مروري بر بيماري هاي تنفسي حاد آنفلوانزا و كوروناويروس جديد دكتر فرشيد رضايي مركز مديريت بيماري هاي واگير وزارت بهداشت درمان و آموزش پزشكي

Coronavirus Family: Coronaviridae – Two genera: similar on electron microscopy 1.Coronaviruses 2.Toroviruses – similar strategies of replication CoVs are important pathogens in animals causing a wide variety of diseases through a wide variety of pathogenic mechanisms, and they have been noted to mutate frequently and infect new species

In human HCoV-229e HCoV-OC43 NL63: croup HCoV-HKU1 SARS MERS …

Viruses Associated with the Common Cold

Causative Agents of Acute Pneumonia— Viruses Children Common Respiratory syncytial virus Parainfluenza virus types 1, 2, 3 Influenza A virus Uncommon Adenovirus types 1, 2, 3, 5 Influenza B virus Rhinovirus Coxsackievirus Echovirus Measles virus Hantavirus Adults Common Influenza A virus Influenza B virus Respiratory syncytial virus Human metapneumovirus Adenovirus types 4 and 7 (in military recruits) Uncommon Rhinovirus Enteroviruses Echovirus Coxsackievirus Epstein-Barr virus Cytomegalovirus Varicella-zoster virus Parainfluenza virus Measles virus Herpes simplex virus Hantavirus Human herpesvirus 6 Coronavirus (SARS)

Pathogenesis replicate Respiratory CoVs replicate in ciliated epithelial cells of the nasopharynx degeneration 1. Producing direct degeneration of ciliated cells similar rhinovirus 2.Outpouring of chemokines : common-cold symptom complex similar to that produced by rhinovirus infection The incubation period: on average, 2 days Peak of symptoms, and viral shedding: 3 or 4 days after inoculation

Feature CoronavirusesRhinoviruses 229EB814Type 2 (HGP or PK)DC No. of volunteers inoculated No. (%) getting colds13 (50)34 (45)78 (37)77 (31) Incubation period (days) Mean Range Duration (days) Mean76910 Range Maximum no. of handkerchiefs used daily Mean Range Malaise (%) Headache (%) Chill (%) Pyrexia (%) Mucopurulent nasal discharge (%) Sore throat (%) Cough (%) The incubation period of CoV colds was longer and their duration somewhat shorter, but the symptoms were very similar. Asymptomatic infection was sometimes seen and, indeed, has been a feature of serologic surveys of natural infection of children and adults.

More than cold?!? More serious respiratory tract illness is probably also caused by all four strains of non-SARS CoV. All strains can produce pneumonia and bronchiolitis in infants, otitis and exacerbations of asthma in children and young adults, Pneumonia in healthy adults, Exacerbations of asthma and chronic bronchitis in adults, Both serious bronchitis and pneumonia in the elderly, Pneumonia in the immuno-compromised host

pathogenicity Infections with respiratory HCoVs are so common, however, it seems likely that they are responsible for a significant portion of serious lower RTI Basic pathogenicity of HCoVs: o = similar to that of rhinoviruses, and o < clearly less than RSV, influenza, certain adenovirus types Infection with NL63 in children is different from other HCoVs: an excess of children with croup

4 strains of non-SARS CoV : infection without disease + co-infection during disease These characteristics are features of many respiratory pathogens, including particularly rhinoviruses, adenoviruses, human metapneumovirus, human bocavirus, parainfluenza viruses, Although less frequently respiratory syncytial virus and influenza virus.

Receptors The two best defined: 1.Amino-peptidase N for strain HCoV-229e 2.Angiotensin-converting enzyme II for NL63.

Two new Cov 1- Sars 2-Mers Although derived from the CoV family, the two viruses are genetically distinct and do not use the same receptor Close contacts of Mers patients have been infected but no sustained chain of human to human transmission outside the hospital has occurred, unlike the SARS corona virus.

Sars uses angiotensin-converting enzyme 2 (ACE2) as its receptor for cell entry The first symptom in most cases of SARS was fever, usually accompanied by headache, malaise, or myalgia. – This was followed, usually in a few days, but as long as a week later, by a nonproductive cough and, in more severe cases, dyspnea.  Interestingly, upper symptoms such as rhinorrhea and sore throat usually did not occur. Approximately 25% of patients had diarrhea

CXR : frequently abnormal – scattered air-space opacification, usually in the periphery and lower zones of the lung Spiral CT : both ground-glass opacification and consolidation, often in a sub-pleural distribution Lymphopenia: common; CD4 and all T-cell phenotypes Normal or somewhat depressed neutrophils – Neutrophilia was associated with poor outcome CPK, LHD, aspartate aminotransferase: often abnormal

