Clinical Management of Pandemic 2009 Influenza A(H1N1) Infection
2009; Elsevier BV; Volume: 137; Issue: 4 Linguagem: Inglês
10.1378/chest.09-2344
ISSN1931-3543
AutoresDavid S.C. Hui, Nelson Lee, Paul K.S. Chan,
Tópico(s)Viral gastroenteritis research and epidemiology
ResumoAntiviral therapy and vaccination are important strategies for controlling pandemic 2009 influenza A(H1N1) but efficacy depends on the timing of administration and is often limited by supply shortage. Patients with dyspnea, tachypnea, evidence of hypoxemia, and pulmonary infiltrates on chest radiograph should be hospitalized. Patients with severe illness or underlying medical conditions that increase the risk of more severe disease should be treated with oseltamivir or zanamivir as soon as possible, without waiting for the results of laboratory tests. Lung-protective ventilation strategy with a low tidal volume and adequate pressure, in addition to a conservative fluid management approach, is recommended when treating adult patients with ARDS. Extracorporeal membrane oxygenation has emerged as an important rescue therapy for critically ill patients. Use of systemic steroids was associated with delayed viral clearance in severe acute respiratory syndrome and H3N2 infection. Low-dose corticosteroids may be considered in the treatment of refractory septic shock. Passive immunotherapy in the form of convalescent plasma or hyperimmune globulin may be explored as rescue therapy. More data are needed to explore the potential role of IV gamma globulin and other drugs with immunomodulating properties, such as statins, gemfibrozil, and N-acetyl-cysteine. Health-care workers must apply strict standard and droplet precautions when dealing with suspected and confirmed case and upgrade to airborne precautions when performing aerosol-generating procedures. Nonpharmacologic measures, such as early case isolation, household quarantine, school/workplace closure, good community hygiene, and restrictions on travel are useful measures in controlling an influenza pandemic at its early phase. Antiviral therapy and vaccination are important strategies for controlling pandemic 2009 influenza A(H1N1) but efficacy depends on the timing of administration and is often limited by supply shortage. Patients with dyspnea, tachypnea, evidence of hypoxemia, and pulmonary infiltrates on chest radiograph should be hospitalized. Patients with severe illness or underlying medical conditions that increase the risk of more severe disease should be treated with oseltamivir or zanamivir as soon as possible, without waiting for the results of laboratory tests. Lung-protective ventilation strategy with a low tidal volume and adequate pressure, in addition to a conservative fluid management approach, is recommended when treating adult patients with ARDS. Extracorporeal membrane oxygenation has emerged as an important rescue therapy for critically ill patients. Use of systemic steroids was associated with delayed viral clearance in severe acute respiratory syndrome and H3N2 infection. Low-dose corticosteroids may be considered in the treatment of refractory septic shock. Passive immunotherapy in the form of convalescent plasma or hyperimmune globulin may be explored as rescue therapy. More data are needed to explore the potential role of IV gamma globulin and other drugs with immunomodulating properties, such as statins, gemfibrozil, and N-acetyl-cysteine. Health-care workers must apply strict standard and droplet precautions when dealing with suspected and confirmed case and upgrade to airborne precautions when performing aerosol-generating procedures. Nonpharmacologic measures, such as early case isolation, household quarantine, school/workplace closure, good community hygiene, and restrictions on travel are useful measures in controlling an influenza pandemic at its early phase. extracorporeal membrane oxygenation health-care worker invasive mechanical ventilation methicillin-resistant Staphylococcus aureus N-acetyl-L-cysteine noninvasive positive pressure ventilation pandemic 2009 influenza A(H1N1) reactive oxygen species reverse transcription-polymerase chain reaction severe acute respiratory syndrome World Health Organization