel dan akan mengintegrasikan materi genetiknya di dalam inti sel hospesnya, dan dengan menggunakan mesin genetik dari sel hospesnya, virus dapat bereplikasi membentuk virion-virion baru, dan virion-virion ini dapat menginfeksi kembali sel-sel disekitarnya. Dari beberapa hasil pemeriksaan terhadap spesimen klinik yang diambil dari penderita ternyata avian influenza H5N1 dapat bereplikasi di dalam sel nasofaring (Peiris JS,et.al. 2004), dan di dalam sel gastrointestinal (de Jong MD, 2005, Uiprasertkul M,et.al. 2005). Virus H5N1 juga dapat dideteksi di dalam darah, cairan serebrospinal, dan tinja pasien (WHO,2005). Fase penempelan (attachment) adalah fase yang paling menentukan apakah virus bisa masuk atau tidak ke dalam sel hospesnya untuk melanjutkan replikasinya. Virus influenza A melalui spikes hemaglutinin (HA) akan berikatan dengan reseptor yang mengandung sialic acid (SA) yang ada pada permukaan sel hospesnya. Ada perbedaan penting antara molekul reseptor yang ada pada manusia dengan reseptor yang ada pada unggas atau binatang. Pada virus flu burung, mereka dapat mengenali dan terikat pada

reseptor yang hanya terdapat pada jenis unggas yang terdiri dari oligosakharida yang mengandung N-acethylneuraminic acid -2,3-galactose (SA -2,3- Gal), dimana molekul ini berbeda dengan reseptor yang ada pada manusia. Reseptor yang ada pada permukaan sel manusia adalah SA - 2,6-galactose (SA -2,6-Gal), sehingga secara teoritis virus flu burung tidak bisa menginfeksi manusia karena perbedaan reseptor spesifiknya. Namun demikian, dengan perubahan hanya 1 asam amino saja konfigurasi reseptor tersebut dapat dirubah sehingga reseptor pada manusia dikenali oleh HPAI-H5N1. Potensi virus H5N1 untuk melakukan mutasi inilah yang dikhawatirkan sehingga virus dapat membuat varian-varian baru dari HPAI-H5N1 yang dapat menular antar manusia ke manusia (Russel CJ and Webster RG.2005, Stevens J. et. al. 2006).

PENULARAN AVIAN INFUENZA A ( H5N1)


Ada dua kemungkinan yang dapat menghasilkan subtipe baru dari H5N1 yang dapat menular antara manusia ke manusia adalah : (i). Virus dapat menginfeksi manusia dan mengalami mutasi sehingga virus tersebut dapat beradaptasi untuk mengenali linkage RNA pada manusia, atau virus burung tersebut mendapatkan gen dari virus influenza manusia sehingga dapat bereplikasi secara efektif di dalam sel manusia. Subtipe baru virus H5N1 ini bermutasi sedemikian rupa untuk membuat protein tertentu yang dapat mengenali reseptor yang ada pada manusia, untuk jalan masuknya ke dalam sel manusia, atau (ii). kedua jenis virus, baik virus avian maupun human influenza tersebut dapat secara bersamaan menginfeksi manusia, sehingga terjadi mix atau rekombinasi genetik, sehingga menghasilkan strain virus baru yang sangat virulen bagi manusia (Herman RA & Strorck M. 2005). Walaupun perkiraan fase dimana penularan antar manusia ini masih belum dapat diketahui, akan tetapi pencegahan transmisi antar manusia ini perlu mendapatkan perhatian yang serius mengingat bahwa telah dilaporkan bahwa seorang perawat di Vietman telah menderita penyakit serius setelah dia menangani pasien yang terinfeksi dengan virus H5N1. Dalam salah satu penelitian ditemukan bahwa mutasi dari H5N1 kemungkinan besar dapat menghasilkan varian virus H5N1 baru yang dapat mengenali reseptor spesifik yang ada pada sel manusia (natural human2-6 glycan), sehingga bila ini terjadi maka penularan virus H5N1 dari manusia ke manusia dapat terjadi dengan mudah (Stevens J. et.al. 2006).

