Flu: 77% With Seasonal, Pandemic Infection Asymptomatic

Laurie Barclay, MD

March 17, 2014

Although 18% of the population was infected in recent outbreaks of seasonal influenza and in the 2009 H1N1 influenza pandemic, only 23% of infections were symptomatic, and only 17% led to medical attention, according to a community-based study published online March 17 in Lancet Respiratory Medicine.

"Reported cases of influenza represent the tip of a large clinical and subclinical iceberg that is mainly invisible to national surveillance systems that only record cases seeking medical attention," lead author Andrew C. Hayward, MD, from University College London, United Kingdom, said in a journal news release. "Most people don't go to the doctor when they have flu, [and] even when they do consult they are often not recognised as having influenza."

The goals of the Flu Watch study were to compare the community burden and severity of seasonal and pandemic influenza among different age groups and study years and to clarify the degree to which traditional surveillance underestimates this burden.

The investigators followed the course of seasonal and pandemic influenza over the course of 5 successive cohorts in England from 2006 to 2011, representing 5448 person-seasons' follow-up.

Before and after each influenza season, participants gave blood samples for influenza serology. Weekly contact with all participating households allowed identification of any cases of cough, cold, sore throat, or influenza-like illness. Any participant with such symptoms was asked to provide a nasal swab on day 2 of illness to identify respiratory viruses using real-time polymerase chain reaction (RT-PCR) testing.

The investigators weighted analyses by age and by the regional structure of England to calculate nationally representative estimates. They used ordinal logistic regression, with symptom severity grade as the outcome variable, to compare symptom profiles during the first week of illness for different strains of PCR-confirmed influenza and noninfluenza viruses.

Most Influenza Infections Were Asymptomatic

Each winter, influenza infected an average of 18% (95% confidence interval [CI], 16% - 22%) of unvaccinated people, based on 4-fold titer increases in strain-specific serology. There were 69 respiratory illnesses per 100 person-influenza seasons among infected persons compared with 44 per 100 among those not infected with influenza.

Most influenza infections (77%) appeared to be asymptomatic, according to the age-adjusted attributable rate of illness among infected persons of 23 illnesses per 100 person-seasons (95% CI, 13 - 34 illnesses). One quarter (25%; 95% CI, 18% - 35%) of all those with serologically confirmed infections had PCR-confirmed disease. Among persons with PCR-confirmed influenza, only 17% (95% CI, 10% - 26%) sought medical attention for their illness.

Findings were similar for pandemic influenza. Among PCR-confirmed cases, symptoms were markedly less severe for 2009 pandemic strain infections than for seasonal H3N2 infections.

Surveillance Based on Ill Patients Underestimates Influenza Prevalence

"Surveillance based on patients who consult greatly underestimates the number of community cases, which in turn can lead to overestimates of the proportion of cases who end up in hospital or die," Dr. Hayward said in the news release. "Information on the community burden is therefore critical to inform future control and prevention programmes."

Across all 5 influenza winter seasons, the rate of influenza was, on average, 22 times higher than rates of disease recorded by the Royal College of General Practitioners Sentinel Influenza-Like Illness Surveillance Scheme.

"Despite its mild nature, the 2009 pandemic caused enormous international concern, expense, and disruption," Dr. Hayward concluded. "We need to prepare for how to respond to both mild and severe pandemics. To do this we need more refined assessments of severity, including community studies to guide control measures early in the course of a pandemic and inform a proportionate response."

Study limitations included the difficulty in obtaining a fully representative sample, even though selection was random, because acceptance rates were low and because of the inability to identify virus shedding during asymptomatic infection.

In an accompanying comment, Peter William Horby, MBBS, DTM&H, FRCP, FFPH, PhD, from the Oxford University Clinical Research Unit, United Kingdom, addresses the unknown extent to which mild and asymptomatic influenza infections may contribute to transmission.

"A large number of well individuals mixing widely in the community might, even if only mildly infectious, make a substantial contribution to onward transmission," Dr. Horby writes. "This might have important implications for the effectiveness of case isolation and social distancing measures in reducing overall transmission rates."

To improve our understanding of the global epidemiology of influenza, Dr. Horby recommends a direct comparison of data from different cohorts.

"[S]urveillance of medically attended illnesses provides a partial and biased picture, and is vulnerable to changes in consulting, testing, or reporting practices," he concludes. "As such, it is clear that reliable estimates of the infection and clinical attack rates during the early stages of an influenza epidemic requires the collection of standardised data across the whole range of disease severity, from the community, primary care, and secondary care."

The Medical Research Council and the Wellcome Trust funded this study, which is a collaboration between researchers at the University College London, Public Health England, University of Oxford, University of Nottingham, London School of Hygiene and Tropical Medicine, and Imperial College London. Some of the study authors reported various financial disclosures involving Roche, GSK, Sanofi, Novartis, CSL, Baxter, the Wellcome Trust, and/or UK national advisory committees involved in planning and response for seasonal and pandemic influenza. Full conflict-of-interest information is available in the journal article. Dr. Horby has disclosed no relevant financial relationships.

Lancet Respir Med. Published online March 17, 2014. Article full text, Abstract full text

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