Table Of Content

Peer-Reviewed Journal Tracking and Analyzing Disease Trends pages 1993–2186 EDITOR-IN-CHIEF D. Peter Drotman Managing Senior Editor EDITORIAL BOARD Polyxeni Potter, Atlanta, Georgia, USA Dennis Alexander, Addlestone Surrey, United Kingdom Senior Associate Editor Timothy Barrett, Atlanta, GA, USA Brian W.J. Mahy, Bury St. Edmunds, Suffolk, UK Barry J. Beaty, Ft. Collins, Colorado, USA Martin J. Blaser, New York, New York, USA Associate Editors Sharon Bloom, Atlanta, GA, USA Paul Arguin, Atlanta, Georgia, USA Christopher Braden, Atlanta, GA, USA Charles Ben Beard, Ft. Collins, Colorado, USA Mary Brandt, Atlanta, Georgia, USA Ermias Belay, Atlanta, GA, USA Arturo Casadevall, New York, New York, USA David Bell, Atlanta, Georgia, USA Kenneth C. Castro, Atlanta, Georgia, USA Corrie Brown, Athens, Georgia, USA Louisa Chapman, Atlanta, GA, USA Charles H. Calisher, Ft. Collins, Colorado, USA Thomas Cleary, Houston, Texas, USA Michel Drancourt, Marseille, France Vincent Deubel, Shanghai, China Paul V. Effl er, Perth, Australia Ed Eitzen, Washington, DC, USA David Freedman, Birmingham, AL, USA Daniel Feikin, Baltimore, MD, USA Peter Gerner-Smidt, Atlanta, GA, USA Anthony Fiore, Atlanta, Georgia, USA Stephen Hadler, Atlanta, GA, USA Kathleen Gensheimer, Cambridge, MA, USA Nina Marano, Atlanta, Georgia, USA Duane J. Gubler, Singapore Martin I. Meltzer, Atlanta, Georgia, USA Richard L. Guerrant, Charlottesville, Virginia, USA David Morens, Bethesda, Maryland, USA Scott Halstead, Arlington, Virginia, USA J. Glenn Morris, Gainesville, Florida, USA David L. Heymann, London, UK Patrice Nordmann, Paris, France Charles King, Cleveland, Ohio, USA Tanja Popovic, Atlanta, Georgia, USA Keith Klugman, Atlanta, Georgia, USA Didier Raoult, Marseille, France Takeshi Kurata, Tokyo, Japan Pierre Rollin, Atlanta, Georgia, USA S.K. Lam, Kuala Lumpur, Malaysia Ronald M. Rosenberg, Fort Collins, Colorado, USA Stuart Levy, Boston, Massachusetts, USA Dixie E. Snider, Atlanta, Georgia, USA John S. MacKenzie, Perth, Australia Frank Sorvillo, Los Angeles, California, USA Marian McDonald, Atlanta, Georgia, USA David Walker, Galveston, Texas, USA John E. McGowan, Jr., Atlanta, Georgia, USA Tom Marrie, Halifax, Nova Scotia, Canada J. Todd Weber, Atlanta, Georgia, USA Philip P. Mortimer, London, United Kingdom Henrik C. Wegener, Copenhagen, Denmark Fred A. Murphy, Galveston, Texas, USA Founding Editor Barbara E. Murray, Houston, Texas, USA Joseph E. McDade, Rome, Georgia, USA P. Keith Murray, Geelong, Australia Copy Editors Claudia Chesley, Karen Foster, Thomas Gryczan, Stephen M. Ostroff, Harrisburg, Pennsylvania, USA Nancy Mannikko, Beverly Merritt, Carol Snarey, P. Lynne Stockton, David H. Persing, Seattle, Washington, USA Caran R. Wilbanks Richard Platt, Boston, Massachusetts, USA Gabriel Rabinovich, Buenos Aires, Argentina Production Carrie Huntington, Ann Jordan, Shannon O’Connor, Mario Raviglione, Geneva, Switzerland Reginald Tucker David Relman, Palo Alto, California, USA Editorial Assistant Christina Dzikowski Connie Schmaljohn, Frederick, Maryland, USA Tom Schwan, Hamilton, Montana, USA Social Media Sarah Logan Gregory Ira Schwartz, Valhalla, New York, USA Intern Kylie L. Gregory Tom Shinnick, Atlanta, Georgia, USA Bonnie Smoak, Bethesda, Maryland, USA Emerging Infectious Diseases is published monthly by the Centers for Disease Rosemary Soave, New York, New York, USA Control and Prevention, 1600 Clifton Road, Mailstop D61, Atlanta, GA 30333, USA. Telephone 404-639-1960, fax 404-639-1954, email [email protected]. P. Frederick Sparling, Chapel Hill, North Carolina, USA Robert Swanepoel, Pretoria, South Africa The opinions expressed by authors contributing to this journal do not neces- Phillip Tarr, St. Louis, Missouri, USA sarily refl ect the opinions of the Centers for Disease Control and Prevention or the institutions with which the authors are affi liated. Timothy Tucker, Cape Town, South Africa All material published in Emerging Infectious Diseases is in the public do- Elaine Tuomanen, Memphis, Tennessee, USA main and may be used and reprinted without special permission; proper citation, John Ward, Atlanta, Georgia, USA however, is required. Mary E. Wilson, Cambridge, Massachusetts, USA Use of trade names is for identifi cation only and does not imply endorsement by the Public Health Service or by the U.S. Department of Health and Human ∞ Emerging Infectious Diseases is printed on acid-free paper that meets the requirements Services. of ANSI/NISO 239.48-1992 (Permanence of