Biologics PREA Labeling Changes

Biologics PREA Labeling Changes
PREA Labeling Changes, Medical, Statistical, and Clinical Pharmacology Reviews of Pediatric Studies Conducted under Section 505B of the Federal Food, Drug, and Cosmetic Act (the Act), as amended by the FDA Amendments Act of 2007 (FDAAA).

These assessments are for CBER regulated drugs approved under section 505 of the Act and biological drugs licensed under section 351 of the Public Health Service Act.

In accordance with section 505B(h)(1) of the Act as amended, links are provided in the table below to the medical, statistical, and clinical pharmacology reviews of pediatric assessments conducted under PREA. In accordance with section 505B(f)(6)(G) of the Act as amended, links are provided in the table below to currently approved labels (package inserts) that contain changes made as a result of a pediatric assessment.

abrir aquí para acceder al documento FDA completo:
Biologics PREA Labeling Changes

Guidance for Industry - Recommendations for Management of Donors at Increased Risk for Human Immunodeficiency Virus Type 1 (HIV-1) Group O Infection

Guidance for Industry - Recommendations for Management of Donors at Increased Risk for Human Immunodeficiency Virus Type 1 (HIV-1) Group O Infection
[PDF Printable Version - 121 KB]
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/UCM180844.pdf

FDA is issuing this guidance for immediate implementation in accordance with 21 CFR 10.115(g)(4)(i). Submit written comments on this guidance at any time to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. Submit electronic comments to http://www.regulations.gov. You should identify all comments with the title of this guidance.

Additional copies of this guidance are available from the Office of Communication, Outreach and Development (OCOD) (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448, or by calling 1-800-835-4709 or 301-827-1800, or email ocod@fda.hhs.gov, or from the Internet at http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ Guidances/default.htm.

For questions on the content of this guidance, contact OCOD at the phone numbers listed above.

U.S.Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
August 2009

abrir aquí para acceder al documento FDA completo (extenso):
Guidance for Industry - Recommendations for Management of Donors at Increased Risk for Human Immunodeficiency Virus Type 1 (HIV-1) Group O Infection

back-up:
Guidance for Industry - Recommendations for Management of Donors at Increased Risk for Human Immunodeficiency Virus Type 1 (HIV-1) Group O Infection

CIENCIAS MÉDICAS NEWS©: Directorio de Documentos editados en AGOSTO 2009

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CIENCIAS MÉDICAS NEWS©: Directorio de Documentos editados en AGOSTO 2009
DIRECTORIO DE DOCUMENTOS de AGOSTO 2009

Desde su creación el 10 de enero de 2009, el BLOG ha recibido 53.300 consultas (31/08/2009 al mediodía de Argentina). Agradezco a todos los anónimos que buscan en estas páginas contenidos científicos fehacientes, lo cual se transfiere a la calidad de las fuentes que los proveen.
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Si bien la intención original era publicar todo en idioma español únicamente, las circunstancias nos fueron impulsando a incluir documentos en idioma inglés, los que hoy ocupan mayoritariamente las ediciones diarias. Pedimos disculpas por ello, pero bajo la evidencia del interés que los mismos documentos en idioma inglés despiertan, sustentamos la conducta prometiendo acrecentar las ediciones en español para aquellos que no son bilingües o no se sienten cómodos leyendo en inglés.
Agradezco profundamente a todas y cada una de las FUENTES: Agencia Europea de Medicamentos, Food and Drug Administration-USA, National Institute of Health- USA; CDC- USA; AHRQ- USA; NGC- USA; NQMC- USA; Sociedad Internacional de Enfermedades Infecciosas [ISID], IntraMed, El HOSPITAL (USA), EL MÉDICO INTERACTIVO (España), JANO.es/Elsevier (España), DIARIO MÉDICO (España), y a todas las demás instituciones del Gobierno de los Estados Unidos de Norteamérica y Europa, que nos aportan diariamente con información altamente calificada.
Este BLOG se nutre de información en red que se distribuye gratuitamente y no monetiza los contenidos por respeto a las necesidades de los profesionales del equipo de la salud. Por dicho motivo, tenemos la libertad de administrar la información que recibimos sin emitir opinión (salvo excepciones de ética y/o bioética explícitas) y sin calificar como así tampoco descalificar a las fuentes. En lo personal entiendo que la información científico-médica debe ser de acceso universal ya que ello habilita a la discusión y al crecimiento del conocimiento. Cerasale©. Agosto 31, 2009.-

