Zhengan Yuan

Clinical Characteristics of 26 Human Cases of Highly Pathogenic Avian Influenza A (H5N1) Virus Infection in China

Background While human cases of highly pathogenic avian influenza A (H5N1) virus infection continue to increase globally, available clinical data on H5N1 cases are limited. We conducted a retrospective study of 26 confirmed human H5N1 cases identified through surveillance in China from October 2005 through April 2008. Methodology/Principal Findings Data were collected from hospital medical records of H5N1 cases and analyzed. The median age was 29 years (range 6–62) and 58% were female. Many H5N1 cases reported fever (92%) and cough (58%) at illness onset, and had lower respiratory findings of tachypnea and dyspnea at admission. All cases progressed rapidly to bilateral pneumonia. Clinical complications included acute respiratory distress syndrome (ARDS, 81%), cardiac failure (50%), elevated aminotransaminases (43%), and renal dysfunction (17%). Fatal cases had a lower median nadir platelet count (64.5×109 cells/L vs 93.0×109 cells/L, p = 0.02), higher median peak lactic dehydrogenase (LDH) level (1982.5 U/L vs 1230.0 U/L, p = 0.001), higher percentage of ARDS (94% [n = 16] vs 56% [n = 5], p = 0.034) and more frequent cardiac failure (71% [n = 12] vs 11% [n = 1], p = 0.011) than nonfatal cases. A higher proportion of patients who received antiviral drugs survived compared to untreated (67% [8/12] vs 7% [1/14], p = 0.003). Conclusions/Significance The clinical course of Chinese H5N1 cases is characterized by fever and cough initially, with rapid progression to lower respiratory disease. Decreased platelet count, elevated LDH level, ARDS and cardiac failure were associated with fatal outcomes. Clinical management of H5N1 cases should be standardized in China to include early antiviral treatment for suspected H5N1 cases.

Intensive Cytokine induction in Pandemic H1N1 Influenza Virus Infection Accompanied by Robust Production of IL-10 and IL-6

Background The innate immune system is the first line of defense against viruses by inducing expression of cytokines and chemokines. Many pandemic influenza H1N1 virus [P(H1N1)] infected severe cases occur in young adults under 18 years old who were rarely seriously affected by seasonal influenza. Results regarding host cytokine profiles of P(H1N1) are ambivalent. In the present study we investigated host cytokine profiles in P(H1N1) patients and identified cytokines related to disease severity. Methods and Principal Findings We retrieved 77, 59, 26 and 26 sera samples from P(H1N1) and non-flu influenza like illness (non-ILIs) cases with mild symptoms (mild patients), P(H1N1) vaccinees and healthy individuals, respectively. Nine and 16 sera were from hospitalized P(H1N1) and non-ILIs patients with severe symptoms (severe patients). Cytokines of IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IFN-γ and TNF-α were assayed by cytokine bead array, IL-17 and IL-23 measured with ELISA. Mild P(H1N1) patients produced significantly elevated IL-2, IL-12, IFN-γ, IL-6, TNF-α, IL-5, IL-10, IL-17 and IL-23 versus to healthy controls. While an overwhelming IL-6 and IL-10 production were observed in severe P(H1N1) patients. Higher IL-10 secretion in P(H1N1) vaccinees confirmed our observation that highly increased level of sera IL-6 and IL-10 in P(H1N1) patients may lead to disease progression. Conclusion and Significance A comprehensive innate immune response was activated at the early stage of P(H1N1) infection with a combine Th1/Th2/Th3 cytokines production. As disease progression, a systemic production of IL-6 and IL-10 were observed in severe P(H1N1) patients. Further analysis found a strong correlation between IL-6 and IL-10 production in the severe P(H1N1) patients. IL-6 may be served as a mediator to induce IL-10 production. Highly elevated level of sera IL-6 and IL-10 in P(H1N1) patients may lead to disease progression, but the underlying mechanism awaits further detailed investigations.

