Mumps Outbreak in Wales: Waning MMR Protection?

 

 

 

 

 

 

 

 

09Jul13      

    The trivalent MMR vaccine is a stalwart of modern health case, conveying lifelong immunity from measles, mumps, and rubella, especially if the patient receives both of the recommended jabs.  A recent article on FierceVaccines by Nick Paul Taylor, citing a report appearing in The Guardian, describes a growing body of data suggesting that while the vaccine works well for measles and rubella, mumps may be another matter.

 

In the first quarter of 2013, the U.K.’s National Health Service reported 948 cases of mumps versus 673 measles cases, numbers that prompted a national effort to increase the uptake of the vaccine. But half of the reported mumps cases were in individuals who had received at least one jab with MMR. As a result, Public Health England reports that "…some waning immunity may be contributing to transmission."   The idea that the protective effects of the vaccine may abate over time is not new for mumps (see, for example, here and here). Exacerbating matters are possible antigenic differences between the vaccine strain and outbreak strains that crop up from time to time (ref1). Moreover, the recent resurgence of mumps in the U.S. and Canada sometimes occurred in the context of high 2-dose vaccination coverage and thus raised the question of the vaccines durable response (ref2).

 

Vaccination rates with MMR have been under steady pressure over the past decades due, in part, to the now fully discredited theory linking autism and other disorders to the vaccine. Falling vaccination rates are a concern since, if vaccination uptake in the population is not sufficient to maintain herd immunity, vaccination becomes the only means to protect a given individual. And for children who have received only a single round of vaccine, this can be problematic (see this report).

 

Mumps is a highly contagious, self-limiting viral disease spread through contact with respiratory droplets from an infected person or by sharing food or drink. Prior to introduction in 1967 of the vaccine, mumps was the leading cause of viral meningoencephalitis in the United States, though the actual rate of encephalitis was rare (<2 per 100,000).  Typically mumps presents with swollen glands, fever, vomiting, and headache. The disease is typically not severe in children, but older individuals can experience painful orchitis or oophoritis and are at risk for long-term fertility complications.

 

Thus, mumps joins other vaccine-preventable diseases, such as pertussis (ref3; ref4), TB (ref5),  and polio (ref6) that have displayed characteristics of waning long-term protection. As noted in The Guardian article, solving the problem of waning protection can be a knotty one, not easily solved. And in the end, these observations point to limitations in our understanding of long-term T- and B-cell immune memory.

 

 

 

MERS-CoV Confirmed Cases Hits 80 with 42 Deaths

 

 

 

 

 

 

 

 

05Jul13      

    The SARS-like corona virus, MERS-CoV, continues to exert its influence on the global stage. The current global count of lab-confirmed cases of human infection with the virus now stands at 80, up from 60 just a few weeks ago. A total of 43 fatalities amongst the 80 confirmed cases have occurred. A complete listing of cases can be found at Sharon Sanders' excellent webpage. The latest WHO update has been published on Friday.

 

A new study just appeared in the The Lancet that examines the pandemic potential of MERS-CoV as compared to pre-pandemic SARS. Importantly, the study concludes "that MERS-CoV does not yet have pandemic potential." But extreme caution are still the watch words, as one should not over-interpret these results. This study cannot predict the future behavior of the MERS-CoV virus, including potential viral mutations.

 

In the meantime, the WHO has convened an emergency committee to assess the dangers that MERS-CoV presents to the international community, according to CBS News. " A spokesperson for the WHO told CBSNews.com that the emergency committee is part of the International Health Regulations (IHR) that were put in place in 2007. The IHR Emergency Committee consists of international experts who will advise the WHO Director-General when the medical issue becomes a "public health emergency of international concern." They also advise on temporary recommendations for travel, surveillance, clinical management, infection control." The Committee last met in 2009 over the H1N1p pandemic.

 

Any virus, such as MERS-CoV, that infects humans with a CFR north of 50% (see this reference) is worthy of close scrutiny and mindful preparation, just as the WHO and CDC are doing.

 

 

H5N1 Claims Another in Cambodia

 

 

 

 

05Jul13

    Cambodia has reported its 13th case of influenza A/H5N1 this year. Sadly, the 6F patient died from the infection on Jun 28th, after falling ill on Jun. 24th. A total of 9 of the 13 confirmed cases this year in Cambodia have been fatal. Since 2003, there have been a total of 34 confirmed cases of H5N1 in Cambodia.

 

Of potential interest, an Indonesian news report is noting the alarmingly sudden deaths of thousands of chickens, ducks, and entog in the village of Cikalahang, Dukupuntang district. Bird flu, possibly H5N1 is suspected.

 

 

 

Another First – Influenza A/H6N1 Infection in Humans

 

 

 

 

28Jun13

    There has been a rash of recent firsts in the infectious disease world. Late last year MERS-CoV was noticed on the scene, just as a new set of H3N2v swine influenza infections was making its way through the US. Early this year we had the first-ever major outbreak of a H7N9 influenza in humans. Now, another: the first documented case of influenza A/H6N1 in humans.

 

The 20F patient was hospitalized on May 5th for mild pneumonia, treated with neuraminidase inhibitors, recovered, and was released from hospital on May 11th. The case was reported to CDC-Taiwan on May 20th. Subsequently, whole genome sequencing efforts by the CDC-Taiwan identified the virus as A/H6N1, typically a low pathogenicity virus broadly found in birds such as chickens. The patient had no history of contact with poultry and had not traveled abroad.

 

The Taiwan CDC has released full sequence of the virus. However, as noted by Recombinomics, the sequences from the human isolate were more closely related to recent healthy chicken sequences obtained by Taiwan’s Animal Health Research Institute. Importantly, sequences from both sources showed key features in the viral hemagglutinin consistent with enhanced binding to mammalian receptors. These included the E189V and G228S mutations in the receptor binding site and the absence of an N-glycosylation site at position 158.  However, N-glycosylation corresponding to position 158 is more typical of seasonal human flu virus than avian influenzas [ see this link]. The H6 HA from the human isolate contains 7-8 potential sites of N-glycosylation (at positions 26/27, 39, 183, 307, 312, 499, and 558; numbering from Met1) that correspond to the number and position of N-glycosylation sites typically found in H6 viruses.

 

Indeed, the HA sequences of the human isolate and the latest chicken isolate are virtually identical to each other. Two notable exceptions to this identity are the presence of P200L and A301T in the human isolate. For the former mutation, inspection of all 42 chicken isolates of H6N1 from Taiwan in GISAID shows the invariant presence of P200.  For the latter mutation, mutations at this position are seen in the ensemble of chicken sequences, but typically as A301V or A301E.

 

Recombinomics concludes:  “The presence of G228S is of concern because it was present in H2N2 in the 1957 pandemic as well as H3N2 in the 1968 pandemic and it was introduce in H5 sequences used in transmission studies.  Q226L was also in the H2N2 and H3N2 pandemic sequences, as well as H7N9 sequences in human cases in the Shanghai area, and a traveler to Taiwan (represented by A/Taiwan/1/2013). “ It may be anticipated that if H6 viruses were to pick up the Q226L mutation, an increase in human transmissivity would result.

 

There have been no further reported cases of human H6N1 infection in Taiwan or elsewhere since this index case. Interestingly, 36 close contacts of the patient were monitored for signs of infection and four of them developed flu-like symptoms, though later testing failed to identify H6N1. H6 influenza viruses were first isolated in Turkey in 1965 and have subsequently been found widely in avian species. A study published in 2008 demonstrated that H6 influenza viruses can infect ferrets and mice productively, suggesting at the time that human infection by H6 viruses was certainly possible. Moreover, these authors were motivated, in part, by the observation the “An H6 influenza virus was identified as a potential progenitor of the H5N1 viruses that emerged in Hong Kong in 1997.” An actual case of human H6N1 infection thereby promotes the possibility of an H6 epidemic or pandemic, though the possibility is clearly still remote.

 

H7N9 Update - Week 24

 

 

 

 

 

 

15Jun13

    No additional confirmed cases of human H7N9 infection have been reported since early May.  However, The Lancet is now reporting  the case of a 15M from Jiangsu province who was co-infected with A/H7N9 and a seasonal A/H3N2 viruses. The patient presented on April 25th and was admitted to hospital the next day, receiving oseltamivir therapy.  The patient recovered and was discharged on May 2nd. The case is of interest for several reasons:

 

1. It is the first documented case of influenza virus co-infection involving H7N9. Co-infection of two influenza A viruses could result in reassortant viruses. Reassortants could possess new characteristics of transmission, virulence, and Tamiflu (oseltamivir) susceptibility.  Co-infections involving 2 influenza A viruses have been documented rarely and the rate of co-infection of two influenza A viruses has been estimated to be 1-3%.

 

2. The case does not appear to have been previously listed by either the Chinese government or the WHO.

 

3. The date of onset places this case near the end of the train in terms of reported cases from China. It is interesting to note that other cases with proximal onset dates (after 15-Apr) also were more mild cases or led to rapid recovery.

 

Not withstanding this case, there is otherwise no news of additional infections or expanded geographical dissemination. Unfortunately, one additional death has been reported (case #19) but, in other good news, there are now only 14 patients remaining hospitalized.  The Chinese government is now moving to monthly updates on H7N9, on the 10th of each month.

 

Two groups have now reported the successful generation and testing of H7N9 vaccines: a group from Medicago with a VLP-based vaccine candidate and, more recently, a team including Inovio Pharmaceuticals. This latest candidate is a DNA vaccine that “…achieved greater than 1:40 hemagglutination inhibition (HAI) in 100% of tested animals (n=10), with a geometric mean HAI titer of 1:130 against the A/Anhui/1/13 strain of H7N9 virus. HAI titers at or above 1:40 are considered to denote protection against the influenza virus in humans.” Notably, the vaccine candidate was “…was designed, optimized, and manufactured within two weeks.” Meanwhile, traditional influenza vaccine production efforts in chicken eggs are off to their usual challenging course [see Link_1  and Link_2].

 

Finally, the reader is referred to an outstanding Perspective that has just appeared in the New England Journal of Medicine from David Morens, Jeffery Taubenberger, and Anthony Fauci. The article is a great summary of the current H7N9 situation.

 

 

 

2009 H1N1pdm: Still Making Noise

 

 

 

 

16Jun13

    The influenza season in the Southern Hemisphere looks to be ramping up and, with it, marked outbreaks of the 2009 H1N1p virus (a.k.a. H1N1 swine flu). While this virus played only a minor role in the just past influenza season in North America and Europe (where H3N2 was more dominant), it was concurrently a particular problem in South and SE Asia, especially in India. And with the coming season in the Southern Hemisphere, it is already making its presence felt.

 

This is especially true in South America and portions of the Caribbean. According to the most recent report from PAHO, South America is already seeing high rates of acute respiratory infections (though not outside of known ranges for this time of year). RSV infections are predominant in many countries, except for Brazil where H1N1p predominates. There appears to be a bifurcation in terms of which respiratory viruses are in co-circulation: with RSV and H3N2 co-circulating in Bolivia, Ecuador, and Peru while H1N1p is co-circulating in Argentina, Columbia, Venezuela, and Chile.

 

Another report tells of over 200 deaths to date this year in South America due to H1N1p. Venezuela appears to be in the “ascent phase of an epidemic outbreak” of 2009 H1N1p  according to another article published in The Universal last Thursday.  According to this article, 414 new cases of 2009 H1N1p were reported in just the past week and bringing the cumulative total of confirmed cases to 1,138. The number of A/H3N2 infections for the year also increased to 129. Citing data from the Weekly Epidemiological Bulletin No. 22, published by the Ministry of Popular Power for Health, the ILI index nearly doubled over the past week (to 1,026) and severe acute respiratory infections also increased from 310 cases the week preceding to 466 this past week, both of these against a backdrop of ~20% week-over-week increases in pneumonia and acute respiratory infections. At least 4 have died from H1N1 this past week. According to another report, “The current outbreak has surpassed one in 2011 that resulted in 900 cases and eight deaths.” And yet another report notes  “Venezuela's doctors' union is warning of a possible resurgence of swine flu in the country and is reporting at least four new deaths this week. “ These most recent data appear consistent with an earlier report at the end of last month citing 250 human 2009 H1N1p infections and 17 deaths.  The H1N1p virus is also making its presence felt in Argentina where “So far, 12 people have died from A/H1N1 in Argentina, including seven in the province of Buenos Aires and one in the northeastern province of Santa Fe.”

 

Meanwhile, in SE Asia, Vietnam has reported its third H1N1p fatality in the past week (its fourth since April).

 

The pH1N1 influenza virus continues to remind us that it is still a dangerous pathogen and perhaps not quite ready to be relegated to mere “seasonal flu” status. Sequence information on the influenza virus from clinical isolates from South America are needed to ascertain if the virus has undergone further genetic alterations.

 

 

 

Confirmed MERS-CoV Cases Pass 60 with 34 Deaths

 

 

 

 

 

 

 

 

14Jun13      

    The WHO today issued a Global Alert and Response (GAR) raising the official number of confirmed cases of human infection by the SARS-Like MERS-CoV virus to 58 with 33 fatalities. But additional news releases during the day immediately added to the count, raising the total number of confirmed cases to 61 with 34 fatalities. A significant number (46) of these cases have been reported from the Kingdom of Saudi Arabia [KSA]. A breakdown of the confirmed cases by reporting country can be found on the CDC website.  A more detailed confirmed case list by Sharon Sanders can be found at this web page.

 

In related news, 4 additional genomic sequences from MERS-CoV isolates (all from the Al-Hasa region of KSA) have now been deposited in GenBank. This brings to nine as the total number of complete sequences of MERS-CoV isolates published to date. A detailed analysis of these nine sequences can be found at this web page, published by the Andrew Rambaut, Institute of Evolutionary Biology, University of Edinburgh.  Of particular interest is the suggestion from this analysis that the recent viral isolates from KSA “…represent an emerging cluster of human-circulating cases with a common ancestor in the second half of 2012, meaning the trees above might represent 3 independent jumps [to humans from an as yet unidentified zoonotic reservoir].” As recently noted by Recombinomics, these sequences “… fully support human transmission of the novel coronavirus in the Middle East, as well as evolution via homologous recombination.”

