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Clinical guidelines
Clinical management guidelines for pandemic (H1N1) 2009 virus infection in the Eastern Mediterranean Region: technical basis and overview S. Al Hajjar,1 M.R. Malik,2 Z. Hallaj, 2 H. El-Bushra,2 M. Opoka 2 and A.R. Mafi 2
ABSTRACT During the spring of 2009, a novel influenza A (H1N1) virus of swine origin caused human infection and acute respiratory illness in Mexico. After initially spreading in North America, the virus spread globally resulting in the first influenza pandemic since 1968. While the majority of illnesses caused by pandemic (H1N1) 2009 were mild and self-limiting, severe complications, including fatalities, were also reported. In view of the increasing number of laboratory-confirmed cases and deaths from pandemic (H1N1) 2009 in the Eastern Mediterranean Region of the World Health Organization, the Regional Office convened a consultation meeting of experts involved in the clinical management of patients infected with pandemic (H1N1) 2009 virus. The consultation resulted in developing an interim guidance and algorithm for clinical management of pandemic (H1N1) 2009 virus infection in health-care settings. This paper describes the process, the technical basis and the components of this interim guidance.
1Infectious Diseases Section, Department of Paediatrics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. 2Communicable Disease Surveillance and Response Unit, Division of Communicable Diseases, World Health Organization Regional Office for the Eastern Mediterranean, Cairo, Egypt (Correspondence to M.R. Malik: [email protected]).
Received: 15/12/10; accepted: 09/03/11
يف إقليم رشق املتوسط: األساس التقني والنظرة العامة H1N1) 2009) الدالئل اإلرشادية للتدبري الرسيري جلائحة فريوس سامي احلجار، مأمون الرمحن مالك، زهري حالج، حسن الُبرَشى، مارتن أوبوكا، علريضا مايف
املكسيك. يف حاد تنفيس باعتالل وإصابتهم البرش عدوى إىل اخلنزير من ومصدره اجلديد A (H1N1 فريوس أدى ،2009 ربيع خالل اخلالصـة: وبعد انتشار الفريوس األويل يف شامل أمريكا، رسعان ما أصبح انتشاره عامليًا، وأّدى إىل ظهور أول جائحة أنفلونزا منذ عام 1968. ومع أن غالبية االعتالالت النامجة عن فريوس H1N1) 2009 كانت خفيفة وحمدودة ذاتيًا، إال أهنا سجلت أيضًا مضاعفات وخيمة بام فيها الوفيات. ونظرًا لزيادة الجتامع اإلقليمي املكتب دعا العاملية، الصحة ملنظمة املتوسط رشق إقليم يف خمتربيًا واملؤكدة H1N1) 2009 عن النامجة والوفيات احلاالت أعداد للتدبري وخوارزمية مؤقت إرشادي دليل ُأعد للمشاورة ونتيجة اجلائحة. بفريوس املصابني للمرىض الرسيري بالتدبري املعنّيني للخرباء استشاري الرسيري للعدوى بفريوس جائحة H1N1) 2009 يف مواقع الرعاية الصحية. ويصف هذا البحث تلك العملية، واألساس التقني، ومكّونات الدليل
املؤقت.
Lignes directrices pour la prise en charge clinique de l'infection par le virus de la grippe pandémique (H1N1) 2009 dans la Région de la Méditerranée orientale : données techniques initiales et présentation générale
RéSuMé Au cours du printemps de l'année 2009 au Mexique, un nouveau virus grippal A (H1N1) d'origine porcine a été la cause d'infections et de pathologies respiratoires aiguës chez l'homme. Après s'être d'abord propagé en Amérique du Nord, le virus s'est étendu mondialement pour devenir la première pandémie grippale depuis 1968. Alors que la majorité des pathologies causées par la grippe pandémique (H1N1) 2009 était modérée et à guérison spontanée, des complications graves, y compris des décès, ont également été signalés. Compte tenu du nombre croissant d'infections et de décès par le virus de la grippe pandémique (H1N1) 2009 confirmés en laboratoire dans la Région OMS de la Méditerranée orientale, le Bureau régional a convoqué une réunion consultative d'experts impliqués dans la prise en charge clinique de patients infectés par ce virus. La consultation a permis d'élaborer des lignes directrices temporaires et un algorithme pour la prise en charge clinique de l'infection par le virus de la grippe pandémique (H1N1) 2009 en milieu de soins. Le présent article décrit le processus, les données techniques et les composantes de ces lignes directrices temporaires.
