‫مروري بر بيماري هاي تنفس ي 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
Virus Group
Rhinoviruses
Coronaviruses
Parainfluenza virus
Respiratory syncytial virus
Influenza virus
Adenovirus
Metapneumovirus
Other viruses:
enteroviruses, bocavirus
Antigenic Types
Over 100 types
5 types
5 types
2 types
3 types*
51 types
2 types
Percentage of Cases
50-40
15-10
5
5
30-25
10-5
5
Causative Agents of Acute Pneumonia—
Viruses
Adults
Children
Common
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
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
• Respiratory CoVs replicate in ciliated epithelial
cells of the nasopharynx
1. Producing direct degeneration of ciliated cells
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
No. of volunteers inoculated
No. (%) getting colds
Incubation period (days)
Mean
Range
Duration (days)
Mean
Range
Maximum no. of handkerchiefs used daily
Mean
Range
Malaise (%)
Headache (%)
Chill (%)
Pyrexia (%)
Mucopurulent nasal discharge (%)
Sore throat (%)
Cough (%)
Coronaviruses
229E
B814
Rhinoviruses
Type 2 (HGP or PK) DC
26
)50( 13
75
)45( 34
213
)37( 78
251
)31( 77
3.3
4-2
3.2
5-2
2.1
5-1
2.1
4-1
7
18-3
6
17-2
9
19-3
10
26-2
23
105-8
46
85
31
23
0
54
31
21
120-8
47
53
18
21
62
79
44
14
38-3
28
56
28
14
83
87
68
18
60-33
25
56
15
18
80
73
56
)77( 10
)71( 24
)80( 63
)47( 36
)15( 2
)20( 7
)15( 12
)36( 28
)8( 1
)9( 3
)5( 4
)17( 13
No. (%) of colds of indicated severity
Mild
Moderate
Severe
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
• 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 2nd 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
• Associated with at least 3 outbreaks of NEC (necrotizing
enterocolitis) in newborns
• Association of gastroenteritis in infants 2 to 12 months of age
with the presence of CoVLPs in the stool
• 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
 possible differences between CoVLP-associated diarrhea and
rotavirus diarrhea:
– = Fever and vomiting were of very similar incidence
– more often occult blood positive (18% vs. 0%) & mucoid (32% vs. 8%)
– 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 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
‫این ویروس جدید که در سپتامبر ‪ 2012‬كشف شد در ابتدا ‪( EMC‬به 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 تنفس ی کشنده‬
‫خاور میانه می باشد‪MERS-CoV :‬‬
‫‪ ‬تا کنون موارد بیماری در !!!‪ 10‬کشور دنیا از سه قاره‬
‫آسیا و اروپا و آفریقا دیده شده است و تعداد افراد آلوده‬
‫به این ویروس ‪165‬نفر شده است که باعث مرگ حدود‬
‫‪ %39‬بیماران (‪71‬نفر) شده است‪:‬‬
‫‪ 157 ‬مورد قطعی و ‪ 19‬مورد محتمل‬
‫‪ ‬اردن‪ ،‬عربستان‪ ،‬امارات متحده عربی‪ ،‬عمان‪ ،‬کویت‪ ،‬قطر‪ ،‬انگلستان‪،‬‬
‫فرانسه‪ ،‬ایتالیا و تونس‬
‫اغلب )‪(132‬از این بیماران در‬
‫عربستان تشخیص داده شده اند‬
‫‪25‬‬
‫پرستاران زن‬
‫جوان‬
‫افزایش موارد بدون عالمت و کم عالمت و‬
