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Speculation Into Darkness.

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As part of my crippled USS Vengeance-like crash course into the workings of influenza viruses over the past nearly 6 weeks, I've been doing some reading. 

A Science Policy Forum article I'm skimming through tonight, from Lipsitch and colleagues in 2012, makes a nice comment: 

We contend that predictions about how particular influenza strains will behave in humans or, even more important, how they will evolve, remain highly speculative. 

While this was written with H5N1 as the subject, it is clearly applicable to H7N9. It nicely sums up my understanding on this late Friday evening as well! And who needs a colon anyway?
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H7N9 more transmissible than H5N1.

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A comment in BMJ by Jane Parry stresses the use of closing live bird markets (LBMs)to halt human H7N9 cases and adds that this virus is more transmissible to/between humans than is H5N1 (45 human cases confirmed in China since 2001 vs H7N9's 132 but in only 5 weeks). 

I wonder how related this is to H7N9 being a low pathogenic avian influenza (LPAI) in birds compared to H5N1's highly pathogenic course in birds. H7N9 can, in theory, stealthily sweep through flocks without setting off veterinary alarm bells (human cases acting as the "sleeping" canary in the mine) whereas H5N1 triggers alarm and can be better controlled by early culling. 

So far 47,8000 samples from 1,000 farms and poultry markets have been been tested and only 39 have been H7N9 positive.
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Market networks.

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A study by Fourni� in PNAS and colleagues looks at risk and H5N1 and live bird markets (LBMs) in North Vietnam. Such sites implicated in H7N9's diverse and rapid spread in South East China, notes the interconnectivity between markets using social network analysis. Some act as hubs, spreading poultry to others. Infection in a hub will more effectively spread virus to outlying nodes. 

A similar, older study of Southern China LBMs provides insight into the number of sites affected by hubs and the vast distances travelled by poultry (with the help of humans and vehicles) in this area. It unfortunately doesn't cover the South East, the H7N9 hot zone, but I presume the pattern can be extrapolated. The 2011 study, by Martin and colleagues, focuses on markets in the Yunnan, Guangxi and Hunan provinces. It shows travel on one of many routes extending 2,500km (Yunnan to Shandong) and the importance of risk reduction measures (for H5N1) including daily poultry cage cleaning and disinfection and manure disposal/processing.
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Le MERS-CoV arrives in France.

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A French citizen has been isolated in an intensive care unit somewhere in Paris after returning to France from the United Arab Emirates. 

The health website of the Ministry of Social Affairs and Health (Le site sant� di Minist�re des Affaires sociales et de la Sant�) cites the National Reference Center at the Institute Pasteur as having confirmed the MERS-CoV (HCoV-EMC) case. 

This is not the Kingdom of Saudi Arabia (KSA) for the geographically challenged among us (I've added a map to the MERS-CoV page), so the virus is active in at least two sites unless this case visited KSA as well.
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Losing control of the numbers?

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That's how it was described to me by my esteemed colleague, the Editor in Chief of FluTrackers. 

For the past 5 week we've had fairly detailed data coming out of China about avian influenza A(H7N9) cases; dates, places, names, deaths, discharges., All these placed into the public domain and not just reported to Health officials through less public channels. 

Sure, I've griped about a missing number here and there in the past, but its not like I have a right to this information. Are these the data I'd like to see? No, I'd like to have seen prospective real-time RT-PCR-based (couple of assays targeting different regions) screening hospital outpatients, the community and including asymptomatic people, of all ages. I'd like to see serology on the vendors and those who frequently visit markets versus those who do not. And I'd like it all done yesterday. But that's flippant, and easy to say from my desk in my environment of instant gratification, some 7,330km away. Are these data from every single H7N9 case? Probably not, for a number of reasons. So, for some pure speculation. 

It just doesn't feel right. 130 cases spread over such a wide area, steep onset curves that suddenly halt, patents like Lee from Taiwan and others who claim no bird contact, so few severe cases among market vendors, evidence for asymptomatic and suspected clusters. 130 cases seems too low. More unreported cases may exist simply because we don't have all the results yet. Those may be coming down the pipeline. The time and effort to conduct screening and sequencing, collate data, cross-check and report results for humans and animals on the scale that is necessary to answer the questions being posed, is vast. China needs to juggle many other social and political issues around the reporting of deaths, illnesses and human-to-human transmission of this new virus. It has its own way of doing that. Most states do.

Nonetheless, scientists, policy makers, healthcare officials and vaccine producers (traditional and cutting edge) already have the information they need to get started on preparing for any future H7N9 pandemic.