 

Finally, CIDRAP, reporting on a CDC conference call yesterday with clinicians, noted “..that more than 30 US patients have been tested for MERS-CoV…”, all of them negative for the virus. It remains unclear how the testing was performed.  The CDC “… is advising clinicians to consider MERS-CoV in patients who have an unexplained, acute respiratory illness, which may include fever or cough, with suspected pneumonia and a history of travel from the Arabian Peninsula or neighboring countries within the past 14 days.”

 

 

 

 

MERS-CoV (hCoV-EMC) Spreads to Italy; 30 Deaths Globally

 

 

 

 

 

 

 

 

03Jun13      

    Five new cases of confirmed infection with the novel SARS-like virus, hCoV-EMC (now MERS-CoV), occurred over the weekend, three of them, for the first time, in Italy. The Italian index case (45M) recently spent 40 days in Jordan with his son, a resident of the latter country, and a suspect case himself. The patient was hospitalized on May 28th after returning to Italy on the 25th. He is in stable condition. The two other cases in Italy (2F and 42F) are close contacts of the Italian index case (daughter and colleague, respectively). They too are in stable condition. Italy is the eighth country to report confirmed cases of MERS-CoV.  The Kingdom of Saudi Arabia also reported three deaths over the weekend and a new case on Monday.

 

These cases bring the global count to 54 confirmed cases since September of last year with 30 fatalities.  For a complete listing of all cases, see Sharon Sander's comprehensive table at FluTrackers.com.

 

 As noted by Recombinomics, "The increase in [MERS-CoV] exports has been dramatic with confirmed or suspect cases imported into France, Tunisia, Morocco, and Italy (all by commercial airline).  None of the exporting countries (UAE, Qatar, Jordan) have reported a case identified by surveillance." Current surveillance efforts do not comprise a winning strategy to contain global dissemination.

 

H7N9 Puts on the Brakes in China

 

 

 

 

17May13           

    The number of confirmed cases of H7N9 influenza in China remains at 130 with one additional case in Taiwan, giving a global total of confirmed human infections of 131.  In other related news of interest:

 

1. The Chinese province of Zhejiang ended its Level IV Emergency Response yesterday in light of the fact that there have been no new human cases of H7N9 in the past 28 days.  Today, two other provinces followed suit: Shandong and Jiangsu.  There have been no new human infections reported for 21 days in either province. The municipality of Shanghai had previously ended its emergency response on May 10.  Medical observation of close contacts of infected patients has also ended.

 

2.  The first patient reportedly infected in Shandong province was discharged from the hospital yesterday. The patient was case #103 in the listing table.

 

3. An article appeared yesterday suggesting that the recent warm weather in China is playing a part in the sudden attenuation of the H7N9 outbreak.

 

4. A paper published yesterday in Eurosurveillance investigated the association in the Chinese province of Zhejiang between exposure to poultry and human H7N9 infection. In brief, the paper finds that, of the 12 studied cases of human infection, all had a prior history of direct exposure to poultry or live poultry markets. In addition, viral RNA was detected in all poultry markets frequented by the infected human subjects. From a total of 135 samples obtained from the markets, 38 tested positive for H7N9. In addition, viral RNA was detected in and around the domiciles of two of the cases. The investigators also tested 339 throat swabs (but not sputum samples) from the close contacts of the patients but none tested positive for H7N9. Interestingly, only a few (4) poultry vendors were infected with the virus. It remains unclear why most vendors remain infection free despite purportedly frequent exposure to infected poultry. Finally, after closure of the markets, the investigators noted that there were no additional cases of human infection, hence suggesting an epidemiological link and an infection source.

 

5. Exports of poultry and poultry related products have been halted out of a farm in the Chinese province of Guangdong after H7N9 was detected in a nearby market.  Confirmation of H7N9 in the market sample would mark only the second time the virus has been detected in the province in poultry, the first occurring last month. Guangdong Province has had no reported cases of human infection by H7N9, but nonetheless has been a point of concern due to its proximity to Hong Kong.

 

6.  Using synthetic biology to re-create the H7N9 virus from its genetic sequences, J Craig Venter and Novartis have teamed up to create a vaccine in less than one week, according to an article in The Boston Globe.  The scientists used a library of flu genes already known, selected certain library entries, and edited them, including synthesis of H7N9-specific sequences, to create the entire H7N9 viral genome. The work was just published in Science Translational Medicine. “After receiving details of its genetic code on Easter Sunday, the researchers were able to synthesize the virus by the following Tuesday and determine the best design for a vaccine by that Saturday.” Impressive and hopefully immunogenic.

 

H1N1p Flu Outbreak in Venezuela Claims 17

 

 

 

 

 

 

28May13           

    An outbreak of 2009 H1N1p has infected some 250 people and killed 17 in Venezuela, according to a report by Reuters and citing media and local authorities. Most of the cases Most of the cases were reportedly in border states near Colombia, but the Venezuelan government has yet to confirm anything yet.

 

 

 

A/H7N9 Influenza Update

 

 

 

 

 

13Jul13

    The Chinese government has provided an update on the status of H7N9 cases. The National Health and Family Planning Commission announced last Wednesday that the official confirmed case count now stands at 132 with 43 fatalities and 4 patients remaining under care. With the additional reported case in Taiwan, the global case count now stands at 133. The CFR for A/H7N9 now stands at 33%.

 

Concerns about the immunogenicity of H7N9 in humans, and hence the ability to create an effective vaccine, have been allayed at bit by news from the vaccine front.  Inovio Pharmaceuticals announced (see this news report) the results of a preclinical challenge study against H7N9. The company’s DNA vaccine, which encodes the sequence of the viral HA gene, conferred 100% protection to vaccinated mice.  Also last week, Novavax, Inc. announced commencement of a Phase I clinical trial to test their H7N9 VLP-based vaccine [see this news report]. “This Phase 1, randomized, observer-blinded, placebo-controlled trial will enroll up to 280 eligible adults. Each subject will be randomized into one of seven treatment groups, including placebo, or varying doses of the A(H7N9) vaccine, with or without an adjuvant. Each subject will receive two identical intramuscular doses at Day 0 and Day 21 and undergo study follow-up for approximately one year after the second dose. All subjects will be evaluated for safety and immunogenicity.”

 

In other news, a new study, published yesterday in the journal The Lancet, is a comparative epidemiological evaluation of laboratory confirmed cases of H7N9 and H5N1 in China. Among other findings of interest, it was observed that the fatality risk on admission to the hospital was 36% for H7N9 versus 70% for H5N1. H5N1 remains the king of deadly avian influenzas.

 

A new conundrum has popped up.  In a letter to the journal Emerging Microbes & Infections, CDC-Shanghai investigators reported striking differences between pediatric and adult cases of H7N9. During the period from early April to late May, Shanghai’s Sentinel Surveillance System for Influenza-like Illness identified 2 H7N9 cases by RT-PCR, out of 1799 screened suspect patients. Both cases were in boys less than four years of age. In contrast, 17 adult H7N9 infected cases were reported by April 10 to the Surveillance System for Pneumonia of Unexplained Origin. The severity of infection was directly linked to lymphopenia (like measles), age, and radiological pathology of the chest. In short, mild H7N9 infections were not common in Shanghai but those that were found were demonstrably milder. On the other hand, examination of all known cases has illuminated a number of “mild cases”, occurring even in adults, leading to the theory that some sort of sustained human-to-human transmission must be occurring, possibly through asymptomatic cases especially in the young.

 

In apparent support of this concept, two major papers appeared this week in the journal Nature on the pathogenesis and transmissivity of H7N9 in animals, including pigs and ferrets: one by Kawaoka and colleagues in Japan and the US (here) and the other from Terrence Tumpey’s lab at the CDC (here).

 

In the former paper, three different H7N9 strains from human isolates were studied in mice, ferrets, and non-human primates and compared to the 2009 H1N1p virus. In brief, the H7N9 viruses were more pathogenic in mice than H1N1p and a control avian H7N9 virus. In non-human primates, both the H7N9 and the non-pathogenic H7N9 control replicated well in both the upper and lower respiratory tracts. All the H7N9 viruses replicated well in the upper respiratory tract of ferrets and one of the pathogenic H7N9 viruses was able to support transmission in ferrets through respiratory droplets, though not well.

 

In the latter paper, two H7N9 viral specimens, isolated from fatal human cases, were evaluated for their ability to cause disease in mice and ferrets as well as to transmit virus to disease-naïve animals.  “Both H7N9 viruses replicated to higher titre in human airway epithelial cells and in the respiratory tract of ferrets compared to a seasonal H3N2 virus. Moreover, the H7N9 viruses showed greater infectivity and lethality in mice compared to genetically related H7N9 and H9N2 viruses. The H7N9 viruses were readily transmitted to naive ferrets through direct contact but, unlike the seasonal H3N2 virus, did not transmit readily by respiratory droplets. The lack of efficient respiratory droplet transmission was corroborated by low receptor-binding specificity for human-like α2,6-linked sialosides.”

 

Despite some difference in the results of the two reports (e.g. over the ability of H7N9 virus to bind to (alpha-2,6)-linked sialic acid receptors typically found in the upper respiratory tract of humans) the overall conclusion is the same: these pathogenic H7N9 viruses can readily replicate in mammalian respiratory tract cells and can readily transmit through direct contact and, to a lesser extent, through airway droplets. Indeed, as these paper were published, Dr. Yuelong Shu, director of the Chinese National Influenza Center at the China CDC in Beijing, was reported as acknowledging that “Contrary to previously published reports, the deadly H7N9 bird flu can spread from person to person and may be a serious threat to humans…”

 

Solid data on possible asymptomatic transmission of the virus will have to await until the virus returns this fall, if it does.

 

 

H7N9 Update - Death Toll Mounts to 43 in 133 Total Cases

 

 

 

06Jul13

    The WHO is reporting that the total number of lab-confirmed cases of H7N9 globally has increased to 133. This represents the addition of a single case since the last update and this single case is the 15M patient from Jiangsu Province who was found to be co-infected with seasonal H3N2 and H7N9 after being hospitalized on April 26th. The patient recovered quickly and was discharged from hospital on May 2nd. The details of this case are close to those described in a recent article in The Lancet (see the note, below, on H7N9 from 15Jun13).

 

Sadly, the WHO report also notes that death toll in China has risen to 43, up from 39 just a few weeks ago. The 4 additional cases should include the fatality (56M) from Shanghai reported in the Chinese press last week.  Sadly, that case (#47) is the husband of case #14 who died earlier. Case #47 had been hospitalized since April 11th.

 

With less than a dozen patients remaining in hospital, it is clear the case fatality rate (CFR) for H7N9 in this outbreak will settle near 35%. this is lower than the CFR of another avian influenza/A virus, H5N1 (at 59%), but substantially higher than the CFR associated with the 2009-2010 swine flu pandemic (around 1%). Thus, a news report earlier this week stating that "H7N9 is most adapted bird flu for human-to-human transmission..." is worrisome since the virus may have a lower barrier to becoming a true human pandemic virus.

 

 

2009 H1N1p Still Deadly Across the Globe

 

 

 

 

06Jul13

    The 2009 H1N1p virus continues to ply its deadly trade in South Asia, Southeast Asia, and South America. An outbreak of H1N1p in northern Chile has reportedly left 11 dead. Notably, the regional rate of infection (at 148 patients per 100,000 population) is more than six times higher than in the rest of the country.  This news follows reports last month of outbreaks of 2009 H1N1p in Argentina, Columbia, and especially Venezuela (see item below from June 16th).

In India, the western state of Maharashtra has already reported 84 deaths from H1N1p in the first six months of the year, on track to beat last year's fatality count of 135. According to the Times of India article, "...experts fear that more Mumbaikars may fall victim as hundreds from the city travel every day to Pune and Nashik...".  And in Vietnam, the 11th death from H1N1p has been reported this year, up from 3 in mid-June.

 

The differential geographic populations of influenza/A remain a matter of great interest. The factors which mitigate the composition of local circulating influenza/A strains remain enigmatic. However, it is clear that the 2009 H1N1p remains a pandemic virus "in play" and hence worthy of continued close scrutiny.

 

 

 

Human Infections with Swine Flu Variant H3N2v Increase

 

 

 

 

05Jul13

    The variant swine influenza, H3N2v, is back, as noted by Recombinomics (see here and here). The first 4 cases of human infection were confirmed in attendees from a fair in Grant County, Indiana, at the end of June. Two of the four cases had reported contact with pigs. Then, on July 4th, another 8 lab-confirmed cases were identified in nearby Hancock County, Indiana. Again, all lab-confirmed cases had attended a county fair but in the latter cases, most had contact with pigs. It should be noted that 29 swine also tested positive for the virus between the two fairs. Sequences from 3/4 of the initial cases from Grant County have been obtained and released. As noted in the latter report from Recombinomics, all three sequences "matched human 2012 H3N2v cases and all three sequences were closely related to each other, signaling clonal expansion." Recombinomics also notes that this year the H3N2v virus has appeared  about a month earlier than last year, potentially signalling a robust season for the virus.

 

As a result of these new infections, the CDC issued, today, an official Health Advisory updating "H3N2v case definitions and recommendations for H3N2v surveillance for the summer and fall of 2013."

 

 

MERS Update – More Deaths & Another Country

 

 

 

 

 

 

 

 

12Jul13      

    The first patient (82M) to be diagnosed and treated within the United Arab Emirates for MERS-CoV was reported by CIDRAP yesterday, citing local sources.  This brings the global total of confirmed cases to 82 with 45 fatalities.