‫کاهش میزان کشندگی بیماری محاسبه شده؛‬
‫‪CFR‍=%49‬‬
‫ابتال موارد متعدد در بيمارستان شرق عربستان‬
‫مقاله ‪ NEJM‬در ابتال پرسنل پزشکی‬
‫اهمیت موارد کم عالمت و بدون عالمت‪:‬‬
‫•امکان انتقال ویروس به افراد تماس یافته در جامعه و بیمارستان و ابتال افراد گروه پرخطر‬
‫‪ .1‬یک سواب نازوفارنژیال و‬
‫انجام دو نوبت ‪PCR‬‬
‫‪ .2‬پرستاران عالمتدار طی‬
‫یکهفته بدون هیچ عارضه‬
‫ای بهبود یافتند‪.‬‬
‫‪ .3‬عربستان تمام موارد تماس‬
‫خانگی را بررسی نمود که‬
‫تقریبا ‪ 3000‬نفر شده‬
‫است!؟‬
‫نزدیکترین ویروس شناخته شده به کوروناویروس‬
‫جدید در آفریقای جنوبی دیده شد‬
‫‪Neoromicia‬‬
‫‪zuluensis‬‬
‫•در ژن ‪ RdRp‬كوروناويروس هاي جدا شده از غنا و چين ‪ %5.5‬تفاوت سكانس ژنتيكي با‬
‫‪ MERS‬داشتند و ويروس جدا شده در اروپا نيز ‪ %1.8‬اختالف داشت‪.‬‬
‫•اما ‪ PML-2011‬كه در تحقيقات ‪ 2011‬و ‪ 2012‬جدا شده بود تنها ‪ 0.3‬درصد تفاوت‬
‫دارد‪.‬‬
‫رد پای کوروناویروس جدید در شترهای عمانی‬
‫در مطالعه اي كه يك تيم بين املللي با سرپرستي دكتر چنتل روزكن در انستيتو ملي‬
‫سالمت و بهداشت محيط هلند انجام داده است اولين نتايج بررس ي حيوانات به‬
‫عنوان مخزن احتمالي ويروس ‪ MERS-CoV‬در طبيعت منشر شده است‪.‬‬
‫گاو‪ ،‬گوسفند‪ ،‬شتر يك كوهانه‪ ،‬شترهاي باختري دوكوهانه‪ ،‬شترهاي بدون‬
‫كوهان آمريكاي جنوبي‬
‫کدام حيوان مخزن است!‬
‫• نمونه خون ‪ 349‬حيوان 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 الما و آلپاكا آمريكاي جنوبي) مورد تحقيق و‬
‫بررس ي قرار گرفت‪.‬‬
‫• تمام ‪ 50‬نمونه خون شترهاي يك كوهانه عربي كشور عمان از نظر ويروس‬
‫‪ MERS-CoV‬مثبت گزارش گرديد (بين ‪1/320‬و ‪) 1/2560‬‬
‫• ‪ FAO‬در بيانيه اي اعالم نمود از اعالم شتر بعنوان مخزن قطعي پرهيز شود‪.‬‬
‫• هرچند كشف كوروناويروس نزديك به ‪ MERS‬در 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
‫•‬
‫•‬
‫•‬
‫•‬
‫‪ 5‬كشور 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 بيماری‬
‫‪Reproductive number‬‬
‫• قدرت انتقال از انسان به انسان و توانایی ایجاد همه گیری‬
‫قابل توجه را با ‪ Rn‬نشان می دهیم‪.‬‬
‫• ‪ 3‬سناریوی احتمالی‪‍:‬‬
‫– ‪ R‬کمتر از یک؛ محتمل ترین‪RN=0.6 – 0.68 <--‬‬
‫– ‪ R‬بیشتر از یک ولی همه گیری در جامعه پایدار نشده است‬
‫– ‪ R‬بیشتر از ‪ 1‬و همه گیری ماندگار شده بین انسانها‬
‫• مراقبت روتین بیماری ها دچار تورش و تاخیر ثبت نمونه می شود‬
‫‪‍:‬بطوریکه بیشتر موارد شدید را ثبت می نمایدو در نتیجه ‪،CFR‬‬
‫بطور كاذب باال ثبت می گردد‬
‫راه حل هاي توصيه شده‬
‫نظام مراقبت سريع و تقويت شده ؛تسهيل خدمات تشخيص ي و درماني‬
‫همكاري دقيق و نزديك كليه سازمان هاي مرتبط با سفرهاي بين املللي 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 باالخص افراد در معرض خطر‬
‫عدم غفلت از مسافرين بين املللي مبتال به ‪ MERS‬و كشف سريع موارد عالمتدار‬
‫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: 1.9-14.7 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:
10.1038/srep01686]
INFECTION PREVENTION AND CONTROL
• 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 (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
– 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.
