Since the detection in April 2009 of the first 2 cases of human infection with pandemic A (H1N1) 2009 influenza virus in Southern California (USA), >100 000 laboratory-confirmed human cases have been notified to WHO from 124 countries (data as of 15 July 2009).
Several countries at advanced stages of the pandemic have changed their strategies for surveillance testing and are no longer attempting to identify all human cases of pandemic A (H1N1) 2009 influenza virus infection.
For example, as of 10 July 2009, the USA had reported 37 246 cases, 4132 hospitalizations and 211 deaths; however, estimates based on mathematical modelling suggest that >1 million people have been infected. In such countries, surveillance of pandemic disease has shifted to “monitoring” the occurrence of disease among outpatients using syndromic surveillance (of influenza-like illness (ILI)) and other traditional methodologies including laboratory-confirmed hospitalizations and mortality from pneumonia and influenza.
Laboratory-based virological surveillance is ongoing, with prioritization on testing of hospitalized patients.
In many countries, the capacity for laboratory diagnosis has been severely stressed; the number of samples to be processed has been overwhelming. Laboratory diagnostic testing for pandemic A (H1N1) 2009 influenza virus infection should be prioritized for (i) samples from patients with severe disease, atypical presentations or unexplained deaths; (ii) samples from patients in whom determination of antiviral resistance will influence clinical management or is considered clinically important; and (iii) random samples from impatients and outpatients to monitor viral characteristics (e.g. antigenic, genetic and antiviral susceptibility data).
The total number of laboratory-confirmed cases reported to WHO no longer reflects the full magnitude of the pandemic, especially for those countries experiencing widespread pandemic activity; the difference between laboratory-confirmed cases and the true number of cases in the population is expected to increase in the future.
WHO has been closely monitoring the clinical severity of the pandemic since its onset. The clinical spectrum of pandemic A (H1N1) 2009 virus infection is broad, from mild upper respiratory tract illness with or without fever and occasional gastrointestinal symptoms such as vomiting or diarrhoea and exacerbation of underlying conditions, to severe complications such as pneumonia resulting in respiratory failure, acute respiratory distress syndrome (ARDS), multi-organ failure and death.
While the vast majority of cases have resulted in mild, self-limited ILI, the global death toll caused by pandemic A (H1N1) 2009 influenza virus infection was 460 (as of 9 July 2009) in only 3 months since its inception and will soon exceed the total mortality caused by highly pathogenic avian influenza A (H5N1) virus infection since 2003.
This report summarizes the clinical features of hospitalized cases of human infection by the pandemic (H1N1) 2009 influenza virus in Canada, Chile, Mexico and the USA. Information has been collected mainly through teleconferences organized by WHO and supported by national public health authorities as well as data reported by clinicians involved in patient care.
Hospitalizations
In May 2009, WHO reported that 2–6% of confirmed cases had been admitted to hospital.(1) Based on data obtained during recent teleconferences, the rate of hospitalization can be as high as 10% of confirmed cases in some cities. These data, however, should be interpreted carefully because clinical samples from severe or hospitalized cases have been preferentially tested; the burden of mild illness is therefore under-reported and the denominator is likely to be underestimated.
For example, initially, Chile reported that 1.7% of cases had been hospitalized, but is now reporting that 3.8% of confirmed cases are being hospitalized (data as of 6 July 2009) after implementing a change of policy in laboratory testing.
The aforementioned USA estimate gives a figure of approximately 0.3% as an overall hospitalization rate. As of 7 July 2009, New York City had reported 1291 cases, with 909 hospitalizations and 47 deaths. However, of an estimated several hundred thousand cases in New York City , the overall percentage of hospitalizations is <1%.
Characteristics of hospitalized cases
The vast majority of cases of pandemic A (H1N1) 2009 virus infection have experienced clinically mild disease (e.g. influenza-like illness). A small proportion have experienced complications requiring admission to hospital.
Hospitalization occurs in all age groups, but the median age of patients tends to be somewhat older (ranging from 15 to 42 years), as reported from various sites, compared with all cases. People aged >65 years old are still relatively rare among hospitalized patients; however, reported deaths have occurred mostly in patients aged >40 years. In California, the median ages of all cases is 17 years, of hospitalized cases 26 years and of fatal cases 45 years. The male:female ratio in hospitalized cases is approximately 1:1.
Severe disease has been reported in some minority populations, but it is unknown whether this represents a higher incidence of severe disease or reflects cultural, economic and social risk factors.
The main reason for hospitalization remains lower respiratory illness due to primary viral pneumonia, often described as “viral pneumonitis,” reflecting direct viral invasion in lung tissues.
Preliminary pathological findings including diffuse alveolar damage, haemorrhagic interstitial pneumonitis with lymphocyte proliferation and a relative paucity of neutrophils (suggestive of viral
pneumonitis) and ARDS. Secondary bacterial pneumonia has been infrequently documented but has been found in some autopsied cases (in Chicago (USA) and Manitoba (Canada)).
Of 50 fatal cases in California, 7 (14%) had microbiological evidence of a secondary bacterial or fungal infection. Nosocomial infection such as ventilator-associated pneumonia has been identified in critically ill cases with a prolonged hospital course.