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Background
At the beginning of April 2009, hu- man infections with a novel strain of influenza A (H1N1) virus emerged in Mexico [1]. After initially spreading among persons in the United States, Mexico and Canada, the virus spread globally, resulting in the first influenza pandemic since 1968 [2,3].
As of 6 August 2010, worldwide more than 214 countries and over- seas territories or communities have reported laboratory-confirmed cases of pandemic (H1N1) 2009 virus infection, and there have been around 18 500 deaths [4].
Kuwait and the United Arab Emir- ates were the first 2 countries in the World Health Organization Eastern Mediterranean Region (WHO-EMR) reporting confirmed cases of pandemic (H1N1) 2009 on 25 May 2009. Up to 6 August 2010, all 22 countries had reported laboratory-confirmed cases of infection, and 1019 deaths had been recorded [5].
Epidemiology
Infection and illness Globally, most illnesses caused by the pandemic (H1N1) 2009 virus were acute and self-limiting, with the highest attack rates reported among children and young adults [6]. The median age of most of the reported cases was 12–25 years, and over 80% of cases occurred among the age group of 5–49 years [7]. The overall case fatality rate amongst the laboratory-confirmed cases was less than 0.5% [8].
Transmission The mechanism of person-to-person transmission of pandemic (H1N1) 2009 virus appeared to be similar to those of seasonal influenza [6]. The main route of transmission was reported to be respiratory through inhalation of large-particle respiratory
droplets, and possibly via droplet nu- clei [9]. Explosive outbreaks and am- plifications of cases have been noted in schools and closed community settings [10].
Clinical features
Incubation period The incubation period was approxi- mately 1.5–3 days, which is similar to that of seasonal influenza [6,9]. Children and immunocompromised or immuno- suppressed persons were contagious for longer periods.
Clinical presentation The clinical manifestations of pandemic (H1N1) 2009 virus infection varied, ranging from afebrile upper respiratory illness to fulminant viral pneumonia. Most patients presenting for care showed typical influenza-like illness with fever and cough, sometimes ac- companied by sore throat and rhinnor- rhoea [11,12].
Risk groups and risk factors for severe disease
Underlying medical conditions which are associated with complications from seasonal influenza were also risk fac- tors for complications from pandemic (H1N1) 2009 virus infection. Globally, nearly three quarters of cases requiring hospitalization involved one or more underlying medical conditions includ- ing asthma, diabetes, heart or lung disease, neurologic disease, pregnancy, morbid obesity, autoimmune disorders and associated immunosuppressive therapies [13,14].
Clinical management
The majority of individuals infected with pandemic (H1N1) 2009 virus were treated with simple supportive
care at home using antipyretics (e.g. acetaminophen or ibuprofen).
The pandemic (H1N1) 2009 virus infection was susceptible to the neu- raminidase inhibitors oseltamivir and zanamivir, but was almost always re- sistant to amantadine and rimantadine [15–17]. Early empirical treatment with neuraminidase inhibitors in patients with pandemic (H1N1) 2009 infection has been shown to have reduced the duration of hospitalization [18] and the risk of progression to severe disease requiring ICU admission or resulting in death [14].
Empiric antiviral therapy needs to be started for persons with suspected, probable or confirmed cases of pan- demic (H1N1) 2009 infection for:
Illness requiring hospitalization•
Progressive, severe or complicated • illness regardless of previous health status and/or
High risk groups for severe disease, • which include:
Children younger than 2 years – Pregnant women up to 2 weeks – post partum (regardless of how the pregnancy ended) Adults 65 years of age or older – Persons younger than 19 years – who are having long-term aspirin therapy Persons with medical conditions – including asthma, neurological and neurodevelopmental conditions (including disorders of the brain, spinal cord, peripheral nerves and muscles, such as cerebral palsy) chronic obstructive lung disease, cardiac disease, diabetes mellitus, immunosuppressive conditions (in- cluding HIV/AIDS, and cancer).