Natural history of Sars in patients ARDS Approximately 25% : severe pulmonary disease that progressed to ARDS – most likely in patients >50 years or with underlying disease such as diabetes, cardiac disease, and chronic hepatitis The overall mortality rate: 9% and 12% – highest rates in the elderly and adults with underlying liver disease. In some patients, during the 2 nd week of illness, as virus levels decreased, suggesting that disease was partly immune mediated

Special patients Pediatric disease was, interestingly, significantly less severe than adult disease, although the features were very similar Disease during pregnancy was very severe, with high mortality in both the mother and fetus Congenital transmission did not occur.

Gastrointestinal coronaviruses and toroviruses 3 outbreaks of NEC (necrotizing enterocolitis) Associated with at least 3 outbreaks of NEC (necrotizing enterocolitis) in newborns gastroenteritis in infants 2 to 12 months Association of gastroenteritis in infants 2 to 12 months of age with the presence of CoVLPs in the stool bloody significant associations between the presence of CoVLPs in the stool and the presence of water-loss stools, bloody stools, abdominal distention, and bilious gastric aspirates CoVLP-associated  possible differences between CoVLP-associated diarrhea and rotavirus diarrhea: – = Fever and vomiting were of very similar incidence occult blood positive 18mucoid 32 – more often occult blood positive (18% vs. 0%) & mucoid (32% vs. 8%) – less watery – less often watery (66% vs. 92%),

Torovirus diarrhea In comparison with rotaviruses or astroviruses: – children were more older: 4 years vs. 2 years – more often acquired in hospital (57% vs. 31%) – Occult blood – Occult blood was more frequent – Symptomatic were more immunocompromised – Vomiting was less frequent

NEUROLOGIC SYNDROMES!? Like many other viruses, CoVs have been sought as possible etiologic agents in multiple sclerosis. (The search in mice and rats) HCoV-OC43 and HCoV-229e have been detected in brain tissue from MS patients using virus isolation, in situ hybridization, immunohistology, and polymerase chain reaction: molecular mimicry of myelin basic protein or HCoV-229e might be a possible pathogenic mechanism Case: a boy with acute demyelinating encephalitis was reported to have HCoV-OC43 RNA in both the respiratory tract and the CSF

Mers vs Sars Both viruses induced a similar activation of pattern recognition receptors and the interleukin 17 (IL-17) pathway, but Mers specifically down-regulated the expression of several genes within the antigen presentation pathway, including both type I and II major histocompatibility complex (MHC) genes. – have an important impact on the ability of the host to mount an adaptive host response. – No glucocorticoids!

Mers

نمودار تعداد موارد بر حسب زمان حج تمتع

جغرافیای کوروناویروس جدید  تا کنون موارد بیماری در 10!!! کشور دنیا از سه قاره آسیا و اروپا و آفریقا دیده شده است و تعداد افراد آلوده به این ویروس 165 نفر شده است که باعث مرگ حدود 39% بیماران (71 نفر ) شده است :  157 مورد قطعی و 19 مورد محتمل  اردن، عربستان، امارات متحده عربی، عمان، کویت، قطر، انگلستان، فرانسه، ایتالیا و تونس این ویروس جدید که در سپتامبر 2012 كشف شد در ابتدا EMC ( به نام مرکز هلندی کاشف ) و سپس کوروناویروس جدید نام گرفته بود، بعد از جلسات متعدد دارای نام جدیدی شد که به معنای ویروس عامل سندرم تنفسی کشنده خاور میانه می باشد : MERS-CoV 25 اغلب (132) از این بیماران در عربستان تشخیص داده شده اند

پرستاران زن جوان افزایش موارد بدون علامت و کم علامت و کاهش میزان کشندگی بیماری محاسبه شده؛ 49%=‍CFR

ابتلا موارد متعدد در بيمارستان شرق عربستان

مقاله NEJM در ابتلا پرسنل پزشکی اهمیت موارد کم علامت و بدون علامت : امکان انتقال ویروس به افراد تماس یافته در جامعه و بیمارستان و ابتلا افراد گروه پرخطر 1. یک سواب نازوفارنژیال و انجام دو نوبت PCR 2. پرستاران علامتدار طی یکهفته بدون هیچ عارضه ای بهبود یافتند. 3. عربستان تمام موارد تماس خانگی را بررسی نمود که تقریبا 3000 نفر شده است ! ؟

نزدیکترین ویروس شناخته شده به کوروناویروس جدید در آفریقای جنوبی دیده شد Neoromicia zuluensis در ژن RdRp كوروناويروس هاي جدا شده از غنا و چين 5.5% تفاوت سكانس ژنتيكي با MERS داشتند و ويروس جدا شده در اروپا نيز 1.8% اختلاف داشت. اما PML-2011 كه در تحقيقات 2011 و 2012 جدا شده بود تنها 0.3 درصد تفاوت دارد.