Ranking de consultas hasta el 31 de AGOSTO de 2009:
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3. España: 7.145 - 13,4 %
4. Venezuela: 3.631 - 6,8 %
5. Perú: 3.617 - 6,8 %
6. Estados Unidos: 3.282 - 6,2 %
7. Colombia: 3.108 - 5,8 %
8. Chile: 2.348 - 4,4 %
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El resto: 7.266 - 13,6 %
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 2285. * IntraMed - Artículos - Tos crónica: diagnóstico en...
 2284. * IntraMed - Noticias médicas - La OMS advierte de u...
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 2282. Reemergence of Bolivian Hemorrhagic Fever, 2007–20...
 2281. Genomic Diversity of Oseltamivir-Resistant Influen...
 2280. Human Infection with G12 Rotaviruses, Germany | CD...
 2279. Saffold Cardiovirus in Children | CDC EID
 2278. Rhinovirus C and Apparently Life-Threatening Event...
 2277. Replication of HBoV-2 in Respiratory Tract | CDC E...
 2276. Surveillance for Hepatitis C Virus, USA | CDC EID
 2275. Merkel Cell Polyomavirus | CDC EID
 2274. HPAI Virus A (H7N3) in Saskatchewan, Canada, 2007 ...
 2273. H1N1 - gripe porcina - ISID/USA: alta transmisibil...
 2272. Hantavirus Infection in the Republic of Georgia | ...
 2271. Coxsackievirus A6, Finland | CDC EID
 2270. Vectors of BTV-8, Germany | CDC EID
 2269. Avian Bornaviruses and Proventricular Dilatation D...
 2268. Genetics and Pathogenesis of Feline Infectious Per...
 2267. Nurses' Contacts and Disease Transmission | CDC EI...
 2266. Kyasanur Forest Disease Virus | CDC EID
 2265. Bocavirus-induced Wheezing in Children | CDC EID
 2264. Influenza A Pandemic (H1N1) 2009 Virus Infection, ...
 2263. Foot-and-Mouth Disease Viruses, Ethiopia, 1981–200...
 2262. Bat Coronaviruses, Ghana | CDC EID
 2261. Backyard Raccoon Latrines and Risk for Baylisascar...
 2260. Lack of Airborne Transmission during Outbreak of P...
 2259. Human Infection with G12 Rotaviruses, Germany | CD...
 2258. Replication of HBoV-2 in Respiratory Tract | CDC E...
 2257. Shiga Toxin–producing E. coli O91 | CDC EID
 2256. Risk Factors for Campylobacter Enteritis, England ...
 2255. H1N1 - gripe porcina - ARGENTINA: 465 decesos
 2254. Salmonella enterica Serovar Typhi with CTX-M β-Lac...
 2253. Admissions for Skin and Soft Tissue Infections | C...
 2252. OMS advierte de una forma más severa de la gripe A...
 2251. Etiology of Encephalitis in Australia, 1990–2007 |...
 2250. Aves de corral, en riesgo tras casos H1N1 en pavos...
 2249. Europa se prepara para un incremento del contagio ...
 2248. Vaccines: Stats-Surv/Immunization Coverage in the ...
 2247. Science Report - Revista Digital de CEDEPAP TV
 2246. CDC Newsroom Press Release August 27, 2009
 2245. Vaccines: News/2009 MMWRs related to immunization
 2244. Blood Thinner Pills: Your Guide to Using Them Safe...
 2243. Human Medicines - Herbal Medicinal Products - Adop...
 2242. EPARs human use - NeuroBloc//Botulinum Toxin Type ...
 2241. EPARs human use - Olanzapine Neopharma//olanzapine...
 2240. EPARs human use - Olanzapine Teva//olanzapine
 2239. EPARs human use - Liprolog//Insulin Lispro
 2238. EPARs human use - Pramipexole Teva//pramipexole
 2237. H1N1 - gripe porcina - CANADÁ: criterios sanitario...
 2236. Triquinosis humana en ARGENTINA
 2235. Extrapulmonary Infections and NTM, CME Activity | ...
 2234. Zika Virus Outside Africa | CDC EID
 2233. Environmental Changes and Infectious Disease | CDC...
 2232. Early Communication about an Ongoing Safety Review...
 2231. Updated Information on Leukotriene Inhibitors: Mon...
 2230. H1N1 - gripe porcina - BRASIL: 557 decesos
 2229. National, State, and Local Area Vaccination Covera...
 2228. Surveillance for the 2009 Pandemic Influenza A (H1...
 2227. 2009 Pandemic Influenza A (H1N1) Virus Infections ...
 2226. Use of Influenza A (H1N1) 2009 Monovalent Vaccine
 2225. H1N1 - gripe porcina - VENEZUELA: deceso
 2224. H1N1 - gripe porcina - COLOMBIA: nuevos decesos
 2223. FDA shortage - Cerezyme (imiglucerase)
 2222. H1N1 - gripe porcina - BRASIL: 512 muertes
 2221. Aprobado en Europa el omalizumab para el asma grav...
 2220. Guidelines for the Prevention and Treatment of Opp...
 2219. Drug Safety Labeling Changes by FDA
 2218. HIV/AIDS Update -New Intelence labeling: severe sk...
 2217. FDA MedWatch - Levemir Insulin (Novo Nordisk)
 2216. *Tamizaje del cáncer colorrectal [IntraMed]
 2215. La mitad de los médicos no ven necesario vacunarse...
 2214. H1N1 - gripe porcina - ESPAÑA: posición de la OMC
 2213. FDA MedWatch - Stabilet Infant Warmer
 2212. Status of OTC Rulemakings
 2211. H1N1 - gripe porcina: Las embarazadas no contagian...
 2210. El sexo no es sólo una Y
 2209. European Medicines Agency - Withdrawals of Applica...
 2208. EPARs human use - Levitra//Vardenafil
 2207. EPARs human use - Humalog//Insulin lispro
 2206. EPARs human use - Vivanza//Vardenafil
 2205. EPARs human use - Mimpara//cinacalcet (as hydrochl...
 2204. EPARs human use - Neupro//Rotigotine
 2203. EPARs human use - Sutent//sunitinib malate
 2202. EPARs human use - Rilutek//Riluzole
 2201. EPARs human use - Toviaz//fesoterodine
 2200. Skin safety protocol: risk assessment and preventi...
 2199. Safe site invasive procedure - non-operating room....
 2198. Prevention of unintentionally retained foreign obj...
 2197. Prevention of falls (acute care). Health care prot...
 2196. Pressure ulcer treatment. Health care protocol.
 2195. ACR Appropriateness Criteria® neuroendocrine imagi...
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 2193. ACR Appropriateness Criteria® fever without source...
 2192. ACR Appropriateness Criteria® developmental dyspla...
 2191. ENCEFALITIS JAPONESA / ISID / INDIA
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 2189. Recommendations from the EGAPP Working Group: can ...
 2188. Recommendations from the EGAPP Working Group: can ...
 2187. Systemic Adjuvant Therapy for Patients at High Ris...
 2186. 2008 focused update incorporated into the ACC/AHA ...
 2185. Early Communication about an Ongoing Safety Review...
 2184. Orlistat (marketed as Alli and Xenical): Early Com...
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 2182. H1N1 - gripe porcina - ISID / OPS
 2181. IntraMed - Artículos - ¿Qué piensan los médicos so...
 2180. IntraMed - Artículos - El Síndrome Burnout en médi...
 2179. IntraMed - Artículos - ¿Cómo imaginan los médicos ...
 2178. H1N1 - gripe porcina - ESPAÑA: instituto carcelari...
 2177. H1N1 - gripe porcina - CHILE: granja avícola [ISID...
 2176. ARGENTINA: son 439 los muertos por la nueva influe...
 2175. WHO | WHO Guidelines for Pharmacological Managemen...
 2174. Health Care-Associated Infections
 2173. Ibuprofen (Unapproved) topical drug products
 2172. H1N1 - gripe porcina - ANTIVIRALES recomendaciones...
 2171. CDC 2009 H1N1 Flu | 2009 H1N1 Flu: International S...
 2170. vigabatrin: Treat Spasms in Infants and Epileptic ...
 2169. Use of Influenza A (H1N1) 2009 Monovalent Vaccine
 2168. Patient Misidentification in Papanicolaou Tests: A...
 2167. Criteria for Determining Disability in Infants and...
 2166. Criteria for Determining Disability in Infants and...
 2165. Criteria for Determining Disability in Infants and...
 2164. Criteria to Determine Disability Related to Multip...
 2163. Carbohydrate and Lipid Disorders and Relevant Cons...
 2162. Barriers and Drivers of Health Information Technol...
 2161. Hispanic Diabetes Disparities Learning Network in ...
 2160. EPARs human use - Kepivance//Palifermin
 2159. EPARs human use - ATryn//antithrombin alfa
 2158. EPARs human use - Pelzont//nicotinic acid / laropi...
 2157. EPARs human use - Trevaclyn//nicotinic acid / laro...
 2156. EPARs human use - Tredaptive//nicotinic acid / lar...
 2155. European Medicines Agency - Human Medicines - Medi...
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 2152. WHO | Pandemic (H1N1) 2009 - update 62
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 2149. Research Activities, May 2008: Women's Health: Ant...
 2148. Management of Eating Disorders: Structured Abstrac...
 2147. INFLUENZA / ISID - ESTRATEGIA SANITARIA
 2146. EPARs human use - Jalra//vildagliptin
 2145. EPARs human use - Zomarist//vildagliptin / metafor...
 2144. EPARs human use - Xiliarx//vildagliptin
 2143. EPARs human use - Abraxane//paclitaxel (as paclita...
 2142. EPARs human use - Icandra//vicandra / metformin hy...
 2141. EPARs human use - Zyprexa Velotab//Olanzapine
 2140. EPARs human use - Zyprexa//Olanzapine
 2139. EPARs human use - Exjade//deferasirox
 2138. EPARs human use - Kepivance//Palifermin
 2137. Guidance for Businesses and Employers to Plan and ...
 2136. H1N1 - gripe porcina - OMS / GLOBAL actualizado
 2135. QuickStats: Percentage of Adults with Selected Res...
 2134. Errata: Vol. 58, No. RR-8
 2133. Oseltamivir-Resistant Novel Influenza A (H1N1) Vir...
 2132. Childhood Lead Poisoning Associated with Lead Dust...
 2131. Alcohol Use Among High School Students --- Georgia...
 2130. Gardasil Vaccine Safety
 2129. FDA Proposes Mandatory Electronic Safety Reporting...
 2128. EPARs human use - Lucentis//ranibizumab
 2127. Influenza Virus Vaccine for the 2009-2010 Season
 2126. Hiberix - Haemophilus b Conjugate Vaccine (Tetanus...
 2125. Drug Safety Oversight Board Meeting, July 16, 2009...
 2124. Issues in the Development of Antiviral Products fo...
 2123. Individual Product Bioequivalence Recommendations
 2122. Rickettsia / ISID - México
 2121. H1N1 - gripe porcina - ISID / VACUNA: ensayos clín...
 2120. AHRQ Innovations Exchange | Staff Training and Sup...
 2119. AHRQ Innovations Exchange | Nursing Home Learning ...
 2118. AHRQ Innovations Exchange | Adaptation and Expansi...
 2117. Center for Drug Evaluation and Research (CDER)
 2116. European Medicines Agency - Withdrawals of Marketi...
 2115. Human Medicines - Herbal Medicinal Products - Adop...
 2114. EPARs human use - Trazec//Nateglinide
 2113. Vaccines: Recs/Schedules/Adult Schedule main page
 2112. Vaccines: Recs/Schedules/Child Schedule main page
 2111. Vaccines: Recs/Provisional/Provisional Recs main p...
 2110. Vaccines: Vac-Gen/Shortages/main page
 2109. Red Book® Online -- News & Features
 2108. AHRQ News and Numbers: Heart Conditions, Cancer, T...
 2107. Chronic Disease: Low omega-3 fatty acid levels fou...
 2106. EPARs human use - Yttriga//Yttrium (90Y) chloride
 2105. EPARs human use - Lyrica//Pregabalin
 2104. EPARs human use - Xeristar//Duloxetine hydrochlori...
 2103. EPARs human use - Xolair//omalizumab
 2102. EPARs human use - Regranex//Homodimer of B-chain o...
 2101. EPARs human use - Pedea//Ibuprofen
 2100. EPARs human use - Glivec//Imatinib mesilate
 2099. EPARs human use - Dynastat//Parecoxib sodium
 2098. EPARs human use - Prepandemic influenza vaccine (H...
 2097. EPARs human use - Vimpat//lacosamide
 2096. EPARs human use - Pandemrix//Pandemic influenza va...
 2095. EPARs human use - Prepandrix//Prepandemic influenz...
 2094. EPARs human use - Ecalta//anidulafungin
 2093. EPARs human use - Flebogammadif//human normal immu...
 2092. EPARs human use - Sprycel//Dasatinib
 2091. EPARs human use - Revatio//sildenafil (as citrate)...
 2090. EPARs human use - Duloxetine Boehringer Ingelheim/...
 2089. CellCept (mycophenolate mofetil) August 2009
 2088. Approved Drug Products with Therapeutic Equivalenc...
 2087. Inpatient treatment for elderly nondementia psychi...
 2086. IntraMed - Noticias médicas - Genética: predice la...
 2085. BRUCELOSIS - ISID / MÉXICO
 2084. Vitamin D in dialysis patients.
 2083. Use of phosphate binders in kidney disease.
 2082. Use of calcimimetic drugs.
 2081. Reducing proteinuria.
 2080. Blood pressure control: targets.
 2079. Blood pressure control: role of specific anti-hype...
 2078. CDC H1N1 Flu | Novel 2009-H1N1 Flu: International ...
 2077. Guidelines for oesophageal manometry and pH monito...
 2076. Guidelines for osteoporosis in inflammatory bowel ...
 2075. ACR Appropriateness Criteria® vomiting in infants ...
 2074. ACR Appropriateness Criteria® solitary pulmonary n...
 2073. ACR Appropriateness Criteria® rib fractures.
 2072. ACR Appropriateness Criteria® acute respiratory il...
 2071. ACR Appropriateness Criteria® acute respiratory il...
 2070. EPARs human use - Velmetia//sitagliptin / metformi...
 2069. EPARs human use - Efficib//sitagliptin / metformin...
 2068. EPARs human use - Janumet//sitagliptin phosphate m...
 2067. OBESITY 3.3. - Preventing Chronic Disease: July 20...
 2066. OBESITY 2.3. Preventing Chronic Disease: July 2009...
 2065. OBESITY 1.3. Preventing Chronic Disease: July 2009...
 2064. Notice to Readers: Final 2008 Reports of Nationall...
 2063. HIV - ISID / CUBA
 2062. OSELTAMIVIR: OMS - CONTROVERSIA
 2061. POLIOMIELITIS - VIRUS VACUNAL - NIGERIA [ISID]
 2060. H1N1 - gripe porcina - ESPAÑA: úndécimo deceso
 2059. H1N1 - gripe porcina - ESPAÑA: 11 decesos y 26.000...
 2058. Oseltamivir-Resistant Novel Influenza A (H1N1) Vir...
 2057. asenapine: Schizophrenia and Bipolar Disorder
 2056. FDA Issues Public Health Notification on Glucose M...
 2055. Dextroamphetamine, Amphetamine 20mg Tablets
 2054. CellCept (mycophenolate mofetil)
 2053. EPARs human use - Fosavance//Alendronic acid as al...
 2052. EPARs human use - Bonviva//Ibandronic acid
 2051. EPARs human use - Cerezyme//Imiglucerase (recombin...
 2050. H1N1 - gripe porcina - ARGENTINA: actualización 14...
 2049. GDH-PQQ (glucose dehydrogenase pyrroloquinoline qu...
 2048. H1N1 - gripe porcina - ISID / LATINOAMÉRICA
 2047. Tamizaje prenatal: Detección de las alteraciones c...
 2046. Vaccines: VFC/State and Territory Coordinators
 2045. Notice to Readers: Final 2008 Reports of Nationall...
 2044. QuickStats: Annual Rate of Nonfatal, Medically Att...
 2043. Hepatitis Temporally Associated with an Herbal Sup...
 2042. Pseudo-Outbreak of Legionnaires Disease Among Pati...
 2041. Carbon Monoxide Exposures After Hurricane Ike --- ...
 2040. H1N1 - gripe porcina - OMS: actualización (13/08/2...
 2039. European Medicines Agency - Human Medicines - CHMP...
 2038. EPARs human use - Cymbalta//Duloxetine hydrochlori...
 2037. EPARs human use - Paxene//Paclitaxel
 2036. EPARs human use - Zonegran//zonisamide
 2035. Authorised Medicines for Human Use - Viramune//NEV...
 2034. EPARs human use - Emend//Aprepitant
 2033. EPARs human use - Ivemend//fosaprepitant dimeglumi...
 2032. EPARs human use - Renvela//sevelamer carbonate
 2031. EPARs human use - Nexavar//sorafenib
 2030. EPARs human use - Sutent//sunitinib malate
 2029. NIAID Media Availability: NIAID Scientists View Pa...
 2028. Final Rules for Expanded Access to Investigational...
 2027. H5N1 - OMS / EGIPTO
 2026. Influenza Virus Vaccine for the 2009-2010 Season
 2025. EPARs human use - Celsentri//maraviroc
 2024. EPARs human use - Baraclude//Entecavir
 2023. EPARs human use - Champix//varenicline tartrate
 2022. EPARs human use - Tygacil//tigecycline
 2021. EPARs human use - ProQuad//Measles virus1 Enders' ...
 2020. H1N1 - OPS / ISID - ACTUALIZACIÓN REGIONAL
 2019. FDA - HIV-1 infection in adults
 2018. EPARs human use - Firmagon//degarelix
 2017. EPARs human use - Luveris//lutropin alfa (recombin...
 2016. EPARs human use - Zometa//Zoledronic acid
 2015. European Medicines Agency - Human Medicines - Medi...
 2014. H1N1 - gripe porcina - ASIA: expansión en época de...
 2013. CDC Novel H1N1 Flu | CDC Response
 2012. EPARs human use - Luveris//lutropin alfa (recombin...
 2011. EPARs human use - Remicade//infliximab
 2010. EPARs human use - Humira//adalimumab
 2009. EPARs human use - Reyataz//Atazanavir sulphate
 2008. EPARs human use - Ovitrelle//choriogonadotropin al...
 2007. 7/7. Treatment of external genital warts and pre-i...
 2006. 6/7. The role of HPV testing. In: Canadian consens...
 2005. 5/7. Screening for cervical cancer. In: Canadian c...
 2004. 4/7. Prevention. In: Canadian consensus guidelines...
 2003. 3/7.Counselling. In: Canadian consensus guidelines...
 2002. 2/7.Cost-benefit analysis of HPV vaccination. In: ...
 2001. 1/7.Clinical manifestations and diagnosis of HPV-r...
 2000. NCTR Research Highlights
 1999. Human Medicines - Herbal Medicinal Products - Adop...
 1998. European Medicines Agency - Human Medicines - Medi...
 1997. European Medicines Agency - Human Medicines - Medi...
 1996. OSELTAMIVIR: EAG´s e inefectividad terapéutica (IS...
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IntraMed - Artículos - Tos crónica: diagnóstico en la práctica general