PCR (Polymerase chain reaction) Pada H5N1 Ekstrak asam ribonukleat yang diperkuat dengan menggunakan 1-langkah nyata-time PCR kit (Qiagen, Valencia, CA) untuk deteksi avian influenza A virus penargetan gen matriks menggunakan primer dan probe digambarkan oleh Spackman et al. (2002): maju primer 5'GTC TTC AGA TGA TAA CCG Agg TCG-3 ', primer 5'-TGC terbalik AAC AAA ATC TTC CTG TCT AAG-3', dan probe 5'-FAM-GGC CCC TCA AAA CTC GCC GA-Tamra-3 '. Tes ini dilakukan di mesin MX3005P Stratagen real-time PCR (La Jolla, CA) dengan menggunakan Laboratorium Badan Hewan (Inggris) protokol yang dijelaskan sebelumnya (Aly et al., 2008). Deteksi H5 dan N1 segmen gen dilakukan oleh AIV Waktu Nyata H5N1 RT-PCR Kit (Roche) sesuai dengan petunjuk produsen menggunakan mesin 2.0 LightCycler (Roche).

PENGOBATAN DAN PENCEGAHAN AVIAN INFLUENZA A (H5N1)

terdapat 4 jenis obat antiviral untuk pengobatan ataupun pencegahan terhadap influenza, yaitu amantadine, rimantadine, zanamivir, dan oseltamivir (tamiflu). Mekanisme kerja amantadine dan rimantadine adalah menghambat replikasi virus. Namun demikian kedua obat ini sudah tidak mempan lagi untuk membunuh virus H5N1 yang saat ini beredar luas (Beigel JH, et.al.2005). Sedangkan zanamivir dan oseltamivir merupakan inhibitor neuraminidase. Sebagaimana kita ketahui bahwa neuraminidase ini diperlukan oleh virus H5N1 untuk lepas dari sel hospes pada fase budding sehingga membentuk virion yang infektif. Bila neuraminidase ini dihambat oleh oseltamivir atau zanamivir, maka replikasi virus tersebut dapat dihentikan. Namun demikian belum ada uji klinik pada manusia yang secara resmi dilakukan untuk mengevaluasi efektifitas dari zanamivir dan oseltamivir untuk pengobatan avian influenza A (H5N1) (Herman RA & Strorck M. 2005). Secara in vitro memang telah diketahui bahwa virus H5N1 sensitif terhadap oseltamivir dan zanamivir, oleh sebab itu dianjurkan bagi penderita yang diduga terinfeksi virus H5N1 dapat diberikan obat oseltamivir atau zanamivir (Leneva IA,et.al.2000, Govorkova EA.et.al. 2001). Namun belakangan ini telah ditemukan bahwa Virus H5N1 yang diisolasi beberapa kasus penderita flu burung telah resisten terhadap oseltamivir (WHO,2005, Gupta, R. K, et.al.2006). Beberapa obat lain sedang diteliti untuk dapat digunakan sebagai penghambat virus H5N1 antara lain adalah peramivir, long-acting topical neuroamidase inhibitor, ribavirin, dan interferon alfa. Disamping pemberian obat antiviral, terapi supportif di dalam perawatan di rumah sakit sangat penting untuk dilaksanakan. Sebagian besar penderita memerlukan oksigenasi, dan pemberian cairan parenteral (infus). Obat lain yang dapat diberikan adalah antibiotika berspektrum luas dan juga kortikosteroid (Beigel JH, et al. 2005). Sampai saat ini belum ada vaksin yang tersedia untuk mencegah manusia terhadap infeksi H5N1. Berbagai upaya pengembangan vaksin H5N1 untuk manusia telah dan sedang dilakukan. The National Institute of Allergy and Infectious Diseases USA (NIAID), menyatakan bahwa uji keamanan terhadap vaksin baru H5N1 telah dilakukan sejak awal tahun 2005. Beberapa perusahaan farmasi antara lain Sanofi Pasteur dan Chiron sedang mengembangkan kandidat vaksin yang akan melakukan uji klinik fase I bekerjasama dengan NIAID. Beberapa negara lain yang juga tengah mengembangkan vaksin H5N1 antara lain adalah Jepang, China, Hongaria, dll. (WHO, 2005). Sebagai upaya pencegahan, WHO merekomendasikan untuk orang-orang yang mempunyai risiko tinggi kontak dengan unggas atau orang yang terinfeksi, dapat diberikan terapi profilaksis dengan 75 mg oseltamivir sekali sehari, selama 7 sampai 10 hari. Beberapa hal yang patut diperhatikan untuk mencegah semakin meluasnya infeksi H5N1 pada manusia adalah dengan menjaga kebersihan lingkungan, menjaga kebersihan diri, gunakan penutup hidung dan sarung tangan apabila memasuki daerah yang telah terjangkiti atau sedang terjangkit virus flu burung, dan amati dengan teliti kesehatan kita apabila telah melaku kan kontak dengan unggas/burung. Segeralah cari perhatian medis apabila timbul gejala-gejala demam, infeksi mata, dan/atau ada gangguan pernafasan.