رد پای کوروناویروس جدید در شترهای عمانی در مطالعه اي كه يك تيم بين المللي با سرپرستي دكتر چنتل روزكن در انستيتو ملي سلامت و بهداشت محيط هلند انجام داده است اولين نتايج بررسي حيوانات به عنوان مخزن احتمالي ويروس MERS-CoV در طبيعت منشر شده است. گاو، گوسفند، شتر يك كوهانه، شترهاي باختري دوكوهانه، شترهاي بدون كوهان آمريكاي جنوبي

کدام حیوان مخزن است ! نمونه خون 349 حيوان از كشورهاي عمان، هلند، اسپانيا و شيلي شامل شتر يك كوهانه عربي ( هندي ) ، گاو، بز و گوسفند و شترهاي نژاد ديگر ( شترهاي دو كوهانه باختر، ‌ شتر بدون كوهان لاما و آلپاكا آمريكاي جنوبي ) مورد تحقيق و بررسي قرار گرفت. تمام 50 نمونه خون شترهاي يك كوهانه عربي كشور عمان از نظر ويروس MERS-CoV مثبت گزارش گرديد ( بين 1/320 و 1/2560) FAO در بيانيه اي اعلام نمود از اعلام شتر بعنوان مخزن قطعي پرهيز شود. هرچند كشف كوروناويروس نزديك به MERS در جغرافياي نزديك و با گستره فراوان آنرا بعنوان مخزن احتمالي بيماري درصدر ليست قرار داده است. و اکنون ویروس را بطور دقیق از شتر جدا نموده اند اما هنوز برای اثبات وجود شتر در چرخه انتقال چند قدم باقی است

صنعت گوشت شتر 5 كشور اول پرورش دهنده و صادركننده شتر در دنيا كشورهاي آفريقايي هستند. استراليا نيز وارد كننده مهم شتر به خاورميانه است. دو كشور اول توليد كننده و صادركننده گوشت شتر نيز عربستان سعودي و امارات متحده عربي هستند بيشتر شترهاي وارده به عربستان و امارات نيز از كشور عمان كه بواسطه از آفريقا وارد مي شود به اهميت مطالعه فوق الذكر مي افزايد.

سناریوی انتقال و گسترش بیماری

Reproductive number قدرت انتقال از انسان به انسان و توانایی ایجاد همه گیری قابل توجه را با Rn نشان می دهیم. 3 سناریوی احتمالی : – R کمتر از یک؛ محتمل ترین --< RN=0.6 – 0.68 – R بیشتر از یک ولی همه گیری در جامعه پایدار نشده است – R بیشتر از 1 و همه گیری ماندگار شده بین انسانها مراقبت روتین بیماری ها دچار تورش و تاخير ثبت نمونه می شود : بطوریکه بیشتر موارد شدید را ثبت می نمایدو در نتیجه CFR ، بطور كاذب بالا ثبت می گردد

راه حل هاي توصيه شده نظام مراقبت سريع و تقويت شده ؛ ‌ تسهيل خدمات تشخيصي و درماني همكاري دقيق و نزديك كليه سازمان هاي مرتبط با سفرهاي بين المللي در تسهيل بيماريابي، ارائه آموزش و خدمات بهداشتي به مسافران هشياري و مراقبت بيماري در مخازن مطرح شده و حيواناتي كه زندگي نزديكي با انسان دارند افزايش آگاهي عموم مردم و بالاخص افراد در معرض خطر عدم غفلت از مسافرين بين المللي مبتلا به MERS و كشف سريع موارد علامتدار

كشورهايي كه بيشترين زائر را دارند

توصيه هاي بهداشتي به مسافران و زائرين

Transmission within health facilities accounted for 21 of 23 cases in a recent report. The incubation period in that outbreak was 5.2 days (95%CI: days). No animal source has been identified although the virus has been isolated from bat guano found in a cave near the home of a case. Results of serological screening animals and humans have not yet been reported!!! No vaccine or antiviral therapy is available..

Mandell 2013 A few cases with mild or asymptomatic infection have been identified. Symptoms are chills, cough, fever, dyspnea, myalgia and, less often, nausea and diarrhea. The majority of cases have been in patients with co-morbidities.