31 AGO 09 | Utilidad de las “pruebas terapéuticas”
Tos crónica: diagnóstico en la práctica general
Las causas más comunes, los procedimientos de estudio y cómo se puede hacer una “prueba terapéutica” cuando el diagnóstico es incierto.

Dr. Kevin Barraclough
BMJ 2009;338:b1218

Presentación del caso

Una mujer de 42 años, fumadora, consulta por padecer tos de 3 meses de antigüedad, que apareció durante una enfermedad con coriza. La tos empeora a la mañana y rara vez produce esputo. No tiene disnea y ha estado tomando un inhibidor de la enzima convertidora de angiotensina (IECA) durante 2 años para el tratamiento de su hipertensión.

Problema diagnóstico

La tos crónica se define arbitrariamente como una tos de 8 semanas de duración y es una causa frecuente de consulta en el consultorio de atención primaria.

El problema diagnóstico es diferencias entre las causas comunes de tos crónica —asma, enfermedad pulmonar obstructiva crónica, goteo posnasal, enfermedad por reflujo gastroesofágico y tos inducida por fármacos—y no diagnosticar causas raras pero graves de tos.

En atención primaria, a causa de tos crónica suele ser incierta siendo el asma el diagnóstico más común. En un estudio de 78 pacientes adultos, no fumadores, atendidos en el segundo nivel, y con una radiografía de tórax normal, en 73 (94%) se consideró que la tos estaba causada por una “triada patogénica”, asma, reflujo gastroesofágico y síndrome de goteo posnasal. En 48 pacientes (62%) se halló más de 1 causa. Los estudios realizados por especialistas clínicos, la causa pudo ser establecida en el 89-100% de los casos, haciendo superfluo el diagnóstico popular previo de “tos psicógena”. En los fumadores, la tos crónica es común y también puede ser la presentación de un cuadro de enfermedad pulmonar obstructiva crónica o de carcinoma broncogénico.

Signos de alarma

Tanto en fumadores como en no fumadores ciertos cuadros requieren estudios precoces:

Producción copiosa de esputo (lo que indica la presencia de bronquiectasias).

Fiebre, sudoración, adelgazamiento, hemoptisis (indicando tuberculosis, linfoma, carcinoma bronquial).

Disnea intensa con la tos (indicando insuficiencia cardiaca, enfermedad obstructiva de la vía aérea, fibrosis pulmonar).
Aproximación diagnóstica: la prueba terapéutica

Si no hay signos de alarma, la “prueba terapéutica” puede ser una herramienta útil en atención primaria—si el paciente está satisfecho con el resultado del tratamiento, el diagnóstico pasa a tener una importancia secundaria, siempre que no hayan desestimado trastornos graves. Si el paciente recae al suspender el tratamiento, es más fácil hacer un diagnóstico alternativo e intentar otro tratamiento. En una serie de 131 pacientes atendidos en el segundo nivel con tos crónica inexplicada, este enfoque tuvo una relación costo efectiva mejor que estudios más costosos como la broncoscopia.
Inicialmente, la evaluación debe recabar la información siguiente:

Duración y frecuencia de la tos

Características de la tos: productiva o seca, nocturna, postural o asociada con la ingestión de alimentos.

Hemoptisis o dolor torácico

Antecedente de tabaquismo y exposición al polvo

Uso de IECA

Signos de alarma—por ejemplo, disnea, sudoración, pérdida de peso

Ausencia de signos focales torácicos (incluyendo ruidos cardíacos normales

Resultado de espirometrías o velocidad del pico flujo espiratorio seriadas cuando se sospecha enfermedad pulmonar obstructiva crónica o cuando la primera prueba terapéutica no dio resultado

Radiografía de tórax si el paciente es fumador o si presenta signos de alarma; considerar también si ha fracasado la primera prueba terapéutica
Método diagnóstico a partir de la “prueba terapéutica”


♦ Haga Click sobre la imagen para ampliarla

Cesación de fumar

Aunque este tópico no tiene relación con el caso aquí presentado, los autores mencionan que los estudios longitudinales muestran que la cesación de fumar reduce la tos (pero, en general, no la resuelve). Los fumadores tienen un riesgo elevado de enfermedad pulmonar obstructiva crónica y cáncer y están indicadas la radiografía de tórax y la espirometría para confirmar o descartar esas enfermedades en los fumadores

Suspensión de los IECA

El tratamiento con IECA produce tos crónica en el 15% de los pacientes. la tos puede comenzar luego de algunos años de tratamiento y suele desparecer en 1 a 4 semanas después de haber suspendido el tratamiento pero puede persistir durante aproximadamente 3 meses.

Estudios necesarios

En atención primaria no siempre están indicados estudios sencillos como la radiografía de tórax, la espirometría y la velocidad del pico flujo espiratorio en los pacientes con tos crónica pero luego de un tratamiento de prueba en los no fumadores hay que tener muy en cuenta los signos de alarma¾asma, empeoramiento con la exposición al polvo o irritantes o, tos recurrente.

