Wednesday, July 05, 2017

ISIRV Journal: Predictors For Fatal Infection With H7N9 Over 4 Epidemic Waves - Jiangsu Province

Jiangsu Province


During the first 4 epidemic waves of H7N9 (Spring 2013- Summer 2016), nearly 800 human cases were reported in, or exported from, Mainland China. Of those, 103 of those infections were reported in Jiangsu Province.

5 Epidemic Waves - Credit FAO
While we've seen some abrupt changes during this 5th epidemic wave, including a huge increase in cases and and the emergence of two new H7N9 variants (see MMWR: Increase in Human Infections with Avian Influenza A(H7N9) In China's 5th Wave), during the first four epidemics changes appeared to occur more slowly.

We've seen earlier analyses published on this changing face of H7N9 (see MMWR: Assessing The 4th Epidemic Wave Of H7N9 In China), which have noted:
Whereas age and sex distribution and exposure history in the fourth epidemic were similar to those in the first three epidemics, the fourth epidemic demonstrated a greater proportion of infected persons living in rural areas, a continued spread of the virus to new areas, and a longer epidemic period.
And this week's ECDC RRA Update on H7N9 highlights the variable (32% to 44%) case fatality rate across all 5 waves (note: The 5th wave % is likely to change).

Just over 3 months ago, in Eurosurveillance: Preliminary Epidemiology & Analysis Of Jiangsu's 5th H7N9 Wave, we looked at some early numbers and epidemiological trends from this year's unprecedented outbreak in Jiangsu Province which noted:
Despite better medical treatment for patients, the mortality rate remains high (30%+), and the authors report an`accelerated disease progression of H7N9 patients', which they write  `suggests that the viral pathogenicity might have become stronger'.
Today we have a new analysis - published yesterday in Influenza and Other Respiratory Viruses - of the epidemiology, course of illness, and predictors of death of Jiangsu's first 103 cases spread across the first four epidemic waves.
Predictors for fatal human infections with avian H7N9 influenza, evidence from 4 epidemic waves in Jiangsu Province, Eastern China, 2013-2016

Wang Ma1, *, Haodi Huang2, *, Jian Chen3,*, Ke Xu2, Qigang Dai2, Huiyan Yu2, Fei Deng2, Xian Qi2, Shenjiao Wang2, Jie Hong2, Changjun Bao2, Xiang Huo2, #, Minghao Zhou1, 2,  

Accepted manuscript online: 4 July 2017
Please cite this article as doi: 10.1111/irv.12461



Four epidemic waves of human infection with H7N9 have been recorded in China up to 1 June 2016, including in Jiangsu Province. However, few studies have investigated the differences in patients’ characteristics among the 4 epidemic waves, and the analyses of factors associated with fatal infection lacked statistical power in previous studies due to limited sample size


All laboratory-confirmed A(H7N9) patients in Jiangsu province were analysed. Patients’ characteristics were compared across 4 waves and between survivors and those who died. Multivariate analyses were used to identify independent predictors of death


Significant differences were found in the lengths of several time intervals (from onset of disease to laboratory-confirmation, to onset of ARDS and respiratory failure, and to death) and in the development of heart failure. The proportions of overweight patients and rural patients increased significantly across the 4 waves. Administration of glucocorticoids and double-dose neuraminidase inhibitors became the norm. Predictors of death included complications such as ARDS, heart failure and septic shock, administration of glucocorticoids, and disease duration


Characteristics of H7N9 patients and clinical treatment options changed over time. Particular complications and the use of particular treatment, along with disease duration, could help clinicians predict the outcome of H7N9 infections.
         (Continue . . . )

As with earlier studies, today's paper notes the increase in rural cases and overweight patients over the first four epidemic waves, although neither appeared to influence survivability. 
After discussing co-morbidities that were associated with bad outcomes (primarily chronic pulmonary disease, chronic cardiovascular disease, and advanced age), the study jumps to the impact of two H7N9 treatments commonly used in Chna.
First, neuraminidase inhibitors (Oseltamivir aka Tamiflu (c)), which were rarely administered during the recommended 1st 48 hours of infection (median time 7-9 days post infection). They note: 
A large majority of the cases were treated with neuraminidase inhibitors, and the implementation of a higher dose (150 mg) because the norm (from 15.8% to 90.5%). However, the higher dose was not found to be associated with a better prognosis in this study.
A little less surprising, given the on-again off-again recommendations for using  glucocorticoids in the treatment of severe influenza (see 2009's Cocktails For Flu), is their warning that their routine use appears detrimental to patient survival.

They write:
Interestingly, administration of glucocorticoids was associated with a significantly elevated risk of death, while its clinical implementation jumped from a proportion of 61.5 to 100% across the observed 4 epidemic waves in this study.

Glucocorticoid is mainly used as an anti-inflammatory agent and is also an alternative for the treatment of septic shock 29-31. The administration of glucocorticoids thus reflects disease severity to some extent. However, as observed in this study, glucocorticoids have been used more and more comprehensively for treating H7N9 patient, not only restricted to these with special need.
Treating influenza with glucocorticoids remains controversial. A number of studies have reported that use of glucocorticoids increased the death risk from H1N1 32-35 and from H5N1 36. Slower viral clearance of influenza A (H3N2) virus was observed in patients treated with systemic glucocorticoid 37.
Furthermore, a systematic review and meta-analysis using data from 19 studies of glucocorticoids treatment and human infection of influenza virus, has concluded that glucocorticoids were related with mortality, nosocomial infection, longer mechanical ventilation and longer ICU stay 38.
As a result, a much more rational use of glucocorticoids based on sturdy scientific evidences is urgently needed.

While we've seen new changes in the behavior of the H7N9 virus during this 5th wave, hopefully the lessons learned from the first 4 epidemic seasons can help guide doctors in the treatment of current and future cases.

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