SYMPTOMS OF MERS-CoV INFECTION All of the laboratory confirmed cases have had respiratory disease as part of the illness, and most have had severe acute respiratory disease requiring hospitalization. Reported clinical features include acute respiratory distress syndrome (ARDS), renal failure requiring hemodialysis, consumptive coagulopathy, and pericarditis. Many patients have also had gastrointestinal symptoms including diarrhea during the course of their illness. One patient, who was immunocompromised, presented with fever, diarrhea and abdominal pain, but had no respiratory symptoms initially; pneumonia was identified incidentally on a radiograph. The National Institutes of Health has found that a combination of two antiviral drugs, ribavirin and interferon-alpha 2b, can inhibit replication of the virus in cell cultures [Falzarano et al. Inhibition of novel human coronavirus-EMC replication by a combination of interferon-alpha2b and ribavirin. Scientific Reports 2013, doi: /srep01686]

INFECTION PREVENTION AND CONTROL Routine Practices Routine Practices: For all patients, at all times, in all healthcare settings including when performing a point-of-care risk assessment, and adherence to respiratory hygiene and hand hygiene. Contact and Droplet Precautions Contact and Droplet Precautions (should be implemented empirically): – Wear gloves and a long-sleeved gown upon entering the patient's room, cubicle or designated bed space. – Wear facial protection (surgical or procedure mask and eye protection, or face shield, or mask with visor attachment) when within two metres of a patient suspected or confirmed to have MERS-CoV infection. Airborne Precautions Airborne Precautions – When performing aerosol-generating medical procedures (AGMPs). – A respirator and face/eye protection should be used by all HCWs present in a room where an AGMP is being performed on a patient suspected or confirmed to have MERS-CoV infection. – Whenever possible, AGMPs should be performed in an airborne infection isolation room. Airborne Precautions (including respirator and airborne infection isolation room) is the recommendation from the Centers for Disease Control (CDC) in the U.S.

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44 Keeping N95 after use

Clusters

Up to Dec 2013

كشورهاي عربي گرفتار بيماري اردن عربستان امارات قطر كويت عمان

KSA; The center of disease

شهر هاي زيارتي مدينه مكه

Seventy-one of the 165 cases have died (crude mortality rate 43%).

اقدامات بهداشتي 51 اقدامات غيربهداشتي كه ممكن است باعث انتقال ببماري گردد

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برخي تعاريف مورد نياز خوشه : –دو نفر يا بيشتر از افرادي كه در عرض 14 روز علائم بيماري را از خود بروز مي دهند و در يك مجموعه ( مانند مدرسه، محل كار مشترك، ‌ يك خانوار، بيمارستان، اقامتگاه مشترك، ‌ كمپ موقت يا دائم و پادگان ها ) حضور داشته اند تماس نزديك : –هركسي كه از بيمار مراقبت نموده باشد، اعم از پرسنل بهداشتي درماني يا اعضاء خانواده بيمار، و يا هركس كه تماس فيزيكي نزديك مشابه ( مكالمه چهره به چهره بيش از 15 دقيقه، دست دادن ، روبوسي مخصوصا در فاصله نزديك زير 1 متر بدون استفاده از ماسك مناسب ) با بيمار داشته باشد. –هركسي كه با بيمار قطعي و يا محتمل ( درحاليكه بيمار علامتدار بوده است ) در مكان بسته مشترك حضور داشته باشد ( اعم از اينكه زندگي كند و يا براي ملاقات درآن مكان حضور يافته باشد )

تعريف موارد مشكوك 1- فردي كه دچار عفونت تنفسي حاد ( عفونت ريه ( پنوموني كلينيكي يا راديولوژيكي ) يا سندرم دشواري تنفسي حاد (ARDS)) شده و نياز به بستري در بيمارستان داشته باشد و بعلاوه يكي از موارد زير باشد : 1. بيماري جزو يك ابتلاي خوشه اي (cluster) باشد كه در عرض 14 روز رخ داده باشد، بدون توجه به سابقه مسافرت و يا اقامت بيمار، ‌ مگر اينكه عامل ديگري براي بيماري شناخته شده باشد. 2. بيماري در يكي از پرسنل بهداشتي درماني رخ داده باشد كه در محيطي كار مي كنند كه از يك بيمار مبتلا به عفونت حاد تنفسي مراقبت شده است، علي الخصوص بيماراني كه در بخش مراقبت ويژه (ICU) بوده اند، بدون توجه به سابقه مسافرت و يا مكان اقامت. 3. سير بيماري، علي رغم درمان مناسب، بطور غير قابل انتظاري شديد باشد، بدون توجه به سابقه مسافرت و يا مكان اقامت، ‌ حتي اگر علت ديگري براي بيماري تعيين شده باشد، اما آن علت نتوانسته باشد بطور كامل توجيه كننده نماي باليني يا سير بيماري باشد.

