Lancet: Community Burden & Severity Of Seasonal And Pandemic Influenza

Photo Credit CDC PHIL 

# 8379

 

Despite decades of research, a surprising number of seemingly basic questions about the influenza virus, and the host’s immune response to infection, remain less than fully answered.  Questions like:

• How is the virus most commonly spread? (Aerosolized virus particles, Large Droplets, Fomites . . . )
• How long are we infectious?
• How effective are NPIs like masks, eye-protection, hand-washing, social distancing?
• How common are asymptomatic infections?
• Can (and do) asymptomatic carriers spread the virus to others?

As you might imagine, public policy decisions - such as when and how long we close schools, what protective gear we should require for health care workers, and how soon those who have been infected should be allowed to return to work - all hinge on having good answers to the above questions.

 

In recent years, research (see PLoS One: Influenza Viral Shedding & Asymptomatic Infections, Influenza Transmission, PPEs & `Super Emitters’ & Study: The Role Of Aerosols In The Spread Of Influenza) has shed considerable light on these issues, but the knowledge gained is incremental, and not always in complete agreement.

 

Today we’ve a major study appearing in The Lancet Respiratory Medicine, that uses  UCL’s FluWatch Study to compile perhaps the most comprehensive multi-year (2006-2011) serological analysis of community influenza we’ve seen to date.

 

The abstract from Cohort Profile: The Flu Watch Study describes the methodology, which involved 5,484 participants from 2,205 households in England.

 

Baseline data were collected on demographic, medical, social and behavioural risk factors and pre-season blood samples taken for immunological assays. Households were contacted weekly to report respiratory symptoms throughout the influenza season and asked to collect nasal swabs during respiratory illnesses for testing for a panel of respiratory viruses using PCR. Post-season blood samples, questionnaires and medical records checks were done.

 

While asymptomatic or sub-clinical infection with the influenza virus is already known to occur with some frequency, this study finds the rate of asymptomatic infection to be higher than commonly suspected.  As many as 75% of those who show serological evidence of infection reported no significant influenza symptoms.

 

First the Abstract, and link to the open access report (which is well worth reading in its entirety), after which I’ll be back with more.

 

Comparative community burden and severity of seasonal and pandemic influenza: results of the Flu Watch cohort study

Dr Andrew C Hayward MD a , Ellen B Fragaszy MSc a c, Alison Bermingham PhD d, Lili Wang PhD f, Andrew Copas PhD a, W John Edmunds PhD c, Neil Ferguson DPhil h, Nilu Goonetilleke PhD f g, Gabrielle Harvey MPH a, Jana Kovar PhD a, Megan S C Lim PhD a i, Andrew McMichael PhD f, Elizabeth R C Millett MSc a c, Jonathan S Nguyen-Van-Tam DM j, Irwin Nazareth PhD b, Richard Pebody MBChB e, Faiza Tabassum PhD a, John M Watson FRCP e, Fatima B Wurie BSc a, Prof Anne M Johnson MD a †, Maria Zambon PhD d †, on behalf of the Flu Watch Group

Summary

Background

Assessment of the effect of influenza on populations, including risk of infection, illness if infected, illness severity, and consultation rates, is essential to inform future control and prevention. We aimed to compare the community burden and severity of seasonal and pandemic influenza across different age groups and study years and gain insight into the extent to which traditional surveillance underestimates this burden.

Methods

Using preseason and postseason serology, weekly illness reporting, and RT-PCR identification of influenza from nasal swabs, we tracked the course of seasonal and pandemic influenza over five successive cohorts (England 2006—11; 5448 person-seasons' follow-up). We compared burden and severity of seasonal and pandemic strains. We weighted analyses to the age and regional structure of England to give nationally representative estimates. We compared symptom profiles over the first week of illness for different strains of PCR-confirmed influenza and non-influenza viruses using ordinal logistic regression with symptom severity grade as the outcome variable.

Findings

Based on four-fold titre rises in strain-specific serology, on average influenza infected 18% (95% CI 16—22) of unvaccinated people each winter. Of those infected there were 69 respiratory illnesses per 100 person-influenza-seasons compared with 44 per 100 in those not infected with influenza. The age-adjusted attributable rate of illness if infected was 23 illnesses per 100 person-seasons (13—34), suggesting most influenza infections are asymptomatic. 25% (18—35) of all people with serologically confirmed infections had PCR-confirmed disease. 17% (10—26) of people with PCR-confirmed influenza had medically attended illness. These figures did not differ significantly when comparing pandemic with seasonal influenza. Of PCR-confirmed cases, people infected with the 2009 pandemic strain had markedly less severe symptoms than those infected with seasonal H3N2.

Interpretation

Seasonal influenza and the 2009 pandemic strain were characterised by similar high rates of mainly asymptomatic infection with most symptomatic cases self-managing without medical consultation. In the community the 2009 pandemic strain caused milder symptoms than seasonal H3N2.

Funding

Medical Research Council and the Wellcome Trust.

The bottom line is that during this five-year study period, just under 20% of the (unvaccinated) study cohort contracted the flu each year, but of those, roughly three-quarters did so without displaying classic influenza symptoms. 

 

There are limitations to this study, of course, including low participation rates, no data gathered from patients < 5 years of age, self-reporting of symptoms, and difficulty in obtaining a fully representative sample.

 

Still, the authors report that `Participants were generally highly diligent at completing weekly illness reports and submitting nasal swabs during illness (>85% completion)’.

 

In a related commentary (see Community studies of influenza: new knowledge, new questions),  Dr Peter William Horby  writes:

 

"In view of the undoubtedly high rates of subclinical influenza infection, an important unanswered question is the extent to which mild and asymptomatic influenza infections contribute to transmission…A large number of well individuals mixing widely in the community might, even if only mildly infectious, make a substantial contribution to onward transmission."

 

The question of asymptomatic transmission is an important one, and may well explain the lack of success in interdicting flu carriers at airports and border checkpoints during the 2009 pandemic (see Pathogens At the Gate).  While many nations are quick to set up thermal scanners at entry points, the evidence that they can forestall a virus from entering a country is seriously lacking (see Branswell: Limitations Of Airport Disease Screening).