Influenza A virus belongs to the genus Orthomyxovirus under the family Orthomyxoviridae. The enveloped virion contains eight segments of single, negative-stranded RNA genome, encoding the surface glycoproteins of hemagglutinin and neuraminidase, RNA polymerase (PA, PB1, PB2), nucleoprotein, matrix protein, and nonstructural protein. There are 16 hemagglutinin subtypes and nine neuraminidase subtypes based on the antigenic characteristics. Introduction of a new subtype into humans can result in a large-scale pandemic with high morbidity and mortality due to the naïve immunity and the absence of an effective vaccine in the initial phase of outbreak. Three influenza pandemics occurred in the 20th century. The most severe influenza pandemic of "Spanish flu" A(H1N1) occurred in 1918 to 1919, with a global mortality of 20 to 25 million. It was estimated that 50% of the global population became infected, of whom half suffered clinical illnesses. The A(H2N2) pandemic that occurred in 1957 to 1958 caused about 70,000 deaths in the United States. In 1968, another new type A(H3N2) emerged and remains in circulation today.1Hui DS Chan PK Viral pneumonia.in: Laurent GJ Shapiro SD Encyclopaedia of Respiratory Medicine. Elsevier, Amsterdam, The Netherlands2006: 456-466Crossref Scopus (4) Google Scholar, 2Smith GJ Bahl J Vijaykrishna D et al.Dating the emergence of pandemic influenza viruses.Proc Natl Acad Sci U S A. 2009; 106: 11709-11712Crossref PubMed Scopus (331) Google Scholar Pandemic 2009 influenza A(H1N1) [A(H1N1)] is a new strain of influenza virus that was first identified in Mexico and the United States in March and April 2009, respectively. The pandemic A(H1N1) virus originated from the triple-reassortment swine influenza (H1) virus circulating in North American pigs.3Trifonov V Khiabanian H Rabadan R Geographic dependence, surveillance, and origins of the 2009 influenza A (H1N1) virus.N Engl J Med. 2009; 361: 115-119Crossref PubMed Scopus (243) Google Scholar, 4Shinde V Bridges CB Uyeki TM et al.Triple-reassortant swine influenza A (H1) in humans in the United States, 2005-2009.N Engl J Med. 2009; 360: 2616-2625Crossref PubMed Scopus (548) Google Scholar Complete genome sequencing has shown that the known molecular markers of pathogenicity (PB1-F2 and nonstructural-1 proteins) are not expressed in the pandemic A(H1N1) virus.5Garten RJ Davis CT Russell CA et al.Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans.Science. 2009; 325: 197-201Crossref PubMed Scopus (2086) Google Scholar Animal studies have shown that the novel influenza virus caused increased morbidity, replicated to higher titers in lung tissue, and was recovered from the intestinal tract of intranasally inoculated ferrets in contrast to seasonal influenza H1N1 virus.6Maines TR Jayaraman A Belser JA et al.Transmission and pathogenesis of swine-origin 2009 A(H1N1) influenza viruses in ferrets and mice.Science. 2009; 325: 484-487Crossref PubMed Scopus (574) Google Scholar, 7Munster VJ de Wit E van den Brand JM et al.Pathogenesis and transmission of swine-origin 2009 A(H1N1) influenza virus in ferrets.Science. 2009; 325: 481-483PubMed Google Scholar, 8Itoh Y Shinya K Kiso M et al.In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses.Nature. 2009; 460: 1021-1025Crossref PubMed Scopus (932) Google Scholar This may explain why the novel virus is relatively more pathogenic than seasonal influenza viruses in its capacity to invade the lower respiratory tract and cause rapidly progressive pneumonia in humans because of our lack of background immunity to the former. Within several weeks from onset, the novel virus has spread throughout the world through international air travel and resulted in an influenza pandemic.9Khan K Arino J Hu W et al.Spread of a novel influenza A (H1N1) virus via global airline transportation.N Engl J Med. 2009; 361: 212-214Crossref PubMed Scopus (361) Google Scholar The World Health Organization (WHO) has raised the level of influenza pandemic alert from phase 5 to phase 6 since June 11, 2009.10World Health Organization What is phase 6?.http://www.who.int/csr/disease/swineflu/frequently_asked_questions/levels_pandemic_alert/en/index.htmlGoogle Scholar As of November 29, 2009, there