ادامه تعريف موارد مشكوك 2- فردي با بيماري تنفسي حاد ( با هر درجه اي از شدت ) ، كه 14 روز قبل از شروع بيماري سابقه تماس نزديك با يك مورد علامتدار ( قطعي يا محتمل ) مبتلا به عفونت ويروس كوروناويروس Mers-CoV داشته باشد  البته پزشكان بايد به خاطر داشته باشند ممكن است تظاهرات نامعمول غيرتنفسي ( مخصوصا در بيماران مبتلا به نقص ايمني ) نيز مشاهده شود :  ممكن است اين بيماري در مبتلايان به نقص ايمني بصورت اسهال تظاهر يابد.

توصيه فعلي سازمان جهاني بهداشت حداقل درخواست : نمونه گيري در تمام موارد مشكوك مبتلا به بيماري تنفسي شديد كه نياز به ونتيلاتور داشته باشد انجام گردد –در هر منطقه اي اگر ظرفيت هاي اقتصادي اجازه مي دهد موارد خفيفتر پنوموني و بيماري تنفسي نيز بررسي مي گردد

تعريف ساير موارد مورد محتمل : –بيمار مشكوكي كه تماس نزديك با بيمار قطعي داشته باشد ولي نتايج آزمايش قطعي نداشته باشد، مانند مثبت بودن تنها يك هدف ژنتيكي با روش PCR و يا منفي بودن تست به دليل ناكافي و نامناسب بودن نمونه ارسالي يا عدم دسترسي به بيمار يا نمونه مورد قطعي : –بيمار مشكوكي كه در تست PCR حداقل دو هدف ژنتيكي بررسي شده، مثبت شده باشد كليه موارد محتمل و قطعي بايد بطور فوري به اطلاع مسئولين بهداشتي منطقه رسيده و در عرض 24 ساعت از زمان دسته بندي بيمار ( محتمل يا قطعي ) ، به مسئول IHR كشوري اطلاع داده شود.

نمونه هاي مورد نياز هرچند نمونه ترشحات قسمت تحتاني ريه ارجح هستند اما توصيه مي شود كه نمونه هاي متعدد، در زمان هاي مختلف و از قسمت هاي مختلف تهيه شود. نمونه هاي كوروناويروس MERS براي حمل و نقل در گروه B مواد بيولوژيك قرار دارند.

انواع نمونه توصيه شده 1. نمونه هاي ترشحات تنفسي تحتاني ( خلط، آسپيره ترشحات ناي، شستشوي ترشحات برونش ): بيشترين تيتر ويروس 2. ترشحات فوقاني دستگاه تنفس : علي الخصوص هنگامي كه امكان تهيه نمونه از ترشحات تحتاني وجود نداشته باشد 3. سرم : دو نمونه به فاصله حداقل 3 هفته از همديگر ( تا اطلاع ثانوي و معرفي روش سرولوژي معتبر در فريزر نگهداري مي شود ). نمونه اول در هفته اول بيماري تهيه مي گردد 4. مدفوع : در كنار سرم و نمونه ترشحات تحتاني تنفسي از نمونه هاي ارجح محسوب مي شود. اما تا اطلاع ثانوي ارسال نگردد.

نمونه ترشحات تنفسي نمونه تنفسي ترجيحا بايد در هفته اول علامتدار شدن و قبل از مصرف داروي ضدويروس تهيه شود اما بعد از يك هفته نيز مخصوصا اگر علامتدار است مي توان نمونه تحتاني تنفسي تهيه نمود. خلط : خلطي كه بطور طبيعي ايجاد مي شود ( امكان تهيه نمونه سرپايي ) –جمع آوری خلط القا شده می تواند باعث آلوده شدن کادر درمانی مسئول گردد و نياز به استفاده از ماسك و لباس مناسب دارد ! لاواژ ترشحات برونشلاواژ ترشحات برونش و آسپيره ترشحات ناي : نياز به اينتوبه بودن بيمار دارد و به همين دليل در آي سي يو انجام ميشود. –بهترين نمونه لاواژ ترشحات برونش (BAL) است. سواب حلق : در كشف ويروس حساسيت كمتري دارد اما توصيه مي شود حتما نمونه صحيح آن در كنار نمونه هاي تحتاني تنفسي تهيه و ارسال شود.

