Human infection with new influenza A (H1N1) virus: clinical observations from Mexico and other affected countries, May 2009 (WHO, May 22, 2009, Edited)

Human infection with new influenza A (H1N1) virus: clinical observations from Mexico and other affected countries, May 2009 (WHO, May 22, 2009, Edited)

Human infection with new influenza A (H1N1) virus: clinical observations from Mexico and other affected countries, May 2009

[From World Health Organization's Weekly Epidemiological Record - N° 21, 2009, 84 - Full Text: LINK. EDITED.]

As of 20 May 2009, 10 243 laboratory-confirmed cases of new influenza A (H1N1) virus infection, including 80 deaths, had been reported to WHO from 41 countries. Most of these cases were from North America (USA, 5469; Mexico, 3734; Canada, 496). The majority of fatal cases (74) were reported from Mexico (Table 1). This article summarizes the clinical features of human infection with new influenza A (H1N1) virus and provides initial WHO guidance on clinical management.*

Clinical features

The spectrum of disease caused by new influenza A (H1N1) virus infection ranges from non-febrile, mild upper-respiratory tract illness to severe or fatal pneumonia.1,2,3 Most cases appear to have uncomplicated, typical influenza-like illness and recover spontaneously. The most commonly reported symptoms include cough, fever, sore throat, malaise and headache (Table 2). Fever has been absent in some outpatients and in up to 1 in 6 surviving hospitalized patients. Gastrointestinal symptoms (nausea, vomiting and/or diarrhoea) have occurred in up to 38% of outpatients in the United States.2

Hospitalized patients.

Approximately 2–5% of confirmed cases in the United States4,5 and Canada, as well as 6% in Mexico,4 have been admitted to hospital. Among patients presenting with acute respiratory illness for care in Mexico, 13% tested positive for new influenza A (H1N1) virus infection (about one-fifth have had seasonal influenza), of whom about 10% have been hospitalized and one-third of those hospitalized required mechanical ventilation.

Almost one-half of the patients hospitalized in the United States,2 and 21 of 45 (46%) fatal cases in Mexico for whom data are available (Table 2), have had underlying conditions, including pregnancy, asthma, other lung diseases, diabetes, morbid obesity, autoimmune disorders and associated immunosuppressive therapies, neurological disorders and cardiovascular disease. Among 20 pregnant women in the United States confirmed to have been infected with new influenza A (H1N1) virus, 3 required hospitalization, 1 of whom died; this patient had started antiviral therapy 13 days after illness onset.6

Among 30 patients hospitalized in California, 64% had underlying conditions and 2 of 5 pregnant women developed complications, including spontaneous abortion and premature rupture of membranes.5

Among 45 fatal cases in Mexico, 54% were among previously healthy people (Table 2), most of whom were aged 20–59 years (Table 1); 1 was a pregnant woman at 34 weeks’ gestation.1

Casefatality ratios were lower in children and teenagers than in adults, for reasons to be determined (Table 1). Rapidly progressive respiratory disease has accounted for most severe or fatal cases. In Mexico, the median time from onset of illness to hospitalization was 6 days (range, 1–20 days) in 45 fatal cases, compared with a median of 4 days in hospitalized cases in the United States. In fatal cases, the presenting manifestations have included fever, shortness of breath, myalgia, severe malaise, tachycardia, tachypnoea, low oxygen saturation and, sometimes, hypotension and cyanosis. Several patients experienced cardiopulmonary arrest shortly after arrival at hospital. Diarrhoea has been uncommon in hospitalized cases.

In Mexico, the clinical course has been notable for severe pneumonia, multifocal infiltrates including nodular alveolar and, less frequently, basilar opacities on chest radiographs, as well as rapid progression to acute respiratory distress syndrome (ARDS) and renal or multi-organ failure (24% of fatal cases). The median time from symptom onset to death was 10 days (range, 2–33 days). Of those hospitalized in California, 15 of 25 (60%) tested had radiographic changes suggestive of pneumonia, including 10 with multilobar infiltrates; 4 (13%) required mechanical ventilation.5

Both leukocytosis and leucopenia have been found in those hospitalized.5 In Mexico, many hospitalized patients have manifested lymphopenia, elevated aminotransferases, elevated lactate dehydrogenase (100% of 16 fatal cases) and, in some, very high levels of creatinine phosphokinase.1 Up to one-half of hospitalized patients have shown some degree of renal insufficiency, perhaps secondary to rhabdomyolysis and myoglobinuria,7 although other causes including hypotension, dehydration and hypoxia may be contributory. Acute myocarditis has been suspected in some patients, but encephalitis has not been described to date.