 

The WHO issued another GAR on 09Jul13 in which it notes an apparent change in the type of confirmed cases reported since its last GAR. Half of the recently reported cases are asymptomatic and are occurring in women and young children, a marked shift from earlier demographics.   It has also updated its current view of MERS-CoV transmission. “The recent mild and asymptomatic cases raise concerns about the possibility of large numbers of milder cases going undetected. While it is clear that human-to-human transmission does occur, it is not clear whether transmission is sustained in the community. The currently observed pattern of disease occurrence could be consistent either with ongoing transmission in an animal reservoir with sporadic spillover into humans resulting in non-sustained clusters, or unrecognized sustained transmission among humans with occasional severe cases.”

 

Hats off to Recombinomics who have long been arguing that unrecognized sustained transmission among humans is a distinct possibility (see here).

 

 

MERS-CoV Confirmed Cases Hits 90 with 45 Deaths

 

 

 

 

 

 

 

 

21Jul13      

    The SARS-like corona virus, MERS-CoV, continues to rack up the number of lab-confirmed cases and fatalities. Last Thursday, the WHO issued another Global Alert & Response update that noted "Globally, from September 2012 to date, WHO has been informed of a total of 88 laboratory-confirmed cases of infection with MERS-CoV, including 45 deaths." The bulk of the GAR idescribes six cases recently reported to the WHO: 2 from The Kingdom of Saudi Arabia [KSA] and 4 from The United Arab Emirates [UAE]. For the latter, "...the four cases are health care workers from two hospitals in Abu Dhabi who took care of an earlier laboratory-confirmed patient. Of these, two cases, a 28-year-old man and 30-year-old woman, did not develop symptoms of illness. The other two cases, both women of 30 and 40 years old, had mild upper respiratory symptoms and are in stable condition."

 

For the cases in KSA, both "...have mild symptoms and are not hospitalized. They are from Asir region. The first case is a 26-year-old man who is a close contact with a previously laboratory-confirmed case and the second case is a 42-year-old woman who is a health care worker."

 

On Friday, the CDC listed on its webpage a total of 90 cases with 45 fatalities. Details on the additional two cases were provided in an update today from the WHO. "WHO has been informed of two additional laboratory-confirmed cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection in Saudi Arabia. Both the cases are currently critically ill and hospitalized in ICUs. The first case is a 41-year-old Saudi male in Riyadh who presented to the hospital with symptoms on 15 July. The second patient is a 59-year-old Saudi female in the Al-Ahsa governorate. She presented with symptoms on 11 July. Both patients have underlying medical conditions, but neither patient has had contact with known MERS-CoV confirmed cases or animals. "

 

Of particular note is the additional descriptions of mild symptoms or cases that were asymptomatic. As laid out by Recombinomics, the existence of mild and/or asymptomatic cases is "indicating MERS-CoV was transmitting in sustained manner by the milder cases not linked to severe hospitalized index cases.  There is no ongoing surveillance for these milder cases." This could prove to be a crucial deficit in controlling viral spread.

 

H7N9: This Week's Developments

 

 

 

 

28May13         Updated 29May13  

    The number of confirmed cases of H7N9 influenza in China was holding steady at 130 (with one additional case in Taiwan; now discharged from hospital) as recently as yesterday, marking an abrupt end to this wave of H7N9 in China, as no new cases of human infection have been reported since early May. That changed today with the Xinhua News agency reporting a new confirmed case of human infection in Beijing. The global count of confirmed cases of H7N9 infection now stands at 132 with 37 deaths and 76 patients having recovered and been discharged from hospital. The CFR for H7N9 is settling in around 30%.

 

The new case in Beijing (6M) "developed symptoms including fever and headache on May 21 and he was sent to a hospital for medical treatment on the same day. His body temperature returned to normal on May 23 and he returned to kindergarten the next day..." according to the Xinhua News agency report. He was subsequently found to be positive for H7N9. This is not the first case of mild or even asymptomatic H7N9 infection in young children and highlights the ability of the virus to operate in "stealth" mode as it propagates, unseen, through the (pediatric) population.

 

The geographic spread of the virus remains a concern not just in humans, but also in relevant zoonotic reservoirs, such as poultry and pigs. Last week, an international team of investigators reported in Science Express that ferrets could transmit the virus by direct contact and, to a lesser degree, via airborne droplets. Ferrets are often used in viral transmission studies to estimate human-to-human spread. The investigators also found that pigs can indeed be infected by H7N9 but do not appear to transmit the virus. In this light, the confirmation last week of H7N9 in a poultry isolate from Guangdong Province marks the spread of the virus ever closer to another high-density urban population.

 

It is also interesting to note that China's Ministry of Agriculture has now nearly completed a massive sweep of avian and poultry environments for H7N9. Of nearly 900,000 samples taken, a mere 53 tested positive for H7N9. Of these 53, "Fifty-one positive samples were from 18 live poultry markets in Shanghai, Anhui, Zhejiang, Jiangsu, Henan, Shandong, Guangdong, Jiangxi and Fujian, the MOA said in a statement. The other two positive samples were from wild pigeons in Nanjing, capital of Jiangsu Province and domestic pigeons in Nantong, in Jiangsu Province." These observations underscore the need to identify the source of human infection and what is happening in widely geodistributed live-poultry markets that is absent from wild birds and poultry farms.

 

Finally, another potential source of great concern was illuminated in a new report that appeared online yesterday in The Lancet from a team of investigators in China and entitled "Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance."  In this study, the investigators followed 14 patients admitted to the Shanghai Public Health Clinical Centre in April of 2013. All of the patients presented with pneumonia and seven of these came to require mechanical ventilation. Three of these patients subsequently required ECMO and 2 of these three patients subsequently died. All of patients were treated with neuraminidase inhibitors (oseltamivir and peramivir)  but those patients on ECMO maintained high viral loads despite oseltamivir and peramivir therapy. Indeed, 2/3 ECMO patient rapidly developed resistance to neuraminidase inhibitors. One of the patients showed dominance of the resistant strain by 9 days after treatment began. The relative ease and rapidity for the onset of neuraminidase inhibitor resistance is worrisome. Oseltamivir (Tamiflu) is the backbone of available antiviral therapies and has been heavily stockpiled by governments around the world for pandemic preparedness. If the utility of these drugs were obviated by the virus, especially for a virus that provokes only weak immune responses in early vaccine efforts, no effective medical interventions would remain.

 

It is widely believed that influenza will die down in China over the summer months before potentially returning again this fall. In anticipation of a possible return, continued surveillance, study, and preparation remain the order of the day.

 

 

Case Count for MERS-CoV (hCoV-EMC) Nears 50

 

 

 

 

 

 

 

 

29May13      

    Five new cases of confirmed infection with the novel SARS-like virus, hCoV-EMC (now MERS-CoV), were reported today, all in the Kingdom of Saudi Arabia (KSA). The five case are from Eastern KSA,  "but not from Al-Ahsa, where an outbreak began in a health care facility in April 2013. The patients had underlying medical conditions which required multiple hospital visits." Three of the five confirmed cases have died. In addition, France's first MERS-CoV patient has died, as has a previously-reported patient from the Al-Ahsa region of KSA.

 

These cases bring the global count to 49 confirmed cases since September of last year with 27 fatalities.  For a complete listing of all cases, see Sharon Sander's comprehensive table at FluTrackers.com.

 

Also, a detail clinical look at the two MERS-CoV patients in France was published today in The Lancet. A major conclusion from this paper is that for the second patient, a French native with no travel to the Middle East, but who shared a hospital room with the first patient for 3 days,  "the incubation period was estimated at 9–12 days for the second case. No secondary transmission was documented in hospital staff despite the absence of specific protective measures before the diagnosis of MERS-CoV was suspected." This a a longer incubation period than previously thought and may suggest that longer quarantine periods are in order to prevent spreading to contacts.

 

Speaking yesterday at the 66th World Health Assembly in Geneva, Dr. Margaret Chan, Director-General of the WHO, stated:

 

"Looking at the overall world health situation, my greatest concern right now is the novel coronavirus [MERS-CoV].

 

We understand too little about this virus when viewed against the magnitude of its potential threat.

 

Any new disease that is emerging faster than our understanding is never under control.

 

We do not know where the virus hides in nature. We do not know how people are getting infected. Until we answer these question, we are empty-handed when it comes to prevention.

 

These are alarm bells. And we must respond."

 

 

H1N1p Flu Outbreak in Tibet - One Pediatric Fatality

 

 

 

 

 

 

16May13           

    An outbreak of influenza, initially reported as H1N1 but later (and apparently mistakenly) as H5N1,  infected 65 children in the Guangxi Autonomous Region of Tibet last week. One child has died and 5 other children have been hospitalized in critical condition. The source of the infection has not been established, but reportedly infected chickens brought in from Nanning and sold at cut-rate prices. It was also reported yesterday that Tibet is wrestling with an avian outbreak of H5N1. As noted in the initial report, 3 other confirmed pediatric cases of H1N1p occurred in early April at a school about 180 km away from the present outbreak. H1N1p has been a recent problem in other South Asian countries. For example, Vietnam has recently reported on an outbreak of H1N1p in one of its northern provinces, an outbreak  at a boarding school where 3 children had tested positive for the virus.

 

 

Another H7N9 Fatality; Toll Now at 33

 

 

 

 

 

 

11May13           

    Another human H7N9 fatality has been reported out of Shanghai in China. The victim (83F; Case # 37) was originally hospitalized in stable condition after first experiencing symptoms on the 7th of April.  Once the initial site of the H7N9 outbreak, Shanghai has but 4 confirmed cases remaining in hospital while 14 have died and 15 have recovered and been discharged.

 

Human H7N9 Cases Now 130 with 31 Fatalities

 

 

 

 

07May13           

    The number of confirmed cases of H7N9 influenza in China has increased to 128 with the announcements (see WebLink) of 2 additional confirmed cases in Fujian Province, increasing the total number of confirmed cases in China to 129. There is also a previously reported confirmed case in Taiwan. One of the two news cases (9M) has already recovered and been discharged from hospital. Four additional fatalities were announced but no other details were provided other than that 2 of the fatalities were in Jiangsu Province, 1 was in Zhejiang Province, and another was in Anhui Province. Our previous description of a recent fatal case (55M) in Hunan province has now been reassigned to a previously reported Jiangxi patient (who was in fact a resident of Hunan province but was being treated in the former province).  A total of 5 H7N9 patients were discharged from the hospital since last Friday lifting the total number of recovered patients to 42.

 

The weekly reporting scheme for new cases, previously announced by the Chinese government, is due for announcement tomorrow. This new information could indicate whether the peak of cases has already occurred in China (or at least in some provinces/municipalities) or whether the lull has been due to the shift to a weekly report. Of note, the SE Chinese province of Guangdong has been added to the list of affected regions after H7N9 was found in an agricultural sample from a poultry market. This continues last week's trend of increasing geographical spread for the H7N9 virus.

 

A full list of the 129 confirmed human cases of H7N9 infection is tabulated at this web page.

 

In other matters of note, the Director of the CDC, Dr. Thomas Frieden, told Reuters, in an article carried by the Huffington Post, that "...the current strain of bird flu that is causing illness and deaths in China cannot spark a pandemic in its current form - but he added that there is no guarantee it will not mutate and cause a serious pandemic." This perspective was confirmed at the end of last week by one of Europe's leading experts, Dr Angus Nicoll. In article published online on Saturday by the Singapore paper Today, Dr. Nicoll is paraphrased as stating that "Human cases of a deadly new strain of bird flu that has killed 27 people in China are likely to crop up in Europe and around the world but that should not cause undue alarm.." Thus, identifying the source of H7N9 infections remains a major priority (perhaps the major priority) for the infectious disease community.

 

 

Human H7N9 Cases Now 129 with 27 Fatalities

 

 

 

 

03May13           

    The number of confirmed cases of H7N9 influenza in China has increased to 128 with the announcements (see here) of 1 additional, fatal case in Hunan province. Two additional fatalities in cases previously reported from Jiangsu province were also announced but no other details were provided. The most recent case (55M) is Hunan province's third confirmed case and first fatality.  A total of 10 H7N9 patients were discharged from the hospital today, including a 38M (Case #49) who is reportedly the first patient with severe symptoms to recover. He was in hospital a total of 22 days.

 

The weekly reporting scheme previously announced by the Chinese government is now clearly in effect and details about specific cases are already becoming scarcer.

 

A full list of the 129 confirmed human cases of H7N9 infection is tabulated at this web page.

 

 

 

Human H7N9 Cases in China Now 109 with 22 Fatalities as Flu Spreads Further

 

 

24Apr13           

    The number of confirmed cases of H7N9 influenza in China has increased to 108 with the announcement of 3 additional cases in Zhejiang (2) and Anhui provinces. The previously reported suspected case in Shandong province has also now been confirmed, bringing the total cases in China to 108. No additional cases or fatalities were reported today in China, but the first report of a confirmed case of H7N9 in Taiwan was announced.

 

The Taiwanese patient (53M) returned from a trip to Jiangsu province on April 9th and came down with his first symptoms on April 12th. He is currently hospitalized in critical condition. This case is notable for three other reasons besides being the first confirmed case in Taiwan:

 

1) The patient tested negative for H7N9 twice previously (by throat swab specimens) while hospitalized, underscoring the problems with identifying H7N9 as the causative agent. It was a third analysis (this time of a of a sputum sample) that led to identification of H7N9 by RT-PCR.

 

2) It is standard practice to monitor close contacts of infected patients for signs of H7N9. In this case, three health care workers (HCWs) tending the patient are now showing symptoms of H7N9 infection and are being monitored. What is interesting about this point is that the three HCWs were wearing full protective gear while tending the patient while three other HCWs, who did not wear protective gear, have not shown any symptoms of infection, at least not yet.

 

3) Among other prior medical conditions, the patient is a carrier of hepatitis B. Given the difficulties in identifying a source of infection so far and the lack of compelling evidence of sustained human-to-human transmission, this observation raises the intriguing possibility that severe cases of H7N9 infection in humans require co-infection by other, heretofore unidentified, viruses.

 

One additional fatality, from previously reported cases, was also reported in Zhejiang province. The fatality (86M; case #81) fell ill on Apr. 13th.