42
43
Keeping N95 after use
44
Clusters
Up to Dec 2013
‫كشورهاي عربي گرفتار بيماري‬
‫اردن‬
‫عربستان‬
‫قطر‬
‫امارات‬
‫عمان‬
‫كويت‬
KSA;
The center of disease
‫شهر هاي زيارتي‬
‫مدينه‬
‫مكه‬
Country
Cases
Deaths
Saudi Arabia
132
55
Qatar
8
5
United Arab Emirates (UAE)
10
4
United Kingdom
3
2
Kuwait
2
0
Tunisia
3
1
Jordan
2
2
France
2
1
Italy
1
0
Oman
1
1
Spain
1
0
TOTAL
165
71
Seventy-one of the 165 cases have died (crude mortality rate
43%).
‫اقدامات بهداشتي‬
‫اقدامات غيربهداشتي كه ممكن است باعث انتقال ببماري گردد‬
‫‪51‬‬
52
53
54
55
56
57
58
59
‫برخي تعاريف مورد نياز‬
‫• خوشه ‪:‬‬
‫– دو نفر يا بيشتر از افرادي كه در عرض ‪14‬روز عالئم 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 ‪:‬‬
‫– هركس ي كه از بيمار مراقبت نموده باشد‪ ،‬اعم از پرسنل بهداشتي درماني يا‬
‫اعضاء خانواده بيمار‪ ،‬و يا هركس كه تماس فيزيكي نزديك مشابه (مكامله چهره‬
‫به چهره بيش از ‪ 15‬دقيقه‪ ،‬دست دادن ‪ ،‬روبوس ي مخصوصا در فاصله نزديك‬
‫زير ‪ 1‬متر بدون استفاده از ماسك مناسب) با بيمار داشته باشد‪.‬‬
‫– هركس ي كه با بيمار قطعي و يا محتمل (درحاليكه بيمار عالمتدار بوده است) در‬
‫مكان بسته مشترك حضور داشته باشد (اعم از اينكه زندگي كند و يا براي‬
‫مالقات درآن مكان حضور يافته باشد )‬
‫تعريف موارد مشكوك‬
‫‪ -1‬فردي كه دچار عفونت تنفس ي حاد (عفونت ريه (پنوموني كلينيكي يا‬
‫راديولوژيكي) يا سندرم دشواري تنفس ي حاد (‪ ))ARDS‬شده و نياز به‬
‫بستري در بيمارستان داشته باشد‬
‫و بعالوه يكي از موارد زير باشد‪:‬‬
‫‪ .1‬بيماري جزو يك ابتالي خوشه اي (‪ )cluster‬باشد كه در عرض ‪14‬روز رخ داده باشد‪،‬‬
‫بدون توجه به سابقه مسافرت و يا اقامت بيمار‪ ،‬مگر اينكه عامل ديگري براي بيماري‬
‫شناخته شده باشد‪.‬‬
‫‪ .2‬بيماري در يكي از پرسنل بهداشتي درماني رخ داده باشد كه در محيطي كار مي كنند كه از‬
‫يك بيمار مبتال به عفونت حاد تنفس ي مراقبت شده است‪ ،‬علي الخصوص بيماراني كه در‬
‫بخش مراقبت ويژه (‪ )ICU‬بوده اند‪ ،‬بدون توجه به سابقه مسافرت و يا مكان اقامت‪.‬‬
‫‪ .3‬سير 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
‫‪ -2‬فردي با بيماري تنفس ي حاد (با هر درجه اي از شدت)‪ ،‬كه ‪14‬روز قبل از‬
‫شروع بيماري سابقه تماس نزديك با يك مورد عالمتدار (قطعي يا محتمل)‬
‫مبتال به عفونت ويروس كوروناويروس ‪ Mers-CoV‬داشته باشد‬
‫‪ ‬البته پزشكان بايد به خاطر داشته باشند ممكن است تظاهرات نامعمول غيرتنفس ي‬
‫(مخصوصا در بيماران مبتال به نقص ايمني) نيز مشاهده شود‪:‬‬
‫‪‬ممكن است اين بيماري در مبتاليان به نقص ايمني بصورت اسهال تظاهر يابد‪.‬‬
‫توصيه فعلي سازمان جهاني بهداشت‬
‫• حداقل درخواست‪:‬‬
‫نمونه گيري در تمام موارد مشكوك مبتال به بيماري تنفس ي شديد كه‬
‫نياز به ونتيالتور داشته باشد انجام گردد‬
‫– در هر منطقه اي اگر ظرفيت هاي اقتصادي اجازه مي دهد موارد خفيفتر‬
‫پنوموني و بيماري تنفس ي نيز بررس ي 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 ‪ PCR‬و‬
‫يا منفي بودن تست به دليل ناكافي و نامناسب بودن نمونه ارسالي يا عدم‬