Microbiology and pathogenesis

Few patients have had evidence of bacterial infection upon admission, but instances of empyema, necrotizing pneumonia and bacterial coinfection, as well as ventilator-associated pneumonias, have occurred. Some cases had received antibiotic treatment before hospitalization. In Mexico, bacterial coinfections were documented in 3 fatal cases.1 Preliminary studies utilizing molecular detection methods found 2 instances of coinfections (1 Streptococcus pneumoniae, 1 adenovirus) among 21 severe or fatal cases.8

Initial autopsy reports from Mexico indicate that the pathology was consistent with ARDS secondary to primary viral pneumonia, including diffuse alveolar damage, peribronchiolar and perivascular lymphocytic infiltrates, hyperplastic airway changes and bronchiolitis obliterans. Muscle biopsies performed in 2 cases showed skeletal muscle necrosis.

Initial WHO guidance on clinical management of human infection with new influenza A (H1N1) virus

Based on the limited clinical information available, and given the evolving situation, WHO advises the following approach to the clinical management of human infection with new influenza A (H1N1) virus.

Mild cases.

Supportive treatment (e.g. paracetamol, fluids) based on symptoms should be provided as needed. Salicylates (such as aspirin and aspirin-containing products) should not be used in children and young adults because of the risk of Reye syndrome. Where antiviral medication is available, early administration in at-risk patients (those with co-morbidities or who are pregnant) with a neuraminidase inhibitor (oral oseltamivir or inhaled zanamivir) is advised. The new influenza A (H1N1) virus is susceptible to neuraminidase inhibitors (oseltamivir, zanamivir) but resistant to M2 ion channel inhibitors (amantadine, rimantadine). Adequate infection control precautions (cough etiquette, hand hygiene and natural ventilation) at home should be implemented.

Hospitalized patients.

Where available, antiviral treatment with oseltamivir is recommended, especially in progressive disease or pneumonia caused by new influenza A (H1N1) virus infection. The findings in severe new influenza A (H1N1)-related pneumonia are similar to those noted in avian influenza A (H5N1) virus infection in humans and, until further data become available, the guidance provided for clinical management of avian influenza A (H5N1) virus infection remains applicable in patients with severe new influenza A (H1N1) virus infection.9

Respiratory support.

The cornerstone of management is early detection and correction of hypoxia with supplemental oxygen or mechanical ventilation as necessary. Treatment of hypoxia requires close attention to practical issues, including oxygen delivery devices and flow rates, monitoring and patient compliance. When mechanical ventilatory support is indicated, a low-volume, low-pressure lung protective ventilation strategy for ARDS should be used.

Antibiotics.

When pneumonia is present, treatment with antibiotics should generally follow recommendations from published, evidence-based guidelines for community-acquired pneumonia. Antibiotic choices should be based on local data regarding frequency of pathogens related to secondary infections, patterns of resistance and drug availability at country level. Of note, seasonal influenza and previous influenza pandemics have been associated with an increased risk of secondary Staphylococcus aureus infections that may be severe, rapidly progressive, necrotizing and, in some areas, caused by methicillin-resistant strains.

Antiviral treatment.

Detailed information regarding antiviral therapy in these patients is not currently available, but use of oral oseltamivir in those with serious illness or pneumonia may be beneficial. In some hospitalized patients with new influenza A (H1N1) virus infection, delays to initiation of antiviral therapy are likely an important factor in poor outcomes. Among 27 fatal cases in Mexico, the median time from onset of symptoms to initiation antiviral therapy was 8 days (range, 1–26 days).1

Corticosteroids.

Routine use of corticosteroids should be avoided in patients with new influenza A (H1N1)-related pneumonia, and no benefit from treatment with corticosteroids was reported by clinical colleagues in Mexico. Use of corticosterioids in higher doses has been associated with serious side-effects and evidence of increased viral replication in SARS (severe acute respiratory syndrome) and other respiratory viral infections, as well as increased mortality in avian influenza A (H5N1) disease.10

Editorial note.

The clinical spectrum of disease caused by new influenza A (H1N1) virus infection is broad and may evolve, especially when infections occur in vulnerable populations. Those with malnutrition, chronic infections such as HIV and other comorbidities may be particularly vulnerable. Consequently, this guidance should be considered provisional. Prospective, systematic studies with appropriate virological studies will be necessary to give a more comprehensive picture.

Serological studies are needed to determine the actual frequencies of mild or sub-clinical infections and the extent of age-related pre-existing immunity in the population that might influence illness patterns. The risk factors for severe or complicated diseases are incompletely defined, and the role of common risk factors for more severe influenza such as smoking11 and possibly air pollution require study. Also, the effect of altitude (Mexico City at >2200 m) on hypoxic injury remains to be determined.