 

Similarly, telling people who are sick to stay home during an epidemic (while excellent advice), isn’t a panacea to prevent community transmission if 75% of those infected are unaware of the fact they are infected. 

 

The good news in all of this is that 75% of people who get the flu don’t get sick enough to notice it.

 

The bad news is, influenza stealthily infects far more people each year than surveillance would suggest.  And that means that should a highly contagious (and pathogenic) novel virus emerge, controlling its spread may be more challenging than previously envisioned.

 

For more on the plans to mitigate the spread of influenza during a pandemic, you may wish to revisit:

 

Pandemic Preparedness: Taking Our Cue From The Experts

NPM13: Pandemic Planning Assumptions

CDC: Updated H7N9 Guidance Docs

Lancet: Clinical & Epidemiological Characteristics Of A Fatal H10N8 Case

 

Jiangxi Province – Credit Wikipedia – Site of 2 H10N8 Cases

 

 

# 8268

 

Last night Robert Roos, editor of CIDRAP NEWS, wrote a detailed piece on a study that appeared yesterday in The Lancet, on the recently detected human infection from H10N8 in China. Overnight, a number of other media outlets have picked up on this report, along with an embedded warning from the author’s that this virus – like H5N1 and H7N9 – needs to be watched closely for signs of spread and adaptation.

 

Over the past couple of months I’ve blogged several times on the emergence of this novel virus, including:

Jiangxi Province Reports Second H10N8 Infection

HK CHP Notified Of Fatal H10N8 Infection In Jiangxi

Since I’m unlikely to produce anything as clear and concise as Robert already has,  I’ll direct you to his piece and a link to the study/abstract, after which I’ll be back with a bit more.

 

Study: H10N8 virus in first human case is novel strain

Robert Roos | News Editor | CIDRAP News

Feb 04, 2014

influenza_virus-cdc.jpg

CDC / Erskine L. Palmer & M. L. Martin

Highly magnified view of influenza virus structure.

Chinese scientists reported today that the first human infection with an H10N8 avian influenza virus involved a new strain that carries genes from H9N2 viruses and has a mutation associated with adaptation to mammals.

 

Writing in The Lancet, the scientists detailed the results of their genomic analysis of the virus, which was isolated from a 73-year-old Chinese woman who died Dec 6. Her illness was the first known human case involving that strain.

 

A second human case in China was reported by the country's government news agency on Jan 27. "The pandemic potential of this novel virus should not be underestimated," the Lancet authors warn.

(Continue . . . )

 

The Lancet article may be accessed here:

 

Chen H, Yuan H, Gao R, et al. Clinical and epidemiological characteristics of a fatal case of avian influenza A H10N8 virus infection: a descriptive study. Lancet 2014 (published online Feb 4) [Abstract]

See also:

Feb 4 Lancet press release

Feb 4 Lancet commentary on the study

 

Of considerable interest is the fact that H9N2 – an avian flu virus that is commonly found across much of Asia – contributed six of H10N8’s internal genes.  A contribution very similar to that which H9N2 has made to other emerging avian viruses over the years, including H5N1 and H7N9.

 

As I wrote last month in Viral Reassortants: Rocking The Cradle Of Influenza, we continue to see new, emerging, `reassorted’ flu viruses from many places around the world, but particularly from Southeast Asia.

Reassorted viruses can result when two different flu strains inhabit the same host (human, swine, avian, or otherwise) at the same time. Under the right conditions, they can swap one or more gene segments and produce a hybrid virus.

 

While most of these reassortant viruses are evolutionary failures, and are unable to compete with the existing wild viruses, every once in awhile a new one appears that is a genuine contender. 

 

Which is why we watch novel influenza viruses – even those that appear only rarely, carefully.

 

Last year we saw the emergence of H7N9 in Eastern China, along with previously unrecognized lineage of the H7N7 virus (see Nature: Genesis Of The H7N9 Virus).  Last December, Hong Kong reported a rare case of avian H9N2 infection -  imported from Shenzhen - and  last May, Taiwan reported a never-seen-before human H6N1 infection.

 

And it is likely that other, novel reassorted viruses were produced last year – and may even have infected humans - without being detected.  Since surveillance for novel viruses is limited, we honestly don’t know how often this happens.

 

But it is probably more common than we know.

 

The good news is that pandemic viruses only appear rarely.  The bad news is that nature’s laboratory is open 24/7, and it is constantly trying to produce the next `successful’ virus.

 

All of which highlights the need for continual and enhanced surveillance of humans, livestock, and wild birds for emerging viral threats. Because it isn’t a question of if another pandemic will emerge.

 

It’s only a matter of when.

The Lancet: Antibiotic Resistance - The Need For Global Solutions

Credit CDC Vital Signs

 

# 7985

 

With tomorrow (Nov. 18th) marking Antibiotic Resistance Awareness Day in Europe, and kicking off the Get Smart About Antibiotics week in the United States, today The Lancet has published a special collection of reports and articles on the growing problems of antimicrobial resistance (note: Free registration required to access articles).

 

Antibiotic resistance—the need for global solutions

Published November 17, 2013

Executive summary

The causes of antibiotic resistance are complex and include human behaviour at many levels of society; the consequences affect everybody in the world. Similarities with climate change are evident. Many efforts have been made to describe the many different facets of antibiotic resistance and the interventions needed to meet the challenge. However, coordinated action is largely absent, especially at the political level, both nationally and internationally. Antibiotics paved the way for unprecedented medical and societal developments, and are today indispensible in all health systems. Achievements in modern medicine, such as major surgery, organ transplantation, treatment of preterm babies, and cancer chemotherapy, which we today take for granted, would not be possible without access to effective treatment for bacterial infections. Within just a few years, we might be faced with dire setbacks, medically, socially, and economically, unless real and unprecedented global coordinated actions are immediately taken. This Commission describes the global situation of antibiotic resistance, its major causes and consequences, and identify key areas in which action is urgently needed.