 

A full list of the 109 confirmed human cases of H7N9 infection is tabulated at this web page. The significance of the current "pause" in new infections in China remains to be determined.

 

 

Human H7N9 Cases in China Now 105 with 21 Fatalities as Flu Expands to New Province

 

 

 

22Apr13           

    The number of confirmed cases of H7N9 influenza in China has increased to 105 with the announcements (see here, here, and here) of 9 additional cases in Shanghai, Jiangsu, and Zhejiang provinces and, for the first time, in Shandong province.  Three additional fatalities, from previously reported cases, were also reported in Shanghai and Zhejiang provinces, though details on the Shanghai fatality are currently limited. One of the deaths (62F; case #53) fell ill on Mar. 29nd while the other (76M; case # 99) fell ill on April 8th.  The other fatality (in Shanghai) is likely Case #78, but confirmation is still outstanding. Several instances of patient recovery were also reported. The Shandong patient tested positive for H7N9 by PCR is awaiting final confirmation by the China CDC.

 

A full list of the 105 confirmed human cases of H7N9 infection is tabulated at this web page.

 

 

First Human H5N1 Fatality in Bangladesh

 

 

 

 

20Apr13           

    The WHO has confirmed the recent death of a 23 month-old boy from Bangladesh as that region's first human fatality due to H5N1 infection. The case is unusual in that the patient experienced none of the typical symptoms associated with H5N1 infections.

 

Since the first H5N1 case was identified in Bangladesh in May of 2008, there have been a total of 7 human cases. The child in this case was in close proximity to poultry. Currently, four influenza viruses are circulating in Bangladesh: H1N1p, H5N1, H3N2 and H9N2.

 

Earlier this month, the first human H5N1 fatality in Vietnam in over a year was reported and Cambodia has experienced 10 cases just this year according to the WHO.

 

As noted by ProMED, "As of 12 Mar 2013 globally there have been 622 human cases of avian A/(H5N1) influenza virus infection, resulting in 371 deaths in 15 countries." Since September of 2012, there have been a total of 16 cases of H5N1 infection in humans, mainly in SE Asia and Egypt, resulting in 12 deaths.

 

Human H7N9 Cases in China Now 60 with 13 Fatalities as Flu Expands to New Provinces

 

 

 

14Apr13           

    The number of confirmed cases of H7N9 influenza in China has increased to 60 with the announcement of 11 additional cases in Shanghai, Jiangsu, and Zhejiang provinces and, for the first time, in Henan province and Beijing.  Two additional fatalities, from previously reported cases, were also announced in Shanghai. One of the deaths (67F; case #12) fell ill on Mar. 22nd while the other (77M; case # 26) fell ill on April 3rd. Case 26 is of note because the last information on this patient listed his condition as "stable".

 

A full list of the 60 confirmed human cases of H7N9 infection is tabulated at on this web page.

 

The expansion of H7N9 cases outside of the initial set (of Shanghai, Zhejiang, Jiangsu, and Anhui) may be another important milestone in this evolving story. The range of reported human infections now spans may more miles and deepens, with the absence of H7N9 in Beijing bird populations so far, the mystery of how humans are being infected.

 

The reader is also directed to two outstanding publications in the New England Journal of Medicine on H7N9 and its pandemic potential. The articles can be found here and here.

 

Human H7N9 Cases in China Increases to 28 with 9 Fatalities

 

 

 

 

 

09Apr13           

    The number of confirmed cases of H7N9 influenza in China has increased to 28 with the announcement of four additional cases (62M, 77M, 79M, & 51F) in Shanghai and Zhejiang provinces and two additional fatalities. Both of the Shanghai patients and one of the Zhejiang patients are in stable condition while the remaining Zhejiang patient is in critical condition. One of the deaths (83M) was the 6th listed case of confirmed H7N9 infection while the other (35M) was the third. A full list of the 28 human cases of H7N9 infection is tabulated at the left.

 

In related news, the CDC has activated its Emergency Operations Center (EOC) in Atlanta yesterday to support the response to the H7N9 influenza outbreak in China, according to a report by CIDRAP. "The EOC was activated at level 2, the second of three levels. Level 1, the highest, signals an agency-wide response."

 

 

 

H1N1p Found in Elephant Seals Off California Coast

 

 

 

 

 

 

16May13           

    An team of scientists from the US and from Chile have made a startling observation.  The scientists were performing research to understand zoonotic transfer of influenza among species, an effort they started in 2007. Starting early in 2009, the investigators took to obtaining some 900 nasal swabs from northern elephant seals and nine other species of marine mammal living off the coast of central California. While influenza virus are known to infect seals, it was nonetheless a big surprise when 30 seals showed ongoing or prior exposure to the 2009 H1N1p virus. This is the first report of H1N1p in a marine mammal.

 

According to one of the investigators, "The seals on land in early 2010 tested negative before they went to sea, but when they returned from sea in spring 2010, they tested positive. So the question is where did it come from?” The seals had satellite tags, so the investigators at least knew where the seals had been in the intervening months when they picked up the virus. The answer: the Northeast Pacific.

 

The study was published yesterday in PLoS ONE. The study "provides evidence for cross species transmission of influenza viruses in free-ranging wildlife and movement of influenza viruses between humans and wildlife." And it sheds yet another light on the complex nature of interspecies transmission dynamics for influenza.

 

More H7N9 Fatalities; Toll Now at 36

 

 

 

 

 

 

15May13           

    Another three human H7N9 fatalities has been reported from  China in the last two days, bringing the death toll to 36.  Yesterday, the death toll was announced at 35 but no details were provided. Today, another death was reported from Hunan Province: a 64F (Case #120) who at one time was reportedly improving.  5 additional patients have been discharged from hospital in the last two days: Case #124 and 4 unspecified patients from Jiangsu Province (see here and here).

 

There has been a virtual dearth of new cases reported over the last week or so. This might reflect a sudden disappearance of H7N9 due to seasonal factors or it could reflect the effectiveness of control measures in the poultry population. As the CFR settles in the mid-30 percent region, one can only await the virus' next move, if any.

 

 

Case Count for MERS-CoV (hCoV-EMC) Tops 40

 

 

 

 

 

 

 

 

15May13      

    A fist full of new cases of confirmed infection with the novel SARS-like virus, hCoV-EMC (now MERS-CoV), have been reported over the past week with 41 confirmed cases since September of last year, 22 of them since mid-April in the Kingdom of Saudi Arabia (KSA). 9 of these 22 cases have been fatal. For a complete listing of all cases, see Sharon Sander's comprehensive table at FluTrackers.com. It also appears that more cases may emanate from France as lab confirmation in several cases is pending. The WHO also provided an update today at their Global alert and Response page.

 

Unfolding events in KSA appear to indicate that at least limited community transmission of the virus is underway (see this story from CIDRAP).

 

Human H7N9 Cases Now 131 with 32 Fatalities

 

 

 

 

09May13           

    The number of confirmed cases of H7N9 influenza in China has increased to 130 with the announcements (see here) of 1 additional confirmed case (79F) in Jiangxi Province. One additional fatality from a  previously reported case in Henan province was also announced. This most recent death (56M) is the province's first fatal case, the other three provincial patients having previously been discharged from hospital. Another patient was discharged from the hospital yesterday, a 80M (Case #123) from Jiangxi Province.

 

A full list of the 131 confirmed human cases of H7N9 infection is tabulated at this web page.

 

There have now been two consecutive days with no newly confirmed cases of human infection by H7N9 in China, marking a dramatic fall from the rapidity with which the first 100 or so cases came in. This may be due to the extensive efforts of the Chinese government in closing poultry markets and culling birds. Let's hope so. Influenza is a particularly tricky beast, so a couple of events to continue to watch:

 

1. A new scientific report just out shows that the number of flu infections in pigs is increasing in south China (see this report from the The Standard (Hong Kong) for a description). The pig is an excellent zoonotic mixing chamber for influenza and a source of previous influenzas that impact humans. Given the mammalian adaptation features of not only H7N9, but also H5N1 (active in SE Asia) and H1N1p (active in Vietnam and South Asia), a geographically focused cauldron of viral reassortment is possible over the coming months. Each virus has specific strengths and weaknesses as a candidate pandemic strain, and their ability to gain additional pandemic   characteristics is greatly facilitated by this geographical cauldron.

 

2. While it is unknown whether H7N9 will ever be a pandemic strain, it is worth remembering that the WHO has called H7N9 an espcially dangerous virus for humans, once infected. As such, there is plenty of activity focused on generating a vaccines to H7N9. But in yesterday's New Scientist, in an article describing the prudent measures of the CDC/FDA to prepare for a H7N9 epidemic or pandemic [including already invoking "Emergency Use Authorization" for H7N9 diagnostic kits], a potentially significant problem is reported: the H7N9 virus elicits only a mild immune response in humans. In fact, the human immune response to the virus is so weak that "Virologists at the European Flu Summit in Brussels last week told New Scientist that early results show 13 times more H7N9 virus is needed to elicit a protective immune response than is needed for ordinary flu." That means more antigen per vaccine dose and less doses produced per unit time.  Unfortunately, this is consistent with earlier statements by the folks at EpiVax (see remarks in 16Apr13 entry below) who predicted that H7N9 would be a "stealth virus" to the human immune system since it presented so few T-cell epitopes on its HA surface. They concluded that " "... it will be difficult to make effective vaccines and low cost diagnostics for the newly emerging virus."

 

3. This spring outbreak of H7N9 is perhaps a heraldic or pre-heraldic wave as has been put forward for the 1918 Spanish flu outbreak in the U.S. (see, for example, this article). This might position the current H7N9 virus as a "precursor" strain" that could circulate for up to several years prior to a pandemic outbreak. In this case, the unique age-distribution of confirmed cases would parallel the excess mortality observed in the elderly during the 1915-16 season, as described in the cited article. Thus, keeping a close eye for a "age signature shift" would seem prudent.

 

Finally, an online news article from the BBC reports on a scientific study just published in JAMA Psychiatry that shows that "Flu during pregnancy may increase the risk of the unborn child developing bipolar disorder later in life...". This result echoes prior studies where influenza infection during pregnancy was associated with a higher risk of schizophrenia (see this article). It should be noted that the risks reported in these studies are relative and the absolute risk remains small.

 

 

 

3 More Cases in Outbreak of Novel Human β2c Coronavirus (hCoV-EMC)

 

 

 

 

 

 

07May13      

    Three new cases of confirmed infection with the novel SARS-like virus, hCoV-EMC, have been reported in the Kingdom of Saudi Arabia [KSA], two of them fatal.

 

As detailed in an email to ProMED by the Deputy Minister for Public Health for the Kingdom of Saudi Arabia, the case specifics are as follows:

 

Case 11: 62F with multiple comorbidities. Start of symptoms [19 Apr 2013] and deceased [3 May 2013]

Case 12: 71M with multiple comorbidities. Start of symptoms [15 Apr 2013], deceased [3 May 2013]

Case 13: 58F with comorbidities. Start of symptoms [1 May 2013] and currently ventilated in critical but stable condition.

 

The Deputy Minister goes on to say that "..there is no apparent community transmission and transmission seem linked to one HCF [health care facility]."

 

An article appearing today on-line at the Wall Street Journal proffers that "Saudi Arabia's announcements in the past five days of seven new deaths from a SARS-like virus have heightened fears that the Mideast outbreak is entering a more-aggressive phase."

 

The specifics surrounding the underlying co-morbidities for these three newest patients (as well as the prior 10 reported this month) could provide insights into the significance of this outbreak.  To date, 22 of the 30 confirmed cases that have occurred globally have been reported in the Kingdom of Saudi Arabia. Thirteen of the cases reported from KSA have occurred this month and so far 7/13 cases have been fatal.

 

On a positive note, Michael Katze (Univ. of Washington) and colleagues have just published a lovely paper on the differences in host response (at the level of the transcriptome) between SARS virus and hCoV-EMC. At 12 hours post infection, "HCoV-EMC induced a massive dysregulation of the host transcriptome, to a much greater extent than SARS-CoV. Both viruses induced a similar activation of pattern recognition receptors and the interleukin 17 (IL-17) pathway, but HCoV-EMC specifically down-regulated the expression of several genes within the antigen presentation pathway, including both type I and II major histocompatibility complex (MHC) genes." In addition, they identified potential drug candidates specifically targeting hCoV-EMC elicited proteins, thus defining a rapid path in response to newly emergent pathogens.

 

Another H5N1 Fatality

 

 

 

 

 

06May13           

    Another human H5N1 fatality has been reported, this time out of Egypt. The victim (25F) was originally hospitalized on the 29th of April complaining of fever and shortness of breath. The patient expired before lab results confirmed the presence of H5N1 influenza.

 

According to the latest (26Apr13) update on H5N1 from the WHO, "...

6 new laboratory-confirmed human cases with influenza A(H5N1) virus infection were reported to WHO from Bangladesh (1), Cambodia (1), Egypt (2) and Viet Nam (2). The investigations into these concluded that they were sporadic cases and that the appearance of sporadic cases is expected and will likely occur in the future."

 

Certainly the mixing pot in SE Asia of H7N9, H1N1p, and H5N1 creates an added dimension of concern given the potential for novel reassortants arising that pick up pandemic characteristics.

 

 

Outbreak of Novel Human β2c Coronavirus (hCoV-EMC) Reported in Saudi Arabia

 

 

 

 

 

 

03May13     Updated 04May13

    The news out of Saudi Arabia yesterday was stunning. Seven more patients were reportedly confirmed as infected with the novel human corona virus hCoV-EMC and five of these patients had died.  Three more confirmed infections were announced on May 4th. Nine of the ten new confirmed cases are male and may involve one or more family clusters. All of the patients had underlying co-morbidities. Besides the five deaths in this group, three other patients are in critical condition and two are hospitalized but doing well.  The global incidence of confirmed human infections by this SARS-like virus has now climbed to 27 with 16 fatalities.

