Comparative Clinical Profile Of Patients Hospitalized With Infection By Avian Influenza A(H7N9),A(H5N1),and PH1N1Human Influenza A Viruses

Background:During the spring of2013, a novel avian-origin influenza A (H7N9) virus emergedand spread among humans in China. Data were lacking on the clinical characteristicsof the infections caused by this virus and the assessment of similarities between illness due to infection with H7N9virus and that caused by other avian or human influenza A viruses, we compared risk factors, clinical presentation, and progression of hospitalized patients with H7N9, H5N1and H1N1/2009(pH1N1) virus infections.Methods:We collected and analyzed individual-level data from patients hospitalized with infection by H7N9virus (n=137), H5N1virus (n=119), and pHlN1virus (n=3486). We assessed risk factors for hospitalization after adjustment for age and gender specific prevalence of risk factors in the general population. Clinical, laboratory and outcome measures were compared between subtypes.Results:Of the137patients we studied,77.4%were admitted to an intensive care unit (ICU), and33.6%died. The median age was61years, and42.3%were65years of age or older;31.4%were female. A total of61.9%of the patients had at least one underlying medical condition. Fever and cough were the most common presenting symptoms. On admission,133patients (98.5%) had findings consistent with pneumonia. Bilateral ground-glass opacities and consolidation were the typical radiologic findings. Lymphocytopenia was observed in88.3%of patients, and thrombocytopenia in73.0%. Treatment with antiviral drugs was initiated in133patients (97.1%) at a median of7days after the onset of illness. The median times from the onset of illness and from the initiation of antiviral therapy to a negative viral test result on real-time reverse-transcriptase-polymerase-chain-reaction assay were1ldays(interquartile range,9to16) and6days (interquartile range,4to7), respectively. Multivariate analysis revealed that the presence of a coexisting medical condition was the onlyindependent risk factor for the acute respiratory distress syndrome (ARDS)(odds ratio,3.42;95%confidence interval,1.21to9.70; P=0.02).We have gained access to samples from a large cohort of H7N9-infected patients and we performed virological and serial immunological studies using40H7N9patient specimens. The plasma hypercytokinemia dynamics were observed concurrently with high pharyngeal viral load in these H7N9patients compared to healthy controls. Furthermore, we show that the plasma levels of HGF, SCF, IL-18, IP-10, MIF and SCGF-beta are highly positively associated with the APACHE II disease severity score in H7N9-infected patients, especially during the second week of disease onset, and they are also positively associated with mortality.Li’s ALS therapy was used in16patients with severe H7N9virus infection when the condition deteriorated rapidly and a cytokine storm was detected. We find Li’s ALS therapy could decrease the elevated levels of ctyokines of patients, especially IP-10, which was correlated with mortality.The median age of patients hospitalized with H7N9virus infection was older than the other patient groups (61years; P<0.001) and a higher proportion was male (P <0.02). After adjustment for age and gender, chronic heart disease (CHD) was associated with an increased risk of hospitalization with H7N9(relative risk9.68;95%CI5.24-17.90). H7N9patients were more likely to report a productive cough and hemoptysis at hospital admission than patients with H5N1infection. H7N9patients had similar patterns of leukopenia, thrombocytopenia, and elevated alanine aminotransferase creatinine kinase, C-reactive protein, and lactate dehydrogenase as H5N1patients, which were all significantly different from pH1N1patients (P<0.005). H7N9patients had a longer duration of hospitalization than either H5N1or pH1N1patients. The hospitalized case fatality risk was highest for H5N1(55%;95%CI47-64%) and death occurred earlier, with a median time from onset to death of11days for H5N1, versus18days for H7N9(P=0.002) and15days for pH1N1(P=0.154).Conclusions:During the evaluation period, the novel H7N9virus caused severe illness, including pneumonia and ARDS, with high rates of ICU admission and death. Our findings identify a group of hypercytokinemia dynamics signature proteins HGF, SCF, IL-18, IP-10, MIF, and SCGF-beta as biomarkers for severe and lethal flu infections, and we suggest the best time to detect these biomarkers is during the second week of disease onset. These results indicate that remedies targeting these proteins might constitute a future viable strategy to treat H7N9infections. Severe H7N9virus infection patients could benefit from Li’s ALS therapy that could decrease the elevated level of cytokines. CHD is a risk factor for H7N9hospitalization. The clinical profile of patients hospitalized with H7N9was similar to patients hospitalized with H5N1, but with a more protracted clinical course than either H5N1or pH1N1patients.