have been > 622,482 laboratory-confirmed cases of pandemic A(H1N1) and 8,768 deaths in 207 countries and territories reported to the WHO. As more and more countries have stopped counting individual cases, particularly of milder illness, the case count is significantly lower than the actual number of cases that have occurred.11World Health Organization Pandemic (H1N1 2009 —update 77.http://www.who.int/csr/don/2009_12_04/en/index.htmlGoogle Scholar The majority of patients with pandemic A(H1N1) infection develop mild upper respiratory tract symptoms similar to seasonal influenza, but gastrointestinal symptoms seem more common in the former. In a study of 642 confirmed cases during the early outbreak in the United States in April 2009, 60% of patients were ≤ 18 years of age. Among those with available data, 18% had history of recent travel to Mexico, whereas 16% were identified from school outbreaks. The most common presenting symptoms were fever (94%), cough (92%), and sore throat (66%); 25% of patients had diarrhea, and 25% had vomiting. Of the 399 patients for whom hospitalization status was known, 36 (9%) required hospitalization and two died.12Dawood FS Jain S Finelli L Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team et al.Emergence of a novel swine-origin influenza A (H1N1) virus in humans.N Engl J Med. 2009; 360: 2605-2615Crossref PubMed Scopus (2754) Google Scholar In a study of 863 confirmed cases in Ontario, Canada, cough, fever, sore throat, and gastrointestinal symptoms were reported in 92%, 91%, 41%, and 24% of patients, respectively, with a hospitalization rate of 3.6% and a case fatality ratio of 0.2%.13World Health Organization Epidemiological summary of pandemic influenza A (H1N1) 2009 virus—Ontario, Canada, June 2009.Wkly Epidemiol Rec. 2009; 84: 485-491PubMed Google Scholar Patients with more severe disease present with fever, cough, dyspnea or respiratory distress, increased serum lactate dehydrogenase levels, and bilateral patchy pneumonia (Figs 1A–C). Other common findings were an increased creatinine kinase level and lymphopenia.14Perez-Padilla R de la Rosa-Zamboni D Ponce de Leon S INER Working Group on Influenza et al.Pneumonia and respiratory failure from swine-origin influenza A (H1N1) in Mexico.N Engl J Med. 2009; 361: 680-689Crossref PubMed Scopus (1198) Google Scholar The WHO has outlined the warning signs for more severe disease as listed in Table 1.15World Health Organization Recommended use of antivirals. Pandemic (H1N1 2009 briefing note 8.http://www.who.int/csr/disease/swineflu/notes/h1n1_use_antivirals_20090820/en/index.htmlGoogle Scholar Although severe disease may occur in otherwise well and young subjects, there are often risk factors for developing more severe disease (Table 2).14Perez-Padilla R de la Rosa-Zamboni D Ponce de Leon S INER Working Group on Influenza et al.Pneumonia and respiratory failure from swine-origin influenza A (H1N1) in Mexico.N Engl J Med. 2009; 361: 680-689Crossref PubMed Scopus (1198) Google Scholar, 16Jain S Kamimoto L Bramley AM 2009 Pandemic Influenza A (H1N1) Virus Hospitalizations Investigation Team et al.Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009.N Engl J Med. 2009; 361: 1935-1944Crossref PubMed Scopus (1536) Google Scholar, 17Webb SA Pettilä V Seppelt I ANZIC Influenza Investigators et al.Critical care services and 2009 H1N1 influenza in Australia and New Zealand.N Engl J Med. 2009; 361: 1925-1934Crossref PubMed Scopus (880) Google Scholar, 18Kumar A Zarychanski R Pinto R Canadian Critical Care Trials Group H1N1 Collaborative et al.Critically ill patients with 2009 influenza A(H1N1) infection in Canada.JAMA. 2009; 302: 1872-1879Crossref PubMed Scopus (1165) Google ScholarTable 1Warning Signs Indicating More Severe Disease15World Health Organization Recommended use of antivirals. Pandemic (H1N1 2009 briefing note 8.http://www.who.int/csr/disease/swineflu/notes/h1n1_use_antivirals_20090820/en/index.htmlGoogle ScholarDyspnea, either during physical activity or while restingCyanosisBloody or colored sputumChest painAltered mental statusHigh fever that persists beyond 3 dHypotensionIn children, danger signs include tachypnea or dyspnea, drowsiness, and little or no desire to play Open table in a new tab Table 2Risk Factors for Developing More Severe Disease14Perez-Padilla R de la Rosa-Zamboni D Ponce de Leon S INER Working Group on Influenza et al.Pneumonia and respiratory failure from swine-origin influenza A (H1N1) in Mexico.N Engl J Med. 2009; 361: 680-689Crossref PubMed Scopus (1198) Google Scholar, 16Jain S Kamimoto L Bramley AM 2009 Pandemic Influenza A (H1N1) Virus Hospitalizations Investigation Team et al.Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009.N Engl J Med. 2009; 361: 1935-1944Crossref PubMed Scopus (1536) Google Scholar, 17Webb SA Pettilä V Seppelt I ANZIC Influenza Investigators et al.Critical care services and 2009 H1N1 influenza in Australia and New Zealand.N Engl J Med. 2009; 361: 1925-1934Crossref PubMed Scopus (880) Google Scholar, 18Kumar A Zarychanski R Pinto R Canadian Critical Care Trials Group H1N1 Collaborative et al.Critically ill patients with 2009 influenza A(H1N1) infection in Canada.JAMA. 2009; 302: 1872-1879Crossref PubMed Scopus (1165) Google ScholarChronic respiratory diseases (eg, asthma, COPD, bronchiectasis, lung surgery)ObesityPregnancySmokingDiabetes mellitusChronic cardiovascular diseasesRenal diseasesImmunosuppression (such as blood disorders, malignancy)Delay in presentation to hospital (and hence delay in initiating antiviral therapy) Open table in a new tab In contrast to seasonal influenza, most severe pandemic A(H1N1) disease and its related mortality have occurred among children and adults aged < 60 years, whereas about 40% of patients who have required hospitalization or died were previously healthy.16Jain S Kamimoto L Bramley AM 2009 Pandemic Influenza A (H1N1) Virus Hospitalizations Investigation Team et al.Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009.N Engl J Med. 2009; 361: 1935-1944Crossref PubMed Scopus (1536) Google Scholar, 17Webb SA Pettilä V Seppelt I ANZIC Influenza Investigators et al.Critical care services and 2009 H1N1 influenza in Australia and New Zealand.N Engl J Med. 2009; 361: 1925-1934Crossref PubMed Scopus (880) Google Scholar, 18Kumar A Zarychanski R Pinto R Canadian Critical Care Trials Group H1N1 Collaborative et al.Critically ill patients with 2009 influenza A(H1N1) infection in Canada.JAMA. 2009; 302: 1872-1879Crossref PubMed Scopus (1165) Google Scholar The number of ICU admissions due to pandemic A(H1N1) infection was 15 times the number due to viral pneumonitis in recent years in Australia and New Zealand.17Webb SA Pettilä V Seppelt I ANZIC Influenza Investigators et al.Critical care services and 2009 H1N1 influenza in Australia and New Zealand.N Engl J Med. 2009; 361: 1925-1934Crossref PubMed Scopus (880) Google Scholar The elderly (> 65 years) are less frequently infected by the novel virus,16Jain S Kamimoto L Bramley AM 2009 Pandemic Influenza A (H1N1) Virus Hospitalizations Investigation Team et al.Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009.N Engl J Med. 2009; 361: 1935-1944Crossref PubMed Scopus (1536) Google Scholar, 17Webb SA Pettilä V Seppelt I ANZIC Influenza Investigators et al.Critical care services and 2009 H1N1 influenza in Australia and New Zealand.N Engl J Med. 2009; 361: 1925-1934Crossref PubMed Scopus (880) Google Scholar, 18Kumar A Zarychanski R Pinto R Canadian Critical Care Trials Group H1N1 Collaborative et al.Critically ill patients with 2009 influenza A(H1N1) infection in Canada.JAMA. 2009; 302: 1872-1879Crossref PubMed Scopus (1165) Google Scholar, 19World Health Organization Human infection with pandemic A (H1N1 2009 influenza virus: clinical observations in hospitalized patients, Americas, July 2009 update.Weekly Epidemiological Record on Pandemic H1N1 2009. 2009; 84: 305-308Google Scholar probably because of some pre-existing cross-reacting immunity against the virus due to their past exposure to previous circulating seasonal influenza A(H1N1) strains similar to the current pandemic A(H1N1) virus.20Hancock K Veguilla V Lu X et al.Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus.N Engl J Med. 2009; 361: 1945-1952Crossref PubMed Scopus (1117) Google Scholar However, it is controversial if the seasonal influenza vaccine antigen components confer any cross-immunity against the pandemic strain.20Hancock K Veguilla V Lu X et al.Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus.N Engl J Med. 2009; 361: 1945-1952Crossref PubMed Scopus (1117) Google Scholar, 21Garcia-Garcia L Valdespino-Gómez JL Lazcano-Ponce E et al.Partial protection of seasonal trivalent inactivated vaccine against novel pandemic influenza A/H1N1 2009: case-control study in Mexico City.BMJ. 2009; 339: b3928Crossref PubMed Scopus (137) Google Scholar Autopsy findings have shown three distinct pulmonary histologic patterns: diffuse alveolar damage, necrotizing bronchiolitis, and diffuse alveolar damage with intense alveolar hemorrhage. There is also evidence of ongoing pulmonary aberrant immune response.22Mauad T Hajjar LA Callegari GD et al.Lung pathology in fatal novel human influenza A (H1N1) infection.Am J Respir Crit Care Med. 2010; 181: 72-79Crossref PubMed Scopus (452) Google Scholar Pulmonary emboli were noted, whereas secondary bacterial or fungal pneumonia were reported in 7/50 (14%) fatal cases in California.23Centers for Disease Control and Prevention (CDC) Intensive-care patients with severe novel influenza A (H1N1) virus infection—Michigan, June 2009.MMWR Morb Mortal Wkly Rep. 2009; 58: 749-752PubMed Google Scholar A fatal case with coinfection with community-acquired methicillin-resistant Staphylococcus aureus (MRSA) occurred in a Filipino sailor who died in Hong Kong.24Cheng VC Lau YK Lee KL et al.Fatal co-infection with swine origin influenza virus A/H1N1 and community-acquired methicillin-resistant Staphylococcus aureus.J Infect. 2009; 59: 366-370Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar In a study of 77 American patients with fatal cases of confirmed pandemic A(H1N1) infection,25Centers for Disease Control and Prevention (CDC) Bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza A(H1N1)—United States, May-August 2009.MMWR Morb Mortal Wkly Rep. 2009; 58: 1071-1074PubMed Google Scholar evidence of concurrent bacterial infection was found in 22 (29%) patients, including 10 with Streptococcus pneumoniae, six with Streptococcus pyogenes, seven with S aureus, two with Streptococcus mitis, and one with Haemophilus influenzae; four cases involved multiple pathogens. The median age of the 22 patients was 31 years and median duration of illness was 6 days. These findings confirm that bacterial lung infections are occurring among patients with fatal cases of pandemic A(H1N1) infection and underscore both the need for early recognition/treatment of bacterial pneumonia in patients with influenza and the importance of pneumococcal vaccination for persons at increased risk for pneumococcal pneumonia.25Centers for Disease Control and Prevention (CDC) Bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza A(H1N1)—United States, May-August 2009.MMWR Morb Mortal Wkly Rep. 2009; 58: 1071-1074PubMed Google Scholar The indications for hospitalization are listed in Table 3.26Kaufman MA Duke GJ McGain F et al.Life-threatening respiratory failure from H1N1 influenza 09 (human swine influenza).Med J Aust. 2009; 191: 154-156PubMed Google ScholarTable 3Indications for Hospital Admission26Kaufman MA Duke GJ McGain F et al.Life-threatening respiratory failure from H1N1 influenza 09 (human swine influenza).Med J Aust. 2009; 191: 154-156PubMed Google ScholarPatients with influenza symptoms should be hospitalized if there is evidence of: hypoxemia (SpO2 < 95%), tachypnea (respiratory rate > 24 breaths/min), or pulmonary infiltrates on chest radiograph.Patients should be referred for ICU assessment if: FIO2 of > 0.5 or oxygen at a rate of > 10 L/min is required to maintain the SpO2 at 92%.SpO2 = oxygen saturation. Open table in a new tab SpO2 = oxygen saturation. Nasal swabs with nasal secretions (from the anterior turbinate area) or nasopharyngeal aspirates or swabs are appropriate specimens for detecting human influenza A and B. Although the rapid influenza diagnostic tests were capable of detecting novel A(H1N1) virus from respiratory specimens containing high levels of virus, the overall sensitivity was low (40%-69%) among all specimens tested and declined substantially as virus levels decreased. Patients with illnesses compatible with pandemic A(H1N1) virus