Clinical and laboratory features distinguishing pandemic H1N1 influenza-related pneumonia from interpandemic communityacquired pneumonia in adults

Abstract
Background Early identification of patients with H1N1 influenza-related pneumonia is desirable for the early instigation of antiviral agents. A study was undertaken to investigate whether adults admitted to hospital with H1N1 influenza-related pneumonia could be distinguished clinically from patients with non-H1N1 community-acquired pneumonia (CAP). Methods Between May 2009 and January 2010, clinical and epidemiological data of patients with confirmed H1N1 influenza infection admitted to 75 hospitals in the UK were collected by the Influenza Clinical Information Network (FLU-CIN). Adults with H1N1 influenzarelated pneumonia were identified and compared with a prospective study cohort of adults with CAP hospitalised between September 2008 and June 2010, excluding those admitted during the period of the pandemic. Results Of 1046 adults with confirmed H1N1 influenza infection in the FLU-CIN cohort, 254 (25%) had H1N1 influenza-related pneumonia on admission to hospital. In-hospital mortality of these patients was 11.4% compared with 14.0% in patients with inter-pandemic CAP (n=648). A multivariate logistic regression model was generated by assigning one point for each of five clinical criteria: age 65 years, mental orientation, temperature 38C, leucocyte count 12109/l and bilateral radiographic consolidation. A score of 4 or 5 predicted H1N1 influenza-related pneumonia with a positive likelihood ratio of 9.0. A score of 0 or 1 had a positive likelihood ratio of 75.7 for excluding it. Conclusion There are substantial clinical differences between H1N1 influenza-related pneumonia and inter-pandemic CAP. A model based on five simple clinical criteria enables the early identification of adults admitted with H1N1 influenza-related pneumonia.

Introduction
In March 2009 the first cases of a novel strain of influenza A virus of swine origin were reported in Mexico1 and, within 3 months, global spread led to declaration of a pandemic by the World Health Organization (WHO). While most cases of pandemic influenza H1N1 infection have been mild or subclinical,24 some patients experienced severe illness from H1N1 influenza infection and others severe influenza-related complications.5 6 Pneumonia is one of the commonest and most important complications of influenza infection. Influenza virus causes primary viral pneumonia, and secondary bacterial infections are also recognised.7 8 In contemporary cohorts of patients admitted with inter-pandemic community acquired pneumonia (CAP), influenza is frequently found as a co-pathogen alongside other respiratory pathogens such as Streptococcus pneumoniae.912 Studies of the 191819 influenza pandemic have suggested that the majority of influenza-related deaths during that

period were caused by secondary bacterial pneumonia.13 More recently, in hospitalised patients with confirmed H1N1 influenza infection, radiological evidence of pneumonia was observed in 1866% of patients.1417 In addition, although not necessarily the cause of death, pneumonia was found in the majority of fatal cases at post-mortem examination.18 19 Overall, fewer than 30% of H1N1 influenza-related pneumonia cases have evidence of bacterial co-infection,2022 suggesting that primary viral pneumonia is often important. Early identification of patients with H1N1 influenza-related pneumonia may enable the early administration of antiviral agents with possible improved outcomes.23 However, there are few data relating to the clinical differentiation of H1N1 influenza-related pneumonia from inter-pandemic CAP. The aims of the current study were (1) to compare and contrast the clinical features of adult patients admitted with CAP versus H1N1 influenza-related pneumonia and (2) to develop a model that identifies H1N1 influenza-related pneumonia using simple clinical criteria.