‫دسترس ي به بيمار يا نمونه‬
‫• مورد قطعي‪:‬‬
‫– بيمار مشكوكي كه در تست ‪ PCR‬حداقل دو هدف ژنتيكي بررس ي شده‪ ،‬مثبت‬
‫شده باشد‪.‬‬
‫‪-----------------------------‬‬‫• كليه موارد محتمل و قطعي بايد بطور فوري به اطالع مسئولين بهداشتي منطقه‬
‫رسيده و در عرض ‪ 24‬ساعت از زمان دسته بندي بيمار (محتمل يا قطعي)‪ ،‬به‬
‫مسئول ‪ IHR‬كشوري اطالع 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 ‪ MERS‬براي حمل و نقل در گروه ‪ B‬مواد‬
‫بيولوژيك قرار دارند‪.‬‬
‫انواع نمونه توصيه شده‬
‫‪.1‬‬
‫‪.2‬‬
‫‪.3‬‬
‫‪.4‬‬
‫نمونه هاي ترشحات تنفس ي تحتاني (خلط‪ ،‬آسپيره ترشحات ناي‪،‬‬
‫شستشوي ترشحات برونش)‪ :‬بيشترين تيتر ويروس‬
‫ترشحات فوقاني دستگاه تنفس ‪ :‬علي الخصوص هنگامي كه امكان تهيه‬
‫نمونه از ترشحات تحتاني وجود نداشته باشد‬
‫سرم‪ :‬دو نمونه به فاصله حداقل ‪ 3‬هفته از همديگر (تا اطالع ثانوي و‬
‫معرفي روش سرولوژي معتبر در فريزر نگهداري مي شود)‪ .‬نمونه اول در‬
‫هفته اول بيماري تهيه مي گردد‬
‫مدفوع‪ :‬در كنار سرم و نمونه ترشحات تحتاني تنفس ي از نمونه هاي ارجح‬
‫محسوب مي شود‪ .‬اما تا اطالع ثانوي ارسال نگردد‪.‬‬
‫نمونه ترشحات تنفس ي‬
‫نمونه تنفس ي ترجيحا بايد در هفته اول عالمتدار شدن و قبل از مصرف داروي‬
‫ضدويروس تهيه شود اما بعد از يك هفته نيز مخصوصا اگر عالمتدار است مي توان‬
‫نمونه تحتاني تنفس ي 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!‬
‫• الواژ ترشحات برونش و آسپيره ترشحات ناي‪ :‬نياز به اينتوبه بودن بيمار دارد و به همين‬
‫دليل در آي س ي يو انجام ميشود‪.‬‬
‫– بهترين نمونه الواژ ترشحات برونش (‪ )BAL‬است‪.‬‬
‫• سواب حلق‪ :‬در كشف ويروس حساسيت كمتري دارد اما توصيه مي شود حتما نمونه صحيح آن‬
‫در كنار نمونه هاي تحتاني تنفس ي تهيه و ارسال شود‪.‬‬
Influenza
• (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 A
Influenza B
Influenza C
Genetics
8 gene segments
8 gene segments
7 gene segments
Structure
10 viral proteins
11 viral proteins
9 viral proteins
M2 unique
NB unique
HEF unique
Humans, swine, equine,
avian, marine mammals
Humans only
Humans and swine
Host range
Epidemiology
Antigenic shift and drift
Antigenic drift only; Antigenic drift only;
two main lineages
multiple variants
co-circulate
Clinical features
May cause large
pandemics with
significant mortality in
young persons
Severe disease
generally confined to
Mild disease without
older adults or
seasonality
persons at high risk;
pandemics not seen
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
(PaO2/FIO2 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 (PaO2/FIO2 at
admission 170)
respiratory
underwent noninvasive mechanical
ventilation: chest
computed
tomography shows
alveolar
consolidation,
peripheral groundglass 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 (PaO2/FIO2
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 (paO2/FIO2
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.