The Lancet Infectious Diseases Commission

Antibiotic resistance—the need for global solutions

Ramanan Laxminarayan, Adriano Duse, Chand Wattal, Anita K M Zaidi, Heiman F L Wertheim, Nithima Sumpradit, Erika Vlieghe, Gabriel Levy Hara, Ian M Gould, Herman Goossens, Christina Greko, Anthony D So, Maryam Bigdeli, Göran Tomson, Will Woodhouse, Eva Ombaka, Arturo Quizhpe Peralta, Farah Naz Qamar, Fatima Mir, Sam Kariuki, Zulfiqar A Bhutta, Anthony Coates, Richard Bergstrom, Gerard D Wright, Eric D Brown, Otto Cars

Related articles and comments in this issue also include:

Antibiotic resistance: global response needed

Simon J Howard, Mike Catchpole, John Watson, Sally C Davies

Global collaboration to encourage prudent antibiotic use

Sarah Earnshaw, Andrea Mendez, Dominique L Monnet, Lauri Hicks, Marilyn Cruickshank, Lynn Weekes, Howard Njoo, Stacie Ross

Antibiotic effectiveness and child survival

Mark Young, Mickey Chopra, Atieno Ojoo

Antibiotic resistance in Ghana

Martha Gyansa-Lutterodt

Light at the end of the tunnel of antibiotic development

Glenn S Tillotson

Antibiotic Action: helping deliver action plans and strategies

Laura JV Piddock

 

Perseverance, persistence, and the Chennai declaration

Abdul Ghafur

Related content published in The Lancet Infectious Diseases

Antibiotic resistance: long-term solutions require action now

 

Despite decades of warnings, the persistent overuse of antibiotics has led us to the precipice, and we now face an uncertain and potentially frightening future where previously curable infections may run rampant.  A few recent warnings include:

 

ECDC: Antibiotic Resistance In the EU – 2012

UK CMO: Antimicrobial Resistance Poses `Catastrophic Threat’

MMWR Vital Signs: Carbapenem-Resistant Enterobacteriaceae (CRE)

CDC HAN Advisory: Increase In CRE Reports In The United States

PNAS: Abundant Antibiotic Resistance Genes In Chinese Swine Farms

Chan: World Faces A `Post-Antibiotic Era’

 

For a more complete look at the complex issues of antibiotic resistance, and the dearth of new drugs on the horizon, I can think of no resource better than Maryn McKenna’s superb book (and recent winner of the 2013 June Roth Memorial Book Award, American Society of Journalists and Authors)  Superbug: The Fatal Menace of MRSA.

And while I dabble in writing about the issues of antibiotic resistance, undoubtedly the best coverage can be found on Maryn’s Superbug blog.

Branswell: Transmission Estimates Of MERS-CoV – Lancet Infectious Disease

Photo Credit NIAID

 

# 7967

 

Helen Branswell has the story this evening on a fresh study, just published in The Lancet Infectious Diseases, that looks at the likely extent of transmission of the MERS virus in the Middle East.  The results – that for every case identified, there are likely 5 to 10 that go undetected –  suggest that this virus may be transmitting more efficiently than previously estimated.

 

First, a link to Helen’s excellent review, then a link to the study, after which I’ll return with a bit more.

 

Most MERS cases going undetected, 'Slow moving epidemic underway': study

Helen Branswell / The Canadian Press
November 12, 2013 03:42 PM

 

A new analysis of MERS case data suggests a large number of infections are going undetected, with the researchers estimating that for each case that has been found, five to 10 may have been missed.

The scientific paper, from European researchers, further suggests that transmission of the MERS virus is occurring at a rate close to the threshold where it would be considered able to pass from person to person in a sustained manner.

In fact, the authors say based on the available evidence they cannot rule out the possibility that person-to-person spread is the main mode of transmission of the virus at this point. The other option, they say, is that the virus is spreading via a combination of animal-to-person and then person-to-person transfer.

(Continue . . .)

 

 

 

Middle East respiratory syndrome coronavirus: quantification of the extent of the epidemic, surveillance biases, and transmissibility

Simon Cauchemez PhD a †, Prof Christophe Fraser PhD a †, Maria D Van Kerkhove PhD a, Prof Christl A Donnelly ScD a, Steven Riley PhD a, Prof Andrew Rambaut PhD b, Vincent Enouf PhD c, Prof Sylvie van der Werf PhD c, Prof Neil M Ferguson DPh

Interpretation

By showing that a slowly growing epidemic is underway either in human beings or in an animal reservoir, quantification of uncertainty in transmissibility estimates, and provision of the first estimates of the scale of the epidemic and extent of case detection biases, we provide valuable information for more informed risk assessment.

 

The epidemiological yardstick by which human transmission of an infectious disease is measured is called the R0 (pronounced R-nought) or Basic Reproductive Number.

Essentially, the number of new cases in a susceptible population likely to arise from a single infection.

With an R0 below 1.0, a virus (as an outbreak) begins to sputter and dies out.

Above 1.0, and an outbreak can have `legs’.

 

Last July, in The Lancet: Transmissibility Of MERS-CoV, we looked at a preliminary analysis that calculated the R0 of the MERS virus to be between .60 and .69.   Too low (at that time) to spark an epidemic.

 

But calculating the R0 is notoriously difficult, particularly since much hinges upon the existence and subtle differences between viral strains, the accuracy of surveillance and reporting, `seasonality’’ of the infection, and individual host responses to the virus (i.e. number of `super spreaders’).

 

Like the CFR (Case Fatality Ratio), the R0 can vary considerably over time or geography, often ends up being described as a `range’, and usually isn’t well established (or at least, generally agreed upon) until long after an outbreak has ended.

 

The authors in today’s study  believe the R0 of the MERS virus is likely close to 1.0, or perhaps even higher, and write:

 

We conclude that a slowly growing epidemic is underway, but current epidemiological data do not allow us to determine whether transmission is self-sustaining in man. Our analysis demonstrates that the transmissibility of MERS-CoV in man is close to the critical threshold of R=1 required for self-sustaining transmission. If R is greater than 1, then the number of human cases we estimate to have occurred to date make it highly likely that self-sustaining transmission has already begun

 

Even assuming low levels of sustained transmission –  with an R0 of greater 1.0 – the timely application of control procedures can sometimes contain, and even halt, an epidemic. 

