As of 6 August 2013, 133 laboratory-confirmed influenza A(H7N9) cases have been officially recorded in mainland China. Among these, 123 requiring hospitalization for medical reasons were included in this study [7]. Ten laboratory-confirmed mild cases were excluded [14]. Data were included for 119 patients hospitalized with H5N1 (Vietnam = 76; China = 43), and 3486 patients hospitalized with pH1N1.

The median age of subjects hospitalized with H7N9 was 63 years, compared to 26 years for H5N1 patients and 25 years for pH1N1 patients (P < .001). A higher proportion of H7N9 subjects were male compared with H5N1 (P = .019) or pH1N1 subjects (P = .001). Subjects hospitalized with H7N9 had the highest prevalence of chronic medical conditions traditionally associated with an increased risk of severe seasonal influenza disease (Table 1). CHD and diabetes were the commonest medical risk factors reported among H7N9 patients, and the prevalence of smoking and hypertension was higher in subjects with H7N9 compared with the other patient groups. Pregnancy was more common in subjects hospitalized with pH1N1. Table 1.

Characteristics of Subjects Hospitalized With Influenza A Virus Subtypes H7N9, H5N1, and pH1N1

Compared with subjects without CHD, the presence of CHD was associated with an increased risk of hospitalization with H7N9 (relative risk [RR], 9.68; 95% CI, 5.24–17.9; Table 2). CHD was also a risk factor for hospitalization with pH1N1 (RR, 16.51; 95% CI, 13.68–19.91). Hypertension was not associated with an increased risk of hospitalization in any group, whereas a history of smoking was associated with a reduced risk of hospitalization. Chronic renal disease was associated with a reduced risk of hospitalization in H7N9 and pH1N1 patients. Once patients were hospitalized, the odds of death were not significantly increased in subjects with any of the risk factors examined (Table 3). Table 2.

Age- and Sex-Adjusted Risk Factors for Hospitalization

Signs and symptoms at hospital admission were compared for H7N9 and H5N1 cases. Subjects with H7N9 virus infection were more likely to report a fever, a productive cough, and hemoptysis than those with H5N1 virus infection (Table 4). Gastrointestinal symptoms were most common in H5N1 cases. Table 4.

Signs and Symptoms on Admission^a

The values of hematological, liver, and renal function tests, and markers of inflammation on admission are shown in Table 5. H7N9 and H5N1 patients showed similar patterns of elevated alanine aminotransferase, creatinine kinase, C-reactive protein, and lactate dehydrogenase, which were all significantly higher than in pH1N1 patients. Leukopenia and thrombocytopenia were equally common in patients with H7N9 and H5N1 virus infections, and more common than in those with pH1N1 virus infection. Lymphopenia was more common in patients with H7N9 compared with H5N1 (88% vs 55%; P < .001), and neutropenia was more common in H5N1 patients. Neutrophilia was equally common in H5N1 and pH1N1 patients, and least common in H7N9 patients. Table 5.

Laboratory Results on Admission^a

The risk of invasive ventilation and death among hospitalized cases by influenza A virus subtype are shown in Figure 1. The cumulative proportion of hospitalized subjects requiring invasive ventilation differs between subtypes, reaching 62% (95% CI, 53%–71%) for H7N9, 54% (95% CI, 45%–63%) for H5N1, and 17% (95% CI, 15%–18%) for pH1N1. Among those ventilated, the interval from onset to invasive ventilation was a median of 7 days for both H7N9 and H5N1 cases (P = .651), and 6 days for pH1N1 cases. The hospitalized case fatality risk was highest for H5N1 (55%; 95% CI, 47%–64%) and death occurred earlier, with a median time from onset to death of 11 days for H5N1, compared with 15 days for pH1N1 patients (P = .154) and 18 days for H7N9 (P = .002). H7N9 patients were hospitalized for a longer duration than either H5N1 (P < .001) or pH1N1 patients (P < .001) (Figure 2). Figure 1.

Case fatality risk and invasive ventilation risk in hospitalized patients. A and B, Case fatality risk by influenza A virus subtype and day of hospitalization (A) and day of illness onset (B). C and D, Invasive ventilation risk by influenza A virus subtype and day of hospitalization (C) and day of illness onset (D). Abbreviation: pH1N1, 2009 pandemic H1N1 virus.

