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**sharon sanders** · June 24, 2013, 08:01 AM

Re: The Lancet. Human infection with avian influenza A H7N9 virus: an assessment of clinical severity

hat tip Michael Coston

Lancet: Clinical Severity Of Human H7N9 Infection

Credit CDC

# 7424

When we want to `cut to the chase? when describing the impact of a particular infectious disease, we almost always go first to its CFR or Case Fatality Ratio; the percentage of people who contract the disease, and then die.

To calculate the CFR, you really only need to know two things; the total number of cases (the denominator), and the total number of deaths due to the illness (the numerator).

Unfortunately, in actual practice, both numbers can be maddeningly difficult to deduce. And without qualifiers, the CFR numbers that get bandied about are almost always misleading.

The example that anyone who follows avian flu is familiar with is the astronomical CFR for H5N1. With 630 cases reported globally since 2003, and 375 deaths, a quick calculation provides:

And so the CFR of 60% is widely used. But is it correct? Or even close to reality?

The problem is, with just about every illness or infection, only a fraction of the cases ? usually the most severe ? are identified. And it doesn?t matter whether we are talking about seasonal influenza, West Nile Virus, Salmonella, or avian flu.

As the pyramid chart above indicates, only a tiny fraction of infectious disease cases are actually reported to health authorities. - Credit CDC

With nearly every infectious disease, we see a wide spectrum of clinical illness, which can range from mild (or even asymptomatic) to severe. Even with SARS in 2003, retrospective testing found asymptomatic cases.

So how confident are we that the denominator in the above equation (630) accurately represents the total number of H5N1 cases since 2003?

Not very.

And and how confident are we that numerator (375) accurately counts the number of deaths due to the virus?

Again, not very.

What we really know, is that among those cases that were sick enough to be hospitalized, tested, and diagnosed ? 60% died.

The limited serological evidence we have suggests there may not be a lot of `missed? cases in the general population (see The Great CFR Divide & Revisiting The H5N1 CFR Debate), but it would only take a few hundred unreported cases to cut the CFR in half.

Which brings us to an article appearing in The Lancet today, that attempts to quantify the relative severity of the H7N9 virus compared to H5N1 and the 2009 H1N1 pandemic virus.

Human infection with avian influenza A H7N9 virus: an assessment of clinical severity

Hongjie Yu MD, Benjamin J Cowling PhD, Luzhao Feng MD, Eric HY Lau PhD, Qiaohong Liao MD, Tim K Tsang MPhil, Zhibin Peng MD, Peng Wu PhD , Fengfeng Liu MD, Vicky J Fang MPhil, Honglong Zhang MD, Ming Li ME, Lingjia Zeng MSc, Zhen Xu MD, Zhongjie Li MD, Huiming Luo MD, Qun Li MD, Zijian Feng MD, Bin Cao PhD, Weizhong Yang MD, Dr Joseph T Wu PhD, Dr Yu Wang PhD, Prof Gabriel M Leung MD
Summary

(EXCERPT)

Findings

Of 123 patients with laboratory-confirmed avian influenza A H7N9 virus infection who were admitted to hospital, 37 (30%) had died and 69 (56%) had recovered by May 28, 2013. After we accounted for incomplete data for 17 patients who were still in hospital, we estimated the fatality risk for all ages to be 36% (95% CI 26?45) on admission to hospital. Risks of mechanical ventilation or fatality (69%, 95% CI 60?77) and of admission to an intensive care unit, mechanical ventilation, or fatality (83%, 76?90) were high.

With assumptions about coverage of the sentinel surveillance network and health-care-seeking behaviour for patients with influenza-like illness associated with influenza A H7N9 virus infection, and pro-rata extrapolation, we estimated that the symptomatic case fatality risk could be between 160 (63?460) and 2800 (1000?9400) per 100 000 symptomatic cases.
Interpretation

Human infections with avian influenza A H7N9 virus seem to be less serious than has been previously reported. Many mild cases might already have occurred. Continued vigilance and sustained intensive control efforts are needed to minimise the risk of human infection.
(Continue . . .)