  • Vaccine seed strains have been circulated worldwide
  • WHO influenza collaboration centres have positive H7N9 RNA controls for their RT-PCRs
  • More RT-PCRs have since been developed to overcome the (not unexpected) deficiencies in first-generation assays
  • Serological reagents are in use in China and in preparation elsewhere
  • Key global health bodies have updated their pandemic plans
  • We have estimates of incubation periods, clinical signs and symptoms indicating that severe acute respiratory disease cases look like....severe acute respiratory disease cases would be expected to look
  • We know transmission may be happening between humans but inefficiently
  • We know closing down wholesale poultry markets seems to correlate with a decrease in severe H7N9 cases in humans
  • We've dusted off (ineffective) heat sensing cameras and (pointlessly) ill-fitting face masks again
  • We have a good idea of what the wild host is (a bird...like it is for all influenza A viruses) just not evidence for which one or where it all started
  • We've officially named our viral nemesis.

So all in all, we're not too badly off.

However Week 6, so far, has provided confirmation that publicly available case details have almost dried up.
The data we've had have been interesting and have allowed me to plot the detailed charts and graphs you've been viewing on the H7N9 page. Half of those views are from repeat visits. 

Today, my last hope faded for an update on those details for the recent 6 H7N9 deaths and the missing details on about 15 discharged patients. The WHO update had no new information in it at all. Perhaps other lists will be updated soon?

Here's hoping for some new data in the future, especially if that data should signal to the rest of the world that H7N9 has changed genetically, or a return of exponential rises in new H7N9 illness onsets such as we saw in Shanghai and Zhejiang. 

I think we have what we need to know that an H7N9 pandemic could emerge, but that one hasn't emerged yet.
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The crowded virus escapes from Hofuf?

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While MERS-CoV (f. HCoV-EMC) cases have been detected in the UK (3-2 fatal), Jordan (2-both fatal), the United Arab Emirates (1, fatal) and Qatar (2) since April 2012, it has been the Kingdom of Saudi Arabia (22 cases-13 fatal) that is the current hot zone. 

These cases are from 5 different clusters according to the FluTrackers. 

The latest news paints a bleak picture. According to the Wall Street Journal, Al Moosa General Hospital is not the only hospital treating patients from the current outbreak. 

Given that human-to-human transmission has been noted for MERS-CoV, this may nor bode well for containment.
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It's an nHCoV, its an EMC...no...its MERS?

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It was an unusual move that apparently required "a great deal of effort to find a name that all parties involved could agree on". Avian Flu Diary reports on a ScienceInsider article noting that the Coronavirus Study Group will propose an entirely new name for the latest human coronavirus type that seems to cause respiratory disease in humans and belongs to a new coronavirus species. 

Usually the International Committee on Taxonomy of Viruses (ICTV) doesn't fiddle around with naming below the level of species and the new human coronavirus type seems to be part of a group of viruses (including bat coronaviruses) that together will likely form a novel species. Do the bat viruses also cause respiratory syndrome in humans...or other animals? There is likely to be some (more) confusion caused by this name change, and it is very possible that the press will not strictly adhere to the new name any more than the old one (an argument that supports either side of the debate).

So far the virus has been called novel coronavirus (NCOV-a name that never should have stuck-what do we call the next one....more novel CoV?) and in the scientific, peer-reviewed literature, HCoV-EMC after the laboratory that characterized the virus (Erasmus Medical Center). Still, its only about 8 months since we learned of the first case subsequently attributed to this virus in Sept 2012 (the patient presented in June 2012). How big could the body of literature be on EMC at this point? Apparently its 23 papers strong according to PubMED.

The new name for the disease and the virus group will change to MERS-CoV (Middle East respiratory syndrome). It will next go before the ICTV for ratification.
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H7N9 reaches high viral loads.

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Large amounts of viral RNA were detected in 2 sputa and 1 throat swab collected from the imported Taiwan cases according to a recent Lancet letter. 

While early throat swabs (days after fever onset)and a chest X-ray did not indicate H7N9 infection, later in the disease course (11-13-days after onset of his 3-day fever) signs and virus became more clearly detectable. 

This case may suggest shedding is possible well before incapacitation and not long after a clinically indistinguishable episode of fever begins.
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H7N9 deaths jump - details dry up.

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H7N9-associated deaths now listed at being at 31 (last count 25-26). 

Details for 6 cases are limited but appear to have come from Anhui (1), Zhejiang (1) and Jiangsu (4). A new 9M case, apparently mild (fever, fatigue, diarrhoea), also reported in Fujian province - he's already discharged - found positive "retrospectively". Two items of interest here: (1) The delay in detecting the virus may simply reflect the lengthy average laboratory turnaround time (9d); (2) it seems the swabs were from the upper airways (throat), a site that has proven problematic for accurate testing so far. 

If sustained human-to-human transmission was an efficient means of spread....