 

The R0 of SARS was estimated to be between 2 and 4, but since patients weren’t infectious prior to developing symptoms, aggressive quarantine efforts were able to quell that outbreak.

 

The question, of course, is whether the current surveillance and testing regimens in place are comprehensive enough to identify and the spreaders of this virus.  And here, the Achilles heel may be asymptomatic or mild cases – which are less likely to be identified and  isolated – but which may still be capable of spreading the virus.

SARS is believed to have had a low percentage of asymptomatic cases (see EID Journal Asymptomatic SARS Coronavirus Infection among Healthcare Workers, Singapore), and they did not appear to be aggressive spreaders of the virus. 

 

Whether that will be the case with MERS remains to be seen.

The Lancet: Transmission And Evolution Of MERS-CoV In Saudi Arabia

Coronavirus – Credit CDC PHIL

 

# 7795

 

This Lancet study, which was embargoed until early yesterday evening, has already generated a good deal of knowledgeable commentary, so rather than re-inventing the wheel, I’ll provide links and excerpts from the study, the press release, Dr. Ian Mackay’s commentary, and CIDRAP’s coverage.

 

First stop, the Lancet study, which – using genomic analysis - finds evidence of multiple spillovers of MERS from an (as yet, unknown) animal host into the human population in Saudi Arabia.

 

 

Copyright © 2013 Cotten et al. Open Access article distributed under the terms of CC BY-NC-ND Published by Elsevier Ltd. All rights reserved.

The Lancet, Early Online Publication, 20 September 2013

doi:10.1016/S0140-6736(13)61887-5

Transmission and evolution of the Middle East respiratory syndrome coronavirus in Saudi Arabia: a descriptive genomic study

Matthew Cotten PhD b †, Simon J Watson PhD b †, Prof Paul Kellam PhD b m †, Abdullah A Al-Rabeeah FRCS a, Hatem Q Makhdoom PhD c, Abdullah Assiri MD a, Jaffar A Al-Tawfiq MD d, Rafat F Alhakeem MD a, Hossam Madani PhD c, Fahad A AlRabiah MD g, Sami Al Hajjar MD g, Wafa N Al-nassir MD h, Ali Albarrak MD i, Hesham Flemban MD j, Hanan H Balkhy MD k, Sarah Alsubaie MD l, Anne L Palser PhD b, Astrid Gall Dr Med Vet b, Rachael Bashford-Rogers MChem b, Prof Andrew Rambaut Prof e f, Prof Alimuddin I Zumla FRCP a m n †, Prof Ziad A Memish FRCP

Summary

Background

Since June, 2012, Middle East respiratory syndrome coronavirus (MERS-CoV) has, worldwide, caused 104 infections in people including 49 deaths, with 82 cases and 41 deaths reported from Saudi Arabia. In addition to confirming diagnosis, we generated the MERS-CoV genomic sequences obtained directly from patient samples to provide important information on MERS-CoV transmission, evolution, and origin.

Methods

Full genome deep sequencing was done on nucleic acid extracted directly from PCR-confirmed clinical samples. Viral genomes were obtained from 21 MERS cases of which 13 had 100%, four 85—95%, and four 30—50% genome coverage. Phylogenetic analysis of the 21 sequences, combined with nine published MERS-CoV genomes, was done.

Findings

Three distinct MERS-CoV genotypes were identified in Riyadh. Phylogeographic analyses suggest the MERS-CoV zoonotic reservoir is geographically disperse. Selection analysis of the MERS-CoV genomes reveals the expected accumulation of genetic diversity including changes in the S protein. The genetic diversity in the Al-Hasa cluster suggests that the hospital outbreak might have had more than one virus introduction.

Interpretation

We present the largest number of MERS-CoV genomes (21) described so far. MERS-CoV full genome sequences provide greater detail in tracking transmission. Multiple introductions of MERS-CoV are identified and suggest lower R0 values. Transmission within Saudi Arabia is consistent with either movement of an animal reservoir, animal products, or movement of infected people. Further definition of the exposures responsible for the sporadic introductions of MERS-CoV into human populations is urgently needed.

 

The press release, from the Wellcome Trust Sanger Institute, provides more background and detail (excerpts follow).

 

 

Genome sequencing identifies multiple chains of MERS Co-V infection in humans

Genome sequencing has identified several infection transmission chains of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in humans. The study published in the Lancet, which produced the largest number of MERS-CoV genomes described to date, provides evidence that MERS-CoV transmission patterns are more complicated than previously considered.

<SNIP>

The findings suggest that human-to-human transmission is more complicated than expected, and indicates that additional sources of the virus, either human or animal, are involved. One possibility is that there may be undetected (and possibly asymptomatic) people who could be carrying and spreading the virus.

 

"The genome differences we discovered in some infected people were too great to be explained by replication errors occurring in the virus as it is passed from human to human during a single chain of infection," explained Professor Paul Kellam, senior author from the Sanger Institute. "Instead our findings suggest that different lineages of the virus have originated from the virus jumping across to humans from an animal source a number of times."

 

As yet no animal with MERS-CoV has been identified in the Middle East or elsewhere and studies based on small sequence fragments suggest that a common ancestor of the virus may have existed in bats many years ago. Field studies of all the likely reservoir species, including camels, bats, goats, sheep, dogs, cats, rodents and others in the Kingdom of Saudi Arabia and other middle-eastern countries are on-going.

(Continue . . .)

 

 

Next stop, Ian Mackay’s Virology Down Under Blog, where we get a virologist’s take on these findings, and a concise bullet list of the highlights (I’ve only included the first 3 of 8).

 

Molecular epidemiology of Middle East respiratory syndrome coronavirus (MERS-CoV)

And a newcomer to the MERS-CoV birthday celebrations! What great timing to have this released today.
The Lancet paper accompanying those recent partial and full genome sequences has been released form its cage. It's a collaborative effort by authors affiliated with the Global Centre for Mass Gatherings Medicine (Ministry of Health Saudi Arabia), Welcome Trust Sanger Institute (United Kingdom) and many other locations.