infection but with negative rapid influenza diagnostic test results should be treated empirically based on the level of clinical suspicion, underlying medical conditions, severity of illness, and risk for complications. If a more definitive determination of infection with influenza virus is required, testing with real-time reverse transcription-polymerase chain reaction (RT-PCR) or virus isolation should be performed.27Centers for Disease Control and Prevention (CDC) Evaluation of rapid influenza diagnostic tests for detection of novel influenza A (H1N1) virus—United States, 2009.MMWR Morb Mortal Wkly Rep. 2009; 58: 826-829PubMed Google Scholar In patients who require invasive mechanical ventilation (IMV), tracheal aspirates may offer higher diagnostic yield than nasopharyngeal flocked swab (Fig 2). Sequential sampling is important because it increases opportunities for positive diagnosis and facilitates understanding of viral load/clearance during illness course, in addition to monitoring development of antiviral resistance. The pandemic virus is currently susceptible to the neuraminidase inhibitors, but resistant to the matrix protein-2 inhibitors. Most patients infected with the pandemic virus experience typical influenza symptoms and fully recover within a week, even without any form of medical treatment. Healthy patients with uncomplicated illness need not be treated with antivirals. For patients who initially present with severe illness or whose condition begins to deteriorate, treatment with oseltamivir should commence as soon as possible and antiviral treatment should be provided even if started later than 48 h. If oseltamivir is unavailable or cannot be used for any reason, zanamivir may be given. This recommendation applies to all patient groups, including pregnant women, and all age groups, including young children and infants.15World Health Organization Recommended use of antivirals. Pandemic (H1N1 2009 briefing note 8.http://www.who.int/csr/disease/swineflu/notes/h1n1_use_antivirals_20090820/en/index.htmlGoogle Scholar The Food and Drug Administration in the United States has approved emergency use of intravenous peramivir for treatment of severe cases,28Birnkrant D Cox E The emergency use authorization of peramivir for treatment of 2009 H1N1 influenza.N Engl J Med. 2009; 361: 2204-2207Crossref PubMed Scopus (185) Google Scholar whereas zanamivir dry powder should not be administered by nebulization as the lactose sugar in this formulation can obstruct proper functioning of mechanical ventilator equipment.29GlaxoSmithKline (GSK) and FDA alert Relenza (zanamivir) inhalation powder.http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm186081.htmGoogle Scholar For patients with underlying medical conditions that increase the risk of more severe disease, the WHO recommends treatment with either oseltamivir or zanamivir as soon as possible after symptom onset, without waiting for the results of laboratory tests. About 30% to 40% of severe cases globally have occurred in previously healthy children and adults, usually under the age of 50 years. Some of these patients experience a sudden and very rapid deterioration in their clinical condition, usually on day 5 or 6 following the onset of symptoms. Clinical deterioration is characterized by primary viral pneumonia and failure of multiple organs, including the heart, kidneys, and liver. These patients require management in the ICU. In cases of severe or deteriorating illness, clinicians may consider using higher doses of oseltamivir and for a longer duration (eg, 150 mg bid for 10 days for adults) than is normally prescribed.15World Health Organization Recommended use of antivirals. Pandemic (H1N1 2009 briefing note 8.http://www.who.int/csr/disease/swineflu/notes/h1n1_use_antivirals_20090820/en/index.htmlGoogle Scholar, 30World Health Organization Clinical management of human infection with pandemic (H1N1 2009 revised guidance.http://www.who.int/csr/resources/publications/swineflu/clinical_management_h1n1.pdfGoogle Scholar Cases of oseltamivir-resistant viruses continue to be sporadic and infrequent, with no evidence that oseltamivir-resistant pandemic A(H1N1) viruses are circulating within communities