Prueba terapéutica para el asma y sus variantes

El asma suele diagnosticarse sobre la base de los síntomas (tos, especialmente nocturna o durante el ejercicio, y disnea) y la presencia de obstrucción reversible de la vía aérea. Sin embargo, puede manifestarse solamente como tos sin reversibilidad de la vía aérea (asma variante tos). Estos pacientes tienen hiperreactividad bronquial en los tests de provocación con metacolina o histamina inhaladas, pero no presentan variación en el pico flujo. Otro grupo se caracteriza por tos con esputo eosinofílico sin hiperreactividad en el test de provocación (bronquitis eosinofílica sin asma). Una buena estrategia es considerar que estas variantes responden a los corticosteroides. Los corticosteroides inhalados deben ser administrados durante 8 semanas. Cierta evidencia muestra que aunque el asma clásica puede responder ya a las 2 semanas de tratamiento, el asma variante tos y la bronquitis eosinofílica pueden tardar hasta 8 semanas en responder.

El asma puede ser descartada si la realización seriada de la velocidad del pico flujo espiratorio o la espirometría antes y después del tratamiento con broncodilatadores muestra una reversibilidad superior al 20%. Sin embargo, un resultado negativo no descarta el diagnóstico, ya que muchos asmáticos no manifiestan obstrucción reversible de la vía aérea en un momento dado. Un estudio retrospectivo de 590 pacientes con asma asistidos en una clínica de atención terciaria mostró que solo el 9% tenía más del 15% de reversibildiad de la vía aérea. En general, los pacientes con bronquitis eosinofílica no muestran reversibilidad. Por lo tanto, la reversibilidad en la espirometría tiene un 100% de especificidad para el asma pero una baja sensibilidad (posiblemente solo el 9%). El asma y sus variantes son el diagnóstico final en el 20-30% de los pacientes con tos que son derivados para su atención en clínicas de neumonología. La evidencia que indica que la tos crónica por asma es la más común en el consultorio de atención primaria es limitada, lo que puede resultar en un sobre diagnóstico de asma y el error de no reconocer otras causas, como la enfermedad por reflujo gastroesofágico.

Prueba terapéutica con inhibidores de la bomba de protones para el reflujo gastroesofágico

La tos crónica puede ser la única manifestación del reflujo gastroesofágico, el cual puede ser la causa etiológica del 10-40% de los individuos con tos crónica. Esta tos raramente ocurre durante el sueño, es más común al caminar o ponerse de pie y puede estar asociada a dolor de garganta, mientras que la tos que acompaña al asma tiene la característica de empeorar durante la noche. Otra manifestación clínica sugestiva es el ardor retroesternal, el cual suele ser posicional y ocurre unas horas después de comer. En estos casos, la tos aparece al comer o hablar.

Un metaanálisis que incluyó 15 estudios mostró que la respuesta o la falta de respuesta de los síntomas a la prueba terapéutica con inhibidores de la bomba de protones tiene una sensibilidad del 78% y una sensibilidad del 54%, determinadas a través del monitoreo del pH durante 24 horas. Por lo tanto, el 20% de los pacientes con reflujo gastroesofágico comprobado no responde a estos inhibidores, pero se aclara que la mayoría de los estudios del metaanálisis evaluaron los síntomas luego de 2 semanas. Hay escasa evidencia sobre cuál es la duración óptima del tratamiento mientras que los inhibidores de la bomba de protones pueden tardar de 1 a 3 meses en resolver la tos crónica.

Tratamiento de la rinitis, la sinusitis y el goteo posnasal

Cuando se trata del síndrome de goteo postnatal la evidencia no es tan clara. Dicho síndrome carece de un estándar diagnóstico objetivo y clínicamente se sospecha cuando el paciente relata la sensación de goteo por detrás de su garganta o tiene un deseo recurrente de carraspear. El diagnóstico se refuerza cuando el síntoma responde a los antihistamínicos, los descongestivos o los corticosteroides nasales. Todavía se debate acerca de la medida en que este problema causa tos crónica como así la duración del tratamiento y la dosis requerida.

Sospecha de tos convulsa

En la actualidad, se considera que la infección por Bortadella pertussis es una causa reconocida de tos crónica en adolescentes y adultos, habiéndose comprobado que el 13-32% de los adultos con tos crónica tienen evidencia serológica de haber sufrido tos convulsa recientemente. Sin embargo, en atención primaria, la importancia de este diagnóstico en individuos con tos crónica es dudosa y no se cuenta con una prueba diagnóstica: los antibióticos, si se administran dentro de los 7 días de enfermedad no afectan su evolución y el 27% de los adultos infectados a los 90 días todavía siguen con tos, sin evidencia de que esa intervención modificara esta evolución.

Análisis del caso

En el caso presentado fue apropiado suspender los IECA y revisar al paciente al cabo de un mes. La tos mejoró pero no desapareció. Como el paciente no es fumador y en ausencia de signos de alarma, se considera que es difícil que sufra una enfermedad grave. La causa posible de la tos puede ser una (o más) de la “triada patogénica”: asma, reflujo gastroesofágico o síndrome de goteo posnasal (tos mientras habla por teléfono). Algunas manifestaciones que hicieron sospechar la presencia de reflujo gastroesofágico (tos cuando habla por teléfono) y la prueba con inhibidores de la bomba de protones 2 veces por día durante 8 semanas resolvieron la tos. Un inconveniente de la prueba terapéutica es que el resultado positivo se haya debido a la remisión espontánea. La suspensión del tratamiento y la repetición del mismo en el caso de una nueva aparición de la tos aproximan más al diagnóstico presuntivo.

Puntos importantes

La tos crónica suele definirse como la tos que persiste más de 8 semanas.

La tos mejora mucho dentro de las 8 semanas de haber dejado de fumar: en general, la tos causada por IECA se resuelve en 1-4 semanas posteriores a la suspensión del tratamiento.

La tos crónica inexplicada en adultos suele deberse a una de las enfermedades que componen la “triada patogénica”: asma, reflujo gastroesofágico o goteo posnasal.

El tratamiento de prueba empírico de 8 semanas es más apropiado como primera intervención que recurrir a los estudios especializados.

♦ Traducción y resumen objetivo: Dra. Marta Papponetti. Especialista en Medicina Interna


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16. Cherry JD. The epidemiology of pertussis: a comparison of the epidemiology of the disease pertussis with the epidemiology of Bordetella pertussis infection. Pediatrics 2005;115:1422-7.
17. Hewlett EL, Edwards KM. Pertussis—not just for kids. N Engl J Med 2005;352:1215-22.
18. Thomas PF, McIntire PB, Jalaludin BB. Survey of pertussis morbidity in adults in western Sydney. Med J Aust 2000;173:74-6.


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IntraMed - Noticias médicas - La OMS advierte de una cepa de gripe A más agresiva

30 AGO 09 | Con grave compromiso respiratorio
La OMS advierte de una cepa de gripe A más agresiva
La influenza H1N1 se encuentra prácticamente en todo el mundo. Donde es temporada habitual de gripe, la cepa H1N1 es la dominante.
El Mundo, España

REUTERS / WASHINGTON
Los médicos informan de una nueva variante de la gripe pandémica H1N1 que ataca directamente a los pulmones, causa enfermedad severa en personas saludables y requiere un tratamiento hospitalario más costoso de lo habitual, según señaló el viernes la Organización Mundial de la Salud (OMS).

Algunos países están informando de que hasta el 15% de los pacientes hospitalizados por contagio con la cepa de la gripe H1N1 necesitan cuidados intensivos, lo que provoca aún más complicaciones en unos sistemas de atención médica que ya están colapsados, según indicó la agencia en una actualización sobre el estado de la pandemia.

"Durante la temporada de invierno en el hemisferio sur, varios países vieron una necesidad de cuidados intensivos, en momentos de gran carga sobre los servicios de salud", añadió la OMS.

"Las medidas de preparación necesitan anticipar este aumento en la demanda de unidades de cuidados intensivos, que podrían verse colapsadas por un incremento repentino en la cantidad de casos severos" de influenza H1N1, destacó la entidad.

La agencia de Naciones Unidas informó que la circulación de la nueva cepa de influenza H1N1 habría superado su punto máximo en la mayor parte del hemisferio sur, aunque aún la zona está atravesando el invierno.

La OMS también indicó que la nueva cepa pandémica ha alcanzado niveles epidémicos en Japón, lo que marca el inicio temprano de lo que sería una larga temporada de gripe en el hemisferio norte, mientras la situación empeora en las regiones tropicales.

"En el hemisferio sur, la mayoría de los países (representados por Chile, Argentina, Nueva Zelanda y Australia) parece haber superado su pico de actividad de influenza", expresó la OMS.

"Algunos otros (representados por Sudáfrica y Bolivia) continúan experimentando altos niveles de actividad de la gripe", añadió la agencia de Naciones Unidas.

La influenza H1N1 actualmente se encuentra prácticamente en todo el mundo y fue declarada pandemia en junio. Pero, como cualquier enfermedad infecciosa, no se expande en todos lados por igual y puede aparecer en distintas comunidades en diversos momentos.

"En Japón, el nivel de actividad de la influenza ha pasado el umbral epidémico estacional, lo que señala un comienzo muy temprano de la temporada anual de gripe", señaló la agencia de Naciones Unidas en su informe semanal sobre la pandemia.