Clinicians should consider empiric treatment with antibacterial drugs if bacterial co-infections are suspected during or after influenza. The use of high dose corticosteroids for pandemic (H1N1) 2009 infection is controver- sial; low-dose steroids may, however, be
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considered in patients with septic shock who require vasopressors [19–21].
Development of guidelines: expert consultation
In order to support the countries of the WHO EMR to manage human cases infected with pandemic (H1N1) 2009 virus in a standardized way, the Regional Office convened an inter- national expert consultation meeting from 9 to 10 September 2009. The purpose of this meeting was to develop a clinical management guideline in or- der to optimize clinical care for human infections with pandemic (H1N1) 2009 virus across all countries in the Region.
Medical experts in the field of pul- monology, infectious diseases, public health, epidemiology, internal medi- cine, intensive care, microbiology and virology came together and reviewed the available international guidelines
[22,23], published evidence and un- published data on epidemiology and clinical manifestations of the disease. Following this expert consultation, an interim guidance and algorithms were developed on clinical management of pandemic (H1N1) virus infection [24]. The algorithms were intended to be used as a decision tree by clinicians to exercise their clinical judgment for treatment and care of patients with pandemic H1N1 virus infection.
The interim guidance on clinical management of pandemic (H1N1) 2009 virus infection used 4 case defi- nitions of influenza (Table 1) for the purpose of clinical diagnosis and initial treatment decisions. These include (i) influenza-like illness (ILI), (ii) severe acute respiratory infection (SARI), (iii) acute respiratory infection (ARI) and (iv) influenza caused by pandemic (H1N1) 2009 virus infection.
Three categories of clinical manifes- tations have been seen during the cur- rent pandemic [13,14] and these have
been presented in the WHO Regional Office Interim Guidance:
Mild illness characterized by fever • (some patients had no fever), cough, sore throat, diarrhoea, myalgias, head- ache. Other frequent findings have included chills and malaise. Vomiting and diarrhoea have been reported in some patients, but no shortness of breath, dyspnoea, or severe dehydra- tion.
Progressive illness characterized • by mild illness with clinical signs or symptoms suggesting a progression to severe illness, which include the fol- lowing signs and symptoms (Table 2 shows differentiation between clinical signs in adults and in children under 5 years) :
chest pain, tachypnoea, or laboured – breathing in children hypotension – confusion or altered mental status – severe dehydration or exacerba- – tions of a chronic conditions (e.g. asthma, cardiovascular conditions)
Table 1 Case definition of influenza caused by pandemic (H1N1) 2009 virus infection
Influenza-like illness (ILI) A person with sudden onset of fever > 38 °C and ≥ 1 of the following 2 respiratory symptoms in the absence of other known causes: dry cough, sore throat
Severe acute respiratory illness (SARI)
A person meeting the case definition of influenza-like illness (above) AND shortness of breath OR difficulty in breathing requiring hospital admission.
Acute respiratory infection (ARI) Acute respiratory tract illness that is caused by an infectious agent transmitted from person to person. The onset of symptoms is typically rapid, over a period of hours to several days. Symptoms include fever, cough, and often sore throat, coryza, shortness of breath, wheezing, or difficulty breathing.
Confirmed case of Pandemic (H1N1) 2009
An individual with an influenza-like illness with laboratory confirmed pandemic (H1N1) 2009 virus infection by ≥ 1 of the following tests: real time reverse-transcription polymerase (RT-PCR) viral culture.
Probable case of Pandemic (H1N1) 2009
An individual with an influenza-like illness who is positive for influenza A that is unsubtypable by real-time PCR, OR An individual with a clinically compatible illness or who died of an unexplained acute respiratory illness who is considered to be epidemiologically linked to a probable or confirmed case.
Suspected case of Pandemic (H1N1) 2009
An individual with acute respiratory illness and fever (reported or documented fever), and one of the followings; cough, sore throat, shortness of breath, difficulty in breathing or chest pains with onset: within 7 days of close contact with a person who is a probable or confirmed case of pandemic (H1N1) 2009 virus infection, OR within 7 days of travel to a country/community where there has been one or more confirmed cases of pandemic (H1N1) 2009 virus infection, OR Resides in a community where there is one or more confirmed cases of pandemic (H1N1) 2009 virus infection.