The main finding here is that the mortality rate for those hospitalized with H7N9 was roughly 36%, and that risk increases with age. This rate is greater than that seen in hospitalized cases with the 2009 H1N1 virus, but lower than we?ve seen with H5N1.

The authors argue against trying to come up with a `one-size-fits-all? CFR for the H7N9 virus, and instead devised a two-stage approach; estimation of fatality risk among hospitalized patients and then estimation of number of symptomatic infections.

Calculating the fatality risk among hospitalized patients was fairly straight forward, but the second part; estimating the likely number of symptomatic H7N9 infections across China as of May 28 was considerably less so.

For this reason the authors listed a number of limitations to their study, particularly when it came to attempting to extrapolate the total number of cases. The authors provide a wide range of possibilities, writing:

Our estimate that between 1500 and 27 000 symptomatic infections with avian influenza A H7N9 virus might have occurred as of May 28, 2013, is much larger than the number of laboratory-confirmed cases.

They further calculated that the `symptomatic CFR? of the virus probably runs between .16% and 2.8%. The authors warn that this estimate relies on a number of `simplifying assumptions?, and should therefore be viewed cautiously.

As I?m not a statistical wizard, I?ll let others with a background in mathematics dissect and analyze their methods.

Lest anyone scoff at an estimated CFR of under 3%, I would remind them that the 1918 Spanish Flu ? which killed somewhere between 50 and 100 million people ? was estimated to have a CFR of roughly 2.5%.

Often, epidemiological data points like the CFR, CAR (Case Attack Rate), R0 (basic reproductive number) are only refined in retrospect, usually after years of analysis.

Complicating matters, these numbers are rarely static over time, or geography.

A second Lancet report (which shares a number of authors with the first study) - after comparing the epidemiological differences between H5N1 and H7N9 human infections - warns that public health officials should be preparing now for a possible resurgence of the H7N9 virus later in the year.

Comparative epidemiology of human infections with avian influenza A H7N9 and H5N1 viruses in China: a population-based study of laboratory-confirmed cases

Benjamin J Cowling PhD, Lianmei Jin MD, Eric HY Lau PhD, iaohong Liao MD, Peng Wu PhD, Hui Jiang MD, Tim K Tsang MPhil, Jiandong Zheng PhD, Vicky J Fang MPhil, Zhaorui Chang MD, Michael Y Ni MPH, Qian Zhang MD, Dennis KM Ip MPhil, Jianxing Yu MD, Yu Li MD, Liping Wang PhD, Wenxiao Tu MD, Ling Meng MD, Joseph T Wu PhD, Huiming Luo MD, Qun Li MD , Yuelong Shu PhD, Zhongjie Li MD, Zijian Feng MD, Weizhong Yang MD, Yu Wang PhD, Prof Gabriel M Leung MD, Dr Hongjie Yu MD
(EXCERPT)
The differences in age distribution of patients with laboratory-confirmed infection with H7N9 and H5N1 are intriguing; presumably, immunity associated with different histories of influenza virus exposures has an important role in addition to differences in exposure patterns. Although we have reported the fatality risk for patients admitted to hospital, the symptomatic case-fatality risk remains to be established and a large portion of the ?clinical iceberg? of infection might have remained undetected so far.

The warm season has now begun in China, and only one new laboratory-confirmed case of H7N9 in human beings has been identified since May 8, 2013. If H7N9 follows a similar pattern to H5N1 (figure 2B), the epidemic could reappear in the autumn. This potential lull should be an opportunity for discussion of definitive preventive public health measures, optimisation of clinical management, and capacity building in the region in view of the possibility that H7N9 could spread beyond China's borders.

Posted by Michael Coston at <a class="timestamp-link" href="http://afludiary.blogspot.ca/2013/06/lancet-clinical-severity-of-human-h7n9.html" rel="bookmark" title="permanent link"><abbr class="published" title="2013-06-24T08:50:00-04:00">8:50 AM</abbr>

**sharon sanders** · June 24, 2013, 08:03 AM

Re: The Lancet. Human infection with avian influenza A H7N9 virus: an assessment of clinical severity

FluTrackers H7N9 case list here.