Paper) Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 11, November 2011 November 2011 On the Cover Dispatches Georges Desarmes (b. 1950) The Bathers (2006) 2035 International Spread of MDR TB from Acrylic on canvas Tugela Ferry, South Africa (61 cm × 50.8 cm) 2038 Seasonal Infl uenza A Virus in Feces of Courtesy of Patrick Lammie Hospitalized Adults 2043 Infl uenza B Viruses with Mutation in the About the Cover p. 2181 Neuraminidase Active Site, North Carolina, 2010–11 Research 2047 Hepatitis E Virus in Rabbits, Virginia 2050 Astrovirus MLB2 Viremia in Febrile Child Deaths Associated with 2053 New Dengue Virus Type 1 Genotype in Pandemic (H1N1) 2009 among Colombo, Sri Lanka Children, Japan, 2009–2010.....................1993 2056 Ultrastructural Characterization of A. Okumura et al. Pandemic (H1N1) 2009 Virus Encephalopathy and unexpected cardiopulmonary arrest 2060 Molecular Subtyping in Cholera Outbreak, were the leading causes of death. Laos, 2010 2063 Clonal Origins of Vibrio cholerae O1 El Tor Strains, Papua New Guinea, 2009–2011 Global Distribution and Epidemiologic Associations of Escherichia coli Commentary Clonal Group A, 1998–2007 .....................2001 J.R. Johnson et al. 2066 In Memoriam: David Judson Sencer, This group was associated with the Western world, p. 2036 A Public Health Giant trimethoprim/sulfamethoxazole resistance, and diverse hosts/specimens. Letters Group A Streptococcus emm Gene Types in Pharyngeal Isolates, Ontario, 2069 Fatal Infectious Diseases during Canada, 2002–2010...................................2010 Pandemic (H1N1) 2009 Outbreak P.R. Shea et al. 2070 Epidemic Meningococcal Meningitis, Determination of emm variations may help improve vaccine Cameroon design. 2072 Foodborne-associated Shigella sonnei, p. 2066 India, 2009 and 2010 2074 Mosquito-associated Dengue Virus, Key Close Similarity between West, Florida, 2010 Sequences of Hepatitis E Virus 2075 Mycobacterium doricum Osteomyelitis and Recovered from Humans and Soft Tissue Infection Swine, France, 2008–2009 .......................2018 J. Bouquet et al. 2077 Disseminated Mycobacterium abscessus Infection and Showerheads, Taiwan Autochthonous human infection may result from consumption of pork products such as raw liver. 2078 Antimicrobial Drug Resistance in Corynebacterium diphtheriae mitis Dynamics of Cholera Outbreaks 2080 Transfusion-transmitted Syphilis in in Great Lakes Region of Africa, Teaching Hospital, Ghana 1978–2008..................................................2026 2082 Congenital Syphilis, Réunion Island, 2010 D. Bompangue Nkoko et al. 2083 Reduced Susceptibility to Vancomycin in Outbreaks fl uctuate on the basis of season, rainfall, plankton Staphylococcus aureus (response) bloom, and fi shing activities. Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 11, November 2011 Book Review 2085 Smallpox: The Death of a Disease and November 2011 House on Fire: The Fight to Eradicate Smallpox 2139 Rapid Assessment of Cholera-related CHOLERA IN HAITI Deaths, Artibonite Department, Haiti 2143 Epidemic Cholera in a Crowded Urban Environment, Port-au-Prince, Haiti, 2010 Synopses 2147 Toxigenic Vibrio cholerae O1 in Water and Lessons Learned during Public Health Seafood, Haiti Response to Cholera Epidemic in Haiti 2151 Drug-Resistance Mechanisms in Vibrio and the Dominican Republic ...................2087 cholerae O1 Outbreak Strain, Haiti, 2010 J.W. Tappero and R.V. Tauxe 2155 Cholera Management and Prevention at Safe water and sewage systems must be constructed to Hôpital Albert Schweitzer, Haiti prevent future epidemics. 2158 Knowledge, Attitudes, and Practices Related to Treatment and Prevention of Nationwide Training Program for Cholera, Haiti, 2010 Cholera Management, Haiti, 2010 ...........2094 R.V. Tauxe et al. p. 2156 2162 Cholera Prevention Training Materials for Community Health Workers, Haiti, Rapid training of health care staff was followed by lower death rates. 2010–2011 2166 Cholera in United States Associated with Cholera—Modern Pandemic Epidemic in Hispaniola Disease of Ancient Lineage .....................2099 2169 Travel Health Alert Notices and Haiti J.G. Morris Jr. Cholera Outbreak, Florida, 2011 Environmental triggers may lead to increases in Vibrio 2172 Multinational Cholera Outbreak after cholerae in environmental reservoirs, with spillover into Wedding in the Dominican Republic human populations. Commentary Considerations for Oral Cholera Vaccine Use during Outbreak after 2175 Haiti in the Context of the Current Global Earthquake in Haiti, 2010–2011 ...............2105 Cholera Pandemic K.A. Date et al. p. 2163 Many logistical and operational challenges prevented Letters implementation of a vaccination campaign. 