or worldwide. All of these viruses show the same H275Y (N1 nomenclature) mutation that confers resistance to the antiviral oseltamivir, but not to the antiviral zanamivir. Thus zanamivir remains a treatment option in symptomatic patients with severe or deteriorating illness due to oseltamivir-resistant virus.31World Health Organization Antiviral use and the risk of drug resistance. Pandemic (H1N1 2009 briefing note 12.http://www.who.int/csr/disease/swineflu/notes/h1n1_antiviral_use_20090925/en/index.htmlGoogle Scholar The risk of resistance is considered higher in patients with severely compromised or suppressed immune systems who have prolonged illness, have received oseltamivir treatment (especially for an extended duration), but still have evidence of persistent viral replication. The risk of resistance is also considered higher in people who receive oseltamivir for postexposure prophylaxis following exposure to another person with influenza and who then develop illness despite taking oseltamivir. In general, it is not recommended to use antiviral drugs for prophylactic purposes. An alternative option is close monitoring for symptoms in people who have had exposure to an infected person and are at a higher risk of developing severe or complicated illness, followed by prompt early antiviral treatment should symptoms develop.30World Health Organization Clinical management of human infection with pandemic (H1N1 2009 revised guidance.http://www.who.int/csr/resources/publications/swineflu/clinical_management_h1n1.pdfGoogle Scholar, 31World Health Organization Antiviral use and the risk of drug resistance. Pandemic (H1N1 2009 briefing note 12.http://www.who.int/csr/disease/swineflu/notes/h1n1_antiviral_use_20090925/en/index.htmlGoogle Scholar About 1% to 10% of patients with clinical illness due to the novel infection have required hospitalization and the overall case fatality ratio has been estimated as < 0.5%.19World Health Organization Human infection with pandemic A (H1N1 2009 influenza virus: clinical observations in hospitalized patients, Americas, July 2009 update.Weekly Epidemiological Record on Pandemic H1N1 2009. 2009; 84: 305-308Google Scholar Rapidly progressive respiratory failure is relatively common and about 10% to 30% of hospitalized patients have required ICU admission.30World Health Organization Clinical management of human infection with pandemic (H1N1 2009 revised guidance.http://www.who.int/csr/resources/publications/swineflu/clinical_management_h1n1.pdfGoogle Scholar IMV, with a lung-protective ventilation strategy, is recommended as the initial approach for managing patients with pandemic A(H1N1) infection complicated by ARDS.26Kaufman MA Duke GJ McGain F et al.Life-threatening respiratory failure from H1N1 influenza 09 (human swine influenza).Med J Aust. 2009; 191: 154-156PubMed Google Scholar, 30World Health Organization Clinical management of human infection with pandemic (H1N1 2009 revised guidance.http://www.who.int/csr/resources/publications/swineflu/clinical_management_h1n1.pdfGoogle Scholar The recommendation is based on the ARDSNet trial demonstrating a relative risk reduction of mortality by 22% in patients with ARDS ventilated with the lower tidal volume (eg, goal of maximum tidal volume 6 mL/kg of predicted body weight with plateau pressures up to maximum 30 cm H2O).32The Acute Respiratory Distress Syndrome Network Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.N Engl J Med. 2000; 342: 1301-1308Crossref PubMed Scopus (10748) Google Scholar Furthermore, it is prudent to adopt a conservative fluid management approach for patients with ARDS/acute lung injury, as this has been shown to increase ventilator-free days and improve oxygenation when compared with a fluid liberal strategy.33Wiedemann HP Wheeler AP Bernard GR National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network et al.Comparison of two fluid-management strategies in acute lung injury.N Engl J Med. 2006; 354: 2564-2575Crossref PubMed Scopus (2847) Google Scholar In ICUs where expertise and technology are available, extracorporeal membrane oxygenation (ECMO), high-frequency oscillation ventilation,
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