A few highlights of the largest MERS-CoV molecular epidemiology study to date, which includes some great transmission figures and trees (hat tip to the graphics people at Lancet):

• Genetic diversity analyses 3 distinct genotypes were identified from human cases in Riyadh
• The Al-Ahsa hospital cluster may have had more than 1 viral introduction
• Other clusters and stand alone cases can be represented as distinct genotypes of MERS-CoV, possibly indicating multiple different virus acquisitions from different sources

(Continue . . . .)

 

 

And last, but certainly not least, Robert Roos and Lisa Schnirring produced a report for CIDRAP news last night, that provides an excellent overview for us.

 

Study suggests multiple MERS-CoV introductions

Robert Roos | News Editor | CIDRAP News

Sep 19, 2013

One of the big mysteries about the Middle East respiratory syndrome coronavirus (MERS-CoV) is whether it jumped from animals to humans just once or has made that jump a number of times. A study released today indicates that the second scenario seems more likely, given the genetic diversity in virus samples from 21 Saudi Arabian patients.

Researchers from Saudi Arabia, the United Kingdom, and the United States sequenced the genomes of the 21 isolates and found too much diversity to support the idea that the virus crossed from animals to humans just once and then traveled from person to person to spark all the other cases, according to their report in The Lancet and related press releases.

The findings also suggest that human-to-human transmission is more complicated than expected and raise the possibility that people with undetected infections are spreading the virus, the authors say.

(Continue . . .)

ECDC Comment On Lancet MERS-CoV Seroprevalence Report

Photo Credit Wikipedia

 

# 7569

 

The publication last week of a study in The Lancet (see Camels Found With Antibodies To MERS-CoV-Like Virus) has led to a series of overreaching headlines implicating camels in the transmission of the MERS coronavirus.  A few examples include:

 

Camels May Be Source Of Deadly Coronavirus Voice of America 

Omani Camels May Be Transmitting Coronavirus, Study Suggests NewsMax

 

Camels linked to spread of Sars-like coronavirus The Irish Times

While the articles beneath these headlines tend to parse the story more accurately, the impression left by these headlines is that scientists have found a `smoking camel’ with the MERS virus.

 

Which, I suspect, is the reason we’ve seen an aggressive effort on the part of the World Health Organization, the FAO,  and others to try to put the Lancet study into better context; to step back a bit from the `camel as vector’ headlines (see FAO: FAQ On The Lancet MERS-CoV – Camel Study).

 

Today, the ECDC has published their own review the MERS-CoV antibody findings in camels.

 

 

Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study

12 Aug 2013

A study published in the Lancet Infectious Diseases on 9 August 2013 by Reusken et al identified antibodies to MERS-CoV in camels both in Oman and Spain.  A total of 50 out of 50 (100%) sera sampled from Omani camels and 15 of 105 (14%) of sera from camels from Spain had antibodies against MERS-CoV. Sera from European and Chilean sheep, goats, cattle and other camelids had no such antibodies.  Generic viral nucleic acid tests used for the analysis of serum and fecal samples from Spanish dromedaries were negative. The authors concluded that MERS-CoV or a virus very similar to MERS-CoV has widely circulated among camels in Oman. (1) Of note, the European Centre for Disease Prevention and Control  partially funded this study.

 

ECDC Comment 12-08-2013:

It is of utmost importance to identify the MERS-CoV reservoir and the transmission route to humans. For that reason, this study of Reusken et al. 2013 provides intriguing information, although it cannot be considered definitive proof that camels are a source of MERS-CoV.

 

Coronaviruses constitute a large family of viruses that may cause a range of illnesses in humans, as well as a number of diseases in a variety of animals.  Previous studies have shown, for example, that coronaviruses can cause severe symptoms in newborn camels (Wuenschmann et al. 2002, Tibary et al. 2006). The high prevalence of antibodies to MERS-CoV in camels in Oman suggests widespread infection with MERS-CoV or a MERS-like virus.

 

There are caveats to the findings of this study. The study does not exclude the possibility that there had been a cross-reaction with a related coronavirus to MERS-CoV (e.g. the laboratory methods identified antibodies to a similar virus as MERS-CoV but not exactly the same). Oman is located on the Arabian Peninsula, bordering with the Saudi Arabia, but no human cases of MERS-CoV have been reported there. The study does not include information on circulation or seroprevalence of MERS-CoV in animals from countries where human MERS-CoV has been found. Finally, since no viral particles were identified in the animals, it is not clear if they are a source of the disease or are incidentally infected.

 

In the epidemiological investigations carried out so far, direct animal contact of most of the MERS-CoV patients has been excluded as the probable route of infection. Few positive human cases have indicated contact with camels.

 

More studies are needed to confirm the reservoir or possible intermediate animal hosts. Results of this study do not explain how humans become infected with MERS-CoV.

 

The previously published ECDC Rapid Risk Assessment is still valid.

References

(1) Reusken et al, Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study, The Lancet Infectious Diseases, 9 August 2013. http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(13)70164-6/fulltext

ECDC staff who contributed to the public health development: Eeva Broberg, Elizabeth Bancroft, Cornelia Adlhoch, Pasi Penttinen, Rene Snacken, Andrew J Amato-Gauci

Referral: Dr. Mackay On The Lancet MERS-CoV Study

Photo Credit WHO

# 7516

 

Dr. Ian Mackay examines this morning’s Lancet study (see Lancet: Epidemiological, Demographic & Clinical Characteristics of MERS-CoV) on his recently redesigned Virology Down Under blog.

 

Follow the link below to read:

 

Biggest Middle East Respiratory syndrome coronavirus (MERS-CoV) case study to date

Assiri and colleagues from the Kingdom of Saudi Arabia (KSA) today described, in The Lancet, the clinical characteristics of 47 cases of MERS-CoV. The largest detailed analysis of MERS-CoV cases to date.

(Continue . . . )

Lancet: Epidemiological, Demographic & Clinical Characteristics of MERS-CoV

Coronavirus – Credit CDC PHIL

 

 

# 7515

 

Overnight The Lancet published an analysis of 47 lab confirmed cases of MERS-CoV diagnosed in Saudi Arabia between September 2012 and June 15th 2013.

 

While the bulk of the study is behind a pay wall, we do have the abstract and several media reports quoting the corresponding author for this study; KSA Deputy Health Minister, Professor Ziad Memish. 