 

As detailed in an email to ProMED by the Deputy Minister for Public Health for the Kingdom of Saudi Arabia, the case specifics are as follows:

 

Case 1: 59M. Date of onset of symptoms [14 Apr 2013] and passed away [19 Apr 2013].

Case2: 24M. Date of symptoms [17 Apr 2013] and still in ICU in critical but stable condition.

Case 3: 87M. Date of symptoms [17 Apr 2013] and passed away [28 Apr 2013].

Case 4: 58M. Date of symptoms [22 Apr 2013] still in ICU in stable but critical condition.

Case 5: 94M. Date of symptoms [22 Apr 2013] and passed away [26 Apr 2013].

Case 6: 56M. Date of Symptoms [22 Apr 2013] and passed away [30 Apr 2013].

Case 7: 56M. Date of symptoms [22 Apr 2013] and passed away [29 Apr 2013].

Case 8: 53F. Date of symptoms [27 Apr 2013] she is in stable but critical condition.

Case 9:   50M. Date of symptoms [30 Apr 2013] with pneumonia and he is well on the inpatient ward.

Case 10: 33M. Family contact of a deceased patient. Date of symptoms [28 Apr 2013]. Inpatient in the medical ward and doing well.

 

The specifics surrounding the underlying co-morbidities for all of these patients could provide insights into the significance of this outbreak.  To date, 19 of the 27 confirmed cases have occurred in the Kingdom of Saudi Arabia.

 

 

Human H7N9 Cases Now 128 with 24 Fatalities;  Is H7N9 on Holiday?

 

 

 

01May13           

    The number of confirmed cases of H7N9 influenza in China has increased to 127 with the announcements (see here and here) of 2 additional cases: one more Fujian and another in Hunan province.  No additional fatalities have been reported in the past two days. Indeed, there has not been a new case of H7N9 reported in Shanghai for 10 days, perhaps due to aggressive closing of poultry markets and extensive culling.  Thus, while the virus has greatly expanded its geographical reach over the past week or so, the number of new confirmed cases has plummeted. As noted today in an editorial in The Boston Globe, "China’s annual “Golden Week” holiday, which started Monday, is a time for millions of Chinese to vacation in neighboring countries, boosting commercial activity and person-to-person contact." The next few weeks will no doubt prove interesting.

 

A full list of the 128 confirmed human cases of H7N9 infection is tabulated at this web page.

 

Also of note, a new paper out today in The Lancet explores the origin and reassortment events that gave rise to pathogenic H7N9.  The authors found that H7N9 virus might have evolved from at least four different avian influenza strains and that the current H7N9 virus behind the ongoing outbreak can likely be divided into two subclades. Specifically, the authors conclude that "The HA and NA genes might originate from duck avian influenza viruses, which might have obtained the viral genes from migratory birds a year previously, whereas the internal genes might come from chicken avian influenza viruses. We believe that the estimated times to most recent common ancestor for the eight genomic fragments and the frequent poultry transportation in China account for the increased number of confirmed sporadic cases of human infection."

 

Finally, Dr. David Fisman (University of Toronto) has submitted a most interesting note on ProMED concerning the unusual age & gender characteristics exhibited by H7N9 patients in China. Dr. Fisman writes that "while concerning, application of basic epidemiology suggests that the current picture of H7N9 influenza in China is subject to case ascertainment bias, which is likely contributing to marked inflation of the apparent CFR. The age and gender distribution of cases relative to the population is reminiscent of that seen in legionellosis, an environmentally abundant pathogen that appears to preferentially cause recognized infection in older males." A corollary to this line of reasoning is that there are many more subclinical cases of human H7N9 infection than currently thought, especially among the young. Indeed, "the true risk of infection in younger people could be approximated by the apparent risk of infection in older individuals" which would raise the total number of infections to ~500 but would substantially reduce the apparent CFR. A widespread ecological distribution of the avian H7N9 could explain the low incidence of detection in various poultry populations.

 

Human H7N9 Cases Now 126 with 24 Fatalities as Flu Expands to New Province

 

 

 

29Apr13           

    The number of confirmed cases of H7N9 influenza in China has increased to 125 with the announcements (see here, here, and here) of 7 additional cases in Shandong, Jiangxi, Fujian, and Zhejiang provinces as well as, for the first time, in Hunan province.  One additional fatality was also reported in Shanghai and one additional recovery was reported in Henan province.  The fatality (89M; case #78) fell ill on April 12 and was initially reported to be in stable condition. The patient apparently succumbed after his condition worsened and a 12 day course of treatment failed.  The reported patient recovery (38M) was initially reported to be in critical condition but was discharged from hospital yesterday. The new confirmed case from Shandong province (4M) is the son of the province's first confirmed case (Case #103) and represents another "microcluster" of likely human-to-human transmission. With the previously reported confirmed case in Taiwan, the global count of confirmed cases now stands at 128. 79 patients remain hospitalized, many of them in serious or critical condition.

 

A full list of the 126 confirmed human cases of H7N9 infection is tabulated at this web page.

 

 

H7N9 Spreads Further Afoot: 119 Confirmed Cases, 23 Fatalities, and 2 New Provinces

 

 

 

26Apr13           

    The number of confirmed cases of H7N9 influenza in China has increased to 118 with the announcements [link1, link2, link3, link4, link5] of 10 additional cases in Zhejiang (3), Jiangsu (3) and Henan (1) provinces, as well as 3 cases appearing in Jiangxi (2) and Fujian (1) provinces for the first time.  The previously announced case of H7N9 in Taiwan brings the global total of confirmed human H7N9 cases to 119. Thus, this week has seen a notable spread of confirmed cases to three new Chinese provinces (Shandong, Jiangxi, and Fujian) and to Taiwan.

 

One additional fatality, previously reported in Jiangsu province on April 24th but without details, was further specified. The fatality (32F; case #7) fell ill on Mar. 21st. The total number of fatalities due to H7N9 infection now stands at 23.

 

A full list of the 119 confirmed human cases of H7N9 infection is tabulated at this web page. The significance of the current "pause" in new infections in Shanghai may be due to aggressive closing of poultry markets and culling or to the new government policy of updating cases weekly (every Wednesday) or both.

 

A set of important papers have been published in the last day or two and the reader is encouraged to review them:

 

1. A study published in The Lancet that shows that avian isolates obtained at local markets in China (and thus epidemiologically related to initial human isolates from 4 patients (two of whom died) with known poultry contact) can contain H7N9 viruses with genomes very similar to those in patients.  From a small sampling of 20 chickens, 57 ducks, 4 quail, and 5 pigeons, H7N9 was detected in 40% of pigeons and 20% of chickens while none of the sampled ducks or quail had the virus. From genomic sequencing of a chicken isolate, “All viral gene segments were of avian origin. The H7 of the isolated viruses was closest to that of the H7N3 virus from domestic ducks in Zhejiang, whereas the N9 was closest to that of the wild bird H7N9 virus in South Korea. We noted Gln226Leu and Gly186Val substitutions in human virus H7 (associated with increased affinity for α-2,6-linked sialic acid receptors) and the PB2 Asp701Asn mutation (associated with mammalian adaptation). Ser31Asn mutation, which is associated with adamantane resistance, was noted in viral M2.” However, important sequence signatures of mammalian adaptation were absent from the poultry isolates though present in clinical isolates (see also this link), specifically the Q226L mutation in HA and the D701N or E627K mutation in PB2. The authors state that these mutations could be acquired upon infection of the patient but it is also possible that another intermediate mammalian species harbors the virus first, prior to human infection. Also of interest was the authors’ observation that “Sputum specimens were more likely to test positive for the H7N9 virus than were samples from throat swabs.”  This may have import for surveillance efforts since it is much more difficult to obtain deep lung samples (sputum) that nasopharyngeal swabs.

 

2. A preliminary report, published in the New England Journal of Medicine, describes initial epidemiological analysis of the H7N9 outbreak in China using the first 82 confirmed patients.  The major conclusion of the report is that “Most persons with confirmed H7N9 virus infection were critically ill and epidemiologically unrelated. Laboratory-confirmed human-to-human H7N9 virus transmission was not documented among close contacts, but such transmission could not be ruled out in two families.”

 

Finally, the reader is referred to two new columns in Nature, both free. The first is an column by Peter Horby that makes the case for why we should keep a critical eye on H7N9 despite having skepticism about a possible global pandemic. And the second is a column by Declan Butler on mapping the H7N9 outbreak and how it is useful in monitoring potential pandemic pathogens.

 

 

Third 2009 H1N1p Flu Fatality in Vietnam This Month

 

 

 

 

24Apr13           

    A news report out of Vietnam describes the third fatality this month from 2009 H1N1p influenza infection.  The victim (12F) came down with the flu after a visit from her brother-in-law who was infected with the virus. Two other family members also became ill but recovered.

 

Earlier this month, two other fatalities (23M and 40M) were reported as succumbing to 2009 H1N1p infection. the news article above cites the vice chief of Vietnam's National Institute of Hygiene and Epidemiology as stating that the 2009 H1N1 type A influenza virus accounts for nearly half of the flu cases detected this year.

 

These reports sound similar to the situation in India these past few months where the severity of the disease (acute respiratory distress) in a younger population of patients echoes "pandemic virus"-like characteristics much more than a mere seasonal flu-like strain. Detailed sequencing of the viral genome from patient isolates is clearly warranted.

 

 

Confirmed H7N9 Cases in China Increase to 96 With 18 Fatalities

 

 

 

 

 

 

 

20Apr13           

    The number of confirmed cases of H7N9 influenza in China has increased to 96 with the announcement of 19 additional cases in Anhui, Jiangsu, and Zhejiang provinces.   An additional two fatalities, one in Jiangsu province, were announced over the past two days.  As of today's total of 96 confirmed cases, the distribution by province is: 1 in Beijing, 33 in Shanghai, 3 in the central province of Henan, 33 in the eastern province of Zhejiang, 23 in the eastern province of Jiangsu and 3 in Anhui Province.

 

A full list of the 96 confirmed human cases of H7N9 infection is tabulated on this web page. The two new fatalities are Case #61 and Case #87. The latter case is of note due to the short time between the case being reported and the announcement of death. In the last two days, three patients have been discharged (out of a total of 7): Cases #18,21, and 27. Sixty seven of the 96 patients remain hospitalized.

 

Recombinomics has described a new H7N9 sequences (A/Zhejiang/DTID-ZJU01/2013) deposited from an April 3 collection from a male patient in Zhejiang Province. The HA gene sequence is identical to that of a prior human isolate: A/Anhui/1/2013. However, unlike the  four prior human sequences, "... the Zhejiang PB2 sequence does not have E627K.  However, the PB2 sequence does have D701N, which also enhances transmisison in mammals, as seen in H5N1 transmission experiments." Thus, all five isolates from humans have PB2 sequences possess mammalian adaptation changes that distinguish them from avian H7N9 sequences currently in circulation in China.

 

Other lines of evidence underscore nagging questions about the source of infection for humans by H7N9. An article in Forbes, citing the state-run newspaper, Shanghai Daily, states that "More than half of the victims have had no contact with poultry, the newspaper said, citing agencies and its own reporting." Along another line, an article in the New York Times, citing China’s state-run news agency, Xinhua, noted that "China’s agricultural authorities were insisting the H7N9 virus was still confined to live poultry markets. The news agency said that 47,801 samples had been collected from 1,000 poultry markets, habitats and farms from across China, and that agricultural authorities said that 39 tested positive for H7N9. " 39 positives out of almost 48,000 avian samples is a very low prevalence and similar testing in pigs has also come up negative.

 

Another perplexing attribute of the human H7N9 virus is found in the characteristics of the confirmed patients. Many more males than females are reported as confirmed cases and, until fairly recently, the age distribution among patients is skewed towards patients over 55. Both of these attributes are at odds with "typical" pandemic viruses as evidenced by the recent behavior of the 2009 H1N1p virus as well as human infections by H5N1. The observed skewing in the age distribution of H7N9-infected patients is more typical of bad seasona influenza. However, the age distribution in confirmed patients may be changing, skewing towards the younger patients typically infected by pandemic viruses where there is no pre-existing immune memory to help ward off the pathogen. Keep an eye on the age demographic in confirmed patients over the next few weeks. A shift towards higher pathogenicity in younger patients would signal acquisition of additional "pandemic virus"-like characterstics for the human H7N9 virus.

 

Human H7N9 Cases in China Increase to 77 With 16 Fatalities

 

 

 

 

 

 

 

16Apr13           

    The number of confirmed cases of H7N9 influenza in China has increased to 77 with the announcement of 17 additional cases in Anhui, Jiangsu, and Zhejiang provinces and a later story, citing the China CDC, announcing six additional cases in Shanghai province. Of particular note is that 5/6 Shanghai cases are reported as retrospective diagnoses. An additional three fatalities, one in Jiangsu province, were announced Monday (with two of three fatalities only mentioned in the late-breaking story).  As of today's total of 77 confirmed cases, there is one in Beijing, 30 in Shanghai, two in the central province of Henan, 21 in the eastern province of Zhejiang, 20 in the eastern province of Jiangsu and three in Anhui Province. With these additions, the case count for H7N9 has now outpaced that for global H5N1 infections last year (see this Commentary).

 

A full list of the 77 confirmed human cases of H7N9 infection is tabulated on this web page. The one known new fatality (out of three today) is Case #45.

 

There were also expressions of extreme concern today (see weblink1 & weblink2) over the announcement yesterday of a 4M in Beijing who is asymptomatic for H7N9 despite testing positive for the virus. The 4M is a neighbor of Case #44, a 7F from Beijing who is scheduled for release from the hospital tomorrow, having fully recovered. The concern is that there may be a large number of asymptomatic patients and that we're only focused on the subset of patients who are most ill and hence directly tested for the H7N9 virus. Such a large number of aysmptomatic patients would be possible if there was sustained human-to-human [H2H] transmission. Almost all official reports state that there is no evidence of sustained H2H. In the case of sustained H2H with large numbers of asymptomatic patients, the recently observed geographical expansion of confirmed cases away from the Eastern coast of China into Beijing and Henan province is very worrisome. The concept of sustained H2H transmission through largely asymptomatic patients is bolstered by the genomic sequencing of clinical isolates of H7N9, as first noted by Recombinomics. These clinical isolates contain mammalian adaptation mutations, some of which are not seen in isolates of H7N9 from recent poultry specimens.