Methods
Study patients H1N1 influenza-related pneumonia cohort (H1N1 cohort)

Between May 2009 and January 2010, the Influenza Clinical Information Network (FLUCIN) collected clinical and epidemiological data on patients admitted to UK hospitals with confirmed H1N1 influenza infection. Seventy-five hospitals in 31 cities or towns were included. The details of data collection and the overall findings from the first wave of the 2009 pandemic have been described elsewhere.24 H1N1 influenza infection was diagnosed by a positive polymerase chain reaction (PCR) result from respiratory samples obtained via a nasopharyngeal swab or bronchoalveolar lavage performed during the admission episode. Data collected included demography, clinical observations, clinical course, laboratory and radiological test results and outcome. The current study cohort comprised adults (aged 16 years) whose admission chest x-rays met one of the following criteria: 1. Chest x-ray report clearly suggestive of pneumonia.25 2. Chest x-ray report showed acute infiltrates but no consolidation. 3. No chest x-ray report available but x-ray documented in the clinical notes as being in keeping with pneumonia (n=24). Patients who had acquired H1N1 influenza infection while in hospital or had been transferred to a study site from another hospital (eg, for extracorporeal membrane oxygenation therapy) were excluded.
Non-H1N1 influenza CAP cohort (CAP cohort)

Between September 2008 and June 2010, consecutive adult patients (aged 16 years) admitted to a large UK teaching hospital trust (Nottingham University Hospitals NHS trust) with CAP were prospectively recruited as part of a population-based observational cohort study. Patients were included if they had at least one acute symptom in keeping with a lower respiratory tract infection (breathlessness, cough, sputum production or fever), had new infiltrates on a chest x-ray and were treated by the admitting team for CAP. Patients were excluded if they had been admitted to hospital in the preceding 10 days, had tuberculosis, or

had post-obstructive pneumonia due to lung cancer. Participants were identified by study investigators on a daily basis from the acute admitting medical wards and enrolled following informed consent. All patients were managed in a similar manner according to trust CAP guidelines at the discretion of the attending clinician. For the purposes of this analysis and to ensure inclusion of only cases without H1N1 influenza infection, participants were excluded if admitted during the period of H1N1 influenza circulation in Nottingham (between 30 April 2009 and 10 February 2010this interval comprising all cases of H1N1 influenza infection in the Nottingham area based on local Health Protection Agency data (unpublished)).
Statistical methods

Data were analysed using SPSS Version 16.0. Continuously distributed variables were compared between H1N1 and CAP cohorts using the Student's t test if data were normally distributed and the MannWhitney U test if non-normally distributed. Categorical data were compared using Pearson 2. In order to derive a clinical diagnostic model for H1N1 influenza-related pneumonia, continuously distributed variables were re-categorised into binary variables based on thresholds derived from established acute severity scores (CURB65 score,26 Pneumonia Severity Index,27 Surviving Sepsis Campaign28) and univariate analysis using 2 allowed calculation of odds ratios with 95% confidence intervals. Variables for inclusion in the final model were selected using automatic stepwise regression with both forwards (selection) and backwards (deletion) variants. The efficacy of the model for predicting H1N1 influenza-related pneumonia was then assessed by calculating the area under the curve (AUC) of the receiver-operating characteristic (ROC) curve.

Results
Patient characteristics

Of 1046 adults with confirmed H1N1 influenza infection in the FLU-CIN cohort, 266 (25.4%) had evidence of either radiographic consolidation or other infiltrates consistent with acute infection. Twelve patients were transferred in from hospitals outside the study area or developed influenza infection while already an inpatient, leaving a study cohort of 254 patients (H1N1 cohort). The comparator group comprised 648 patients with inter-pandemic CAP (CAP cohort). The patient characteristics are summarised in table 1 and the relative age distribution of both cohorts is shown in figure 1. Despite having similar in-hospital mortality (H1N1 cohort 11.4%; CAP cohort 14.0%), the two groups differed substantially. The median age of patients in the H1N1 cohort was 42 years compared with 75 years in the CAP cohort (p<0.001). The most common comorbid illnesses in the H1N1 cohort were asthma (25.2%) and diabetes mellitus (9.8%) compared with chronic obstructive pulmonary disease (COPD) (26.1%) and diabetes mellitus (15.4%) in the CAP cohort. In the H1N1 cohort, 9.4% of patients had 3 comorbid illnesses compared with 11.9% of controls. In addition, patients in the H1N1 cohort were more likely to be febrile, tachycardic, have bilateral radiographic abnormalities and have lower leucocyte counts and levels of C-reactive protein. Confusion, comorbidity and blood urea levels were higher among patients in the CAP cohort. Within the H1N1 cohort, 11 (4.3%) were pregnant and 21 (8.3%) were obese. The value of the CURB65 score in predicting inpatient mortality was assessed by calculating the AUC for ROC curves for each group; the AUC for the H1N1 cohort was 0.650 compared with 0.741 for the CAP cohort.