 

Dr. Memish has been quoted by Reuters as stating that, "So far there is little to indicate that MERS will follow a similar path to SARS."   At the same time, this new study concedes:

 

Major gaps in our knowledge of the epidemiology, community prevalence, and clinical spectrum of infection and disease need urgent definition

 

First stop, a link to the abstract, then a couple of links to media coverage.

 

Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study

Abdullah Assiri MD a b †, Jaffar A Al-Tawfiq FACP c †, Abdullah A Al-Rabeeah FRCS a, Fahad A Al-Rabiah MD d, Sami Al-Hajjar MD d, Ali Al-Barrak MD e, Hesham Flemban MD f, Wafa N Al-Nassir MD g, Hanan H Balkhy MD h, Rafat F Al-Hakeem MD a i, Hatem Q Makhdoom PhD j, Prof Alimuddin I Zumla FRCP a k l †, Prof Ziad A Memish FRCP a m n

Findings

47 individuals (46 adults, one child) with laboratory-confirmed MERS-CoV disease were identified; 36 (77%) were male (male:female ratio 3·3:1). 28 patients died, a 60% case-fatality rate. The case-fatality rate rose with increasing age.

 

Only two of the 47 cases were previously healthy; most patients (45 [96%]) had underlying comorbid medical disorders, including diabetes (32 [68%]), hypertension (16 [34%]), chronic cardiac disease (13 [28%]), and chronic renal disease (23 [49%]). Common symptoms at presentation were fever (46 [98%]), fever with chills or rigors (41 [87%]), cough (39 [83%]), shortness of breath (34 [72%]), and myalgia (15 [32%]). Gastrointestinal symptoms were also frequent, including diarrhoea (12 [26%]), vomiting (ten [21%]), and abdominal pain (eight [17%]).

 

All patients had abnormal findings on chest radiography, ranging from subtle to extensive unilateral and bilateral abnormalities. Laboratory analyses showed raised concentrations of lactate dehydrogenase (23 [49%]) and aspartate aminotransferase (seven [15%]) and thrombocytopenia (17 [36%]) and lymphopenia (16 [34%]).

 

 

A key finding is that 96% (45 of 47) of these cases had pre-existing medical conditions.

• diabetes (32 [68%])
• hypertension (16 [34%])
• chronic cardiac disease (13 [28%])
• chronic renal disease (23 [49%])

 

BBC coverage of this report includes extended comments by Professor Memish, where he compares the threat from MERS-CoV with that of SARS a decade ago.

 

Mers: New virus 'not following Sars' path'

By James Gallagher Health and science reporter, BBC News

 

<Excerpt>

The lead researcher and Deputy Minister for Public Health, Prof Ziad Memish, said: "Despite sharing some clinical similarities with Sars, there are also some important differences.

 

"In contrast to Sars, which was much more infectious especially in healthcare settings and affected the healthier and the younger age group, Mers appears to be more deadly, with 60% of patients with co-existing chronic illnesses dying, compared with the 1% toll of Sars.

 

"Although this high mortality rate with Mers is probably spurious due to the fact that we are only picking up severe cases and missing a significant number of milder or asymptomatic cases.

 

"So far there is little to indicate that Mers will follow a similar path to Sars."

(Continue . . . )

 

 

In an accompanying article (Is MERS another SARS?), MERS researcher Professor Christian Drosten (see The Lancet: Virological Analysis Of A MERS-CoV Patient & Nature: Receptor For NCoV Found) - as reported in this Medscape article MERS and SARS: Similar Not Identical - is less sanguine in his analysis.

 

He notes that the incidence of diabetes among elderly male Saudis is fairly close to that reported among these cases, and that a high rate of chronic kidney disease and hypertension among patients is not unexpected, given that many of these cases were linked to nosocomial spread at a dialysis clinic.

 

Without broader community seroprevalence studies, Drosten argues that it is premature to regard this virus as primarily a threat to those with underlying disorders.

 

Complicating matters, since this study’s cut-off date in June, we’ve seen a growing number of asymptomatic cases reported among younger, presumably healthier, individuals. 

 

This from the most recent ECDC Rapid Risk Assessment on MERS-COV.

 

Ten asymptomatic cases have been reported since 8 June, eight by Saudi Arabia and two by the United Arab Emirates (UAE). Six of these asymptomatic cases have been health care workers. All the new cases reported since the previous update have been reported by Saudi Arabia and UAE.

 

This broad range of clinical presentation (asymptomatic to severe, even fatal illness) leaves investigators unsure whether the 90+ cases that have so far been identified represent the bulk of the infected cases or are just the `tip of a much larger iceberg’.

 

Crucial questions for which answers, right now, are frustratingly few.

Lancet: Tropism Of H7N9 In the Human Respiratory Tract

 

ex vivo bronchus culture – Credit University Of Hong Kong

 

# 7513

 

An important new study from researchers at the University of Hong Kong appears today in The Lancet Respiratory Medicine, that finds that China’s emerging H7N9 virus infects and replicates in the cells of the human respiratory tract about as well as the 2009 H1N1 virus.

 

While we’ve seen a welcome reduction in human H7N9 infections over the summer, this is the latest in a series of studies that suggests this virus may have substantial pandemic potential (for more see Science: H7N9 Transmissibility Study In Ferrets).

 

In today’s study, researchers led by Dr. Malik Peiris inoculated in-vitro and ex-vivo cultures representing human bronchus and lung tissues with six different virus strains (H5N1, H1N1, 2 Human-derived H7N9 strains, 1 duck-derived H7N9, and the H7N7 2003 Netherlands outbreak stain)  and compared how well they infected and replicated within the cells. 

While the duck-derived H7N9 failed to replicate, both human H7N9 viruses replicated efficiently, far better than H5N1, and on a par with the 2009 H1N1 pandemic virus. 

 

We’ve three stops this morning for this paper, after which I’ll return with a bit more. 

 

First, a link to the abstract in the Lancet, then a companion piece by Jessica A Belser & Terrence M Tumpey of the CDC’s NCIRD, and finally a press release from the University of Hong Kong on this research.