 

In other events today, the CDC has updated their "Interim Guidance for Infection Control Within Healthcare Settings When Caring for Patients with Confirmed, Probable, or Cases Under Investigation of Avian Influenza A(H7N9) Virus Infection". The WHO announced that "An international team of flu experts will go to China this week to help with investigations into the deadly H7N9 virus..." Finally, a team at EpiVax is predicting that human H7N9 is a "stealth virus" largely unseen by the human immune system (due to a very low number of T cell epitopes) and that "... it will be difficult to make effective vaccines and low cost diagnostics for the newly emerging virus (also called H7N9/A/Shanghai/1/2013)." They conclude that the H7N9 virus has "...serious potential for rapid expansion on a global scale."

 

Human H7N9 Cases in China Jumps to 43 with 11 Fatalities

 

 

 

 

 

12Apr13           

    The number of confirmed cases of H7N9 influenza in China has increased to 43 with the announcement of 15 additional cases in Shanghai, Jiangsu, and Zhejiang provinces and two additional fatalities. One of the deaths (74M; case #17)) fell ill on Mar. 28th while the other (74M; case # 36) fell ill on Mar. 31st. Both fatalities were from Shanghai. A full list of the 43 human cases of H7N9 infection is tabulated at the left.

 

In related news, the CDC has announced today that, based on previous experience with H5N1,"...it’s likely that some limited human-to-human spread of this H7N9 virus will be detected." In the same announcement, the CDC reported that "On Thursday April 11, CDC received the first H7N9 virus isolate from China..." and this isolate will be used to support standard pandemic preparedness, including vaccine generation. Yesterday, the CDC updated its interim guidance for infection control involving possible H7N9 infections.

 

In their H7N9 update published yesterday, WHO noted that "If the current pattern of sporadic infections continues, WHO will cease frequent reporting of case numbers, and focus its Disease Outbreak News on new developments or changes in the pattern or presentation of infections."

 

 

Human H7N9 Cases in China Increases to 24 with 7 Fatalities

 

 

 

 

 

08Apr13           

    The number of confirmed cases of H7N9 influenza in China has increased to 24 with the announcement of two additional cases (85M & 25F) in Jiangsu and an additional fatal case (64M) in Shangai. For the fatal case, the diagnosis of H7N9 infection was arrived at posthumously. Both of the Jiangsu patients are in critical condition. A full list of the 24 human cases of H7N9 infection is tabulated at the left.

 

In related news, another report today from the South China Morning Post noted that "There is no proof that the H7N9 bird flu virus is being transmitted between people in China, the World Health Organisation said on Monday, despite several members of a family falling ill in Shanghai." And still another story notes that the 4 yr old Shanghai boy hospitalized with H7N9 has now "basically recovered".

 

 

 

Human H7N9 Infections in China Expand to 21 with 6 Fatalities

 

 

 

 

 

 

05Apr13        Updated: 06Apr13 & 07Apr13    

    The number of confirmed cases of H7N9 influenza in China has increased to 16 with six fatalities according to the WHO in an update   released today.  The table (left) summarizes the 16 cases to date. Also of note, more than 520 close contacts of the confirmed cases are being closely monitored.  An investigation is currently ongoing in Jiangsu province of a contact that has developed disease symptoms. WHO officials have been quoted as saying that that there was no sign of 'sustained human-to-human transmission' of the H7N9 virus in China. On April 6th, a Canadian news source has reported the number of confirmed cases has climbed to 18.

 

In related events, Chinese authorities have closed three public markets in Shanghai, banned poultry imports from elsewhere in the country, and culled over 20,000 poultry in the city in an effort to curb the virus [link]. Culling has also been reported in a second Chinese city (Hangzhou; 100 miles SW of Shanghai) after quail were identified bearing H7N9.

 

In a curious note, a report out of China describes a lake near Shanghai suddenly filled with dead fish. This follows an analogous set of reports [mid-March; link]citing the sudden deaths of more than 6,000 pigs, recovered in rivers near Shanghai and dumped there by nearby breeding facilities. The cited report also quotes several months where 6-7000 pigs were dying per month, though their deaths were largely attributed to porcine circovirus (due, in part, to the absence of any known swine zoonoses).  But as noted by Recombinomics, pigs could provide a secondary or intermediate zoonotic reservoir for the virus, but one that could facilitate mammalian adaptation.

 

In the U.S., the CDC has issued a health advisory to physicians to help identify H7N9 infections, though no cases have been found anywhere in the U.S. [link].  The CDC has developed a diagnostic test to evaluate ill travelers returning from China. The CDC is also “…developing diagnostic test kits that it will distribute to China and other countries to ensure rapid diagnosis of this strain of flu.” The CDC is also already working with vaccine manufactures to develop an H7N9 vaccine just in case.

 

An avian influenza strain, newly capable of infecting humans while already displaying molecular features of mammalian adaptation and resulting in severe disease in humans but not in birds, warrants careful, wary scrutiny. To this end, public health officials from around the world are beginning “to lay out their concerns”  [link] as we wait for the virus to show us its next card.

 

Still More Worries Around Influenza 2009 H1N1p

 

 

 

 

 

 

20Mar13

    Earlier this week, the BBC reported that Australian scientists have found that a significant fraction of the influenza 2009 H1N1p virus now in global circulation is resistant to Tamiflu (oseltamivir), a major anti-viral drug that has been massively stockpiled by governments across the globe. This could suggest that the pandemic virus is following the path of its seasonal H1N1 cousin in becoming Tamiflu resistant virtually everywhere in the globe, effectively rendering the drug useless against that virus.  In particular, the scientists have observed Tamiflu-resistant virus in people outside of a hospital setting and who have never taken the drug. Presently, the resistant virus is found in about 2% of clinical isolates globally. Though still a small percentage, this level may be sufficient to catalyze rapid propagation around the world.  The Australian scientists report that the virus they have studied in circulation is still sensitive to Relenza (zanamivir), another anti-influenza A drug.

 

 

 

CDC Issues Alerts Over Deadly, Novel Corona Virus [N-CoV]

 

 

 

 

 

 

 

08Mar13

    The CDC today issued a Health Advisory Notice to health care providers, giving guidance for the evaluation of severe respiratory illness associated with a novel coronavirus. This follows the publication yesterday in Morbidity and Mortality Weekly Report of an update to the public health community in the U.S. concerning the emergent novel corona virus (N-CoV , a.k.a. London1_novel CoV 2012) that has already claimed 8 lives since September of last year, the most recent just last month.  The WHO has issued a Global Alert & Response (GAR) on this same coronavirus in December of 2012.

 

The CDC states in their note that they will continue to “….work closely with the World Health Organization (WHO) and other partners to better understand the public health risk posed by a novel coronavirus...” and have provided updated guidance on their website.  The CDC update was motivated by new developments including a recent cluster that provides the first clear evidence of human-to-human transmission of the N-CoV, coinfection of N-CoV with another pathogen (influenza A), and a case of mild illness associated with N-CoV infection.

 

While there have been no reports of infection in the U.S., a total of 14 people (in Saudi Arabia, Qatar, Jordan, and the United Kingdom) have been confirmed as having an infection caused by the novel coronavirus. The virus is a distant relative of the SARS CoV that emerged in 2002-4, causing severe acute respiratory infections, flu-like symptoms (fever, chills, headache, and myalgia), lymphopenia, and potentially ARDS.  All told, the SARS virus resulted in roughly 8000 cases worldwide with an overall fatality rate of 10%.

 

The new guidance from the CDC on N-CoV states:

 

“Persons who develop severe acute lower respiratory illness within 10 days after traveling from the Arabian Peninsula or neighboring countries* should continue to be evaluated according to current guidelines.  In particular, persons who meet the following criteria for “patient under investigation” (PUI) should be reported to state and local health departments and evaluated for novel coronavirus infection:

 

• A person with an acute respiratory infection, which may include fever (≥ 38°C , 100.4°F) and cough; AND

• suspicion of pulmonary parenchymal disease (e.g., pneumonia or acute respiratory distress syndrome based on clinical or radiological evidence of consolidation); AND

• history of travel from the Arabian Peninsula or neighboring countries* within 10 days; AND

• not already explained by any other infection or etiology, including all clinically indicated tests for community-acquired pneumonia† according to local management guidelines.

 

CDC requests that state and local health departments report PUIs for novel coronavirus to CDC.”

 

The N-CoV commands careful monitoring since it results in symptomology similar to SARS and has already been shown to be well-adapted to infect human cells: it easily penetrate the passageways of the lung, easily grows on human epithelial cells, and can evade the innate immune system as readily as a cold virus.  It is often and repeatedly stated that the N-CoV virus is most closely related to a corona virus found in bats but, as pointed out by Recombinomics, there are significant differences in the nucleotide sequences  between N-CoV and bat viruses. Finally, there is likely a bias in the tracking of persons infected with N-CoV towards only the most severe cases, as evidenced by the high case fatality rate (>50%),  and the low level of the virus in the upper respiratory tract which could lead to false negatives in standard testing. All of this strongly suggests human-to-human transmission of N-CoV without the benefit of a direct zoonotic intermediary.

 

If N-CoV behaves as SARS did a decade ago, the CDC Health Advisory Notice will be viewed as timely and we can expect more human cases in the near term.

 

 

Rare Superbugs Here and Abroad

 

 

 

 

 

06Mar13

    This week’s early release version of the CDC’s Morbidity and Mortality Weekly Report highlights the rise in carbapenem-resistant Enterobacteriaceae in U.S. health-care facilities. The Enterobacteriaceae are a large family of gram-negative bacilli that are normal inhabitants of the gastrointestinal tract of mammals, including humans. These pathogens are a common cause of community-acquired and health-care–acquired infections. In particular, the health-care–associated Enterobacteriaceae most commonly reported to the CDC are Escherichia coli, Klebsiella , and Enterobacter species.

 

The past several decades have seen the spread of Enterobacteriaceae with resistance to broad-spectrum antimicrobials. Physicians in the U.S. have used carbapenem antibiotics (e.g. imipenem, meropenem, doripenem, and ertapenem) to treat infections caused by resistant organisms. There isn't much left in the quiver after carbapenems.

 

Carbapenem-resistant Enterobacteriaceae (CRE) were relatively uncommon in the U.S. before 2000. The latest data from the CDC now shows that the proportion of Enterobacteriaceae that were CRE increased from 1.2% in 2001 to 4.2% in 2011 and to 4.6% in 2012. While antibiotic resistance in CREs can be complex and resistance factors are easily exchanged with other bacteria, a common mechanism of resistance is the bacterial production of enzymes that can inactivate carbapenems, such as carbapenemases. Two well-known examples of carbapenemases are KPC (Klebsiella pneumoniae carbapenemase) and NDM (New Delhi metallo-beta-lactamase).

 

The issue of CREs is important since such infections, though still low in incidence, can have associated mortality rates of 40-50%.  According to a report in the Washington Post,  Thomas Frieden, director of the Centers for Disease Control and Prevention, said at a news conference: “It’s not often that our scientists come to me and say we have a very serious problem and we need to sound an alarm. But that’s exactly what we are doing today.” The CDC recommends a six-step "detect and protect" program for healthcare providers aimed at stemming the spread of CRE.

 

Meanwhile, officials at the UK Health Protection Agency (HPA) have noted a staggering 25% increase in the number of cases of gonorrhea over the past year in England. This increase is occurring as drug-resistant strains of pathogens causing sexually transmitted infections (STIs) spread globally. According to the CDC, the number of cases In the US alone is estimated at about 700,000 a year.  According to a report on Medscape News, itself citing a Reuters story,  "...effective treatment with antibiotics has been compromised by growing resistance, the HPA said, noting "a drift towards decreased susceptibility" of gonorrhea infections to the cephalosporins that are normally recommended as treatment".

 

Finally, a news report out of the University of Rochester spotlights a potential weakness of at least one superbug, drug-resistant E. coli. Drs. Gloria Culver and Keith Connolly have focused their research on bacterial ribosomes, an essential cellular component for viability. Specifically, they found that a balance is necessary between two bacterial proteins, RbfA and KsgA, for ribosomes to assemble and carry out their mission in protein biosynthesis. Disrupting the balance between these two proteins could disrupt bacterial protein synthesis and therefore would constitute a novel mechanism of antibiotic action.

 

Cambodia Reports 8th H5N1 Flu Fatality This Year

 

 

 

 

 

 

 

26Feb13

    Health official in Cambodia have reported the country's eighth fatality this year from H5N1 infection. The victim (35M), from the northeastern province of Kampong Cham, died Monday after eating two ducks that had died due to infection. The total number of confirmed H5N1 cases in Cambodia this year now stands at nine.

 

This event is worrisome for several reasons. Cambodia has pursued vigorous culling efforts as well as public education efforts. Yet at least one news story out of Cambodia tells of rural villages where “…almost all poultry had died…” weeks before officials were informed or any official culling had been performed. In addition, a Ministry of Health official is quoted as noting that the cases of human H5N1 infection, while rising, do not seem to be connected. From an epidemiological perspective, this is unsettling. Finally, this news comes on the heels of a 2nd H5N1 fatality in China where, as highlighted by Recombinomics, the identity of the H5N1 strains may not be the same in both countries. Further, the sequence from the fatal Chinese isolates show changes in HA shared amongst human cases but absent from any recent poultry sequences.

 

Since 2003, Cambodia has now aggregated a total of 30 human H5N1 infections, all but three of them fatal and fully one third of which occurred in the first two months of this year.  The WHO is reportedly monitoring events closely.