2.
3.
The first patient was an 87-year old male with
a history of COPD with no known exposure to
birds.
The second was a 27-year-old man who
worked at a market selling live birds.
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 (Tamiflu®) and zanamivir (Relenza®).
– Neuraminidase inhibitors:
1.
2.
have activity against both influenza A and B
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
Oseltamivir phosphate
(Tamiflu)
Relenza
combined with M2 inhibitors or ribavirin show enhanced antiviral activity (H5N1)
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
Antiviral Medications Recommended for
Treatment and Chemoprophylaxis of Influenza
Antiviral Activity
Agent
Against
Oseltamivir
(Tamiflu)
Use
Not
FDA
Recommended
Approved For
for Use in
Treatment
>=2 wks
N/A
Chemoprophylaxis
>=1 yr
N/A
A and B
Adverse Events
Adverse events:
nausea, vomiting.
Sporadic, transient
neuropsychiatric events (self
injury or delirium) mainly
reported among Japanese
adolescents and adults.
Allergic reactions:
Treatment
>=7 yrs
Chemoprophylaxis
>=5 yrs
Zanamivir
A and B
(Relenza)
people with oro-pharyngeal or facial
underlying edema.
respiratory Adverse events:
diarrhea, nausea, sinusitis,
disease (e.g., nasal signs and symptoms,
asthma,
bronchitis, cough,
headache, dizziness, and
COPD)
ENT infections.
Summary of Influenza Antiviral
Treatment Recommendations
•
Early antiviral treatment: especially within 48 hours of illness onset.
1.
2.
3.
•
shorten the duration of fever and symptoms
reduce the risk of complications (e.g., otitis media in young children, pneumonia, respiratory
failure) and death, and
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.
2.
3.
4.
5.
6.
7.
8.
children aged <2 years;
adults aged >65 years;
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);
persons with immuno-suppression, including that caused by medications or by HIV infection;
women who are pregnant or postpartum (within 2 weeks after delivery);
persons aged <19 years who are receiving long-term aspirin therapy;
Morbidly obese (i.e., BMI>=40);
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 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.
Recommended Dosage and Duration of Treatment or
Chemoprophylaxis for Influenza Antiviral Medications
Antiviral
Agent
Use
Children
Adults
Oseltamivir
(Tamiflu)
Zanamivir
(Relenza)
Chemo-prophylaxis
Treatment
If <1 yr old, the dose is 3 mg/kg/dose twice daily
If >1 yr and weigh <15 kg ,
If >1 yr and weigh >15 to 23 kg,
If >1 yr and weigh >23 to 40 kg,
If >1 yr and weigh >40 kg,
the dose is 30 mg twice a day. (per/Kg)
the dose is 45 mg twice a day.
the dose is 60 mg twice a day.
the dose is 75 mg twice a day.
75 mg
twice daily
(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.
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)
75 mg
once daily
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.
Treatment
10 mg (2 inhalations) twice daily (Not FDA approved for use in children <7 yrs old)
Chemoprophylaxis
10 mg (2 inhalations) once daily (Not FDA approved for use in children <5 yrs old)
10 mg
twice daily
10 mg
once daily
Duration of Treatment or Chemoprophylaxis
Treatment
Recommended duration for antiviral treatment is 5 days. Longer
treatment courses for patients who remain severely ill after 5 days
of treatment can be considered.
Recommended duration is 7 days after exposure.
For control of outbreaks in long-term care facilities (e.g. elderly
nursing homes) and hospitals, CDC recommends antiviral
Chemo
chemoprophylaxis for a minimum of 2 weeks, and continuing up to
prophylaxis
1 week after the last known case was identified.
Especially for elderly long-term care facilities, for all exposed
residents, including those who have received influenza vaccination.
H5N1 treatment
• 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.
• 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 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.
2.
3.
4.
5.
6.
the patient’s age,
weight and
renal function;
presence of other medical conditions;
indications for use (i.e., chemoprophylaxis or therapy);
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.
‫با تشکر از صبر و حوصله شما‬