Influenza (H1 to H16) (N1 to N9) (H1 to H16) (N1 to N9) Today: more than H18 and N10 17 December: Human fatal case of avian influenza A H10N8 in china (Jiangxi)

Shift and drift

Differences among Influenza A, B, and C Viruses Influenza AInfluenza BInfluenza C Genetics8 gene segments 7 gene segments Structure10 viral proteins11 viral proteins9 viral proteins M2 uniqueNB uniqueHEF unique Host range Humans, swine, equine, avian, marine mammals Humans onlyHumans and swine EpidemiologyAntigenic shift and drift Antigenic drift only; two main lineages co-circulate Antigenic drift only; multiple variants Clinical features May cause large pandemics with significant mortality in young persons Severe disease generally confined to older adults or persons at high risk; pandemics not seen Mild disease without seasonality

Correlation of non-virologic indexes of epidemiologic influenza with number of isolates

A 53-year-old man with Influenza A (H1N1) virus pneumonia and bacterial coinfection (Staphylococcus aureus) and severe respiratory failure (PaO 2 /FIO 2 at admission 250). Chest computed tomography shows prominent interstitial opacity with ground-glass areas and air bronchogram.

A 39-year-old man with Influenza A (H1N1) virus pneumonia and severe respiratory failure (PaO 2 /FIO 2 at admission 170) respiratory underwent non- invasive mechanical ventilation: chest computed tomography shows alveolar consolidation, peripheral ground- glass opacities in both middle and lower lung zones and small bilateral pleural effusions.

A 28-year-old man with severe obesity and sleep apnea with influenza A (H1N1) virus pneumonia and not severe respiratory failure (PaO 2 /FIO 2 at admission 340): chest computed tomography exhibits bilateral, patchy, confluent areas of consolidation in all lung zones

A 40-year-old man with influenza A (H1N1) virus pneumonia and severe respiratory failure (paO 2 /FIO 2 at admission 180) who underwent non-invasive mechanical ventilation: chest computed tomography demonstrates patchy bilateral interstitial infiltrates and peripheral focal ground-glass opacities in the middle and lower lung zones.

H7, H9 and H5 Infections with H7 Viruses – The most characteristic finding in human cases has been conjunctivitis – A marine worker: during an outbreak of H7N7 viral pneumonia that involved seals, – In 2003, a large outbreak of H7N7 infection involved poultry in the Netherlands. Conjunctivitis was also the most common clinical presentation in this outbreak, but one fatal case of progressive pneumonia was reported in a veterinarian who had visited the poultry farm Infections with H9 Viruses: mild influenza-like illness – The H9N2 virus infection of humans was described in two children with mild influenza-like illness in Hong Kong in 1999 – H9N2 virus was also isolated in cultures of nasopharyngeal aspirate from another child with similar clinical illness in 2003 in Hong Kong – contact with infected poultry Infections with H5 Viruses: avian H5N1 – Human cases have been reported since 1997:assigned to clade 3 – A second wave of infections was noted in 2004 from viruses of clade 1 – In the most recent years, human infections have primarily been from clade 2 viruses.

H7N9 in China 1.The first patient was an 87-year old male with a history of COPD with no known exposure to birds. 2.The second was a 27-year-old man who worked at a market selling live birds. 3.The third was a 35-year-old woman who had visited a poultry market one week prior to onset of illness.

Influenza antiviral medications Medications are an important adjunct to influenza vaccine – used to treat influenza or to prevent influenza. Two FDA-approved are recommended for use in the 2013 inf. season: – oseltamivir zanamivir – oseltamivir (Tamiflu®) and zanamivir (Relenza®). – Neuraminidase inhibitors – Neuraminidase inhibitors: A and B 1.have activity against both influenza A and B 2.Limit release of virus from infected cells and for spread within the respiratory tract Antiviral resistance to oseltamivir and zanamivir among circulating influenza viruses is currently low – But can emerge during or after treatment in immuno-suppressed, … – Oseltamivir therapy has been associated with recovery of viruses with reduced susceptibility in about 1% of immunocompetent adult and 18% of pediatric recipients  Resistant variants has not been associated with clinical worsening