 

Tropism and innate host responses of a novel avian influenza A H7N9 virus: an analysis of ex-vivo and in-vitro cultures of the human respiratory tract

Michael CW Chan PhD a †, Renee WY Chan PhD a †, Louisa LY Chan BSc a †, Chris KP Mok PhD a †, Kenrie PY Hui PhD a, Joanne HM Fong MSc a, Kin P Tao PhD a, Leo LM Poon DPhil a b, Prof John M Nicholls FRCPA c, Prof Y Guan PhD a b d, Prof JS Malik Peiris DPhil a b

ABSTRACT (Excerpt)

Methods

We obtained ex-vivo cultures of the human bronchus, lung, nasopharynx, and tonsil and in-vitro cultures of primary human alveolar epithelial cells and peripheral blood monocyte-derived macrophages. We compared virus tropism and induction of proinflammatory cytokine responses of two human influenza A H7N9 virus isolates, A/Shanghai/1/2013 and A/Shanghai/2/2013; a highly pathogenic avian influenza H5N1 virus; the highly pathogenic avian influenza H7N7 virus that infected human beings in the Netherlands in 2003; the 2009 pandemic influenza H1N1 virus, and a low pathogenic duck H7N9 virus that was genetically different to the human disease causing A H7N9 viruses.

Findings

Both human H7N9 viruses replicated efficiently in human bronchus and lung ex-vivo cultures, whereas duck/H7N9 virus failed to replicate in either. Both human A H7N9 viruses infected both ciliated and non-ciliated human bronchial epithelial cells and replicated to higher titres than did H5N1 (p<0·0001 to 0·0046) and A/Shanghai/1/2013 replicated to higher titres than did H7N7 (p=0·0002—0·01). Both human A H7N9 viruses predominantly infected type II alveolar epithelial cells and alveolar macrophages in the human lung and replicated to higher titres than did H5N1 (p<0·0001 to 0·0078); A/Shanghai/1/2013 replicated to higher titres than did H1N1 (p=0·0052—0·05) and H7N7 (p=0·0031—0·0151). Human H7N9 viruses were less potent inducers of proinflammatory cytokines compared with H5N1 virus.

Interpretation

Collectively, the results suggest that the novel H7N9 viruses are better adapted to infect and replicate in the human conducting and lower airways than are other avian influenza viruses, including H5N1, and pose an important pandemic threat

 

 

In a companion article, Belser and Tumpey explore these findings further (full access with free registration) in:

 

Tropism of H7N9 influenza viruses in the human respiratory tract

Jessica A Belser a, Terrence M Tumpey a

 

While referring to the `remarkable ability of this low pathogenic avian influenza virus to cause severe human disease’  the authors caution that this study leaves a good many questions unanswered.

And our last stop is a press release from the University of Hong Kong (excerpts below).

 

HKU’s finding on avian influenza A (H7N9) virus well adapted to infect human respiratory tract reveals why numerous human infected cases in a short period of time

25 Jul 2013

HKU research team reveals why the avian influenza (H7N9) virus led to over 130 human cases in a relatively short period of time.  By using human respiratory tract tissues maintained in culture, the researchers discover that the avian influenza A (H7N9) virus is as efficient as the 2009 pandemic H1N1 virus, commonly known as swine influenza, in infecting the human respiratory tract.  Compared to the avian influenza A (H5N1) virus, H7N9 virus might pose an even more important pandemic threat to human. 

<SNIP>

Research findings
The researchers used human respiratory tract tissues (bronchus and lung) maintained in culture to compare infection with the avian influenza A (H7N9) virus, the 2009 pandemic influenza A (H1N1) virus (commonly known as swine influenza) and highly pathogenic avian influenza A (H5N1) virus.  They find that the H7N9 virus infects and replicates in both human bronchus as well as the H1N1 virus, and far more efficiently than the H5N1 virus.

 

These studies also identify the type II alveolar epithelial cells within the lung as a key target for H7N9 virus replication.  This is the key cell type supporting regeneration and repair of damaged lung tissues.  Thus infection and damage to these cells will prevent the repair processes that allow the lung to recover from injury or infection.

 

Taken together, this study demonstrates that the H7N9 viruses are better adapted to infect and replicate in the human airways and pose an important pandemic threat, perhaps even more so than H5N1 virus.

 

 

This latest research, along with a number of other recent studies, continue to show that the H7N9 virus has many of the qualities we would expect to find in an pandemic strain of influenza:

 

• it is a novel strain to which humans appear to have little or no immunity
• it can infect human (a2,6) receptor cells
• it replicates efficiently in human tissue;
• and it is capable of producing severe disease.

 

Yet, despite these worrisome traits in the lab, we’ve not seen sustained human-to-human transmission of the virus in the field. 

 

Exactly why that is, and whether or not this virus can gain the necessary changes to overcome that limitation, remain unanswered.

 

About the only thing we can say with any certainty is that none of the studies we’ve seen  over the summer have done anything to lower the level of concern over this emerging virus.

 

Which is why all eyes will be on China later this year to see if, and with how much vigor, this virus returns in the fall or winter.

The Lancet: Transmissibility Of MERS-CoV

 

 

# 7449

 

The epidemiological yardstick by which human transmission of an infectious disease is measured is called the R0 (pronounced R-nought) or Basic Reproductive Number.

 

Essentially, the number of new cases in a susceptible population likely to arise from a single infection.

 

With an R0 below 1.0, a virus (as an outbreak) begins to sputter and dies out.

 

Above 1.0, and an outbreak can have `legs’.

 

Calculating the R0 is notoriously difficult, particularly since much hinges upon the existence and subtle differences between viral strains, the accuracy of surveillance and reporting, `seasonality’, and individual host responses to the virus (i.e. number of `super spreaders’).

 

Like the CFR (Case Fatality Ratio), the R0 can vary considereably over time or geography, often ends up being described as a `range’, and usually isn’t well established (or at least, generally agreed upon) until long after an outbreak has ended.

 

Today The Lancet publishes an analysis – based on very early surveillance numbers  - that attempts to quantify the R0 of MERS-CoV, and its `pandemic potential’.