References
1. www.highwire.standforduniversity.edu 2. www.nejm.org 3. Center for Disease Control (CDC). Outbreak of swine-origin influenza A(H1N1) virus infection Mexico, MarchApril 2009. MMWR Morb Mortal Wkly Rep 2009;58:467 70. [Medline] 4. 1. Gilsdorf A, 2. Poggensee G , on behalf of the working group pandemic influenza A(H1N1)v. Influenza A(H1N1)v in Germany: the first 10,000 cases. Euro Surveill. 2009:14(34)14. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19318. 5. 1. 2. 3. 4. 5. Dawood FS, Jain S, Finelli L, et al., Novel Swine-Origin Influenza A(H1N1) Investigation Team

. Emergence of a novel swine-origin influenza A(H1N1) virus in humans. N Engl J Med 2009;360:260515. [CrossRef][Medline] 6. 1. 2. 3. 4. Miller E, Hoschler K, Hardelid P, et al

. Incidence of 2009 pandemic influenza A H1N1 infection in England: a crosssectional serological study. Lancet 2010;375:11008. [CrossRef][Medline][Web of Science] 7. 1. Webb SAR, 2. Pettil V, 3. et al

ANZIC Influenza InvestigatorsWebb SAR, Pettil V, et al. Critical care services and 2009 H1N1 influenza in Australia and New Zealand. N Engl J Med 2009;361:1925 34. [CrossRef][Medline] 8. 1. 2. 3. 4. Kumar A, Zarychanski R, Pinto R, et al

. Critically ill patients with 2009 influenza A(H1N1) infection in Canada. JAMA 2009;302:18729. [Abstract/FREE Full text] 9. 1. Rothberg MB, 2. Haessler SD, 3. Brown RB . Complications of viral influenza. Am J Med 2008;121:25864. [CrossRef][Medline][Web of Science] 10. 1. Klugman KP, 2. Chien YW, 3. Madhi SA . Pneumococcal pneumonia and influenza: a deadly combination. Vaccine 2009;27(Suppl 3):C914. [CrossRef][Medline][Web of Science] 11. 1. 2. 3. 4. Templeton KE, Scheltinga SA, van den Eeden WCJFM, et al

. Improved diagnosis of the etiology of community-acquired pneumonia with real-time polymerase chain reaction. Clin Infect Dis 2005;41:34551.

Immunization-Safety Monitoring Systems for the 2009 H1N1 Monovalent Influenza Vaccination Program
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Abstract
The effort to vaccinate the US population against the 2009 H1N1 influenza virus hinged, in part, on public confidence in vaccine safety. Early in the vaccine program, >20% of parents reported that they would not vaccinate their children. Concerns about the safety of the vaccines were reported by many parents as a factor that contributed to their intention to forgo vaccination (see www.hsph.harvard.edu/news/press-releases/2009-releases/survey-40-adultsabsolutely-certain-h1n1-vaccine.html and www.med.umich.edu/mott/npch/reports/h1n1.htm). The safety profiles of 2009 H1N1 monovalent influenza vaccines were anticipated to be (and have been) similar to those of seasonal influenza vaccines, for which an excellent safety profile has been demonstrated. Here we describe steps taken by the US government to (1) assess the key federal systems in place before 2009 for monitoring the safety of vaccines and (2) integrate and upgrade those systems for optimal vaccine-safety monitoring during the 2009 H1N1 monovalent influenza vaccination program. These efforts improved monitoring of 2009 H1N1 vaccine safety, hold promise for enhancing future national monitoring of vaccine safety, and may ultimately help improve public confidence in vaccines.
Key Words:

vaccine safety H1N1 influenza

Central to the federal response to the 2009 H1N1 influenza pandemic was a vaccination program unprecedented in its size and scope in the United States. The 2009 H1N1 monovalent influenza vaccines were approved by the US Food and Drug Administration (FDA) of the US Department of Health and Human Services (HHS) as a strain change to each manufacturer's seasonal influenza vaccine. There is considerable experience with seasonal influenza vaccine development and production. Influenza vaccines have a long track record of safety and effectiveness in the United States. The 2009 H1N1 monovalent influenza vaccines underwent the same testing and lot-release procedures that are in place for seasonal influenza vaccines. Consequently, the safety profiles of 2009 H1N1 monovalent influenza vaccines were anticipated to be similar to the excellent safety profile of seasonal influenza vaccines. In addition, the safety of the 2009 H1N1 monovalent influenza vaccines was carefully assessed in multiple clinical trials. The sample sizes of these trials limited the ability to detect rare adverse events. Populations at high risk, such as those with chronic diseases, are sometimes not well represented in clinical studies; however, additional efforts were made for 2009 H1N1 monovalent influenza vaccines to include in clinical trials pregnant women and people with underlying illness such as asthma and HIV infection. A key component of any immunization program is postlicensure safety monitoring.1 Such a monitoring system must have the ability to quickly identify and characterize adverse events after vaccination. A vaccine-safety monitoring system should have the capacity to distinguish a potential increased risk of an adverse event caused by the vaccine from events that occur as

part of the background incidence of these diseases in temporal association with vaccination.1 Broad and integrated efforts that monitor vaccine safety after licensure are important for rapidly and effectively defining the safety profile of a vaccine. The vaccine-safety monitoring process includes 3 primary activities: 1. Signal detection, strengthening, and verification involve detection of medical events after vaccination and an evaluation of whether these adverse events could be occurring more frequently after vaccination than expected by chance alone. For this activity, potential signals are evaluated to assess whether they warrant further investigation. This evaluation includes examining if the reported events were well defined and properly coded, if the events were reported from multiple reporting sources or only by a few, or if there was a pattern of association between vaccination and adverse events (eg, temporal or demographic relationships or subpopulations affected). Efforts are also made to look for unexpected clinical clusters and positive rechallenges (symptoms that reoccur after readministration of vaccine). 2. Assessment of association involves evaluating whether there is an association between vaccination and an adverse event. If an association between the vaccine and the outcome is found, it is important to determine the magnitude of the association and whether potential subpopulations are at increased risk. 3. Assessment of the evidence and causality involves evaluating whether the available science favors acceptance or rejection of a relationship between the vaccine and the adverse event, which often requires population-based active surveillance and formal epidemiologic studies. Causality assessments typically include consideration of the strength or magnitude of the association, consistency, specificity, temporality, biological gradient, biological mechanism, coherence, experimental evidence, and analogy.2 Before the initiation of the 2009 H1N1 monovalent influenza vaccination program, a number of existing systems addressed these 3 activities of the safety monitoring system. The HHS led an effort to enhance existing systems and integrate new vaccine-safety monitoring systems. These efforts were deemed to be integral to the immunization program given its size and prominence and residual concerns about the 1976 pandemic influenza vaccination program in which the vaccine was associated with Guillain-Barr syndrome (GBS). In this article, we discuss the existing systems for monitoring vaccine safety and enhancements that were made to support the 2009 H1N1 influenza vaccination program.
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FEDERAL SYSTEMS FOR MONITORING VACCINE SAFETY BEFORE THE 2009 H1N1 MONOVALENT INFLUENZA VACCINES
The US vaccine-safety system is composed of a number of programs managed by federal agencies within the HHS, the Department of Veterans Affairs (VA), and the Department of Defense (DoD). A brief description of the vaccine-safety system before the 2009 H1N1 monovalent influenza vaccines follows. A more comprehensive review of federal vaccinesafety monitoring systems is available elsewhere.3