**Giuseppe** · June 24, 2013, 10:01 AM

Re: The Lancet. Human infection with avian influenza A H7N9 virus: an assessment of clinical severity

The curious aspect of the media outlets coverage of this paper is the headline ''New birdflu kills 1/3 of the patients''. If the purpose of the paper was solely to tell us this, a thing we know already - it could have been not written at all.

To say, further, that it 'will return with cold weather' is another guess, because we haven't yet understood the actual direction of H7N9 evolution and ecology.

We have seen in the past H5N1 behaviour, and this virus is really more active during nothern hemisphere winter season.

However, H7N9 may survive well even during warm seasons, especially in regions with high poultry density.

Since we do not know whether human hosts immune status counts or is a driving force in the emersion and spread of H7N9, we cannot exclude that - when H1pdm09 or H3N2 will be again in circulation, the human immune response toward one of the two seasonal strain will cause a reduction in the innate response to heterotypic influenza viruses such as H7N9.

Health and veterinary authorities should take into account the great degree of uncertainty around this novel influenza virus with pandemic potential and should act accordingly, reducing opportunity for this zoonotic pathogen to jump again to mammals (including humans) and to prepare for a major outbreak even through vaccinations and targeted antiviral treatment of the suspected cases.

(GM)

**Ronan Kelly** · December 14, 2014, 06:18 AM

Re: The Lancet. Human infection with avian influenza A H7N9 virus: an assessment of clinical severity

Eurosurveillance, Volume 19, Issue 49, 11 December 2014
Research articles
CLINICAL SEVERITY OF HUMAN INFECTIONS WITH AVIAN INFLUENZA A(H7N9) VIRUS, CHINA, 2013/14

Feng L, Wu JT, Liu X, Yang P, Tsang TK, Jiang H, Wu P, Yang J, Fang VJ, Qin Y, Lau EH, Li M, Zheng J, Peng Z, Xie Y, Wang Q, Li Z, Leung GM, Gao GF, Yu H, Cowling BJ. Clinical severity of human infections with avian influenza A(H7N9) virus, China, 2013/14. Euro Surveill. 2014;19(49):pii=20984. Available online: http://www.eurosurveillance.org/View...rticleId=20984

Date of submission: 18 June 2014

Abstract

Assessing the severity of emerging infections is challenging because of potential biases in case ascertainment. The first human case of infection with influenza A(H7N9) virus was identified in China in March 2013; since then, the virus has caused two epidemic waves in the country. There were 134 laboratory-confirmed cases detected in the first epidemic wave from January to September 2013. In the second epidemic wave of human infections with avian influenza A(H7N9) virus in China from October 2013 to October 2014, we estimated that the risk of death among hospitalised cases of infection with influenza A(H7N9) virus was 48% (95% credibility interval: 42?54%), slightly higher than the corresponding risk in the first wave. Age-specific risks of death among hospitalised cases were also significantly higher in the second wave. Using data on symptomatic cases identified through national sentinel influenza-like illness surveillance, we estimated that the risk of death among symptomatic cases of infection with influenza A(H7N9) virus was 0.10% (95% credibility interval: 0.029?3.6%), which was similar to previous estimates for the first epidemic wave of human infections with influenza A(H7N9) virus in 2013. An increase in the risk of death among hospitalised cases in the second wave could be real because of changes in the virus, because of seasonal changes in host susceptibility to severe infection, or because of variation in treatment practices between hospitals, while the increase could be artefactual because of changes in ascertainment of cases in different areas at different times.

.....

Discussion

The resurgence of human infections with avian influenza A(H7N9) virus in a second epidemic wave in 2013/14 demonstrates the continued public health risk of this novel strain [10]. Control of the virus in animals is complicated, because the infections in poultry are asymptomatic [11]. Human-to-human transmissibility of the virus remains limited, as evidenced by the very small number of potential secondary infections identified through detailed contact tracing of confirmed cases [1,2,12-14].