The virological course of new influenza A (H1N1) virus infection, including viral loads in the upper and lower respiratory tract, needs to be defined. Whether the virus causes extrapulmonary dissemination in some patients remains to be determined. Given the apparently higher frequency of gastrointestinal symptoms compared with seasonal influenza, further studies are needed to assess whether the virus infects the gastrointestinal tract and whether faeces or vomitus might be infectious.

Initial guidance on the clinical management of human infection with new influenza A (H1N1) virus is available from the WHO web site.12,13 Updates on the evolving situation will be published in the Weekly Epidemiological Record.14

Acknowledgement

WHO thanks colleagues from the following institutions in Mexico for their response and contributions to this challenging situation.

Secretary of Health Promotion and Prevention, Ministry of Health (Secretaría de Salud, México, http://portal.salud.gob.mx ); Directorate General of Epidemiology, Ministry of Health (Dirección General Adjunta de Epidemiología, http://www.dgepi.salud.gob.mx ); National Institutes for Epidemiological Reference and Diagnostics (Institutos de Diagnóstico y Referencia Epidemiológicos; http://www.cenavece.salud.gob.mx/indre/ ); National Commission of Medical Arbitrage (Comisión Nacional de Arbitraje Médico, http://www.conamed.gob.mx/ ); National Institute for Respiratory Diseases (Instituto Nacional de Enfermedades Respiratorias, http://www.iner.salud.gob.mx ); General Hospital of Mexico (Hospital general de Mexico, http://www.hospitalgeneral.salud.gob.mx ); Salvador Zubirán National Institute for Medical Sciences and Nutrition (Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ, INNSZ), http://www.innsz.mx ); and colleagues throughout the health-care community for their professional and rapid response to this challenging situation.

1 Update: new virus influenza A (H1N1): regional report 6(32). Washington DC, Pan American Health Organization, 2009 (available at http://new.paho.org/hq/index.php?option=com_
content&task=view&id=1377&Itemid=1167 ; accessed May 2009).
2 Novel Swine-Origin Influenza A (H1N1) Investigation Team. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. New England Journal of Medicine, 2009, 361, 7 May 2009 (available at http://content.nejm.org/cgi/content/full/NEJMoa0903810 ; accessed May 2009).
3 Epidemiology of new influenza A (H1N1) in the United Kingdom, April–May 2009, Eurosurveillance, 14(9):1–2 (available at http://www.eurosurveillance.org/View...aspx?ArticleId
=19213 ; accessed May 2009).
4 Update: novel influenza A (H1N1) virus infections — worldwide, May 6, 2009. Morbidity and Mortality Weekly Report, 2009, 58(17):453–458 (available at http://www.cdc.gov/mmwr/
preview/mmwrhtml/mm5817a1.htm ; accessed May 2009).
5 Hospitalized patients with novel influenza A (H1N1) virus infection — California, April–May, 2009. Morbidity and Mortality Weekly Report, 2009, 58, (early release, 18 May 2009; available
at http://www.cdc.gov/mmwr/pdf/wk/mm58e0518.pdf ; accessed May 2009).
6 Novel influenza A (H1N1) virus infections in three pregnant women — United States, April– May, 2009. Morbidity and Mortality Weekly Report, 2009, 58(18):497–500 (available at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5818a3.htm ; accessed May 2009).
7. Muscal E. Rhabdomyolysis. emedicine, 2008 – updated 8 December 2008 (available at http://emedicine.medscape.com/article/1007814-overview ; accessed May 2009).
8 M. Shaw, United States Centers for Disease Control and Prevention, 2009 [unpublished observations].
9 Clinical management of human infection with avian influenza A (H5N1) virus. Geneva, World Health Organization (updated advice 15 August 2007; available at http://www.who.int/csr/disease/avian...nagement07.pdf ; accessed May 2009).
10 Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus. Update on avian influenza A (H5N1) virus infection in humans. New England Journal of Medicine, 2008, 358:261–273 (available at http://content.nejm.org/cgi/reprint/358/3/261.pdf ; accessed May 2009).
11 Kark JD, Lebiush M, Rannon L. Cigarette smoking as a risk factor for epidemic a(h1n1) influenza in young men. New England Journal of Medicine, 1982, 307(17):1042–1046 (available at http://content.nejm.org/cgi/content/...ct/307/17/1042 ; accessed May 2009).
12 Clinical management of human infection with new influenza A (H1N1) virus: initial guidance. Geneva, World Health Organization, 2009 (available at http://www.who.int/csr/resources/pub.../en/index.html ; accessed May 2009).
13 WHO has also published a checklist on care of patients (available at http://www.who.int/csr/resources/pub.../en/index.html ; accessed May 2009).
14 See http://www.who.int/wer/en/