2177 Preparing Health Care Workers for a Research Cholera Epidemic, Dominican Republic, Comparative Genomics of Vibrio cholerae 2010 from Haiti, Asia, and Africa ......................2113 2178 Understanding the Cholera Epidemic, Haiti A.R. Reimer et al. (response) A strain from Haiti shares genetic ancestry with those from Correction India and Cameroon. 2180 Vol. 16, No. 11 Characterization of Toxigenic About the Cover Vibrio cholerae from Haiti, 2010–2011 ....2122 D. Talkington et al. 2181 Persistence of Memory and the Comma A virulent clone from Africa or southern Asia was likely Bacillus introduced at a single time point. Etymologia 2104 Cholera Historical Review Cholera in Haiti and Other Conference Summary Caribbean Regions, 19th Century ...........2130 D. Jenson et al. Academic Consortia: Untapped Resources for Preparedness, Response, and Recovery— Epidemic cholera did not occur in Haiti before 2010. Examining the Cholera Outbreak in Haiti http://dx.doi.org/10.3201/eid1711.110727 Dispatches 2136 Risk Factors Early in the 2010 Cholera Epidemic, Haiti Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 11, November 2011 Deaths Associated with Pandemic (H1N1) 2009 among Children, Japan, 2009–2010 Akihisa Okumura, Satoshi Nakagawa, Hisashi Kawashima, Takashi Muguruma, Osamu Saito, Jun-ichi Fujimoto, Chiaki Toida, Shuji Kuga, Toshihiro Imamura, Toshiaki Shimizu, Naomi Kondo, and Tsuneo Morishima Medscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Coun- cil for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Emerging Infectious Diseases. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s)TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certifi cate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journal/eid; (4) view/print certifi cate. Release date: October 21, 2011; Expiration date: October 21, 2012 Learning Objectives Upon completion of this activity, participants will be able to: • Distinguish the most common presenting symptom in fatal cases of pandemic (H1N1) 2009 infection among children • Assess the most common causes of death among children with pandemic (H1N1) 2009 infection • Analyze the causes of death in fatal cases of pandemic (H1N1) 2009 infection among children. Editor Caran Wilbanks, Technical Writer/Editor, Emerging Infectious Diseases. Disclosure: Caran Wilbanks has disclosed the following relevant fi nancial relationships: partner is employed by McKesson Corporation. CME Author Charles P. Vega, MD, Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine. Disclosure: Charles P. Vega, MD, has disclosed no relevant fi nancial relationships. Authors Disclosures: Akihisa Okumura, MD, PhD; Satoshi Nakagawa MD, PhD; Hisashi Kawashima, MD, PhD; Takashi Muguruma, MD, PhD; Osamu Saito, MD; Jun-ichi Fujimoto, MD; Chiaki Toida, MD; Shuji Kuga, MD; Toshihiro Imamura, MD; Toshiaki Shimizu, MD, PhD; Naomi Kondo, MD, PhD; and Tsuneo Morishima, MD, PhD, have disclosed no relevant fi nancial relationships. To clarify the cause of deaths associated with pandemic studied 41 patients <20 years of age who had died of (H1N1) 2009 among children in Japan, we retrospectively pandemic (H1N1) 2009 through March 31, 2010. Data were collected through interviews with attending physicians and chart reviews. Median age of patients was 59 months; Author affi liations: Juntendo University Faculty of Medicine, one third had a preexisting condition. Cause of death was Tokyo, Japan (A. Okumura, T. Shimizu); National Center for Child categorized as unexpected cardiopulmonary arrest for 15 Health and Development, Tokyo (S. Nakagawa, T. Muguruma, O. patients, encephalopathy for 15, and respiratory failure Saito, J. Fujimoto, C. Toida, S. Kuga, T. Imamura); Tokyo Medical for 6. Preexisting respiratory or neurologic disorders were University, Tokyo (H. Kawashima); Gifu University Graduate School more frequent in patients with respiratory failure and less of Medicine, Gifu, Japan (N. Kondo); and Okayama University frequent in patients with unexpected cardiopulmonary Graduate School of Medicine, Dentistry and Pharmaceutical arrest. The leading causes of death among children with Sciences, Okayama, Japan (T. Morishima) pandemic (H1N1) 2009 in Japan were encephalopathy and unexpected cardiopulmonary arrest. Deaths associated with DOI: http://dx.doi.org/10.3201/eid1711.110649 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 11, November 2011 1993 RESEARCH respiratory