Risk Factors for Influenza A(H7N9) Disease—China, 2013

BACKGROUND The majority of human cases of novel avian influenza A(H7N9), which emerged in China in spring 2013, include reported exposure to poultry. However, specific host and exposure risk factors for disease are unknown, yet critical to design prevention measures. METHODS In April-June 2013, we conducted a case-control study in 8 Chinese provinces. Patients with laboratory-confirmed A(H7N9) (n = 89) were matched by age, sex, and neighborhood to controls (n = 339). Subjects completed a questionnaire on medical history and potential exposures, including poultry markets and other poultry exposure. We used conditional logistic regression to calculate matched and adjusted odds ratios (ORs) for the association of A(H7N9) virus infection with potential risk factors. RESULTS Fifty-five percent of patients compared with 31% of controls reported any contact with poultry (matched OR [mOR], 7.8; 95% confidence interval [CI], 3.3-18.8). Sixty-seven percent of patients compared with 35% of controls visited a live poultry market (mOR, 5.4; CI, 3.0-9.7). Visiting live poultry markets increased risk of infection even after adjusting for poultry contact and other confounders (adjusted OR, 3.4; CI, 1.8-6.7). Backyard poultry were not associated with increased risk; 14% of cases did not report any poultry exposure or market visit. Obesity (mOR, 4.7; CI, 1.8-12.4), chronic obstructive pulmonary disease (mOR, 2.7; CI, 1.1-6.9), and immunosuppressive medications (mOR, 9.0; CI, 1.7-47.2) were associated with A(H7N9) disease. CONCLUSION Exposures to poultry in markets were associated with A(H7N9) virus infection, even without poultry contact. China should consider permanently closing live poultry markets or aggressively pursuing control measures to prevent spread of this emerging pathogen.

Human Influenza A (H5N1) Cases, Urban Areas of People’s Republic of China, 2005–2006

We investigated potential sources of infection for 6 confirmed influenza A (H5N1) patients who resided in urban areas of People’s Republic of China. None had known exposure to sick poultry or poultry that died from illness, but all had visited wet poultry markets before illness.

Emergence of a new GII.17 norovirus variant in patients with acute gastroenteritis in Jiangsu, China, September 2014 to March 2015.

From September 2014 to March 2015, 23 outbreaks of norovirus (NoV) acute gastroenteritis occurred in Jiangsu, China. Partial sequencing of the NoV capsid gene suggested that 16 of the 23 outbreaks were related to a new GII.17 variant. This variant was first detected in sporadic specimens in October 2014, and became predominant in February 2015. Analysis of the RNA-dependent RNA polymerase (RdRp), and complete capsid including the protruding domain P2 sequences confirmed this GII.17 variant as distinct from previously identified GII variants.

High human bocavirus viral load is associated with disease severity in children under five years of age.

Human bocavirus (HBoV) is a parvovirus and detected worldwide in lower respiratory tract infections (LRTIs), but its pathogenic role in respiratory illness is still debatable due to high incidence of co-infection with other respiratory viruses. To determine the prevalence of HBoV infection in patients with LRTI in Shanghai and its correlation with disease severity, we performed a 3-year prospective study of HBoV in healthy controls, outpatients and inpatients under five years of age with X-ray diagnosed LRTIs. Nasopharyngeal aspirates were tested by PCR for common respiratory viruses and by real time PCR for HBoV subtypes 1–4. Nasopharyngeal swabs from healthy controls and serum samples and stools from inpatients were also tested for HBoV1-4 by real time PCR. Viral loads were determined by quantitative real time PCR in all HBoV positive samples. HBoV1 was detected in 7.0% of inpatients, with annual rates of 5.1%, 8.0% and 4.8% in 2010, 2011 and 2012, respectively. Respiratory syncytial virus (RSV) subtype A was the most frequent co-infection detected; HBoV1 and RSVA appeared to co-circulate with similar seasonal variations. High HBoV viral loads (>106 copies/ml) were significantly more frequent in inpatients and outpatients than in healthy controls. There was a direct correlation of high viral load with increasing disease severity in patients co-infected with HBoV1 and at least one other respiratory virus. In summary, our data suggest that HBoV1 can cause LRTIs, but symptomatic HBoV infection is only observed in the context of high viral load.