Aunque la influenza rara vez surge en medio de temperaturas cálidas, la enfermedad siguió expandiéndose, a niveles bajos, en el hemisferio norte durante todo el verano. E incluso donde aún está en marcha la temporada de gripe, la cepa H1N1 es dominante y afecta a más personas que los virus estacionales.

Una forma más agresiva con los pulmones

"Quizá lo más importante es que los médicos de todo el mundo están informando una forma muy severa de la enfermedad, también en jóvenes y personas saludables, lo que es extraño en el caso de las infecciones por gripe estacional", indicó la OMS.

"En esos pacientes, el virus directamente infecta el pulmón, causando insuficiencia respiratoria severa. Salvar esas vidas depende de unidades de cuidados intensivos altamente especializadas, habitualmente con estadías largas y costosas", agregó.

La OMS dijo que está aconsejando a los países del hemisferio norte a que se preparen para la expansión de una segunda ola de la pandemia. Cada año, la gripe estacional infecta a entre el 5 y el 20 por ciento de una población determinada y causa entre 250.000 y 500.000 muertes a nivel global.

Dado que prácticamente nadie tiene inmunidad al nuevo virus H1N1, expertos creen que infectará a más personas de lo habitual, hasta un tercio o más de la población mundial.

Asimismo, a diferencia de la gripe estacional que ataca fundamentalmente a los ancianos, la cepa pandémica afecta desproporcionadamente a las personas más jóvenes, por lo que causaría más enfermedad severa y muertes entre los adultos jóvenes y los niños que la influenza estacional.

Las personas que corren más riesgo son las mujeres embarazadas, quienes padecen enfermedades crónicas como asma o diabetes y algunos estudios sugieren que también los obesos.


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Cross-reactive Antibodies against Avian Influenza Virus A (H5N1) | CDC EID

Volume 15, Number 9–September 2009
Letter
Cross-reactive Antibodies against Avian Influenza Virus A (H5N1)
Sathit Pichyangkul, Anan Jongkaewwattana, Arunee Thitithanyanont, Peeraya Ekchariyawat, Suwimon Wiboon-ut, Amporn Limsalakpetch, Kosol Yongvanitchit, Utaiwan Kum-Arb, Rangsini Mahanonda, Pongsak Utaisincharoen, Stitaya Sirisinha, Carl J. Mason, and Mark M. Fukuda
Author affiliations: Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand (S. Pichyangkul, A. Limsalakpetch, K. Yongvanitchit, U. Kum-Arb, C.J. Mason, M.M. Fukuda); National Center of Genetic Engineering and Biotechnology, Bangkok (A. Jongkaewwattana); Mahidol University, Bangkok (A. Thitithanyanont, P. Ekchariyawat, S. Wiboon-ut, P. Utaisincharoen, S. Sirisinha); and Chulalongkorn University, Bangkok (R. Mahanonda)

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To the Editor: Intravenous immunoglobulin (IVIg) is used to treat bacterial and viral infections in patients with primary immunodeficiency disease and those with autoimmune and inflammatory disorders (1). IVIg contains pooled IgG from >1,000 blood donors and antibodies against various common human pathogens, including influenza virus A.

We tested the efficacy of commercial preparations of IVIg (50 mg/mL of highly purified immunoglobulin) against homosubtypic influenza viruses A (H1N1 and H3N2) and their cross-reactivity against avian influenza virus A (H5N1). IVIg preparations (Octagam; Octapharma, Vienna, Austria and Flebogamma; Instituto Grifols, Barcelona, Spain) had hemagglutination inhibition (HI) titers against subtypes H1N1 and H3N2 ranging from 20 to 40. Human Immunoglobulin, pH 4.0, (Harbin Sequel Bio-Engineering Pharmaceutical, Harbin, People's Republic of China) had lower HI titers against avian influenza viruses (10 for subtype H3N2 and <10 for subtype H1N1). As expected, we did not detect antibodies against hemagglutinin (HA) of subtype H5N1 (A/open-billed/stork/Nahkonsawan/BBD0104F/2004) in any of the IVIg preparations (HI titer <10).

Human influenza subtype H1N1 shares the same neuraminidase (NA) subtype (human N1) as subtype H5N1 (avian N1). We therefore tested whether IVIg preparations would react and inhibit NA activity of human and avian influenza viruses by using a neuraminidase inhibition (NI) assay (2). NI titer was defined as the reciprocal of the highest dilution that gave 50% reduction compared with that of the virus control.

All 3 IVIg preparations inhibited NA activity of human N1 (NI titer against subtype H1N1 range 258–986) and human N2 (NI titer against subtype H3N2 range 1,309–3,274). Enzyme activity of avian N1 (7:1 reassortant; PR8 + NA [A/Vietnam/DT-0361/2005 H5N1]) was inhibited by all IVIg preparations (NI titer range 143–231). These findings support the recent observation of neutralizing antibodies against human N1 in human serum, which could inhibit enzyme activity of avian N1 from subtype H5N1 (3,4). We also tested IVIg preparations against reverse genetics subtype H5N3 virus in which the N3 NA was derived from H2N3 virus (6:1:1 reassortant; 6 internal genes from PR8 + HA (A/Vietnam/DT-0361/05 H5N1) + NA (A/duck/Germany 1207 H2N3) and observed no effect (NI titer <10). The N3 subtype belongs to avian influenza NA. Thus, antibodies against NA in IVIg appear to be specific for those circulating human influenza viruses (human N1 and human N2).

Unlike HA and NA, virus matrix 2 ectodomain (M2e) is highly conserved. Its presence on the surface of the viral particle makes it a potential target of antibody response similar to that for HA and NA (5,6). We assessed reactivity of IVIg preparations against a consensus M2e peptide derived from human influenza viruses of H1, H2, and H3 subtypes (MSLLTEVETPIRNEWGCRCNDSSD) and those derived from A/Hong Kong/156/97 H5N1 (MSLLTEVETLTRNGWGCRCSDSSD and A/Thailand/ SP-83/2004 H5N1 (MSLLTEVETPTRNEWECRCSDSSD) by using ELISA (7). Antibody titer was defined as the reciprocal of the highest dilution that had an optical density of 0.5 at 414 nm in our assay.

Figure

Figure. Neutralization of avian influenza virus A (H5N1) by intravenous immunoglobulin (IVIg) preparations measured by percentage reduction in plaque number (A) and plaque size (B)...

Results showed considerable variation among IVIg preparations, caused by M2e peptides derived from different influenza viruses (titer range 88–23,614). Among the 3 preparations, Human Immunoglobulin, pH 4.0, IVIg showed the highest titers against all M2e peptides (consensus, 9,639; H5N1 Hong Kong, 3,519; and H5N1 Thailand, 23,614). Variation of antibody titers against M2e in IVIGs may be geographically dependent. Unlike Octagam and Flebogamma, Human Immunoglobulin, pH 4.0, IVIg was likely derived from blood donors in China. Octagam and Immunoglobulin, pH 4.0, IVIg were more reactive with M2e of avian influenza virus (H5N1) (A/Thailand/SP-83/2004) than with other M2e peptides.

We measured the ability of IVIg preparations to inhibit influenza subtype H5N1 replication by using a plaque-reduction assay. Subtype H5N1 (A/open-billed stork/ Nakhonsawan/BBD0104F/2004) was maintained as described (8). MDCK cells were infected with virus and agar containing various concentrations of IVIg was layered on top of these cells and incubated for 2 days. Results are shown in the Figure. IVIG inhibited plaque formation in a dose-dependent manner. Although plaques of heterogeneous size were observed in infected plates without IVIg, larger plaques were preferentially neutralized with increasing concentrations of IVIg in the agar (Figure).

Premixing excess M2e peptide with IVIg to absorb M2e-specific antibodies had no effect on plaque formation, indicating that antibodies against M2e in IVIg preparations were not responsible for neutralization of influenza subtype H5N1. Antibodies against M2e may have a role in protection against subtype H5N1 by another mechanism.

Our data suggest that the neutralizing activity against influenza subtype H5N1 in all 3 IVIg preparations was likely contributed by cross-reactive antibodies against avian N1. IVIg has been reported to have antiinflammatory activity (9,10). The immune suppressive effect of IVIg may benefit patients by reducing the cytokine storm. These data suggest use of IVIg, especially preparations containing high neutralizing activity against subtype H5N1, as adjunctive treatment for infection with highly pathogenic avian influenza virus (H5N1).

This study was supported by grant Y1-AI-5026-01 from the National Institutes of Health, National Institute of Allergy and Infectious Diseases, International Research in Infectious Disease.