Signal Detection, Strengthening, and Verification

The Vaccine Adverse Event Reporting System (VAERS), established in 1990, is co-managed by the FDA and the Centers for Disease Control and Prevention (CDC). The VAERS is a national passive surveillance system that receives reports of potential adverse events from many sources including health care providers and the public. The VAERS can assess early indicators of a possible vaccine-safety problem that may present as new or unusual adverse events or patterns of reports. For example, in 1999, the VAERS was the first postlicensure source to signal an increased risk of intussusception after the first dose of the rotavirus vaccine RotaShield (Wyeth Laboratories, Marietta, PA). This signal was later confirmed to be a true association.4 Because the VAERS is a passive reporting system for those who have been vaccinated, it is not able to determine how many people have been vaccinated or the rates of events among persons not vaccinated. In addition, as a passive reporting system, the VAERS suffers from underreporting and incomplete reporting. Consequently, it is useful for signal detection, whereas other systems are used to determine associations between vaccination and adverse events.5 Four related systems take advantage of administrative and clinical data available in health care systems. The Vaccine Safety Datalink (VSD), administered by the CDC, uses rapid cycle analysis (RCA) to strengthen and verify signals of prespecified outcomes and to assess associations (discussed more later). The VSD consists of a large linked database of 8 managed care organizations (MCOs) that cover 9 million people, or 3% of the US population. MCOs contribute demographic and vaccination data linked to diagnoses from medical encounters. The VSD can be used for a broad range of studies, because it has fairly complete data on vaccine exposures and health outcomes coupled with chart review as needed. The DoD uses the Defense Medical Surveillance System (DMSS) as a central repository of medical surveillance data for the US armed forces (1 million persons). Military health records in this system can be used to examine medical outcomes after vaccination.6,,8 The DMSS can be used for signal detection through data-mining as well as signal strengthening and verification. The VA has collaborated with the FDA since 2008 to use data from the VA national databases to detect potential vaccine-safety signals among the veteran and VA employee populations. Early evaluations have assessed the safety of influenza and pneumococcal vaccines. The FDA and the Centers for Medicare and Medicaid Services initiated a pilot project in 2006 to assess the feasibility of using Medicare data for prospective rapid safety assessment of vaccines administered in the Medicare population. Medicare insures persons who are 65 years old or older and younger persons with disabilities or end-stage renal disease. More than 45 million persons (including 38 million people aged 65 years) are enrolled in Medicare. Claims data are available for 35 million persons with fee-for-service Medicare. Although largely limited to older populations, the size of the enrolled population provides opportunities to evaluate rare adverse events that other systems may not be able to address.

Assessment of Association

The VSD is the primary system for assessing associations between vaccines and adverse events, because it links vaccination status and health outcomes, which provides the infrastructure to rapidly test hypotheses. The VSD is used for a large number of vaccinesafety studies and is widely considered to be the backbone of the US vaccine-safety system. A broad range of study designs are used by the VSD, including cohort, case-control, and selfcontrolled case-series studies. The Defense Medical Surveillance System has capabilities similar to those of the VSD and is widely used within the DoD to investigate a broad array of exposures and outcomes that are often unique to the military population. Additional studies may be conducted, in coordination with state health departments and/or epidemic intelligence service officers, as part of outbreak investigations to evaluate potential vaccine-safety concerns. Because these studies typically investigate rare events, case-control studies can be conducted, such as those examining intussusception after the rotavirus vaccine. A variety of approaches can be used to identify cases for case-control studies, including active surveillance systems.4,9
Assessment of the Evidence and Causality

In 2001, the CDC established the Clinical Immunization Safety Assessment (CISA) Network. Centers in the CISA Network investigate the pathophysiologic mechanisms and biological risks of vaccine adverse events, which are important considerations for causality assessment. These centers conduct in-depth immunologic, pathologic, and genetic assessments to elucidate underlying mechanisms of vaccine adverse events. In addition to contributing to the body of evidence needed for causality assessments, the CISA Network assists clinicians in evaluating and managing the conditions of people with possible vaccine adverse reactions. For independent expert review of the evidence for causality of particular vaccines and adverse events, the US government has periodically relied on independent, nongovernmental review through the Institute of Medicine (IOM) of the National Academies. The IOM conducted its first report on vaccine safety in 1977 and has subsequently published 6 adverseevent reviews. These reviews cover a range of adverse events such as encephalopathy, GBS, and sudden infant death syndrome. Reviewers consider potential biological mechanisms, epidemiologic and clinical data, the burden of the adverse event, the burden of the vaccinepreventable disease, and salience to the public. The IOM is currently conducting a comprehensive review of the epidemiologic, clinical, and biological evidence regarding adverse health events associated with specific vaccines covered by the National Vaccine Injury Compensation Program.
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ENHANCING THE VACCINE-SAFETY MONITORING SYSTEM TO SUPPORT THE 2009 H1N1 MONOVALENT INFLUENZA VACCINE PROGRAM