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Severe illness characterized by the • following:
profound hypoxemia, abnormal – chest radiograph, and mechanical ventilation encephalitis or encephalopathy – shock, multisystem organ failure – myocarditis and rhabdomyolysis – invasive secondary bacterial infec- – tion (e.g. pneumococcal disease).
When influenza viruses are known to be circulating in the community, patients presenting with mild influenza can be diagnosed on clinical and epide- miological grounds alone. Based on the clinical evidence and judgment, the In- terim Guidance recommends empirical antiviral therapy with a neuraminidase
inhibitor in appropriate dose (Table 3) as soon as possible (i) whenever the illness requires hospitalization; (ii) whenever the person shows signs of progressive illness; (iii) and/or when- ever the person belongs to the high risk group for severe disease.
The clinical algorithms (Figures 1 and 2) for management of patients with pandemic (H1N1) 2009 virus infection, as presented in the Interim Guidance, can be applied to every pa- tient diagnosed on the basis of clinical suspicion alone without waiting for laboratory confirmation. The Interim Guidance, however, emphasizes that all patients treated at home need to be in- structed to return for follow-up should they develop any signs or symptoms of
progressive disease or fail to improve within 72 hours of the onset of symp- toms.
Future directions
As of 10 August 2010, the world has moved into the post-pandemic period [25]. Based on the knowledge about past influenza pandemics, pandemic (H1N1) 2009 virus is expected to con- tinue to circulate as a seasonal virus for some years to come [25]. While the level of concern might have greatly diminished, vigilance on the part of national health authorities as well as treatment of all suspected influenza cases with standard care remain criti- cal in the immediate post-pandemic
Table 2 Clinical signs indicating rapid progression and need for urgent medical care
In adults In children
Difficulty in breathing or shortness of breath Tachypnoea or laboured breathing
Pain or pressure in the chest or abdomen Skin colour change, grey or blue
Episodes of sudden dizziness Inadequate intake of oral fluids
Severe or continuous vomiting Severe or continuous vomiting
Influenza-like illness that improves but then returns with fever and cough
Influenza-like illness that improves but then returns with fever and cough
Confusion Irritable or not waking up
Table 3 Treatment regimen for Oseltamivir and Zanamivir for human infection caused by pandemic (H1N1) 2009 virus
Age group Treatment (5 days) Chemoprophylaxis (10 days)
Oseltamivir
Adults 75 mg twice per day 75 mg once per day
Children (≥ 12 months)
≤ 15 kg 30 mg twice per day 30 mg once per day
15–23 kg 45 mg twice per day 45 mg once per day
20–40 kg 60 mg twice per day 60 mg once per day
> 40 kg 75 mg twice per day 75 mg once per day
Children
3 – < 12 months 3 mg/kg/dose twice per day 3 mg/kg/dose once per day
0 – < 3 months 3 mg/kg/dose twice per day Not recommended, unless situation judged critical (limited data)
Zanamivir
Adults 2 × 5 mg inhalations (10 mg total) twice per day
2 × 5 mg inhalations (10 mg total) once per day
Children ≥ 7 years for treatment; children ≥ 5 years for chemoprophylaxis
2 × 5 mg inhalations (10 mg total) twice per day
2 × 5 mg inhalations (10 mg total) once per day
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period since the behaviour of pandemic (H1N1) 2009 virus can not be reliably predicted.
The Interim Guidance and the algorithms for clinical management of human infection with pandemic (H1N1) 2009 virus were developed in September 2009 based on clinical evidence and best clinical outcome fol- lowing available treatment practices known globally at that time. The Interim
Guidance and its clinical algorithms were adopted by many countries in the Region. It is expected that this Interim Guidance will pave the way towards de- veloping national clinical management protocols for influenza as well as other epidemic- and pandemic-prone acute respiratory infections in the countries of the Region. The uncertain evolution of the pandemic virus, however, high- lights the importance that the treatment
guidelines and the supplementary algorithms need to be revised and continuously updated as soon as new evidence on clinical manifestation of influenza in the post-pandemic period, antiviral resistance pattern, effective- ness of the currently available antivirals, and virulence of the circulating seasonal influenza virus become available in the post-pandemic period.