References
McClelland DB, Yap PL. Clinical use of immunoglobulins. Clin Haematol. 1984;13:39–74.
Lambre CR, Terzidis H, Greffard A, Webster RG. Measurement of anti-influenza neuraminidase antibody using a peroxidase-linked lectin and microtitre plates coated with natural substrates. J Immunol Methods. 1990;135:49–57. PubMed DOI
Sandbulte MR, Jimenez GS, Boon AC, Smith LR, Treanor JJ, Webby RJ. Cross-reactive neuraminidase antibodies afford partial protection against H5N1 in mice and are present in unexposed humans. PLoS Med. 2007;4:e59. PubMed DOI
Lynch GW, Selleck PW, Axell A-M, Downton T, Kapitza NM, Boehm I, et al. Cross-reactive anti-avian H5N1 influenza neutralizing antibodies in a normal 'exposure-naive' Australian blood donor population. The Open Immunology Journal. 2008;1:13–9. DOI
Neirynck S, Deroo T, Saelens X, Vanlandschoot P, Jou WM, Fiers W. A universal influenza A vaccine based on the extracellular domain of the M2 protein. Nat Med. 1999;5:1157–63. PubMed DOI
Zharikova D, Mozdzanowska K, Feng J, Zhang M, Gerhard W. Influenza type A virus escape mutants emerge in vivo in the presence of antibodies to the ectodomain of matrix protein 2. J Virol. 2005;79:6644–54. PubMed DOI
Tompkins SM, Zhao ZS, Lo CY, Misplon JA, Liu T, Ye Z, et al. Matrix protein 2 vaccination and protection against influenza viruses, including subtype H5N1. Emerg Infect Dis. 2007;13:426–35.
Thitithanyanont A, Engering A, Ekchariyawat P, Wiboon-ut S, Limsalakpetch A, Yongvanitchit K, et al. High susceptibility of human dendritic cells to avian influenza H5N1 virus infection and protection by IFN-alpha and TLR ligands. J Immunol. 2007;179:5220–7.
Ephrem A, Misra N, Hassan G, Dasgupta S, Delignat S, Van Huyen JP, et al. Immunomodulation of autoimmune and inflammatory diseases with intravenous immunoglobulin. Clin Exp Med. 2005;5:135–40. PubMed DOI
Ephrem A, Chamat S, Miquel C, Fisson S, Mouthon L, Caligiuri G, et al. Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis. Blood. 2008;111:715–22. PubMed DOI
Figure
Figure. Neutralization of avian influenza virus A (H5N1) by intravenous immunoglobulin (IVIg) preparations measured by percentage reduction in plaque number (A) and plaque size (B)...

Suggested Citation for this Article
Pichyangkul S, Jongkaewwattana A, Thitithanyanont A, Ekchariyawat P, Wiboon-ut S, Limsalakpetch A, et al. Cross-reactive antibodies against avian influenza virus A (H5N1) [letter]. Emerg Infect Dis [serial on the Internet]. 2009 Sep [date cited]. Available from http://www.cdc.gov/EID/content/15/9/1537.htm

DOI: 10.3201/eid1509.090471

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Reemergence of Bolivian Hemorrhagic Fever, 2007–2008 | CDC EID

Volume 15, Number 9–September 2009
Letter
Reemergence of Bolivian Hemorrhagic Fever, 2007–2008
Patricia V. Aguilar, Wilfredo Camargo, Jorge Vargas, Carolina Guevara, Yelin Roca, Vidal Felices, V. Alberto Laguna-Torres, Robert Tesh, Thomas G. Ksiazek, and Tadeusz J. Kochel
Author affiliations: US Naval Medical Research Center Detachment, Lima, Peru (P.V. Aguilar, C. Guevara, V. Felices, V.A. Laguna-Torres, T. Kochel); Centro Nacional de Enfermedades Tropicales, Santa Cruz, Bolivia (J. Vargas, Y. Roca); El Servicio Departamental de Salud, Beni, Bolivia (W. Camargo); University of Texas Medical Branch, Galveston, Texas, USA (R. Tesh); and Centers for Disease Control and Prevention, Atlanta, Georgia, USA (T.G. Ksiazek)

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To the Editor: Bolivian hemorrhagic fever (BHF) was first described in 1959 during outbreaks affecting isolated human communities in eastern Bolivia. However, it was not until 1963 that the etiologic agent, Machupo virus, was isolated from the spleen of a patient who died from this disease (1). Although no cases were reported between 1976 and 1993, an outbreak occurred in 1994 and sporadic cases have been observed since then.

In February and March 2007, at least 20 suspected BHF cases (3 fatal) were reported to the El Servicio Departamental de Salud (SEDES) in Beni, Bolivia. In February 2007, physicians at the Hospital Santa Maria Magdalena reported 3 male patients (23, 27, and 29 years of age), who worked at a ranch in Magdalena, Itenez Province (13°14´0´´S, 64°12´0´´W). The patients sought treatment for fever, gingivorrhagia, petechiae, nausea, hematemesis, melena and tremors; clinical laboratory examinations showed thrombocytopenia (<130,000 cells/mm3), leukopenia (<3,900 cells/mm3), and hematuria. Because physicians suspected BHF, patients received supportive therapy, including intravenous hydration, corticoids, antipyretic drugs, antimicrobial drugs, and blood transfusions from donors who had survived Machupo virus infection. Nonetheless, 2 of the patients died 3 and 4 days after admission.

In February 2008, at least 200 suspected new BHF cases (12 fatal) of BHF were reported to SEDES. A febrile hemorrhagic illness developed in a 19-year-old man from Huacaraje, Itenez Province (13°33´S, 63°45´W). On first examination at the Hospital Santa Maria Magdalena, the patient had fever, tremor, gingivorrhagia, petechiae, bruises, asthenia, and anorexia and was admitted with a presumptive diagnosis of BHF. Despite supportive treatment (including administration of plasma from a BHF survivor), his condition worsened; hematemesis, melena, hematochezia, hematuria, anuria, respiratory alkalosis, and metabolic acidosis developed in the patient, eventually resulting in death. A fifth case was detected in a 46-year-old man from San Ramon, Mamore Province (13°17´0´´S, 64°43´0´´W). A febrile hemorrhagic illness developed in the patient and he was admitted to the Hospital German Busch in Trinidad. The patient recently had been hired as a farm worker. When first seen by the attending physicians, he had fever, thrombocytopenia, leukopenia, petechias, tremors, gingivorrhagia, and dehydration, consistent with symptoms of BHF. The patient received hydration, corticoids, antipyretic therapy, and a plasma transfusion from a BHF survivor. The patient's condition improved and he was subsequently discharged from the hospital ≈10 days after admission.

Nineteen serum samples collected from suspected BHF patients, including the cases described above, were sent to Centro Nacional de Enfermedades Tropicales (Santa Cruz, Bolivia) and the US Naval Medical Research Center Detachment (Lima, Peru) for testing. Serum was injected into Vero and C6/36 cells; 10 days later, the cells were tested for flaviviruses, alphaviruses, and arenaviruses by indirect immunofluorescent assay and PCR. Five arenavirus isolates were obtained from the patients described in this report.

Figure

Figure. Neighbor-joining phylogenetic tree of Machupo virus derived from the glycoprotein precursor gene sequence...

Viral RNA was extracted from the cell culture supernatant and the small (S) segment (≈3,200 bp) was amplified and sequenced. Phylogenetic analyses were conducted using the neighbor-joining and maximum likelihood program implemented in PAUP 4.0 software (Sinauer Associates, Inc., Sunderland, MA, USA). Sequence analyses confirmed the isolates as Machupo virus (Figure). Eight major Machupo phylogenetic lineages were described based on partial sequence of the nucleocapsid protein gene (2). We observed a similar tree topology based on the glycoprotein gene sequences (Figure). Two distinct lineages were distinguished among the isolates from the Itenez and Mamore provinces: V and VII and I and II, respectively. The recent isolates (2007–2008) from Magdalena and Huacaraje (Itenez Province) grouped within lineage V whereas the 2008 isolate from San Ramon (Mamore Province) belonged to lineage II. These isolates showed 10% nucleotide difference within the S segment and a 6% amino acid difference within the glycoprotein precursor gene. Similar genetic diversity has been described with Machupo virus and other arenaviruses (2–4). Sequences generated were deposited in GenBank (accession nos. FJ696411, FJ696412, FJ696413, FJ696414, and FJ696415).

It is not known whether lineage VII and I viruses continue to circulate or have been replaced by lineage V and II viruses, respectively. This study confirms the long-term maintenance of distinct phylogenetically forms of Machupo virus in a small area within Beni. Although the distribution of the Machupo virus rodent reservoir (Calomys callosus) extends beyond the geographic area of the Machupo cases described, factors that limit the endemic distribution of the virus remain unknown. However, population differences among C. callosus may account for the natural nidality of BHF (5). Studies are needed to fully identify and understand the ecology of the rodent reservoir and Machupo virus transmission.

Machupo virus continues to cause sporadic cases and focal outbreaks of BHF in Bolivia. We describe 5 confirmed human cases (3 fatal) of Machupo virus infection in Beni Department, Bolivia, an area in which BHF is endemic. That all 5 patients were farmers suggests their infections were probably acquired through occupational exposure. Although all the patients received plasma transfusion from patients who had survived BHF infection, 3 patients still died. An early diagnosis and the rapid administration of Machupo immune plasma before the hemorrhagic phase may increase the chance of survival, as has been observed with other arenavirus infections (6–8).

Acknowledgments
We thank Roxana Caceda and Juan Sulca for excellent technical assistance and the personnel of the Bolivian Ministry of Health for supporting our febrile illness surveillance study. Local activities were approved by the Ministry of Health of Bolivia and were developed by CENETROP personnel through local coordinators.

This study was funded by the United States Department of Defense Global Emerging Infections Systems Research Program, Work Unit No. 800000.82000.25GB.B0016.