Total H7N9 cases listed as 131 (likely to exclude Taiwan case [imported from mainland] and asymptomatic child case) and discharged patients now number 42.
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Speaking of things we know little about...HCoV

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HCoV-EMC cases have risen by three to a total of 30 (FluTrackers are running a nice tally). 

The latest severe acute respiratory illness (SARI) cases occur in Al-Ahsa and comprise a cluster of 13 cases. This is becoming a rapidly developing situation given that 18 cases have died overall. 

The spectre of underlying disease lurks here as it does with H7N9 but the evidence for human-to-human transmission seems more clear than for the flu. 

No host and little patient detail are also features of this outbreak.
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Prof Peiris posits poultry progressing problem.

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Esteemed virologist Professor Malik Peiris believes the drop in H7N9 cases linked to the shutdown in wet markets, underscores the impact of the large, fast-moving and diverse poultry trade in the south east of China. 

Wet markets have closed in all affected areas and cases have subsequently dropped. Prof Peiris noted that a study of human blood samples is underway. 

This will shed light on the proportion of cases, if any, that did not have severe enough disease to put them on the hospital radar or to lift them above the "noise" of normal upper respiratory tract infections, other respiratory diseases or pollution-exacerbated lung problems. 

The new study will provide a key piece of the H7N9 puzzle.
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Anger over anti-vaccination comment.

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The entirely confusingly named Australian Vaccination Network (next month they will face a court battle to retain their misleading name), actually a cabal of anti-vaccination advocates, has encouraged parents to avoid vaccinating their children and do not rely on your GP's opinion. You know, those experts in community ills who often have there own children and have trained and worked for over a decade to ensure the community is healthy.

Instead, consult books, especially those penned by fringe writers who may have not knowledge or expertise in the science and medicine of infectious disease whatsoever.
As Australian Medical Association president Dr Steve Hambleton suggested, you can obtain facts from the Immunise Australia website and there is an excellent publication, produced by the Australian Academy of Science, The Science of Immunisation: questions and answers. 

The documents on these sites are fully up front about their being some risks, its just that these risks are generally very minor things like redness, soreness and swelling - probably nothing like that bruise little Johnny is sporting from school today or that bite Jenny inflicted on herself when she bit her own cheek at dinner last night.

 In comparison to acquiring the unadulterated disease against which these vaccines protect, its nothing to be unusually worried about.
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H7N9 outbreak Week 6 begins.

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We start week 6 of the H7N9 outbreak with confirmation...or new test results....that H7N9 (not some other H7) is indeed among the poultry in Guangdong province, which is adjacent to Hong Kong. 

One sample was positive from s wholesale market in the city of Dongguan, which had previously (see post on 28.04) been positive for an H7 virus that was not H7N9.

Previous testing of 542 poultry workers (method unknown) in Guangdong had not identified H7N9 infection. As ProMED noted, in "AVIAN INFLUENZA, HUMAN (71): CHINA H7N9 UPDATE", this makes animals sentinels, instead of humans, for H7N9's presence for the first time during this outbreak. 

Shows the benefits of screening for virus without relying on symptomatic presentations hmm?
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H7N9 Weekly wrap-up. Bird flu, what bird flu?

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We finished Week 5 with astonishingly few new notifications and a lot more difficulty finding key dates for hospitalization, death and discharge. For example, a 55-year old male named Jiao from Hunan province has been variously cited as being the 25th or 27th death associated with H7N9. No-one seems to have a name for the 26th death. Just 1 disease onset and 2 deaths deaths during that period (see the many charts on the H7N9 page) making it the least fatal week of the outbreak. A total of 26 cases have been discharged from hospital (see Case chart on H7N9page, with perhaps another 9 unnamed discharges from Zhejiang. No new cases reported from Shanghai, Beijing, Anhui, Jiangsu, Henan or Shandong. Lab confirmations for cases with dates of onset preceding Week 5 appeared for Jiangxi, Fujian, Hunan and Zhejiang. 

Considering how steep the rate of confirmations was for Zhejiang in particular, the drop off is quite remarkable. The wet market closures seem to be the most popular factor in the decline of new (severe) human cases but there is still no word on prospective PCR screening for H7N9 among non-severe cases or among those without chronic underlying conditions.

So, as far as we know, pneumonia remains the most frequent indicator of H7N9 infection and that seem to be among mostly males with a constellation of underlying disease and infection. 

Week 5 saw a flurry of peer-reviewed scientific papers emerge. Some better-defined the clinical cases, other reported risks based on what we know from past influenzaviruses and others described the avian and genetic pathways for the parent and grandparent H7 and N9-containing viruses that seem to lead to the creation of H7N9. Intriguingly, there are still very few reports of H7N9 in the ducks, chickens and wild birds proposed as the hosts from which humans catch the virus.