Multiple pulmonary emboli have been observed in several very severe cases in patients admitted to intensive care units (ICUs) with refractory ARDS in the USA.(2)
Anecdotal reports from Manitoba indicate that the viral pneumonia progresses rapidly to respiratory failure and ARDS that is unusually refractory to standard oxygenation strategies; they also report that in such patients, nasopharyngeal sampling is substantially inferior to deep tracheal aspirates for confirming the diagnosis of pandemic A (H1N1) 2009 influenza virus infection by realtime reverse transcription polymerase-chain reaction.
Underlying medical conditions
The relative proportion of patients with or without comorbidities differs by reporting sites. Canada as a whole reports that 37% of hospitalized patients have at least 1 co-morbidity; the most frequent underlying medical conditions are chronic lung disease (including asthma), heart disease, kidney disease, immunosuppression and pregnancy.
In the USA, >70% of hospitalized patients and approximately 80% of fatal cases have had underlying conditions considered high risk for complications of seasonal influenza. Severe cases and deaths have been reported in pregnant women from all sites, especially in their third trimesters, with intrauterine fetal demise or spontaneous abortion; in some cases, treating physicians have performed emergency Caesarean section to rescue mother and baby.
A high prevalence of obesity in very severe or fatal cases was initially reported from clinicians in Mexico,(3) and this finding has been anecdotally supported by clinicians from California, Chile and Manitoba. A recent report(2) of 10 ventilated ICU patients from Michigan (USA) in which 9 had a BMI >30 and 7 had a BMI />40 highlights this finding. Of 50 fatal cases in California, 30 (60%) had a BMI >30, of whom 14 (47%) had a BMI >40.
Of the 30 fatal cases with a BMI >30, 11 (37%) did not have known risk factors for complications of seasonal influenza; 3 of the 11 (27%) had other comorbidities, including hypertension (2) and gastroesophageal reflux disease (1).
Further population-based studies, with careful documentation of BMI and comorbidities, are highly desirable in order to learn more about the role of obesity in severe disease from pandemic influenza.
Atypical presentations
Gastrointestinal symptoms, including vomiting and diarrhoea, have been reported in up to 50% of patients with mild to moderate illness not requiring hospitalization. However, gastrointestinal symptoms have been reported less frequently among hospitalized patients.
One 23 month-old baby in New York City (USA) has been reported as sudden infantile death attributed to pandemic A (H1N1) 2009 influenza virus infection. Paediatric cases of infl uenza-associated encephalopathy have been reported in the USA, Chile and other countries.
Additionally, invasive bacterial infections have been also reported in Chilean paediatric patients (including Staphylococcus aureus, Group A Streptococcus and Streptococcus pneumoniae).
Editorial note.
The increasing burden of disease associated with pandemic A (H1N1) 2009 influenza virus infection is severely stressing emergency departments and ICUs in some localities. Clinicians participating in the periodic WHO teleconferences agreed that almost all ICU hospitalizations were primarily a result of ARDS caused by viral pneumonia; secondary bacterial pneumonia has rarely been diagnosed.
However, in some areas with high levels of community-wide pandemic influenza virus activity, characteristics of severe hospitalized cases are changing from previously healthy young people (aged 20–35 years) with primary viral pneumonia to older people with underlying chronic medical conditions (aged >55 years old, at high-risk for seasonal influenza risk complications).
One Manitoba intensivist reported 2 “waves” of patients, the first being young adults without pre-existing co-morbid conditions, with rapidly progressive pneumonitis and high oxygen requirements who were very difficult to ventilate, and a second, older cohort, with pre-existing conditions traditionally linked to progressive disease with seasonal influenza, who generally had a more benign course.
The ICU critical care specialists from the pandemic A (H1N1) 2009 influenza virus “hot spots” report that a considerable proportion of severely ill patients have not received influenza antivirals until very late in the course of their illness.
A frequently reported pattern is for clinicians to start empirical antimicrobial therapy for community-acquired pneumonia, while deferring antiviral therapy until laboratory test results have confirmed H1N1 infection.
Where pandemic A (H1N1) 2009 influenza virus activity has been detected in the community, clinicians should not delay antiviral treatment, especially for patients with pneumonia or progressive
lower respiratory tract symptoms. Empirical antiviral treatment with a neuraminidase inhibitor (oseltamivir or zanamivir) should be initiated as soon as possible upon hospital admission for any suspected case of pandemic influenza.
Health authorities need to inform health-care workers and the general public that although most cases of H1N1 disease are mild and will not require antiviral therapy, medical consultation when
appropriate should not be discouraged and home isolation should not be over-emphasized.
The general public should be made aware of pre-existing conditions as well as danger signs that ought to trigger timely consultation with health-care providers and appropriate antiviral treatment.
Acknowledgement
WHO thanks colleagues from the following institutions in Canada, Chile, Mexico and the USA for their response and contributions.
Public Health Agency of Canada, Manitoba Province; Ministerio de Salud, Chile; United States Centers for Disease Control and Prevention; Chicago Department of Public Health; New York Cit y Department of Health and Mental Hygiene; Northwestern University (Chicago); the Michigan Department of Community Health; the University of Michigan; New York-Presbyterian Hospital; California Department of Health Services; and CONAMED, Mexico.
1 See No. 21, 2009, pp. 185–189.
2 Morbidity and Mortality Weekly Report Dispatch, 2009, 58:1–4 (available at http://www.cdc.gov/mmwr/preview/mmwr...58d0710a1.htm; accessed July 2009).
3 See No. 21, 2009, pp. 185–196 (available at http://www.who.int/wer/2009/wer8421/en/index.html; accessed July 2009).
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