The 2009 H1N1 monovalent influenza vaccine program prompted the federal government and the National Vaccine Advisory Committee (NVAC), a federal advisory committee that provides recommendations to the Assistant Secretary for Health, to assess the capacity of the existing safety-monitoring systems. The NVAC made 5 recommendations10,11 regarding 2009 H1N1 vaccine-safety monitoring: (1) enhance active surveillance for signal confirmation and evaluation of possible associations between vaccines and adverse events; (2) establish a transparent and independent review of vaccine-safety data as it accumulates; (3) develop and disseminate a federal plan to monitor 2009 H1N1 monovalent influenza vaccine safety; (4) assemble background rates of adverse events that occur in the general population; and (5) develop and, when possible, test in advance a strong and organized response to scientific and public concerns about vaccine safety. Actions taken to respond to these recommendations are described below.
Signal Detection, Strengthening, and Verification

A number of efforts were made to facilitate adverse-event reporting. The CDC developed an influenza vaccination record card for immunization providers to give to the vaccine recipient with the vaccine. The card included information on how to report an adverse event to the VAERS. Providers were asked to record vaccine type, dose, date, and lot number on the card. At the time of vaccination, cards were given to the vaccine recipient (or caregiver) to keep for 1 year after the last 2009 H1N1 influenza vaccine received. All reports of serious events to the VAERS were reviewed daily, and the frequency of events after 2009 H1N1 monovalent influenza vaccines was compared with the frequency of events after seasonal influenza vaccines. Medical records from people who experienced serious adverse events were quickly obtained and reviewed. In addition, the CDC actively monitored newspaper articles and blogs to quickly identify public concerns that might indicate a vaccine-safety signal. The HHS Indian Health Service developed and deployed in May 2009 the Influenza Awareness System. This system covered seasonal and 2009 H1N1 vaccination and potential vaccine adverse events. The Real Time Immunization Monitoring System (RTIMS), developed at Johns Hopkins University and sponsored by the CDC, used an automated Web-based active surveillance system to track adverse events among vaccines. Previously, the DoD piloted a similar electronic monitoring system to assess patient experiences after smallpox and seasonal influenza vaccination.12,13 The RTIMS was pilot-tested by Johns Hopkins in the 20082009 influenza season. During the 20092010 influenza season, vaccine recipients either gave permission to be contacted for follow-up at the time of their immunization or chose to log onto a Web site and answer an electronic questionnaire. Follow-up e-mail reminders provided a link to questionnaires to provide answers to a series of health-related questions at various time points after vaccination. Answers were analyzed by using a rule-based algorithm in real time. Like the VAERS, this system only collected data on vaccine recipients and lacked data from a nonvaccinated comparison group. Comparisons between types of vaccines (eg, seasonal versus 2009 H1N1 monovalent influenza vaccines and live versus inactivated) were made. RTIMS investigators collected supplemental information by follow-up telephone and e-mail contact with vaccine recipients and their health care providers. Reporting rates for adverse events among those who received 2009 H1N1 monovalent influenza and seasonal influenza vaccines were assessed. Strengths and limitations of the VAE

1. 1. 2. 3. 4. Black S, Eskola J, Siegrist CA, et al

. Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccines. Lancet. 2009;374(9707):21152122 MedlineWeb of Science 2. 1. Hill AB . The environment and disease: association or causation?Proc R Soc Med. 1965;58:295300 MedlineWeb of Science 3. Inter-Agency Vaccine Group, Department of Defense and Veterans Affairs. A comprehensive review of federal vaccine safety activities. Available at: www.hhs.gov/nvpo/nvac/documents/vaccine-safetyreview.pdf. Accessed March 10, 2010 4. Centers for Disease Control and Prevention. Intussusception among recipients of rotavirus vaccine: United States, 19981999. MMWR Morb Mortal Wkly Rep. 1999;48(27):577581 Medline 5. 1. 2. 3. 4. Varricchio F, Iskander J, Destefano F, et al

. Understanding vaccine safety information from the Vaccine Adverse Event Reporting System. Pediatr Infect Dis J. 2004;23(4):287294 MedlineWeb of Science 6. 1. Rubertone MV, 2. Brundage JF . The Defense Medical Surveillance System and the Department of Defense serum repository: glimpses of the future of public health surveillance. Am J Public Health. 2002;92(12):19001904 Abstract/FREE Full Text

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