We identified differences in the severity of illness of hospitalised cases in the earlier part of the first epidemic wave in 2013, with greater risk of mechanical ventilation, ICU admission and death among cases hospitalised before 31 March 2013 when the first confirmed human cases of influenza A(H7N9) were officially announced (Figure 2) [15]. One explanation for this is more timely antiviral treatment and more appropriate supportive care for cases hospitalised after 31 March 2013. Another possible explanation is detection bias in the early phase of the spring 2013 epidemic wave, where more severe cases were prioritised for repeated laboratory testing, and cases with prolonged virus shedding or higher virus shedding had a greater chance of confirmation.

In the second epidemic wave in 2013/14, we identified a significantly greater HFR compared with the latter part of the first epidemic wave in 2013 (Figure 2) and in persons under 60 years of age in Zhejiang province where cases occurred in both epidemic waves, but no difference in the symptomatic CFR (Table). It is possible that this significant difference in HFRs is due to ascertainment bias in cases in different locations at different times, even within the same province. Alternatively, the HFR could have increased, because hospitalised cases in the second epidemic wave in 2013/14 were less likely to be transferred to larger referral hospitals (Dr Enfu Chen, Chief Epidemiologist in Zhejiang Provincial CDC, personal communication, June 2014), because of changes in the virus, or because of seasonal changes in the prevalence of other pathogens that could cause secondary or co-infections and modify the severity of influenza A(H7N9) virus infections [16]. Whereas ascertainment of infections in hospitalised cases may have changed over time due to changes in awareness and testing capacity, the ascertainment of influenza A(H7N9) cases through the established sentinel ILI network should have remained more stable over time.

Large population-based serological studies in affected areas would permit assessment of severity with a denominator of infections, rather than cases of symptomatic disease or hospitalisation, and infection-based severity measures could be less susceptible to biases due to differential healthcare seeking behaviours or diagnostic capacity [3,7]. To date, few serological studies have been reported and such analyses are not yet possible [17-19].

Our estimates of the risks of serious outcomes in hospitalised cases are limited by the potential for under-ascertainment of cases, due to lack of access to laboratory testing in some areas, and the potential for imperfect sensitivity of laboratory testing for the A(H7N9) virus [20,21]. While we accounted for unknown final status of cases that remain hospitalised in our analysis, the eventual estimates may change slightly once all outcomes are known. It is challenging to estimate the symptomatic CFR based on a small number of confirmed cases with milder disease identified through sentinel ILI surveillance, and our estimates are dependent on the assumptions that coverage of the sentinel system was similar in 2013/14 compared with 2009, and that healthcare seeking behaviours for ILI were similar whether illness was caused by influenza A(H7N9) virus or the 2009 pandemic influenza A(H1N1) virus [3]. In addition, the estimation of sCFR were based on data from geographic locations in which influenza A(H7N9) virus infections were identified through sentinel ILI surveillance, and a more comprehensive analysis could also incorporate data on ILI surveillance in other areas.

In conclusion, it remains important to assess the severity of human infections with influenza A(H7N9) virus, as part of ongoing risk assessment of this virus. While the overall picture is that the severity of human infections has not substantially changed (Table), we found some evidence that the HFR was higher in the second epidemic wave in 2013/14 (Figure 2). Our results again highlight that many influenza A(H7N9) virus infections can cause mild disease [3,5,6] and that the risk of death among laboratory-confirmed cases is a misleading measure of severity. If another epidemic of human infections with influenza A(H7N9) virus occurs in the winter of 2014/15, proactive control measures on the poultry-human interface may be preferable to reactive measures [10,22-24]. Comprehensive surveillance of avian influenza virus infections in animals and humans is essential in order to monitor risk and guide the use of control measures.

Full Paper available at; http://eurosurveillance.org/ViewArti...rticleId=20984

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The Lancet. Human infection with avian influenza A H7N9 virus: an assessment of clinical severity

The Lancet. Human infection with avian influenza A H7N9 virus: an assessment of clinical severity

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