failure were infrequent and occurred primarily website. As of March 31, 2010, a total of 41 patients <20 among children with preexisting conditions. Vaccine use years of age were listed. and public education are necessary for reducing infl uenza- Infection with pandemic (H1N1) 2009 virus was associated illness and death. confi rmed with nasal swab specimens or aspirates from the nose, throat, or tracheal tube by using real-time A novel reassortant strain of infl uenza A (H1N1) virus reverse transcription PCR (RT-PCR) at local public health containing swine, avian, and human elements (1) laboratories or the National Institute of Infectious Diseases emerged in Mexico in March 2009. The virus initially in Japan, according to the institute’s recommended protocol. spread within North America, causing severe respiratory Samples for RT-PCR could not be obtained for 3 patients; illnesses in Mexico (2) and the United States (3,4), and however, rapid antigen tests were positive for infl uenza A then began to spread rapidly worldwide. On June 11, 2009, for all 41 patients. Because infl uenza A viruses other than the World Health Organization confi rmed an infl uenza pandemic (H1N1) 2009 virus were rarely isolated in Japan pandemic. during the study, these 3 patients were included in our In Japan, the fi rst case of pandemic (H1N1) 2009 was analysis. confi rmed on May 16, 2009. The fi rst outbreak occurred Two research groups collaborated to collect detailed in western Japan, where the number of cases increased data on deaths associated with pandemic (H1N1) 2009 then decreased quickly. The second outbreak started in among children. The collaborative study group comprised early June and quickly spread to all parts of Japan. The 3 chief members (A.O., S.N., and H.K.) and 6 assistant fi rst death associated with pandemic (H1N1) 2009 in members (T.M., O.S., J.F., C.T., S.K., and T.I.). During Japan was confi rmed August 15, and the fi rst death of February–June 2010, members of the collaborative study a child occurred September 17. As of March 31, 2010, group contacted the attending physician of each child who the Ministry of Health, Labour, and Welfare (MHLW) died and visited the hospital to obtain detailed information. reported on its website (www.mhlw.go.jp/kinkyu/kenkou/ We abstracted data from medical records by using a infl uenza/houdou.html) that 198 patients in Japan with structured report form and obtained demographic, clinical, pandemic (H1N1) 2009 had died, of whom 41 were laboratory, and radiologic data from interviews with children <20 years of age. attending physicians and chart reviews. Onset of infl uenza Several authors have reported that respiratory diseases was considered the time at which a temperature >38°C associated with pandemic (H1N1) 2009, including viral was fi rst recorded. The chief members of the study group pneumonia and acute lung injury, that required intensive reevaluated chest radiographs; computed tomography care occurred most often in children (5–16). In Japan, (CT) scan of the head, chest, and abdomen; and magnetic hospitalizations of children because of severe pneumonia resonance images of the head, including those obtained at or other respiratory complications increased (17). Concerns autopsy. were raised regarding deaths among children from acute Cause of death (Table 1) for each patient was encephalopathy in association with pandemic (H1N1) 2009 categorized after the 3 chief members reviewed the detailed because acute encephalopathy has been associated with clinical course and laboratory and radiologic data. At fi rst, death from seasonal infl uenza in Japan (18,19). Neurologic each chief member independently presumed the cause of complications associated with pandemic (H1N1) 2009, death for each patient. When they agreed on the presumed including acute encephalopathy, altered mental status, cause of death, it was adopted as a cause of death. When the and status epilepticus, also have been reported from other chief members disagreed, they reached a consensus on the countries (20–23). cause of death after discussion. Accurate data on the causes of death associated with Because the study was considered to be a public health pandemic (H1N1) 2009 among children are necessary for activity entailing surveillance of deceased persons, approval making a counterplan against future pandemic infl uenza. from an ethics committee or institutional review boards We investigated detailed clinical data collected by MHLW at participating hospitals and informed consent were not