Molecular form  Oseltamivir is active against viruses containing all nine influenza A in nature, including more recent pathogenic avian viruses (H5N1, H7N7, H9N2)  Influenza B viruses are 10-fold to 20-fold less susceptible than influenza A  The metabolite is approximately 50-fold more potent than prodrug  combined with M2 inhibitors or ribavirin show enhanced antiviral activity (H5N1) removed by hemodialysis  Excreted unchanged through the kidney and removed by hemodialysis  Probenecid reduces renal clearance of oseltamivir by about 50% Compared with oseltamivir, zanamivir is more active against influenza B, (that this difference is clinically important). Zanamivir inhibits certain influenza A variants that are resistant to oseltamivir. Combinations of zanamivir + rimantadine inhibit strains of influenza A/H1N1 and H3N2 viruses synergistically Only 1 variant, cross-resistant to oseltamivir has been recovered from an immunocompromised child with prolonged virus excretion despite receiving nebulized zanamivir. Zanamivir should not be administered from 48 hours before to 2 weeks after intranasal administration of an attenuated influenza vaccine Side effect: a potential risk for acute bronchospasm, respiratory arrest, or worsening of COPD accompanied by pulmonary edema after zanamivir inhalation, particularly in patients with underlying airway disease Oseltamivir phosphate (Tamiflu) Relenza

Antiviral Medications Recommended for Treatment and Chemoprophylaxis of Influenza Antiviral Agent Activity Against Use FDA Approved For Not Recommended for Use in Adverse Events Oseltamivir (Tamiflu) A and B Treatment >=2 wks N/A Adverse events : nausea, vomiting. Japanese Sporadic, transient neuropsychiatric events (self injury or delirium) mainly reported among Japanese adolescents and adults. Chemo- prophylaxis >=1 yr N/A Zanamivir (Relenza) A and B Treatment >=7 yrs people with underlying respiratory disease (e.g., asthma, COPD) Allergic reactions : oro-pharyngeal or facial edema. Adverse events: diarrhea, nausea, sinusitis, nasal signs and symptoms, bronchitis, cough, headache, dizziness, and ENT infections. Chemo- prophylaxis >=5 yrs

Summary of Influenza Antiviral Treatment Recommendations Early antiviral treatment: especially within 48 hours of illness onset. 1.shorten the duration of fever and symptoms 2.reduce the risk of complications (e.g., otitis media in young children, pneumonia, respiratory failure) and death, and 3.shorten the duration of hospitalization. Treatment: as early as possible for any patient with confirmed or suspected influenza who – is hospitalized; – has severe, complicated, or progressive illness; or – is at higher risk for influenza complications: 1.children aged <2 years; 2.adults aged >65 years; 3.persons with chronic pulmonary (including asthma), cardiovascular (except hypertension alone), renal, hepatic, hematological (including sickle cell disease), metabolic disorders (including diabetes mellitus), or neurologic and neurodevelopment conditions (including disorders of the brain, spinal cord, peripheral nerve, and muscle such as cerebral palsy, epilepsy [seizure disorders], stroke, intellectual disability [mental retardation], moderate to severe developmental delay, muscular dystrophy, or spinal cord injury); 4.persons with immuno-suppression, including that caused by medications or by HIV infection; 5.women who are pregnant or postpartum (within 2 weeks after delivery); 6.persons aged <19 years who are receiving long-term aspirin therapy; 7.Morbidly obese (i.e., BMI>=40); 8.residents of nursing homes and other chronic-care facilities

Higher risk for influenza complications chronic pulmonary (including asthma), chronic cardiovascular (except hypertension alone), chronic renal, chronic hepatic, chronic hematological (including sickle cell disease), chronic metabolic disorders (including diabetes mellitus), or chronic neurologic and neurodevelopment conditions – disorders of the brain, spinal cord, peripheral nerve, and muscle  cerebral palsy,  epilepsy [seizure disorders],  stroke,  intellectual disability [mental retardation],  moderate to severe developmental delay,  muscular dystrophy,  spinal cord injury

Starting antiviral treatment Might still be beneficial in patients with severe, complicated or progressive illness and in hospitalized patients when started after 48 hours of illness onset – For example, antiviral treatment of pregnant women (of any trimester) with influenza A (2009 H1N1) virus infection has been shown to be most beneficial in preventing respiratory failure and death when started within less than 3 days of illness onset, but still provided benefit when started 3– 4 days after onset compared to 5 or more days (Siston, et al JAMA 2009) Starting antiviral after illness onset had improved survival compared to untreated critically ill patients (Louie, et al. Clinical Infectious Diseases 2012). Another systematic review found treatment up to 2 days a 65% mortality reduction – Decisions about starting antiviral treatment should not wait for laboratory confirmation of influenza

Treatment after vaccination History of influenza vaccination does not rule out ill compatible History of influenza vaccination does not rule out the possibility of influenza virus infection in an ill patient with clinical signs and symptoms compatible with influenza (While influenza vaccination is the first and best way to prevent influenza) Outpatient: Tx can be considered for any previously healthy, symptomatic outpatient not at high risk with confirmed or suspected influenza on the basis of clinical judgment, if treatment can be initiated within 48 hours of illness onset.