No symptoms of ILI Assess and treat
as indicated
Direct patient to triage area for assessment
Assess general state and hydration, measure body temperature (> 38 °C/100.4 °F)1. Measure respiratory rate2. Observe colour of skin, nails and mucosa3. Perform pulmonary auscultation to identify crepitation4.
Does patient have influenza-like illness (ILI) (temperature > 38 °C + dry cough or sore throat)?
Patient has clinical signs of severe illness indicating
rapid progression (detailed in Table-2)
Apply home isolation and manage the patient
at home DO NOT AUTHORIZE
ANTIVIRAL TREATMENT
AUTHORIZE ANTIVIRAL TREATMENT
IMMEDIATELY Apply home isolation and
manage the patient at home
Immediately refer the pa- tient to secondary level care for hospitalization and further necessary
treatment
Standard and droplet precautions
Patient: Surgical mask Staff: Hand hygiene, mask,
gown and gloves
Community protection Patient: wears surgical mask,
covers mouth and nostrils when coughing or sneezing
and frequently washes hands
The patient: Avoids public transport . uses a surgical mask . Covers mouth and . nostrils during coughing and sneezing Avoids close contact .
Patient has mild ILI with no signs of severe illness
BuT is in a high risk group for complications
Patient has mild ILI (i) without any signs of
severe illness and (ii) not in a high risk group
YesNo
Yes Yes Yes
Infection control measures
Figure 1 Algorithm for clinical management of patients at the primary health care level
Assessment of patients
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Figure 2 Algorithm for clinical management of patients at secondary or tertiary health care level
One of the best ways to evaluate this Interim Guidance would be to assess the diagnostic validity of its clinical algorithms prospectively in some selected clinical settings that should include both resource-inten- sive and resource-limited countries.
The effectiveness of clinical algorithms in truly detecting patients with sus- pected influenza needs to be assessed. Solid data on such an evaluation will in- crease the sensitivity and specificity of the clinical algorithms of the guidelines in detecting and identifying patients
with suspected influenza, guide treat- ment decisions in the post-pandemic period, and ensure that no cases with potentially fatal outcome are missed by clinicians when using these algorithms as a decision tree to exercise their clini- cal judgement.
YesNo Yes
Infection control measuresAssessment of patients
The patient is showing clinical signs of illness indicating rapid progression and need for urgent medical care (Detailed in Table 2)
Refer case for home management
Immediately hospitalize patient
Manage case at home
AUTHORIZE ANTIVIRAL TREATMENT immediately along with
other supportive treatment
Patient’s condition is improving and responding to treatment as indicated by:
Becoming afebrile; . Tolerating oral fluid; . Absence of dyspnoea; . No evidence of dehydration; . Respiratory rate ≤ 30 bpm . Oxygen saturation ≥ 92% . underlying chronic health condi- . tions not exacerbated (for patients in high risk group for complica- tions)
Patient’s condition is not improving and not responding to treatment as indicated by:
Progressive pulmonary infiltrates . Persistent hypoxia (Sp O .
2 < 92%)
despite maximum oxygen saturation; Progressive hypercapnoea; . Presence of compromised . haemodynamics; Signs of sepsis and imminent . shock
Consult specialist for advice and admission to Intensive Care unit (ICu)
Standard and droplet precautions
Patient: Surgical mask and strict isolation or cohorting. Isolation precaution may be discontinued after the patients has received anti- viral treatment for 72 hours and remained afebrile for 24 hours even in the absence of antipyretics. Staff: Hand hygiene, mask, gown, gloves and eye protection if there is a risk of splash.
Standard and droplet precautions
Patient: Surgical mask Staff: Hand hygiene, mask, gown and gloves
In addition to the above, patient is presenting with:
Refractory hypoxaemia . Compromised haemo- . dynamics Signs of sepsis and immi- . nent shock
Discharge criteria met Discharge the patient
with proper advice (Patients should be discharged after
receiving the full 5-day course of antivirals or 24 hours after becoming
afebrile, whichever is earlier) Consider admission to ICu on
advice from specialists
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