for children whose deaths were associated with pandemic required. Anonymous data were collected retrospectively (H1N1) 2009. We focused on the direct cause of death and and were kept confi dential. clinical differences by cause of death. Statistical analyses were performed to identify differences among patients by cause of death. Because Materials and Methods the number of patients who died of myocarditis and viral After the fi rst patient was identifi ed in May 2009, sepsis was small, these cases were excluded from statistical all medical professionals were required to report deaths analyses. We also excluded 1 patient who died of presumed associated with pandemic (H1N1) 2009 to MHLW. Press incidental intracranial hemorrhage. The Kruskal-Wallis test releases on patient deaths were provided on MHLW’s was used to compare numerical variables. When a p value 1994 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 11, November 2011 Pandemic (H1N1) 2009 among Children, Japan another 2 against seasonal infl uenza virus. The other 38 had Table 1. Causes of death for 41 patients <20 years of age with pandemic (H1N1) 2009, Japan, May 2009–March 2010 not been vaccinated against pandemic (H1N1) 2009 virus Cause Definition or seasonal infl uenza virus. Close contact with a person Unexpected Cardiopulmonary arrest without clear findings who had infl uenza within a few days before symptom onset cardiopulmonary of respiratory failure, cardiomyopathy, or was reported for 15 (44%) of 34 patients for whom this arrest encephalopathy information was available. Respiratory Desaturation, need for oxygen failure supplementation or mechanical ventilation or Information about clinical signs and symptoms of both, associated with radiologic findings of infection with pandemic (H1N1) 2009 virus was available pneumonia or acute lung injury for all but 1 patient. Clinical signs included temperature Myocarditis Markedly reduced cardiac output, severe and >38°C (40 [100%] patients), cough (20 [50%]), rhinorrhea refractory arrhythmia, or severe circulatory collapse (12 [30%]), tachypnea (10 [25%]), dyspnea (12 [30%]), and Viral sepsis Refractory hypotension and rapidly wheezing (6 [15%]). Vomiting was observed in 8 (20%) progressing multiorgan failure associated patients; diarrhea (3 patients), tachycardia (3), headache with at least 2 of the following: tachypnea; (1), and myalgia (2) were rare. leukopenia <4000 cells/(cid:80)L or leukocytosis >12,000 cells/(cid:80)L; tachycardia; body Infl uenza was diagnosed by rapid antigen test within temperature >38.0(cid:113)C or <36.0(cid:113)C; cold 2 days after onset of fever for 39 (95%) patients. Before extremities; and increased capillary refill time the life-threatening event, 19 (46%) patients received Encephalopathy At least 1 of the following: altered mental oseltamivir and 5 (12%) received zanamivir. These antiviral state without profound respiratory and cardiac failure or neuroimaging findings drugs were prescribed soon after diagnosis of infl uenza by consistent with encephalopathy such as rapid antigen test. Acetaminophen was administered to marked brain edema, focal lesions, and 13 (39%) of 33 patients for whom this information was blurred gray-white matter junction available. Incidental Other findings that are not directly attributable to influenza infection <0.05 was obtained by Kruskal-Wallis test, post hoc testing was performed by using the Tukey test. We compared categorical variables by using the χ2 test. When the χ2 test gave a p value <0.05, adjustment residual analysis was performed. An absolute value of the adjustment residual >2 was considered signifi cant. Results Study Population Deaths included in the study were distributed almost evenly throughout Japan. The timing of infection with pandemic (H1N1) 2009 virus was concentrated primarily during October 2009–January 2010 (Figure 1). Median age of children was 59 months (range 7–206 months); 20 (49%) patients were 0–4 years of age and 12 (29%) were 5–9 years of age (Figure 1). Twenty-fi ve (61%) patients were boys. Fourteen (34%) patients had >1 preexisting conditions. Respiratory disorders (at least 1 of asthma, chronic lung disease, or a disorder necessitating tracheostomy) were present in 9 patients, none of whom were receiving systemic corticosteroids. Neurologic disorders (at least 1 of cerebral palsy, mental retardation, epilepsy, or neuromuscular disease) were present in 11 patients, 9 of whom had >2 neurologic disorders, and 7 had concurrent respiratory disorders. No patients had endocrine Figure 1. Timing of onset of pandemic (H1N1) 2009 in children and or immunologic disorders or obesity. History of febrile patient age, Japan, May 2009–March 2010. A) Date of illness onset seizures was noted for 6 (15%) patients. One patient had for children >15 years of age compared with those <15 years of been vaccinated against pandemic (H1N1) 2009 virus and age. B) No. patients at each age at time of illness onset. Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 11, November 2011 1995 RESEARCH For 34 (83%) children, a life-threatening event presumed to have been found several hours after CPA. occurred within 2 days after infl uenza onset (Figure 2). Two patients experienced unexpected CPA in the hospital, Twenty-nine (71%) children died within 4 days after 1 in the outpatient clinic and 1 during hospitalization. infl uenza onset (Figure 2). Patient age, interval between Chest radiographs and CT scans of the head and chest were onset of fever and life-threatening event, or interval unremarkable for all children examined. between onset of fever and death did not differ by presence Encephalopathy was considered the cause of death or absence of preexisting conditions. Death was confi rmed for 15 patients (median age 62 months). Five of these in an emergency department for 14 patients, intensive care patients had a preexisting condition, and 3 had preexisting unit for 13, inpatient ward for 12, outside of a hospital for neurologic disorders. All 15 patients had altered mental 1, and outpatient clinic for 1. state or convulsions or both and marked brain edema Blood culture test results were positive for only 1 of according to head CT scan or magnetic resonance images or 21 patients who had at least 1 blood culture; this patient both, which suggests increased intracranial pressure. Nine had had pneumonia associated with methicillin-resistant patients also had low-density areas in the bilateral thalami Staphylococcus aureus (MRSA) before infection with or brainstem or both. Most patients had clinical brain pandemic (H1N1) 2009 virus. Bacterial cultures from death within several hours after onset of encephalopathy respiratory tract samples were positive for 2 of 16 patients in association with multiple organ failure. For some (1 with MRSA and 1 with Streptococcus pneumoniae patients, mild infi ltration was seen on chest radiograph, but infection). Information about pathologic fi ndings was not pulmonary involvement was not likely the cause of death. available for any of the 6 patients for whom postmortem Six patients were judged to have died of respiratory examinations were conducted. failure; their median age was 78 months. Five of these patients had preexisting neurologic conditions and had Causes of Death radiologic fi ndings consistent with severe pneumonia. Two Cause of death was categorized as unexpected cardio- had been hospitalized because of pneumonia attributable pulmonary arrest (CPA) for 15 patients, encephalopathy for to other pathogens (MRSA for 1 and undetermined for the 15, respiratory failure for 6, myocarditis for 2, viral sepsis other) before infection with pandemic (H1N1) 2009 virus; for 2, and incidental for 1. Median age of patients who died their respiratory state markedly worsened after infection. of unexpected CPA was 43 months. Only 1 of these patients Nosocomial transmission was strongly suspected, and had a preexisting condition. For 13 patients, unexpected infl uenza was diagnosed for both patients on the day after CPA occurred outside the hospital; most patients were fever onset. One previously healthy patient had severe and Figure 2. Days from onset of pandemic (H1N1) 2009 illness to A) life-threatening event or B) death among patients <20 years of age, Japan, May 2009–March 2010. 1996 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 11, November 2011 Pandemic (H1N1) 2009 among Children, Japan rapidly progressive dyspnea and hypoxemia. Chest CT respiratory failure. Levels of aspartate aminotransferase, scan performed at autopsy indicated severe infi ltration in lactate dehydrogenase, and creatinine did not differ by the entire lungs, corresponding to acute lung injury. cause of death. Two patients died of myocarditis; both were >12 years of age and previously healthy. One had unexpected Discussion circulatory collapse in a local pediatric clinic; the other We investigated the causes of death associated with was found lying on the fl oor at home without preceding pandemic (H1N1) 2009 among children in Japan. Most respiratory or neurologic symptoms. At admission, both