Dosage and Duration Recommended Dosage and Duration of Treatment or Chemoprophylaxis for Influenza Antiviral Medications Antiviral Agent UseChildrenAdults Oseltamivir (Tamiflu) Treatment If <1 yr old, the dose is 3 mg/kg/dose twice daily 75 mg twice daily If >1 yr and weigh <15 kg, the dose is 30 mg twice a day. (per/Kg) If >1 yr and weigh >15 to 23 kg, the dose is 45 mg twice a day. If >1 yr and weigh >23 to 40 kg, the dose is 60 mg twice a day. If >1 yr and weigh >40 kg, the dose is 75 mg twice a day. Chemo-prophylaxis (Not FDA approved for use in children younger than 1 yr old) If child is <3 months old, chemoprophylactic use is not recommended unless situation is judged critical due to limited data on use in this age group. 75 mg once daily If child is > 3 months and <1 yr old, dose is 3 mg/kg/dose once per day. If >1 yr, and <weigh 15 kg, the dose is 30 mg once a day. (per child's weight) If >1 yr and weigh >15 to 23 kg, the dose is 45 mg once a day. If >1 yr and weigh >23 to 40 kg, the dose is 60 mg once a day. If >1 yr and weigh > 40 kg, the dose is 75 mg once a day. Zanamivir (Relenza) Treatment 10 mg (2 inhalations) twice daily (Not FDA approved for use in children <7 yrs old) 10 mg twice daily Chemo- prophylaxis 10 mg (2 inhalations) once daily (Not FDA approved for use in children <5 yrs old) 10 mg once daily

Duration of Treatment or Chemoprophylaxis

H5N1 treatment Oseltamivir Oseltamivir, possibly at a higher dose (150 mg twice daily [bid]) and for a longer duration (10 days) than standard therapy. Inhaled zanamivir is not recommended because of the lack of data in human cases of influenza A (H5N1) Adamantanes are not recommended as first-line therapy!!! – Combinations of oseltamivir + amantadine or rimantadine might be considered if the viral isolate is likely to be susceptible to M2 inhibitors Corticosteroids have not been shown to be beneficial and may be harmfu

Antiviral Chemoprophylaxis Antiviral medications are approximately 70% to 90% effective in preventing influenza and are useful adjuncts to influenza vaccination. Not routine or widespread use of antiviral medications for chemoprophylaxis: resistant viruses could emerge. Close monitoring and early initiation After a suspected exposure for some persons: Close monitoring and early initiation of antiviral treatment is an alternative to chemoprophylaxis. Drug Following vaccination: until immunity after vaccination develops – Antibody development after vaccination takes about 2weeks in adults and can take longer in children depending on age and vaccination history). If >48 hours If >48 hours have elapsed since the last exposure: chemoprophylaxis generally is not recommended Patients receiving antiviral chemoprophylaxis should be encouraged to seek medical evaluation as soon as they develop a febrile respiratory illness that might indicate influenza.

Antiviral Chemoprophylaxis after exposure to an infectious person: 1.Prevention in high risk during the first two weeks following vaccination after expo… 2.severe immune deficiencies or who might not respond to vaccination, such as persons receiving immunosuppressive medications, after expo… 3.high risk for complications who cannot receive vaccine due to a contraindication after expo… Prevention among residents of institutions, such as long-term care facilities, during influenza outbreaks in the institution. (IDSA guidelines)

Chemoprophylaxis to control outbreaks in nursing home residents use chemoprophylaxis for 1.all exposed or at-risk residents and 2.unvaccinated health care personnel is recommended. chemoprophylaxis – Oseltamivir chemoprophylaxis: influenza A – M2 inhibitor : influenza B For vaccinated staff, antiviral chemoprophylaxis can be administered up to 2 weeks following influenza vaccination. IDSA guidelines

Children at higher risk for complications Although all children <5 years are high risk, the highest risk is for those <2 years, infants <6 months highest hospitalization and death rates among

Must consider  When considering use of antiviral medications, clinicians must consider: 1.the patient’s age, 2.weight and 3.renal function; 4.presence of other medical conditions; 5.indications for use ( i.e., chemoprophylaxis or therapy ); 6.the potential for interaction with other medications.

Health departments The likelihood of influenza virus infection in a patient: – the prevalence of influenza activity in the local community and on the patient’s signs and symptoms.  For information on local community influenza activity, clinicians should contact their local and state health departments.  knowledge about other respiratory viruses ( respiratory syncytial virus, rhinovirus, parainfluenza virus, or human metapneumovirus ) as well as influenza virus strains circulating in the community is important for treatment decisions.

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