Limited human-to-human transmission of avian influenza A(H7N9) virus, Shanghai, China, March to April 2013

In April 2013, two members of one family were successively confirmed as cases of avian influenza A(H7N9) virus infection in Shanghai, China. Respiratory specimens from the two cases and their close contacts were tested using real-time reverse-transcription (RT)-PCR. Paired serum specimens from contacts were tested by haemagglutination inhibition assay and microneutralisation test. The index patient developed severe pneumonia. Her husband presented with pneumonia shortly thereafter. Both cases had highly similar clinical features and infection with A(H7N9) virus was confirmed in both cases by genetic analysis. Phylogenetic analysis revealed a high level of similarity between the sequences from the two patients and environmental samples collected from wet markets in Minhang and Changning districts. Six samples from the Changning wet market were confirmed as A(H7N9) positive. Of 27 close contacts, one developed mild respiratory symptoms and another tested positive for A(H7N9) antibodies, but both were negative by real-time RT-PCR. The other 25 close contacts of both cases were A(H7N9) negative. Limited human-to-human transmission of the virus most likely occurred in the family cluster. However, other close contacts did not test positive for the virus, suggesting limited potential for extensive human-to-human transmission of the virus.

Novel Avian Influenza A(H7N9) Virus in Tree Sparrow, Shanghai, China, 2013

In spring 2013, influenza A(H7N9) virus was isolated from an apparently healthy tree sparrow in Chongming Dongping National Forest Park, Shanghai City, China. The entire gene constellation of the virus is similar to that of isolates from humans, highlighting the need to monitor influenza A(H7N9) viruses in different species.

Applied Mixed Generalized Additive Model to Assess the Effect of Temperature on the Incidence of Bacillary Dysentery and Its Forecast

Background Association between bacillary dysentery (BD) disease and temperature has been reported in some studies applying Poisson regression model, however the effect estimation might be biased due to the data autocorrelation. Furthermore the temperature effect distributed in the time of different lags has not been studied either. The purpose of this work was to obtaining the association between the BD counts and the climatic factors such as temperature in the form of the weighted averages, concerning the autocorrelation pattern of the model residuals, and to make short term predictions using the model. The data was collected in the city of Shanghai from 2004 to 2008. Methods We used mixed generalized additive model (MGAM) to analyze data on bacillary dysentery, temperature and other covariates with autoregressive random effect. Short term predictions were made using MGAM with the moving average of the BD counts. Main Results Our results showed that temperature was significant linearly associated with the logarithm of BD count for temperature in the range from 12°C to 22°C. Optimal weights in the temperature effect have been obtained, in which the one of 1-day-lag was close to 0, and the one of 2-days-lag was the maximum (p-value of the difference was less than 0.05). The predictive model was showing good fitness on the internal data with R2 value 0.875, and the good short term prediction effect on the external data with correlation coefficient to be 0.859. Conclusion According to the model estimation, corresponding Risk Ratio to affect BD was close to 1.1 when temperature effect goes up for 1°C in the range from 12°C to 22°C. And the 1-day incubation period could be inferred from the model estimation. Good prediction has been made using the predictive MGAM.

Live Poultry Market Closure and Control of Avian Influenza A(H7N9), Shanghai, China