cases were in young, previously healthy children who died patients had markedly elevated creatine kinase (>9,000 after a brief fulminant illness. Unexpected CPA and acute IU/L) and markedly reduced cardiac output on cardiac encephalopathy were the leading causes of death. Children ultrasonography; chest radiographs were unremarkable. In who died of respiratory failure often had preexisting the clinic patient, intensive resuscitation, including intra- conditions, whereas unexpected CPA occurred among aortic balloon pumping and continuous hemodiafi ltration, younger children without preexisting conditions. was performed but was ineffective. Our fi nding that encephalopathy was a leading cause Viral sepsis resulting from pandemic (H1N1) 2009 of death associated with pandemic (H1N1) 2009 among virus developed in 2 patients; 1 was severely disabled. children in Japan differs from reports from other countries Tachypnea, cold extremities, and lethargy were noted that few children have died of neurologic complications for both patients at the local pediatric clinic; shock was (5,24). Children with acute encephalopathy or encephalitis diagnosed, and they were immediately transferred to associated with pandemic (H1N1) 2009 have been tertiary emergency hospitals. Both had rapidly progressive reported outside Japan (20–23), but most survived with multiple organ failure with refractory hypotension. For no or mild neurologic sequelae. Most children with acute both patients, chest radiographs were unremarkable. encephalopathy, such as acute necrotizing encephalopathy Cause of death was presumed to be incidental to (25) and acute encephalopathy with biphasic seizures pandemic (H1N1) 2009 virus infection for 1 patient. and late reduced diffusion (26), were of Japanese or east This patient was hospitalized because of intracranial Asian descent. Children in Japan are presumed to have an hemorrhage, which neuroimaging suggested resulted from underlying genetic predisposition for development of acute rupture of an arteriovenous malformation. On day 12 of encephalopathy (26). The median age of children who illness, infection with pandemic (H1N1) 2009 virus was died of encephalopathy (62 months) was older than that confi rmed by RT-PCR. of patients with encephalopathy associated with seasonal infl uenza (median 2–3 years) (19,27). This difference in age Comparisons by Cause of Death may be related to the age of infected patients; in Japan, more We compared demographic and laboratory data patients 5–9 years or 10–14 years of age were infected with of 36 patients by cause of death (Table 2). Patients who pandemic (H1N1) 2009 than were those 0–4 years (28). A died of myocarditis, viral sepsis, or incidental intracranial fulminant clinical course and marked brain edema were hemorrhage were excluded. Patients with unexpected characteristic and common in the encephalopathy patients CPA were younger than other patients, although these in our study, irrespective of age, presence or absence of differences were not signifi cant (p = 0.053). Respiratory or preexisting conditions, and neuroradiologic fi ndings. neurologic disorders occurred signifi cantly more often in Unexpected CPA was another leading cause of death patients with respiratory failure and signifi cantly less often associated with pandemic (H1N1) 2009 among children in patients with unexpected CPA. The interval between in Japan. Most cases of unexpected CPA occurred in infl uenza onset and life-threatening event did not differ previously healthy children <5 years of age. The elevated by cause of death. Most life-threatening events occurred alanine transaminase and creatine kinase levels in these on the day of or 1 day after infl uenza onset. Although the children could be attributable to postmortem changes. The percentage of clinical signs and symptoms did not differ direct cause of unexpected CPA is diffi cult to determine. by cause of death, tachypnea/dyspnea or wheezing were One possible explanation is severe brain damage resulting frequent in patients with respiratory failure. Drugs taken in CPA; however, none of the patients in our study had before a life-threatening event did not differ by cause of obvious neurologic signs or symptoms until CPA, nor did death. Leukocyte and platelet counts did not differ by cause they have any evidence of brain herniation. Abrupt onset of of death. Alanine transaminase and creatine kinase levels CPA suggests a cardiogenic origin such as fatal arrhythmia were signifi cantly higher in patients with unexpected CPA