While markets have been found to contain H7N9-positive birds, there are remarkably few human cases among market vendors or those working with the feather plucking machines (another proposed transmission route proposed during Week 5). Could vendors have pre-existing immunity? 

So another curious week with plenty of questions raised, but cases and deaths declining.
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Practicing Neurology in Tumbes, Peru


Shibani Mukerji, MD/PhD
Neurology Resident, PGY3
Travel Grant:  Infectious and Cardiovascular diseases in Peru


Greetings from Tumbes, Peru!




Colored by child with schizencephaly 
Tumbes is a small city that sits near the border of Peru and Ecuador.  It is a town of approximately 200,000 people with three hospitals and a satellite site for the Center of Global Health for the Universidad Peruana 
Cayetano Heredia in Lima, Peru.  It was started as a Neurocysticercosis (NCC)  elimination center where the focus was on decreasing the incidence of taeniasis and cysticercosis through
Study pigs at the Center for Global Health
active treatment campaigns of both humans and pigs and education.  In the past decade, they have effectively decreased the rates of cysticercosis in Tumbes and now will begin survelleince and treatment programs in the neighboring community of Piura.


NCC is one of the most common parasitic infections of the human CNS and a frequent cause of epilepsy worldwide. Neurocysticercosis  is caused by an infection of the human central nervous system (CNS) by the larval stage of the pork tapeworm Taenia solium.
Understanding the life cycle of taeniasis and cysticercosis 
The Center of Global Health Clinic-Tumbes is now conducting studies in the epidemiology of epilepsy in this region.  Here they see and treat patients with epilepsy.  In their cohort of over 1000 patients,  approximately 40% have epilepsy due to NCC.  Other main causes are CNS malformations, neonatal hypoxia, tumors and other CNS infections.  The neurological care in this area is severely limited by several key issues: 1) there is only one neurologist in this city who is able to see patients in the Center of Global Health Clinic once per month; 2)  Tumbes has one CT scanner located at the clinic and is used by all three hospitals.  The hours of use by the scanner are 1-6pm and a technologist can be called in for emergencies.  A MRI is located 3-4 hours drive in the neighboring town of Piura; 3) There are no EEGs available and so diagnosis and treatment of epilepsy is performed solely through clinical history.  Like most developing countries, there is a limitation with the types of antiepileptic agents that can be used due to availability and cost.  Typical agents used are Carbamazapine, Dilantin and Phenobarbital.  Keppra and Depakote are available but expensive. 


Donated EEG machine that sadly does not work


The diagnosis and treatment of epilepsy is through a group of highly intelligent and dedicated internists led by Dr. Luz Maria Moyano.  Dr. Moyano has taken it upon herself to learn about epilepsy and fundamentals of neurology through reading and telemedicine with neurologists in Lima.  In the past several months, they were able to diagnose a family from the highlands with spinocerebellar ataxia type 10 with the help of neurologists at the National Institute of Neurological Sciences, and a young boy with Poland Syndrome and AVMs.   
From right to left: Dr. Moyano, Dr. Azabache, Lily, Vilma and myself




On this trip to Tumbes, Dr. Moyano and I went to one of the local hospitals for consultation rounds where three Global Health clinic patients were admitted.  One patient with well controlled seizures was recovering from Dengue.  One patient with idiopathic epilepsy was admitted after a seizure of unknown etiology.  Another patient recently started on Dilantin developed a allergic reaction but did not realize it and continued to take the medication despite developing oral mucosal breakdown. We were able to develop a plan for all these patients with a few limitations given that we don't have EEG machines, and antiepileptic levels are not typically gathered in real time.  Given the limited access to neurologists, and no pediatric neurologists,  Dr. Moyano and I plan to use Skype in the future to discuss interesting and complex cases with residents in the Partners neurology program.  It is my hope that we can get more Partners neurology residents to this site for education and our own understanding of diseases here.  


It is hard to believe that my time in Peru is coming to an end.  This visit has provided me with an incredible insight into the fundamental understanding of the epidemiology and neurological manifestations of diseases endemic to Peru.  There is an amazing network of physicians and projects here for research.  I am incredibly grateful to Dr. Joseph Zunt and Silvia Montano for helping me arrange this visit and Dr. Hugo Garcia, his lab, Dr. Moyano and the people in the Global Health Center who welcomed me to both Lima and Tumbes and allowing me to participate in the care of their patients. 

My sincerest thanks again to the  Partners Global Health Travel Grant and Partners Neurology Residency, especially Vanya Sagar and Silvya Eaton and Drs.  Tracey Milligan and Tracey Cho who actively encourage residents to seek out these opportunities and expand our focus globally.   

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