To the Editor: China reported its first human infections with avian influenza A(H7N9) virus in late March 2013 (1). In the following weeks, 131 human infections were confirmed; 33 occurred in Shanghai (http://www.moh.gov.cn). Because infection with this novel virus had a high fatality rate and posed a pandemic risk, Shanghai disease control authorities launched rapid investigations to identify the source of the infections. Migratory birds, mammals, poultry, and humans could be potential reservoirs of H7 subtype avian influenza viruses (2,3), so all of these possibilities were simultaneously evaluated immediately after the discovery of the novel virus. To investigate human-to-human transmission, we evaluated 45 close contacts of the first 6 reported case-patients. The only suspected human-to-human transmission was in 1 family cluster with 2 confirmed cases. Intensive follow-up monitoring (20 contacts of this cluster and 25 of the other 4 case-patients) did not identify any further infections, which suggests that sustained human-to-human transmission did not occur. Migratory birds are natural reservoirs for avian influenza viruses (2,4), and Shanghai is in the eastern Asia–Australian migratory shorebird flyway. Thus, transmission of these viruses from wild birds to humans is possible. The Shanghai forestry authority has conducted surveillance for influenza virus among migratory birds since 2004. During January 2010–April 2013, a total of 884 throat/cloacal swab, serum, and fecal samples from 496 birds were tested, and no infections with influenza viruses of subtypes H7 or N9 were found. After human infections with influenza A(H7N9) virus occurred, an additional 229 samples were collected from migratory birds at Chongming Island, Shanghai Zoo, and Shanghai Wildlife Park. All were negative for the virus. Avian influenza surveillance in domesticated animals (e.g., minks, raccoons, tigers, and pigs) in high-risk regions of Shanghai has been conducted since 1995. During 2010–2012, a total of 13,691 samples from these animals were tested, and all were negative for H7 subtype influenza viruses. After human infections with influenza A(H7N9) virus were identified, another 1,129 samples were collected from domesticated mammals for enhanced surveillance; all were negative for H7 subtype influenza viruses. Live poultry was also considered a potential source of influenza A(H7N9) infection because poultry in wet markets have been previously found to be infected with H7 subtype avian influenza viruses (5–7). Shanghai residents could be exposed to influenza A(H7N9) virus from live poultry in 2 ways: by raising poultry at home or by visiting live poultry markets (LPMs). To assess the risk from home-raised poultry, we collected 405 blood, cloacal/throat swab, and environmental samples from poultry raised in family courtyards or in communities surrounding the residences of the first 6 identified case-patients. The samples were tested for antibodies to H7 subtype viruses and RNA for subtype H7N9 virus, and all results were negative. Previous studies have shown that LPMs are potential locations for virus transmission through human-poultry contact (8,9). Our field investigation of the 6 initially confirmed influenza A(H7N9) case-patients revealed that 2 had visited LPMs, 2 had direct contact with live poultry from LPMs, and 1 had experienced both exposures. To assess the risk for infection at LPMs, we collected 280 water, soil, cloacal swab, and throat swab samples from the LPMs surrounding the locations of the initial 6 cases. PCR testing found that 20 samples were positive for influenza A(H7N9) virus. These results indicate that the human case-patients were most likely infected from poultry in LPMs. On the basis of the epidemiologic and laboratory evidence, the Shanghai municipal government temporarily closed all 464 LPMs on April 6, 2013. The markets were cleaned and disinfected, and relevant authorities in the neighboring provinces were notified of the action and requested not to transport live poultry to Shanghai. The municipal government reimbursed the poultry traders and raisers for these measures. After the closure of LPMs, 4 additional human influenza A(H7N9) cases were detected in Shanghai within the first 7-day incubation period, and no new cases were detected during the rest of 2013, although other influenza virus subtypes continued to be detected. Meanwhile, in other provinces where closure of LPMs was not implemented in a timely manner, 31 cases were reported during the first incubation period and 13 during the second incubation period (Figure). In addition, Shi et al. reported that isolates from the LPMs showed 99.1%–99.9% nucleotide sequence homology with isolates from 2 of the first 6 human case-patients (10), which further indicates that the virus spread from infected poultry in the LPMs. Figure Illness onset dates for 33 confirmed cases of influenza A(H7N9) infection in Shanghai (A) and 78 cases in other provinces (B) in China, February 12–May 10, 2013. Solid vertical line indicates date live poultry markets (LPMs) in Shanghai were suspended ... The closure of LPMs after epidemiology and laboratory investigations proved timely and effective in the control of human infection with this novel virus. In early 2014, Shanghai lifted the ban on LPMs. Eight new influenza A(H7N9) cases were identified in early January 2014, but LPMs were again closed on January 31, 2014, and no further cases have been reported. The long-term effectiveness of the LPM closures remains to be determined.