from undetected myocarditis (29,30). Myocarditis than in those with respiratory failure. Blood urea nitrogen associated with pandemic (H1N1) 2009 has been reported concentration was signifi cantly higher in patients with (31,32). Gdynia et al. reported an unexpected death of a encephalopathy than in those with unexpected CPA or young adult caused by pandemic (H1N1) 2009–associated Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 11, November 2011 1997 RESEARCH Table 2. Comparisons by cause of death among patients <20 years of age, Japan, May 2009–March 2010* Unexpected CPA, Encephalopathy, Respiratory failure, Characteristic n = 15† n = 15† n = 6† p value Median age, mo (range) 43 (7–164) 62 (17–200) 78 (45–206) 0.053 Male sex, no. (%) patients 9 (60) 10 (67) 2 (33) NS Preexisting condition, no. (%) patients Any 1 (7)‡ 5 (33) 5 (83)§ <0.05 Respiratory disorders 0‡ 3 (20) 4 (67)§ <0.05 Neurologic disorders 1 (7)‡ 3 (20) 5 (83)§ <0.05 Previous history of febrile seizures 2 (13) 3 (20) 0 NS Days from influenza onset to life-threatening 1 (0–9) 1 (0–2) 1 (0–9) NS event (range) Days from influenza onset to death (range) 1 (0–9) 3 (0–45) 1.5 (1–11) <0.05¶ Clinical signs, no. (%) patients Cough 5 (36), n = 14 11 (73) 3 (50) NS Rhinorrhea 4 (29), n = 14 7 (47) 1 (17) NS Tachypnea or dyspnea 1 (7), n = 14 4 (27) 3 (50) NS Wheezing 1 (7), n = 14 1 (7) 2 (33) NS Vomiting or diarrhea 2 (14), n = 14 5 (33) 0 NS Drugs received before life-threatening event, no. (%) patients Oseltamivir 7 (47) 6 (40) 5 (83) NS Zanamivir 1 (7) 2 (13) 2 (33) NS Acetaminophen 3 (30), n = 10 7 (50), n = 14 2 (40), n = 5 NS Leukocyte count, cells/(cid:80)L, median (range) 6,600 (4,200–11,100), 9,350 (3,100–28,730), 10,500 (8,650–101,200), NS n = 11 n = 14 n = 5 Platelet count, (cid:117) 104 cells/(cid:80)L, median (range) 20.5 (11.4–45.8), 15.1 (6.2–32.2) 11.5 (8.4–49.0), NS n = 11 n = 5 Aspartate aminotransferase, IU/L, 248 (55–1,981), 233 (18–1,760) 52 (34–73), 0.060 median (range) n = 12 n = 4 Alanine transaminase, IU/L, median (range) 157 (32–845), 70 (9–1,058) 26 (16–57), <0.05¶ n = 12 n = 4 Lactate dehydrogenase, IU/L, median (range) 704 (215–4,801), 899 (160–3,610), 535 (222–1,022), NS n = 12 n = 14 n = 4 Creatine kinase, IU/L, median (range) 302 (136–10,612), 190 (63–1,026), 64 (16–211), <0.01# n = 12 n = 14 n = 4 Blood urea nitrogen, mg/dL, median (range) 11.2 (7.0–31.0), 22.5 (11.7–40.0), 10.0 (4.0–15.0), <0.01** n = 12 n = 14 n = 4 Creatinine, mg/dL, median (range) 0.65 (0.17–1.40), 1.01 (0.62–1.39) 0.25 (0.08–1.00), <0.05** n = 12 n = 4 *CPA, cardiopulmonary arrest; NS, not significant. †n is for all values unless indicated otherwise. ‡Percentage significantly lower than for the other groups. §Percentage significantly higher than for the other groups. ¶p<0.05 unexpected CPA vs. encephalopathy. #p<0.05 unexpected CPA vs. respiratory failure. **p<0.01 unexpected CPA vs. encephalopathy; p<0.05 respiratory failure vs. encephalopathy. myocarditis (31). The clinical course in this patient was Respiratory failure was an uncommon cause of death characterized by sudden collapse at home followed by fatal among children in Japan. In other countries, diffuse viral arrhythmia. Viral sepsis may also be related to unexpected pneumonia or pneumonitis with severe hypoxemia were CPA. Clinical signs of viral sepsis are nonspecifi c and may strongly associated with intensive care unit admission be missed. Considering that most cases of unexpected CPA associated with pandemic (H1N1) 2009 (8–13). Several occurred outside the hospital, rapid progression of viral reports on cases of pandemic (H1N1) 2009 in children also sepsis may have occurred. Unexpected CPA has also been showed that respiratory distress is most common among reported in some case series (5–7,24,33). Cardiac arrest hospitalized children (5–7,14–16,24,34,35). In a study outside the hospital was observed for 67 of 270 children of children in Argentina, refractory hypoxemia caused who died in the United States (24). In a report from 62% of all deaths (14). A report from England described England, 16 of 70 children who died were in CPA when predominantly respiratory symptoms when care was sought seen in an emergency department (7). Detailed postmortem in 53 of 70 children who died (7). Most children who died examinations are necessary to clarify the mechanism of of respiratory failure in Japan had preexisting neurologic unexpected CPA. or respiratory disorders or both; this fi nding is similar to 1998 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 11, November 2011