 

First a link to the abstract (and an excerpt), then a link to informative report by Helen Branswell that explains why we shouldn’t be lulled by these preliminary findings.

 

 

Interhuman transmissibility of Middle East respiratory syndrome coronavirus: estimation of pandemic risk

Romulus Breban PhD, Julien Riou, Prof Arnaud Fontanet PhD

Results

With our most pessimistic scenario (scenario 2), we estimated MERS-CoV R0 to be 0·69 (95% CI 0·50—0·92); by contrast, the R0 for prepandemic SARS-CoV was 0·80 (0·54—1·13). Our optimistic scenario (scenario 1) yielded a MERS-CoV R0 of 0·60 (0·42—0·80). Because of recent implementation of effective contact tracing and isolation procedures, further MERS-CoV transmission data might no longer describe an entire cluster, but only secondary infections directly caused by the index patient. Hence, we calculated that, under scenario 2, eight or more secondary infections caused by the next index patient would translate into a 5% or higher chance that the revised MERS-CoV R0 would exceed 1—ie, that MERS-CoV might have pandemic potential.

Interpretation

Our analysis suggests that MERS-CoV does not yet have pandemic potential. We recommend enhanced surveillance, active contact tracing, and vigorous searches for the MERS-CoV animal hosts and transmission routes to human beings.

 

Based on an extremely limited data-set, and hobbled by limited surveillance and reporting out of Saudi Arabia, the authors have produced an early estimate of the virus’ apparent R0 (which they fix at between .60 and .69).

 

Too low (at this time) to spark a pandemic.

 

But in the following Canadian Press article, Helen Branswell quotes a number of experts - including Drs. Allison McGeer, Marc Lipsitch, and Chris Bauch (who co-authored a commentary on this study) - who warn that past performance is no guarantee how this virus will behave in the future.

 

Follow the link below to read:

 

MERS doesn't have pandemic potential – yet

By Helen Branswell The Canadian Press

TORONTO – The new MERS coronavirus currently doesn’t spread well enough among people to trigger a pandemic, says a new study that calculates the rate at which the virus is transmitting person to person.

 

But the senior author says the pattern of how the virus is spreading now cannot be used to predict whether MERS will become a bigger threat in the future.

 

“There is absolutely no guarantee that this virus will stay as it is. It could very well follow the same path as SARS did 10 years ago,” Dr. Arnaud Fontanet, who heads the emerging diseases epidemiology unit at the Institut Pasteur in Paris, said in an interview.

(Continue .  .  .)

 

Highly recommended.

Lancet: MERS-CoV – New Disease, Old Lessons

Coronavirus – Credit CDC PHIL

# 7431

 

The Lancet today has published two related MERS-CoV articles, one of which we examined several weeks ago when it was released early online (see Lancet: Clinical Findings On 2 French MERS-CoV Cases). 

 

The new article - Middle East respiratory syndrome: new disease, old lessons  by Charles D Gomersall & Gavin M Joynt – consolidates what has been learned from the imported case in France (and its nosocomial transmission), along with sparse details from cases in the Middle East, and discusses their findings.

 

Of the two French cases which provide a good deal of the clinical data used in their discussion, one died in late May (see France’s 1st MERS-CoV Patient Dies), while the other (the index case’s roommate) remains in critical condition a month later.

 

The original Lancet article (published online May 30th) provides a detailed review of the clinical findings on both patients, including lab results, radiographs and CT scans, and genetic analysis of specimens.

 

Clinical features and viral diagnosis of two cases of infection with Middle East Respiratory Syndrome coronavirus: a report of nosocomial transmission

Benoit Guery, Julien Poissy, Loubna el Mansouf, Caroline Séjourné, Nicolas Ettahar, Xavier Lemaire, Fanny Vuotto, Anne Goffard, Sylvie Behillil, Vincent Enouf, Valérie Caro, Alexandra Mailles, Didier Che, Jean-Claude Manuguerra, Daniel Mathieu, Arnaud Fontanet, Sylvie van der Werf, and the MERS-CoV study group*

Interpretation

Patients with respiratory symptoms returning from the Middle East or exposed to a confirmed case should be isolated and investigated for MERS-CoV with lower respiratory tract sample analysis and an assumed incubation period of 12 days. Immunosuppression should also be taken into account as a risk factor.

 

 

This first report served to increase the supposed incubation period from 10 days to 12, and warned that lower respiratory samples are more likely to return a positive PCR result than samples retrieved from the upper respiratory system.

 

The second report, available online (free registration req.) can be accessed at the link below:

 

Middle East respiratory syndrome: new disease, old lessons

Charles D Gomersall, Gavin M Joynt

In 2003, severe acute respiratory syndrome coronavirus caused an epidemic of severe viral pneumonia. The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) has raised concerns of a similar epidemic. Although 55 laboratory-confirmed cases have been reported to WHO,1 published clinical details are sparse. In The Lancet, Benoit Guery and colleagues2 give a detailed description of two cases, occurring without co-infection.

This report is important not only because it provides information about the clinical features of the disease, but also because it confirms human-to-human transmission, shows the importance of travel and contact history-taking, draws attention to the need for analysis of lower respiratory tract specimens to exclude disease, and suggests that previous estimates of the incubation period might be too short.

(Continue . . .)

 

While you’ll want to read the entire article, some of the points made include:

 

• Some patients with MERS-CoV infection might present with atypical, or mild symptoms.
• Patients with mild symptoms are less likely to be thoroughly investigated and current case counts might not reflect the true burden of the disease.
• Testing is difficult, and samples taken from the upper respiratory system may be unreliable.
• Repeated negative test results of of lower respiratory tract specimens are required to rule out infection.
• While many exposed HCWs have not fallen ill, it is prudent to take precautions against airborne transmission.
• Further investigations are needed into the presence or absence of MERS viral shedding via the stool.
• The authors stress the importance of travel and contact history-taking

 

 

The most recent MERS-CoV update (June 26th) from the World Health Organization puts the case count at:

 

Globally, from September 2012 to date, WHO has been informed of a total of 77 laboratory-confirmed cases of infection with MERS-CoV, including 40 deaths.

 

There are a number of other exposed individuals for whom serological testing is not completed, and so these numbers are subject to revision.