 

 

 

Cambodia’s H5N1 2013 Death Toll Climbs to Seven

 

 

 

 

 

 

 

21Feb13

    The government of Cambodia is reporting yet another victim of H5N1 infection. The news of the most recent victim  (2M) follows last week’s death of a three-year-old girl from the same region. This brings the total number of fatalities due to H5N1 infection in Cambodia to seven for just this year. Since the disease was first verified in Cambodia in 2004, a total of 29 human cases have been recorded with 26 associated deaths. Eight of the recorded 29 human cases have occurred just this year. Thus, Cambodia maintains a H5N1 case fatality rate of nearly 90% both this year and historically.

 

 

New Avian Influenza Strain Leaves 2 Dead in China

 

 

 

 

 

 

01Apr13                    Updated 02Apr13

    Chinese health authorities notified the WHO yesterday of three confirmed cases of human infection with a novel avian influenza strain H7N9, according to a Global Alert & Response (GAR) notification issued today by the WHO.  Two of the three confirmed cases have been fatal. Laboratory confirmation was obtained by the China CDC on 29 March and additional testing for influenza A(H3N2), A (H1N1)pdm09 and A(H5N1), as well as for novel coronavirus, was negative. The cases eminate out of China's Shanghai and Anhui provinces. On Tuesday, Apr. 2, Recombinomics, quoting an online story from China News, reported another 4 confirmed cases of H7N9 in nearby Jiangsu Province. For three out of the four Jiangsu cases, no obvious link to poultry is apparent nor are there readily evident epidemiological links between the four cases.

 

As noted in today’s GAR, “…The cases were reported from Shanghai (2 cases) and Anhui province (1 case). All three cases presented with respiratory tract infection with progression to severe pneumonia and breathing difficulties. Disease onset was between 19 February and 15 March 2013. Two of the cases died. The third case is currently in critical condition.” In addition, two sons of one of the Shanghai fatalities were also sick with respiratory illness during the same period and one of the sons has reportedly expired due to pneumonia. Thus, there may well be 2 more “suspected” cases as well. The table, at left, summarizes the confirmed and suspect cases to date.

 

The WHO-Chinese Influenza Research Center has deposited complete sequences from the first three confirmed cases at GISAID.  As noted today in a Commentary at Recombinomics, the sequences from the three human isolates possess a number of sequence signatures for adaptation to humans:

 

1. All three sequences contain a 15 base pair deletion in their neuraminidase genes. A larger deletion in the same neuraminidase stem region has been linked to human adaptation of H5N1.

 

2. All three sequences bear the E627K mutation in their PB2 genes. This same mutation was present in the only other known case of fatal H7 influenza infection in humans: a 2003 incident in The Netherlands. Previous studies have demonstrated that the polymerase activity of avian-origin influenza viruses can be dramatically increased in human cells with the PB2 E627K mutation (see for example this link and this link).

 

3. Two of the three sequences bear the mutation Q226L in their HA genes. This mutation has been linked to higher affinity for human receptors in prior studies on H5N1 transmissivity.  Recombinomics has described briefly the prior three H5N1 transmission studies where this mutation enhanced the affinity of the virus for mammalian receptors.

 

The situation bears close monitoring as the as the potential for the spread of a novel influenza strain among the humans is of great concern. The possibility also exists that this strain of H7N9 is of low pathogenicity in birds but of high pathogenicity in humans.

 

 

 

 

Update on Novel Human β2c Coronavirus (hCoV-EMC)

 

 

 

 

 

 

 

 

20Mar13

    Yesterday, the WHO issued updated surveillance recommendations  for human infection by the novel  β2c coronavirus (nCoV; hCoV-EMC) that has so far yielded 15 laboratory-confirmed human infections, nine of them fatal. Of note, the WHO is advising clinicians to be watchful for the virus in patients with severe respiratory disease even when other etiological agents are confirmed present. This advice is predicated, in part, by a third cluster of hCoV-EMC cases in the UK that provides “...clear evidence of limited, non-sustained human-to-human transmission…”, though the exact mode of transmission has not been determined.  Included in this cluster was a patient who originally tested positive for influenza A but was subsequently found to be co-infected with hCoV-EMC. In addition, the update has specific recommendations for countries where the novel virus has been detected (mainly the WHO Eastern Mediterranean Region) as well as guidelines for investigations to help describe  “…critical clinical and epidemiological features of the virus”.

 

The issue of nCoV surveillance is critical, all the more so since the publication last week in Nature of the identity of the cellular receptor (target) for the new virus. The receptor is an evolutionarily well-conserved protein present on human airway cells known as dipeptidyl peptidase 4 (DPP4; a.k.a in humans as CD26). This enzyme receptor (though the enzymatic activity of DPP4 appears irrelevant to hCoV binding) suggests that direct transmission to and from humans from a variety of species may be possible. This finding heightens concerns that absent proper surveillance with adequate tests, many more cases of human infection may be occurring that are milder in symptomology or mistakenly credited to other infectious agents. Exactly this concern has been vigorously discussed at Recombinomics (see for example, this  Commentary). As also noted by Recombinomics, ongoing linkage of hCoV-EMC to related viruses identified in bats has served as a “red herring” that obscures the need for better human surveillance.

 

 

 

Increased HIV Infection Risk Among Low-SES Hetero-sexuals in the U.S.

 

 

 

 

 

15Mar13

    In this week’s preview edition of the CDC’s Morbidity and Mortality Weekly Report (MMWR), the results of a second round of surveying for HIV prevalence, incidence, and HIV-associated behaviors conducted by the National HIV Behavioral Surveillance System (NHBS) during 2010 were reported. As noted within the report, the “NHBS monitors HIV prevalence and HIV-associated behaviors among populations at high risk for acquiring HIV in 21 metropolitan statistical areas with high prevalence of AIDS. During 2010, NHBS collected data and conducted HIV testing among heterosexuals using respondent-driven sampling, a peer-referral sampling method.” The surveying effort focused on individuals with low socioeconomic status (SES; defined as having a household income (adjusted for household size) at or below the poverty level guidelines or no more than a high school education) since an earlier pilot study showed that “…persons with low SES were more likely than persons with high SES to be infected…”

 

The major finding in the report is that the HIV prevalence in this low-SES heterosexual population was 2.3% overall, a prevalence roughly 5 times that estimated for the U.S. population over 13 years of age. In addition, a prevalence of 1.1% was found in the sub-pool of respondents who did not report a prior HIV test result.  Indeed, among this 1.1% prevalence group, a whopping 43.9% reported that they had never even been tested for HIV infection until they participated in the current survey.  Even among the entire survey population, some 25.8% had never previously been tested for HIV.

 

The study highlights the need for aggressive HIV testing in target populations such as these. As laid out in the accompanying Editorial Note, “A key step to reducing the number of new HIV infections in the United States, as indicated in the National HIV/AIDS Strategy (Link), is to increase the percentage of persons living with HIV who know their serostatus through HIV testing. Persons aware of their HIV infection often take steps to reduce their risk behaviors substantially and can be referred for treatment and care, which can reduce HIV transmission ( link2 ).” The study also highlights the clear socioeconomic divisions that so often underscore disease persistence in the presence of ample medical and public health resources: nearly 92% of the survey participants were African Americans and Hispanics or Latinos.

 

 

 

HIV Infection Tied to Greater Risk of MI

 

 

 

 

05Mar13

    The current success of ART in battling HIV to a standstill in infected patients means that HIV patients are living longer and are at-risk for the usual set of age-related diseases, apparently with higher co-morbidity risk. But how much prior HIV infection affects the risk for these diseases is not clear and is difficult to assess. Recently, investigators have turned to military veterans to constitute a suitable cohort for observational study.

 

A report by Michael Smith at MedPage Today summarizes two studies that show, at least preliminarily, that HIV infection correlates with a two-fold higher risk for myocardial infarction and elevated risk for end-stage renal disease and certain cancers. One of the studies was presented at the ongoing Conference on Retroviruses and Opportunistic Infections (CROI) and the other appears online at JAMA Internal Medicine. The former study examined a cohort of 84,444 veterans (without a history of heart disease) and found that “Although HIV+ adults are at a substantially greater risk of MI, cancer, and ESRD than HIV– adults in care, these age-related co-morbidities occur at similar ages after accounting for traditional risk factors.”  The latter study examined a cohort of 82,429 veterans and found that “Infection with HIV is associated with a 50% increased risk of AMI beyond that explained by recognized risk factors.“ As noted in an accompanying “Invited Commentary” for the JAMA article, these studies and other work “…may provide a platform for the development of HIV-specific interventions to reduce this excess MI risk and ensure that the benefits derived from safe, effective, long-term control of HIV replication by ART translate into reduced mortality for all people living with HIV.”

 

 

 

A Medical First: A Cure in a Pediatric HIV Case

 

 

 

 

 

04JMar13

    The New York Times is reporting a first-ever "functional cure" of HIV in a 26 month-old pediatric case. The infant, born in rural Mississippi to a mother who did not know she was HIV-positive, was subjected to a novel treatment regimen: aggressive anti-retroviral therapy (ART) starting just a mere 30 hours after birth. An oral abstract describing the case was presented today at the 20th Conference on Retroviruses and Opportunistic Infections in Atlanta by Dr. Deborah Persaud (Johns Hopkins University School of Medicine) and colleagues from UMass Medical School, the NIAID, the University of Mississippi Medical Center, and the UCSD/VA San Diego Heathcare System. The 18 month-long ART regimen commenced after positive testing for HIV RNA & DNA (as HIV subtype B) on day 2. Undetectable levels of virus were first detected on day 29 (27 days of treatment).

 

     These results are so important since mother-to-child transmission of HIV is such a major problem.  If a mother is known to be infected, prophylactic drug regimens (usually AZT) are typically administered to the newborn. But in this case, Dr. Hannah Gay at the University of Mississippi Medical Center commenced treatment with an aggressive tripartite regimen of anti-retroviral drugs. Extensive testing for HIV when the baby was 5 months-of-age failed to find HIV virus, even in latent reservoirs.

 

  Given the relatively immature state of newborn immune systems, the Times article  cites the hypothesis that aggressive ART can be successful in newborns because the virus hasn't had a chance to populate the "hidden reservoirs" that enable the virus to evade host immune responses and drug therapy.

 

   While documented cases of mother-to-child HIV transmission are rare in the U.S (~200 cases per year), the situation is quite different in the developing world where ~300,000 babies were infected in 2011 alone. Today, over 3 million children are infected with HIV worldwide.

 

  While there are multiple reports of HIV patients apparently able to control the virus subsequent to infection (notably the "long term non-progressors"), including at least one pediatric example of HIV clearance, the best most patients can do is battle HIV to a draw employing so-called highly active anti-retroviral therapy [HAART].  There is only one other documented case of curing an HIV infection: a German patient suffering both from leukemia and HIV who received a bone-marrow transplant from a donor whose cells were genetically missing a key receptor for HIV infection.

 

     These results constitute an exciting medical finding and should catalyze many additional studies to ascertain whether early detection and aggressive treatment can save the lives of young children and potentially avoid a lifetime of HAART.

 

Short Telomeres Linked to Contracting the Common Cold

 

 

 

 

19Feb13

    An article appearing on MedPage Today covers a recent report in the literature from investigators at Carnegie Mellon University that establishes a correlation between an increased rate of infection by rhino viruses and shorter telomeres  on CD8+CD28- T cells.  Telomeres are regions of repetitive nucleic acids at the end of each chromatid that serve to protect the end of the chromosome from degradation. Each time a cell divides the telomeres shorten since the enzymatic apparatus for their replication cannot proceed past the end of the chromatid.  An enzyme known as telomerase can extend telomeres but this enzyme is present only in select cells, such as stem cells. Thus, telomere length can be taken as a measure of cell age and prior studies have led to the suggestion of a general correlation between telomere length and age-related functional decline.

 

 In the present study, published in the Journal of the American Medical Association, the investigators studied telomere length on 152 adults aged 18 to 55 years of age. Patients were given nasal drops containing either control or rhinovirus 39 and subsequently monitored for five days for “Infection (virus shedding or 4-fold increase in virus-specific antibody titer) and clinical illness (verified infection plus objective signs of illness).” Four distinct sets of leukocytes (including PBMCs and CD4+ T cells) were then evaluated for telomere length. Only CD8+CD28- T cell telomere length was associated with greater risk of infection and clinical illness.

 

There is other evidence to support a possible causative link between telomere length and viral infection.  A prior report had examined the same 4 leukocyte subsets in healthy adults and had found “...that CD8+CD28- T cells are replicatively senescent cells, they had the lowest telomerase activity and shortest telomere length.” More specifically, it has also been previously reported that sustained CD28 expression delays features of replicative senescence (e.g. “enhanced telomerase activity, increased overall proliferative potential, and reduced secretion of pro-inflammatory cytokines” ) in CD8 T cells. Perhaps not surprisingly then, the abundance of CD8+CD28- T cells correlates with accelerated AIDS progression (see link1). Continued research on the correlations and potential causality of immunosenescence and viral infections could lead to diagnostic biomarkers of disease and even new therapies.

 

 

 

Recently Discovered Virus Claims Its Spot Among U.S. Pediatric Respiratory Infections

 

 

 

15Feb13

    In a a new article appearing in the New England Journal of Medicine, investigators from the New Vaccine Surveillance Network have reported the results of a prospective surveillance study of a new respiratory virus discovered only in 2001.

 

The virus is human metapneumovirus (HMPV), a paramyxovirus [ssRNA] virus related to measles, mumps, and respiratory syncytial viruses, as well as human parainfluenza virus 1-4, though its closest neighbor is avian metapneumovirus (AMPV) subgroup C.  As noted by the investigators in their article, HMPV “…is associated with acute respiratory illness among infants and children worldwide. In addition, HMPV causes acute respiratory illness and results in hospitalization among older adults and persons with underlying chronic conditions, including asthma, cancer, and chronic obstructive pulmonary disease.”

 

The present study illuminates the disease-burden of metapneumovirus among children under five, since prior work was retrospective and was missing asymptomatic controls.  In this case, data was collected from region surrounding three US cities over six years (2003-2009) and involved over 12,000 children.  New types of data were also collected including rates of hospitalization, as well as emergency department and outpatient visits.