Table 1 Age distribution of laboratory-confirmed human cases of new influenza A (H1N1) virus infection and deaths in Mexico, data as of 20 May 2009

[Age group (years) – No. of laboratory-confirmed cases – % total confirmed cases – No. of laboratory-confirmed deaths – % total confirmed deaths – Case-fatality ratio (%)a]

0–9 - 1046 - 28.0 - 6 - 8.1 - 0.6
10–19 - 943 - 25.3 - 4 - 5.4 - 0.4
20–29 - 754 - 20.2 - 21 - 28.4 - 2.8
30–39 - 413 - 11.1 - 17 - 23.0 - 4.1
40–49 - 306 - 8.2 - 12 - 16.2 - 3.9
50–59 - 183 - 4.9 - 10 - 13.5 - 5.5
≥60 - 68 - 1.8 - 4 - 5.4 - 5.9
Unknown - 21 - 0.6 - 0 - 0.0 –
- Total - 3734 - 100% - 74 - 100% - 2.0%

a Based only on laboratory-confirmed cases and deaths reported to the Ministry of Health of Mexico.

Table 2 Clinical features of fatal cases (Mexico) and other patients with confirmed new influenza A(H1N1) virus infection

[Fatal cases, Mexico (n=45)a – United States (n=642)b – Province de l’Ontario, (Canada) (n=119)c - Hospitalized, California, United States (n=30)d – United Kingdom (n=53)e]

Age distribution (years) - Median 31 (range 0–75) - 60% <_18 - Median 22-24 (range 1–61) - Median 27.5 (range 27 days–87 years) – 58% - 10–29

Co-morbidities – 46% - 41% of 22 hospitalized – 7% of 54 - 64% - 0
Hospitalized for illness – 100% - 36 (9%) of 399 – 6 (3%) of 173 – 100% - 1(2%)
Fever - 93% - 94%f - 87%g - 97% - 94%
Cough – 87% - 92%f - 87%g - 77% NA
Sore throat – NA – 66%f - 48%g - 33% - 82%
Rhinorrhoea – NA - NA – 27%g - 30% - NA
Dyspnoea – 80% - NA - 14%g - 43% - NA
Sputum – 60% - NA - 16%g - NA – NA
Malaise/fatigue - 56% - NA - 35%g - 7% - 80%
Chills – NA – NA – 28%h - 37% - 80%
Myalgia – NA – NA – 35%g - 33%i - NA
Arthralgia – NA – NA – 13%g - NA – 56%
Headache – NA – NA – 38%g - 17% - 81%
Diarrhoea – ~5% - 25%f - 23%g - 10% - 28%
Vomiting – NA – 25%f - 15%g - 46% - NA
Oseltamivir therapy – 19 (42%) - 14 (74%) of 19 hospitalized – 6% of 54 - 50% - 98%
Fatality – 100% - 2 (0.3%) - 0 - 0 (7 of 30 still hospitalized as of 17 May 2009) – 0

NA = not available.
a PAHO, 2009 [personal communication].
b Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. New England Journal of Medicine, 2009 (published
online 7 May 2009; available at http://content.nejm.org/cgi/reprint/NEJMoa0903810.pdf ; accessed May 2009).
c Ontario Ministry of Health and Long-Term Care. H1N1 flu virus – 13 May 2009 (available at http://www.health.gov.on.ca/english/...r/default.html ; accessed May 2009); British Columbia Centre for Disease Control, Health alerts
d Hospitalized patients with novel influenza A (H1N1) virus infection — California, April–May, 2009. Morbidity and Mortality Weekly Report, 2009, 58, (early release, May 18, 2009; available
at http://www.cdc.gov/mmwr/pdf/wk/mm58e0518.pdf ; accessed May 2009).
e Epidemiology of new influenza A (H1N1) in the United Kingdom, April–May 2009, Eurosurveillance, 14(9):1–2 (available at http://www.eurosurveillance.org/View...rticleId=19213 ;
accessed May 2009).
f Symptom analysis based on 295–397 confirmed cases.
g Symptom analysis based on 165 confirmed cases.
h The number of patients was 111.
i Listed as body aches.

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Human infection with new influenza A (H1N1) virus: clinical observations from Mexico and other affected countries, May 2009 (WHO, May 22, 2009, Edited)

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Human infection with new influenza A (H1N1) virus: clinical observations from Mexico and other affected countries, May 2009 (WHO, May 22, 2009, Edited)