References
Johnson KM, Wiebenga NH, Mackenzie RB, Kuns ML, Tauraso NM, Shelokov A, et al. Virus isolations from human cases of hemorrhagic fever in Bolivia. Proc Soc Exp Biol Med. 1965;118:113–8.
Cajimat MN, Milazzo ML, Rollin PE, Nichol ST, Bowen MD, Ksiazek TG, et al. Genetic diversity among Bolivian arenaviruses. Virus Res. 2009;140:24–31. PubMed DOI
Fulhorst CF, Charrel RN, Weaver SC, Ksiazek TG, Bradley RD, Milazzo ML, et al. Geographic distribution and genetic diversity of Whitewater Arroyo virus in the southwestern United States. Emerg Infect Dis. 2001;7:403–7.
Weaver SC, Salas RA, de Manzione N, Fulhorst CF, Travasos da Rosa AP, Duno G, et al. Extreme genetic diversity among Pirital virus (Arenaviridae) isolates from western Venezuela. Virology. 2001;285:110–8. PubMed DOI
Salazar-Bravo J, Dragoo JW, Bowen MD, Peters CJ, Ksiazek TG, Yates TL. Natural nidality in Bolivian hemorrhagic fever and the systematics of the reservoir species. Infect Genet Evol. 2002;1:191–9. PubMed DOI
Fisher-Hoch SP, Tomori O, Nasidi A, Perez-Oronoz GI, Fakile Y, Hutwagner L, et al. Review of cases of nosocomial Lassa fever in Nigeria: the high price of poor medical practice. BMJ. 1995;311:857–9.
Maiztegui JI, Fernandez NJ, de Damilano AJ. Efficacy of immune plasma in treatment of Argentine haemorrhagic fever and association between treatment and a late neurological syndrome. Lancet. 1979;2:1216–7. PubMed DOI
Enria DA, Briggiler AM, Sanchez Z. Treatment of Argentine hemorrhagic fever. Antiviral Res. 2008;78:132–9. PubMed DOI
Figure (please, see the full-text)
Figure. Neighbor-joining phylogenetic tree of Machupo virus derived from the glycoprotein precursor gene sequence...

Suggested Citation for this Article
Aguilar PV, Carmago W, Vargas J, Guevara C, Roca Y, Felices V, et al. Reemergence of Bolivian hemorrhagic fever, 2007–2008 [letter]. Emerg Infect Dis [serial on the Internet] 2009 Sep [date cited]. Available from http://www.cdc.gov/EID/content/15/9/1526.htm

DOI: 10.3201/eid1509.090017

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Genomic Diversity of Oseltamivir-Resistant Influenza Virus A (H1N1), Luxembourg, 2007–08 | CDC EID

Volume 15, Number 9–September 2009
Letter
Genomic Diversity of Oseltamivir-Resistant Influenza Virus A (H1N1), Luxembourg, 2007–08
Nancy A. Gerloff, Jacques R. Kremer, Joël Mossong, Matthias Opp, and Claude P. Muller
Author affiliations: National Health Laboratory, Luxembourg, Luxembourg

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To the Editor: The prevalence of oseltamivir-resistant influenza viruses A (H1N1) (ORVs) increased dramatically worldwide during the winter of 2007–08 (1). Recent reports indicated that by early 2009 most influenza virus (H1N1) strains were resistant to oseltamivir (2). Resistant viruses were transmitted readily and were as viable and pathogenic as oseltamivir-sensitive viruses (OSVs) (3,4). The His275Tyr (N1 numbering) mutation in the neuraminidase (NA) genes of influenza virus A (H1N1) that confers resistance to oseltamivir has previously been associated with impaired virus replication, infectivity, and pathogenicity (5,6).

We investigated the genetic diversity in all 8 gene segments of representative ORVs and OSVs collected during December 2007–March 2008 by the National Influenza Sentinel Surveillance System in Luxembourg (www.lns.public.lu/statistiques/grippe). Phylogenetic analyses were performed by using MEGA version 4.0 (7). Tree topology and posterior probabilities were calculated by using MrBayes version 3 (8). The sequences have been submitted to GenBank (accession nos. FM174406–60, FN401430–45, and FN401487–FN401518).

Figure

Figure. Phylogeny of A) neuraminidase (NA, complete gene) and B) polymerase complex 2 (C-terminal 1,300 nt) genes for selected influenza viruses A (H1N1) from Luxembourg and other countries...

Among 140 viruses, 34 strains (24.3%) had the oseltamivir-resistant genotype (Tyr275) in the NA gene. Bayesian analyses of NA genes showed that ORVs formed a distinct cluster supported by high posterior probability (1.00) on the common node (Figure). One resistant strain (LNS-365) was more closely related to OSVs (minimal Kimura distance 0.3%, 4 nt) than to ORVs (minimal Kimura distance 0.5%, 6 nt). In NA protein, 33 ORVs showed the common Asp354Gly substitution in addition to the Tyr275 mutation. The resistant outlier LNS-365 encoded Asp354 like all other OSVs (n = 106). Similarly, only 4 other resistant strains from Europe from the same season shared Asp354 with all 2007–08 sensitive influenza virus (H1N1) strains (n = 251) available in public databases.

A total of 18–44 selected sequences from each of the other genes of ORVs and OSVs were generated to investigate which other genetic markers cosegregated with the resistant genotype. Sequences derived from most of the other genes (polymerase proteins PB1 and PA, hemagglutinin, nucleoprotein, matrix protein, nonstructural protein) of ORVs and OSVs were phylogenetically interspersed with no distinct clustering. In contrast, matching the phylogeny of NA, PB2 sequences of genotypically resistant strains (n = 14) formed a distinct cluster supported by high posterior probabilities (1.00) and separate from all OSVs (n = 16) and the resistant outlier LNS-365 (Figure). On the PB2 amino acid level, all OSVs and the resistant outlier LNS-365 shared Pro453, whereas all ORV encoded serine at the same position (Ser453). The outlier LNS-365 differed only by 2 aa from OSVs but by 4 aa from the closest resistant strain.

All published PB2 sequences for influenza virus (H1N1) strains collected since 1918 (n = 720) encoded either Pro453 or His453. Until the emergence of ORVs in 2007, Ser453 was only present in 3 other strains (A/Wilson-Smith/1933 and 2 strains from 1976 and 1988). Located on the surface of the PB2 cap-binding domain (9), the Pro453Ser mutation may influence polymerase function and virus replication. The fact that PB2 sequences of ORVs and OSVs are phylogenetically segregated suggests a link between the genetic background and the unexpected fitness of ORVs. There was no amino acid mutation in any of the other genes that segregated in the same way between ORVs and OSVs other than Ser453 (PB2).

Only 1 OSV strain from Luxembourg in 2007–08 (LNS-110) was derived from subclade 2C, unlike the other 139 influenza virus (H1N1) strains (subclade 2B, Figure). Like many other subclade 2C strains, which were recently identified, this virus encoded the amantadine-resistance marker Asn31 in the matrix 2 protein (10). Although we did not identify any reassortments between ORVs and OSVs, double-resistant strains may result from co-circulation of amantadine-resistant and ORVs in the same region.

The phylogeny of ORVs identified worldwide (2) indicates multiclonal emergence of resistance, which suggests that OSVs may contain low levels of ORV subpopulations. Using pyrosequencing, we determined the incidence and level of mixed alleles in codon 275 of the NA gene (CAT, sensitive and TAT, resistant). In 98 clinical specimens (78 sensitive and 20 resistant strains) no minority alleles were reliably detected above the 3% threshold of the assay. Six OSVs with values between 2.1% and 2.9% were further analyzed by cloning of partial NA genes. No evidence of ORVs was found (Tyr275) in 227 clones.

In summary, we have described amino acid markers in NA (Gly354) and PB2 (Ser453) proteins, which were present in ORVs but absent in all OSVs from Luxembourg in 2007–08. ORVs without this background did not spread as efficiently and were rarely found in Europe. At least 1 resistant virus was more similar to OSV, which suggests >2 clones of resistant viruses in Luxembourg, potentially with different viral fitness. We speculate that the unexpected fitness of the 2007–08 influenza viruses (H1N1) may be caused by a new genetic background that is most likely encoded in the PB2 gene.

Acknowledgments
We thank Emilie Charpentier, Aurélie Sausy, and Sébastien de Landtsheer for technical assistance, and the clinicians who participated in the Influenza Sentinel Surveillance in Luxembourg.

N.A.G. was supported by an Aides à la Formation-Recherche fellowship of the Ministry of Research and Higher Education, Luxembourg.

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Figure (please, see the full-text)
Figure. Phylogeny of A) neuraminidase (NA, complete gene) and B) polymerase complex 2 (C-terminal 1,300 nt) genes for selected influenza viruses A (H1N1) from Luxembourg and other countries...

Suggested Citation for this Article
Gerloff NA, Kremer JR, Mossong J, Opp M, Muller CP. Genomic diversity of oseltamivir-resistant influenza virus A (H1N1), Luxembourg, 2007–08 [letter]. Emerg Infect Dis [serial on the Internet]. 2009 Sep [date cited]. Available from http://www.cdc.gov/EID/content/15/9/1523.htm

DOI: 10.3201/eid1509.090452

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Genomic Diversity of Oseltamivir-Resistant Influenza Virus A (H1N1), Luxembourg, 2007–08 | CDC EID

Human Infection with G12 Rotaviruses, Germany | CDC EID

Volume 15, Number 9–September 2009
Dispatch
Human Infection with G12 Rotaviruses, Germany
Corinna Pietsch and Uwe G. Liebert
Author affiliation: Leipzig University, Leipzig, Germany

Suggested citation for this article

Abstract
Rotavirus group A G12 genotypes were detected in 3 (1.5%) of 198 stool samples positive for human rotavirus. G12P[6] was present in 2 samples, and a mixed G3G12P[8] was found in 1 sample. Phylogenetic analysis of complete open reading frames of all 11 genomic RNA segments proved their Wa-like genogroup affiliation.