One of the most striking differences in this and other comparative analysis is the high median age of H7N9 patients [16]. This age distribution is unlikely to be due to differences in humoral immunity as the prevalence of neutralizing antibodies to H7N9 virus is probably low in all ages [17–20]. It might arise either because elderly people are more often exposed to the animal or environmental reservoir of H7N9 viruses, or because elderly people have a greater propensity to become infected or severely ill following exposure. After adjusting for the age- and sex-specific prevalence of chronic illnesses in the general Chinese population, we found that CHD was associated with an increased risk of hospitalization with H7N9 virus infection (RR, 9.68; 95% CI, 5.24–17.9). The age distribution of H7N9 patients may therefore be partially explained by an increased propensity in persons with CHD (who are mostly older) to develop severe disease following infection with H7N9 virus. The overrepresentation of males among H7N9 patients may also be partially explained by this association, because in China coronary heart disease is commoner in males than females (male prevalence, 0.74%; female prevalence, 0.51%) [10]. In agreement with our results, an age- and sex-matched case control study of 25 H7N9 cases has reported that the presence of a preexisting chronic medical condition (excluding hypertension) was associated with H7N9 disease (odds ratio, 5.1; 95% CI, 1.5–16.9) [21]. Although only 11% of H7N9 patients reported a history of CHD, unrecognized CHD may have been present in some individuals, and other unmeasured age-related factors, such as impaired innate and cell-mediated immunity, might also contribute to the observed age distribution of hospitalized H7N9 cases [17, 22, 23]. H7N9 viruses isolated from humans exhibit a mixed receptor specificity, binding both α2–6- and α2–3-linked sialidases [3, 4, 20]. H7N9 virus can infect cells of both the upper and lower respiratory tract of humans and ferrets, and disease in ferrets is more severe following intratracheal inoculation [5, 6, 20]. This raises the possibility that susceptibility of humans to severe H7N9 disease may be a consequence of an impaired ability to control virus replication in the lower respiratory tract.

A history of chronic renal disease was associated with a reduced risk of hospitalization with H7N9 virus infection, but the number of patients with this condition was small, so this finding should be interpreted with caution. A history of smoking was associated with a reduced risk of hospitalization with H7N9, H5N1, and pH1N1 virus infections. This is an unexpected finding that might be biased by inconsistent definitions and methods of ascertaining smoking history, which were not standardized in the clinical datasets.

The clinical presentation and laboratory indices at hospital admission are similar for H7N9 and H5N1 patients, except that a productive cough, hemoptysis, lymphopenia, and neutropenia were more common in H7N9 patients. Neutropenia, thrombocytopenia, and elevated liver enzymes are common in H5N1 patients and have been associated with more severe outcomes [9, 24–29]. A low absolute lymphocyte count has been associated with poor outcomes in patients hospitalized with pH1N1, H5N1, and severe acute respiratory syndrome [9, 30–32]. The hematological and serum chemistry abnormalities suggest that subjects hospitalized with H7N9 have a severe systemic illness. It remains to be determined if this is a consequence of severe pneumonia and poor tissue oxygenation or is the result of an excessive inflammatory response (as is seen with H5N1 virus infection) [33]. High levels of chemokines and cytokines have been identified in patients with H7N9 virus infection [20]. Extrapulmonary virus replication is an alternative explanation for the severity of hospitalized H7N9 cases, but H7N9 virus does not posses the polybasic amino acid motif at the HA cleavage site normally associated with extrapulmonary virus replication, and experimental H7N9 virus infection of ferrets has provided little evidence of systemic replication [2, 34, 35]. H7N9 viral RNA has been detected in the serum, urine, and feces of H7N9 patients but it is not known if this represents viral replication occurring outside of the respiratory tract [35].

Hospitalized H7N9 patients had a case fatality risk that was intermediate between pH1N1 and H5N1 patients, and a more protracted clinical course than either H5N1 or pH1N1 patients, with the longest median time to death and the longest hospitalization. Whether this reflects the natural history of severe H7N9 virus infection, patient characteristics, or differences in the clinical management of patients with severe H7N9 compared with H5N1 patients, including increased frequency of rescue modalities such as extracorporeal membrane oxygenation, is unknown.

The comparisons we have made are limited by a lack of standardization of the methods of case ascertainment and inclusion, and of the recording of clinical and other data. As such, the patients and data included in this study may be subject to unmeasured selection and information biases and differences in practices over time and between locations. However, we have tried to minimize these potential biases by restricting our analysis only to hospitalized subjects and to variables where data were available for a reasonable proportion of all cases. Although the H5N1 patients from China and Vietnam had very similar demographic characteristics, underlying medical conditions, and behavioral risk factors, there were some differences in clinical presentation (Supplementary Data), and we cannot exclude that the clinical phenotype of H5N1 virus infections may be heterogeneous. We used univariate analysis that adjusted for age and sex to explore possible risk factors for hospitalization with H7N9; interactions effects were not assessed and the estimated odds ratios and RRs might be confounded by other unmeasured confounders; as such, these risk factors should not be considered to be causal without further validation.

In conclusion, this comparative analysis shows that patients hospitalized with H7N9 virus infection share some risk factors with those hospitalized with pH1N1 infection but have a clinical profile more closely resembling that of H5N1 patients. The identification in H7N9 patients of known risk factors for severe seasonal influenza and the more protracted clinical course compared with H5N1 patients suggests that host factors may be an important contributor to the severity of H7N9 virus infection. This is consistent with the observation that there have probably been a large number of undetected mild H7N9 virus infections, and to date the patients with detected mild infection have been predominantly young (mean age, 13 years) [7, 14]. H7N9 virus has recently reemerged in China. People with chronic medical conditions that are traditionally associated with a higher risk of severe complications following seasonal influenza virus infection should be targeted for preventive interventions and for early treatment with antiviral drugs should they develop a respiratory illness.

Supplementary materials are available at Clinical Infectious Diseases online (http://cid.oxfordjournals.org). Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all supplementary data are the sole responsibility of the authors. Questions or messages regarding errors should be addressed to the author.