Risk Factors for Severe Outcomes following 2009 Influenza A (H1N1) Infection: A Global Pooled Analysis

Abstract

This study analyzes data from 19 countries (from April 2009 to Jan 2010), comprising some 70,000 hospitalized patients with severe H1N1 infection, to reveal risk factors for severe pandemic influenza, which include chronic illness, cardiac disease, chronic respiratory disease, and diabetes.

Abstract

Background

Since the start of the 2009 influenza A pandemic (H1N1pdm), the World Health Organization and its member states have gathered information to characterize the clinical severity of H1N1pdm infection and to assist policy makers to determine risk groups for targeted control measures.

Methods and Findings

Data were collected on approximately 70,000 laboratory-confirmed hospitalized H1N1pdm patients, 9,700 patients admitted to intensive care units (ICUs), and 2,500 deaths reported between 1 April 2009 and 1 January 2010 from 19 countries or administrative regions—Argentina, Australia, Canada, Chile, China, France, Germany, Hong Kong SAR, Japan, Madagascar, Mexico, the Netherlands, New Zealand, Singapore, South Africa, Spain, Thailand, the United States, and the United Kingdom—to characterize and compare the distribution of risk factors among H1N1pdm patients at three levels of severity: hospitalizations, ICU admissions, and deaths. The median age of patients increased with severity of disease. The highest per capita risk of hospitalization was among patients <5 y and 5–14 y (relative risk [RR] = 3.3 and 3.2, respectively, compared to the general population), whereas the highest risk of death per capita was in the age groups 50–64 y and ≥65 y (RR = 1.5 and 1.6, respectively, compared to the general population). Similarly, the ratio of H1N1pdm deaths to hospitalizations increased with age and was the highest in the ≥65-y-old age group, indicating that while infection rates have been observed to be very low in the oldest age group, risk of death in those over the age of 64 y who became infected was higher than in younger groups. The proportion of H1N1pdm patients with one or more reported chronic conditions increased with severity (median = 31.1%, 52.3%, and 61.8% of hospitalized, ICU-admitted, and fatal H1N1pdm cases, respectively). With the exception of the risk factors asthma, pregnancy, and obesity, the proportion of patients with each risk factor increased with severity level. For all levels of severity, pregnant women in their third trimester consistently accounted for the majority of the total of pregnant women. Our findings suggest that morbid obesity might be a risk factor for ICU admission and fatal outcome (RR = 36.3).

Conclusions

Our results demonstrate that risk factors for severe H1N1pdm infection are similar to those for seasonal influenza, with some notable differences, such as younger age groups and obesity, and reinforce the need to identify and protect groups at highest risk of severe outcomes.

Please see later in the article for the Editors' Summary

Editors' Summary

Background

In April 2009, a new strain of influenza A H1N1 was first identified in Mexico and the United States and subsequently spread around the world. In June 2009, the World Health Organization (WHO) declared a pandemic alert phase 6, which continued until August 2010. Throughout the pandemic, WHO and member states gathered information to characterize the patterns of risk associated with the new influenza A H1N1 virus infection and to assess the clinical picture. Although risk factors for severe disease following seasonal influenza infection have been well documented in many countries (for example, pregnancy; chronic medical conditions such as pulmonary, cardiovascular, renal, hepatic, neuromuscular, hematologic, and metabolic disorders; some cognitive conditions; and immunodeficiency), risk factors for severe disease following infection early in the 2009 H1N1 pandemic were largely unknown.

Why Was This Study Done?

Many countries have recently reported data on the association between severe H1N1 influenza and a variety of underlying risk factors, but because these data are presented in different formats, making direct comparisons across countries is difficult, with no clear consensus for some conditions. Therefore, to assess the frequency and distribution of known and new potential risk factors for severe H1N1 infection, this study was conducted to collect data (from 1 April 2009 to 1 January 2010) from surveillance programs of the Ministries of Health or National Public Health Institutes in 19 countries―Argentina, Australia, Canada, Chile, China, France, Germany, Hong Kong (special administrative region), Japan, Madagascar, Mexico, the Netherlands, New Zealand, Singapore, South Africa, Spain, Thailand, the United States, and the United Kingdom.

What Did the Researchers Do and Find?

As part of routine surveillance, countries were asked to provide risk factor data on laboratory-confirmed H1N1 in patients who were admitted to hospital, admitted to the intensive care unit (ICU), or had died because of their infection, using a standardized format. The researchers grouped potential risk conditions into four categories: age, chronic medical illnesses, pregnancy (by trimester), and other conditions that were not previously considered as risk conditions for severe influenza outcomes, such as obesity. For each risk factor (except pregnancy), the researchers calculated the percentage of each group of patients using the total number of cases reported in each severity category (hospitalization, admission to ICU, and death). To evaluate the risk associated with pregnancy, the researchers used the ratio of pregnant women to all women of childbearing age (age 15–49 years) at each level of severity to describe the differences between levels.

The researchers were able to collect data on approximately 70,000 patients requiring hospitalization, 9,700 patients admitted to the ICU, and 2,500 patients who died from H1N1 infection. The proportion of patients with H1N1 with one or more reported chronic conditions increased with severity—the median was 31.1% of hospitalized patients, 52.3% of patients admitted to the ICU, and 61.8% of patients who died. For all levels of severity, pregnant women in their third trimester consistently accounted for the majority of the total of pregnant women. The proportion of patients with obesity increased with increasing disease severity—median of 6% of hospitalized patients, 11.3% of patients admitted to the ICU, and 12.0% of all deaths from H1N1.

What Do These Findings Mean?

These findings show that risk factors for severe H1N1 infection are similar to those for seasonal influenza, with some notable differences: a substantial proportion of people with severe and fatal cases of H1N1 had pre-existing chronic illness, which indicates that the presence of chronic illness increases the likelihood of death. Cardiac disease, chronic respiratory disease, and diabetes are important risk factors for severe disease that will be especially relevant for countries with high rates of these illnesses. Approximately 2/3 of hospitalized people and 40% of people who died from H1N1 infection did not have any identified pre-existing chronic illness, but this study was not able to comprehensively assess how many of these cases had other risk factors, such as pregnancy, obesity, smoking, and alcohol misuse. Because of large differences between countries, the role of risk factors such as obesity and pregnancy need further study—although there is sufficient evidence to support vaccination and early intervention for pregnant women. Overall, the findings of this study reinforce the need to identify and target high-risk groups for interventions such as immunization, early medical advice, and use of antiviral medications.

Additional Information

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001053.

• WHO provides a Global Alert and Response (GAR) with updates on a number of influenza-related topics

• The US Centers for Disease Control and Prevention provides information on risk factors and H1N1