Rotaviruses are worldwide enteric pathogens in humans and animals. Most prevalent human strains in Europe are group A rotaviruses with genotypes G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8] (1,2). Oral live attenuated vaccines were licensed in 2006 in Germany after they were found to be efficient and safe. Monovalent Rotarix (GlaxoSmithKline Biologicals, Rixensart, Belgium) contains a G1P[8] strain, whereas RotaTeq (Merck and Co., West Point, PA, USA) contains 5 bovine-human reassortants representing genotypes G1–4 in association with P[5] and G6P[8] (3,4). To evaluate rotavirus vaccine efficacy and possible escape of genotypes from host immunity, post-marketing monitoring of circulating wildtype rotaviruses is necessary. That G12, which was detected 1987 in the Philippines, will be a predominant genotype in the future has been assumed. In recent years, a growing number of countries worldwide have reported the occurrence of G12, both sporadically and as a genotype of notable incidence (5).

The Study
A total of 2,752 stool specimens were collected in 2008 from inpatients with diarrhea at Leipzig University Hospital. The samples were derived from 1,804 patients, of whom 715 were <6 years of age. Several aliquots of a 10% stool suspension in phosphate-buffered saline were prepared from each specimen. One aliquot was screened on rotavirus group A antigen by IDEIA (Dako Ltd, Ely, UK). RNA of antigen-positive samples was extracted from a second aliquot by NucliSens easyMAG system (bioMérieux, Boxtel, the Netherlands). Rotavirus gene segments coding for structural viral proteins (VP) 1, VP2, and VP3 were amplified by reverse transcription–PCR with consensus primers (Metabion, Martinsried, Germany): VP1-F 5´-GGCTATTAAAGCTGTACAATG-3´ (nt 1–21), VP1-R 5´-GGTCACATCTAAGCACTC-3´ (nt 3302–3285), VP2-F 5´-GGCTATTAAAGGCTCAAT-3´ (nt 1–18), VP2-R 5´-GGTCATATCTCCACAGTGG-3´ (nt 2717–2699), VP3-F 5´-GGCTATTAAAGCAATACTAG-3´ (nt 1–20), VP3-R 5´-GGTCACATCATGACTAGT-3´ (nt 2591–2574), and the other gene segments with primers described elsewhere (6–8). In the case of gene segments with short untranslated regions, primer ligation and reverse transcription steps were performed as described by Lambden et al. (9). Their primer 2 and gene-specific primers were used in subsequent PCRs to determine entire open reading frames.

Amplicons were gel purified by using Wizard SV Gel and PCR Clean-Up System (Promega, Mannheim, Germany) and sequenced by PCR primers and internal primers with the BigDye Terminator v1.1 Cycle Sequencing kit (Applied Biosystems, Foster City, CA, USA) on an ABI Prism 310 Genetic Analyzer (Applied Biosystems). To separate amplicons of mixed infections, the amplicons were cloned into pCRII-TOPO vector and transformed into Escherichia coli (Invitrogen, Carlsbad CA, USA). Plasmids were purified by QIAprep Spin Miniprep Kit (QIAGEN, Hilden, Germany) and sequenced with M13 primers (Invitrogen). Corrected chromatograms were assembled by using ContigExpress Module of VectorNTI Suite (Invitrogen). Full-length amino acid sequences were aligned by AlignX (a module of VectorNTI Suite). Phylogenetic analyses were conducted by MEGA version 4.0 software (www.megasoftware.net). Genetic distances were calculated by using the Poisson correction parameter. The dendrograms were constructed by the neighbor-joining method. Statistical support was assessed by bootstrapping with 1,000 replicates (10). The sequences of the 2 German G12 rotavirus strains were deposited in GenBank (Table).

Of samples from 1,804 patients, 198 (11%) were positive for rotavirus; of those with positive samples, 174 patients were <6 years of age. Genotyping showed G1P[8], G2P[4], G3P[8], G4P[8], G9P[8], G12P[6], G1G9P[8], and G3G12P[8]. G12 rotavirus strains were detected in 3 stool specimens. Strain GER126–08 was derived from the specimen of a 10-year-old boy who had been admitted to the hospital on April 14 because of a first manifestation of type 1 diabetes. After 1 week, he was transferred to our pediatric ward where diarrhea and vomiting developed 3 days later. Rotavirus genotypes of concurrently hospitalized children on the same ward were distinct. G12 strain GER172–08 was found in samples of 2 bottle-fed young infants who had gastroenteritis: a 15-day-old boy on July 31 and a 30-day-old girl on August 11. There was no direct contact between the 3 patients, and none of the patients or their close family members had any migration background or recent travel abroad. They also had not been previously vaccinated against rotavirus.

Figure 1

Figure 1. Phylogenetic dendrogram of viral protein 7 (VP7) of G12 rotavirus at the amino acid level. Bootstraps values (1,000 replicates) >65% are shown...


Figure 2

Figure 2. Phylogenetic dendrogram of viral protein 4 (VP4) P[6] and P[8] rotaviruses at the amino acid level. Bootstraps values (1,000 replicates) >65% are shown...

Direct sequencing of gel-purified GER126-08 VP7 amplicons resulted in peak superpositions in sequencing gels; the sequencing of clones of this isolate showed a mixture of G3 and G12 genotypes. Contamination was excluded by a second RNA extraction and by comparing sequences to all G3 and G12 types detected in 2008, which were distinct. An amino acid alignment of VP7 G3 showed highest identity (97.5%) to G3 strains from Southeast Asia (data not shown). The G12 genotype belonged to G12-III lineage but was distinct from published full-length sequences, including the only European sequence from Belgium (Figure 1). Highest homology (97.8%) was shown in comparison to the Indian strain 14B2 (Appendix Table). Partial sequence data from European isolates showed no closer relationship, and G12 was not detected in 19 porcine rotaviruses from different piggeries of Saxony (data not shown). Amplification of VP1–4, VP6, and NSP1–5 by gene segment-specific consensus primers within conserved regions in the respective 5´ and 3´ ends was performed. No peak superposition occurred in sequencing of these amplicons, that is, only 1 variant of each genomic RNA segment could be detected. This finding indicates recent reassortment events. Although less likely, minor species of these 10 genomic RNA segments are not entirely excluded; they might have been missed in amplification or cloning and sequencing. The deduced amino acid sequences (Appendix Table) signified a Wa-like genogroup virus (G3G12-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1) (11,12). Its VP4 genomic RNA segment was phylogenetically related to those of Japanese G3 and G4 genotypes (Figure 2) and distinct from all other P[8] genotypes of this collection (data not shown). The origin of the associated genomic RNA segments from either a G3 or a G12 type rotavirus remains unclear, due to the lack of substantial numbers of available full-length sequences.

Rotavirus sequences in stool samples of the 2 newborns were identical. Full-length VP7 amino acid alignments of GER172-08 with published sequences showed 100% homology to G12-III strains ISO16 and ISO29 from India and to strains 04N245, 04N338, 05K021, 05K046, 05K066, and 05N138 from Nepal. The P[6] genotype of GER172-08 was not shared by other rotaviruses in this study, and it showed the highest homology to strains from Bangladesh and South Korea (Figure 2). Analysis of deduced amino acid sequences of all proteins showed a Wa-like genogroup affiliation (G12-P[6]-I1-R1-C1-M1-A1-N1-T1-E1-H1) (data not shown) (11,12). In a comparative analysis, GER126-08 is clearly distinct from GER172-08 (Appendix Table).

Conclusions
Two distinct G12 rotaviruses with different P type associations were detected. The findings suggest that they were individually introduced into the local rotavirus diversity. Although GER172-08 is closely related to Southeast Asian strains, the origin of GER126-08 remains unclear. No conclusively related G12 sequence was published or detected in local piggeries.

A G3 VP7 sequence was found in addition in the stool sample GER126-08, however. Mixed infections are fairly common in crowded areas where population density is high and diverse rotavirus strains are co-circulating. They are required for reassortment, the major mechanism of rotavirus evolution (13,14). Pediatric wards match this setting during rotavirus seasons, because children with different rotavirus strains may be hospitalized simultaneously. Successive nosocomial rotavirus infections during hospitalization may facilitate asynchronous infections that favor reassortment (15). The case of the 10-year-old boy in this study fits into this pattern. Indications for recent reassortment events of strain GER126-08 have been detected consistently.

The detection of G12 rotavirus strains in Germany accentuates the need for extended multicenter studies to describe rotavirus diversity and control vaccine efficacy. Rotaviruses in animals should also be included to evaluate the origin of emerging genotypes.

Acknowledgments
We thank Bernd-Andreas Schwarz for providing the porcine rotavirus samples.

Ms Pietsch is a scientific assistant at Leipzig University. She is currently pursuing research on the molecular epidemiology of virus infections.

Dr Liebert is head of the Department of Virology, Leipzig University. His research focuses on pathogenesis of virus infections and clinical virology.

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Figures
Figure 1. Phylogenetic dendrogram of viral protein 7 (VP7) of G12 rotavirus at the amino acid level. Bootstraps values (1,000 replicates) >65% are shown...
Figure 2. Phylogenetic dendrogram of viral protein 4 (VP4) P[6] and P[8] rotaviruses at the amino acid level. Bootstraps values (1,000 replicates) >65% are shown...

Tables (please, see the full-text)
Table. GenBank accession numbers of both G12 strains of rotavirus found in Germany
Appendix Table. Amino acid identity rates of all genomic RNA segments between rotavirus reference strains and GER126-08

Suggested Citation for this Article
Pietsch C, Liebert UG. Human infection with G12 rotaviruses, Germany. Emerg Infect Dis [serial on the Internet]. 2009 Sep [date cited]. Available from http://www.cdc.gov/EID/content/15/9/1512.htm
DOI: 10.3201/eid1509.090497

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Human Infection with G12 Rotaviruses, Germany | CDC EID