 

 It was found that “HMPV infection is associated with a substantial burden of hospitalizations and outpatient visits among children throughout the first 5 years of life, especially during the first year. Most children with HMPV infection were previously healthy.”   Specifically HMPV was detected in 6% of pediatric inpatients and 7% of pediatric outpatients. Moreover, the rate of HMPV hospitalizations for children less than five years of age was one per 1,000, similar to that for influenza but below that due to RSV (3/1,000).  The authors estimate, based on census data, then approximately 20,000 HMPV hospitalizations occur annually for children less than five years of age.

 

The study underscores the importance of the need for a diagnostic test for HPMV, especially in light of the shared symptomology with RSV and influenza. In addition, there is a clear impetus for an effective vaccine.

 

 

More H5N1 Fatalities in Asia

 

 

 

 

 

 

 

13Feb13

    Two more individuals have died in Asia from H5N1infection. Xinhua News Agency, China’s official news agency citing government Health Ministry officials, is reporting that one of two individuals recently confirmed with H5N1 infection has died. The patient (21F) from Guiyang, China passed away today from multiple organ failure, 11 days after first showing influenza symptoms. The other individual (31M) with confirmed H5N1 infection is also from Guiyang and is reported to be in critical condition. Interestingly, cited “epidemic control experts" have not found any indication that either patient had close contact with birds nor is there any apparent epidemiological connection between the two cases.

 

Meanwhile, Cambodia has registered its seventh case and sixth death this year from H5N1.  The details were outlined in a joint statement from the WHO and Cambodia’s Ministry of Health.  The victim (3F) was tested positive for H5N1 on 11Feb after developing a fever and rash on 03Feb.  The child reportedly had contact with poultry prior to being infected.  As noted in the joint statement, “Globally since 2003, there have been 619 laboratory confirmed human cases of avian influenza with 366 related deaths.” But Cambodia has suffered much more with a total of 28 confirmed cases and 25 deaths, most in children.

 

 

 

Recently Discovered Virus Claims Its Spot Among U.S. Pediatric Respiratory Infections

 

 

 

15Feb13

    In a a new article appearing in the New England Journal of Medicine, investigators from the New Vaccine Surveillance Network have reported the results of a prospective surveillance study of a new respiratory virus discovered only in 2001.

 

The virus is human metapneumovirus (HMPV), a paramyxovirus [ssRNA] virus related to measles, mumps, and respiratory syncytial viruses, as well as human parainfluenza virus 1-4, though its closest neighbor is avian metapneumovirus (AMPV) subgroup C.  As noted by the investigators in their article, HMPV “…is associated with acute respiratory illness among infants and children worldwide. In addition, HMPV causes acute respiratory illness and results in hospitalization among older adults and persons with underlying chronic conditions, including asthma, cancer, and chronic obstructive pulmonary disease.”

 

The present study illuminates the disease-burden of metapneumovirus among children under five, since prior work was retrospective and was missing asymptomatic controls.  In this case, data was collected from region surrounding three US cities over six years (2003-2009) and involved over 12,000 children.  New types of data were also collected including rates of hospitalization, as well as emergency department and outpatient visits.

 

 It was found that “HMPV infection is associated with a substantial burden of hospitalizations and outpatient visits among children throughout the first 5 years of life, especially during the first year. Most children with HMPV infection were previously healthy.”   Specifically HMPV was detected in 6% of pediatric inpatients and 7% of pediatric outpatients. Moreover, the rate of HMPV hospitalizations for children less than five years of age was one per 1,000, similar to that for influenza but below that due to RSV (3/1,000).  The authors estimate, based on census data, then approximately 20,000 HMPV hospitalizations occur annually for children less than five years of age.

 

The study underscores the importance of the need for a diagnostic test for HPMV, especially in light of the shared symptomology with RSV and influenza. In addition, there is a clear impetus for an effective vaccine.

 

 

 

Breathprints Identify Lung Infections in Mice

 

 

 

 

 

28Jan13

    According to a news article on Medwire News,  a team of investigators led by Jane Hill at the University of Vermont-Burlington have used mass spectrometry to identify significant differences in the volatile organic compounds (VOCs) present in the exhaled breath of mice infected with Pseudomonas or Staphylococcus, as compared to the breath of non-infected mice. Such “breathprints” could be eventually used to detect whether patients have a bacterial respiratory infection, a notoriously difficult task in the clinic where culturing a pathogen from patients is time-consuming and frequently ambiguous.

 

 As just reported in the Journal of Breath Research, the investigators used secondary electrospray ionization mass spectrometry (SESI – MS) to qualitatively assess VOCs in vivo. Most intriguingly, the team found that the breathprints of mice infected with Pseudomonas differed from those from mice infected with Staphylococcus. Moreover, the investigators found that as SESI – MS could distinguish between infections in mice of two different strains of Pseudomonas. Finally, it was “…observed that only 25–34% of peaks are shared between the in vitro and in vivo SESI-MS fingerprints.”

 

The eventual development of new diagnostic tools using technologies such as SESI – MS promises to revolutionize the diagnosis of respiratory infections. The vast majority of debilitating lower respiratory tract infections is caused by bacterial, viral, or fungal pneumonia and treatment of patients is frequently hampered by the lack of fast and reliable in situ diagnostic tests that can determine the offending pathogen.

 

WHO: Two More Human Deaths from H5N1 in Cambodia

 

 

 

 

 

29Jan13

    The WHO is today reporting two additional cases of human H5N1 in Cambodia. The patients, girls aged 17 months and nine years old, were confirmed positive for the H5N1 virus earlier this month and died yesterday. In both cases, there is evidence of recent deaths among poultry in their respective villages. The monthly total of H5N1 human infections in Cambodia now stands at a total of five, with four fatalities.  This number exceeds the total number of H5N1 cases in Cambodia all of last year.

 

 The relatively high number of H5N1 infections in Cambodia so far this year is worthy of careful watch, especially as the country heads towards the Chinese New Year, which starts February 10th. This holiday presents a golden opportunity for an increase number of infections since it is a time when many chickens, some of them possibly infected, make their way to market and possibly enhance the probability of human infection. To support this possibility, local health officials are pursuing a number of measures, including the additional calling of poultry suspected of being infected.

 

 

WHO Declares Dengue the Fastest-Growing Tropical Disease.

 

 

 

 

16Jan13

    In a statement issued this week, the WHO declared dengue as the fastest-growing tropical disease in the world, with an estimated 50 million cases each year. Dengue, which was first found just over 60 years ago in three countries, has increased its geographical spread to over 120 countries and all inhabited continents.  Over the decades, the number of cases has continued to increase and officially over 2 million cases of dengue are reported each year. In other words, dengue has registered a 30-fold increase in disease incidence over the past 50 years.

 

But according to a recent story published by Reuters, the WHO now estimates that the actual number of cases of dengue is more like 50 million and may be as high as 100 million cases a year. Moreover, the disease now represents a pandemic threat and is overtaking malaria as the mosquito-borne disease with the greatest reach. The “exponential explosion” of dengue is believed due to climate change, globalization, and changes in the geographical distribution of the mosquito vectors, Aedes aegypti and Aedes albopictus. Dengue now has a global reach.

 

There are currently no therapeutic treatments for dengue. A number of vaccine candidates are under development. The most mature program is that led by Sanofi SA which, in clinical trials published last year, appears safe but is only about 30% effective.

 

 

Rotavirus Vaccination Can Protect Familial Bystanders

 

 

 

 

24Jan13

    One of the most interesting public health insights of recent years, translated into policy as vaccination recommendations to the public, has been the realization that more aggressively vaccinating children against influenza virus can significantly impact the level of disease in older adults. Now, a newly published study indicates that the same principle maybe operative when vaccinating children against rotavirus.

 

In a study just published in Clinical Infectious Diseases and reported by MedPage Today, a group of investigators at Emory University found a reduction in the relative percentage of rotavirus positive stool cultures (of between 42.5 and 49.3%)  and an absolute decline from 4.35% to 2.24% in adult samples obtained at a single medical center before and after the widespread use of the pediatric vaccine. A marked reduction in rotaviral disease in both the vaccinated and unvaccinated pediatric populations shortly after the FDA approved the road attack vaccine in 2006 has been well documented already.

 

 These are early results, limited by a number of factors and subject to further refinement through additional study. However, the possibility that vaccinating children can beneficially impact the adult population against rotavirus disease is an exciting development that warrants further study.

 

 

 

 And Lest We Forget Pandemic H1N1

 

 

 

 

 

29Jan13

    While attention is naturally focused on this year’s intense seasonal influenza (A/H3N2) outbreak, norovirus, and troubling news concerning H5N1 in Cambodia, a spate of other recent reports serves to remind us that pandemic H1N1 (2009 pH1N1) has not yet left the world stage.

 

The 2009 pH1N1 pandemic was officially declared over by the WHO in August 2010.  And confirmed cases of 2009 pH1N1 infection are relatively infrequent in North America and Europe this season, the virus having been displaced by the H3N2 virus. Similarly, the southern hemisphere experienced relatively minor problems with 2009 pH1N1 last year during their winter season. However, a recent study put the global pH1N1 infection rate after the first year of exposure at 24%, leaving large populations under exposed and under-vaccinated. Thus, other parts of the world are still dealing with troubling outbreaks of the 2009 pH1N1 virus.

 

A report out today from Tel Aviv sites over 700 pH1N1 infections this season, resulting in 25 deaths in recent weeks in the Occupied Palestinian Territory.  India is dealing with an outbreak of 2009 pH1N1 this season (for example, see the following links: link1, link2, link3, and link4). China has already reported 5 deaths due to pH1N1 in Beijing this year. A swath of other countries, from Jordan to Bosnia, have recently reported outbreaks of 2009 pH1N1.

 

What do all of these reports mean? Primarily, these reports underscore the need for continued surveillance and vigilance.  As a zoonotic pathogen, influenza is constantly undergoing alterations via recombination and reassortment with other influenza strains. These are the mechanisms by which deadly new influenza strains arise. So in this very active flu season, it is best to remind us to survey a broad horizon and not to focus solely on local, immediate problems.

 

Candidate Dengue Vaccine   Shows Promise in Phase 1 Study

 

 

 

 

23Jan13

    A press release out today from the NIH has announced the a candidate dengue vaccine developed by scientists at the NIH has been found to be safe and generate a strong immune response in recipients participating in a phase 1 clinical trial sponsored by the NIAID. The results of the trial have just been published online in the Journal of Infectious Diseases.

 

The WHO estimates that 50 to 100 million cases of dengue occur worldwide every year with a resulting 500,000 hospitalizations of patients with more severe forms of the disease, most of them children. One third of the world’s population is chronically at risk each year for this viral infection and there are currently neither therapies nor vaccines for this disease.

 

Dengue fever can because by any of four related viruses, and the NIH’s vaccine candidate, Tetra-Vax DV, is composed of a live attenuated form of each virus. In the Phase I trial, a randomized, placebo-controlled study, the safety and immunogenicity of four different admixtures of a live attenuated tetravalent vaccine were evaluated in 113 naïve adults. Participants were randomized into four groups of 28. Within each group, 20 individuals received a single s.q. injection of one of the tetravalent candidate vaccine combinations, and eight others received placebo.

 

As described in the press release, "The researchers found that all four candidate vaccine combinations induced antibody responses against each of the dengue viruses. However, one vaccine combination, TV003, appeared to induce the most balanced antibody response against the dengue viruses. A single dose of TV003 resulted in an antibody response to all four dengue viruses in 45 percent of participants and against three of the four viruses in an additional 45 percent. Overall, an immune response to at least three viruses was seen in 90 percent of vaccinees given TV003.

 

All of the candidate LATV vaccines were also found to be safe: no participants experienced fever or dengue-like illness after vaccination, though 64% of recipients did develop a faint rash at the site of injection.

 

As also noted in the NIH press release, "...TV003’s inexpensive production cost—less than $1 per dose—is critical to its potential use in developing countries, noted Dr. Whitehead. Manufacturers in Brazil, India and Vietnam—countries where dengue is prevalent – have licensed the vaccine technology for production and further evaluation. Phase II trials to evaluate the safety of TV003 and its capacity to create an immune response will begin soon in Brazil and Thailand."

 

This news comes on the heels of disappointing clinical results for a more advanced dengue candidate vaccine last fall and provides additional hope for an eventual effective vaccine.

 

CDC: A New Strain of Norovirus Takes Over

 

 

 

 

25Jan13

    In a new Morbidity and Mortality Weekly Report [MMWR] released today, the CDC has announced that a new strain of norovirus, known as GII.4 Sydney, is sweeping the globe, including the United States. The new strain was first identified last March in Australia. During the period of September–December 2012, a total of 141 (53%) of the 266 norovirus outbreaks reported to the CDC were caused by GII.4 Sydney.

 

Sometimes mistakenly called the stomach flu, norovirus is the leading cause of epidemic gastroenteritis in the U.S., causing bouts of vomiting and diarrhea for 2 to 3 days.  The virus is best known for being highly contagious and spreading quickly amongst humans in close confinement, such as cruise ships and nursing homes. Each year, noroviruses viruses cause an estimated 21 million illnesses and 800 deaths [ ].

 

As noted in the MMWR, “Noroviruses belong to the family Caliciviridae and can be grouped into five genogroups (GI through GV), which are further divided into at least 34 genotypes. Human disease primarily is caused by GI and GII noroviruses, with most outbreaks caused by GII.4 strains. During the past decade, new GII.4 strains have emerged every 2–3 years, replacing previously predominant GII.4 strains. Emergence of these new norovirus strains has often, but not always, led to increased outbreak activity. For example, the previously dominant GII.4 New Orleans strain was not associated with increased norovirus outbreak activity in the United States.”

 

WHO: Two Cambodians Die from H5N1 Bird Flu

 

 

 

25Jan13

    According to a news report in the Terra Daily, the World Health Organization reported last Friday that two individuals have died from H5N1 infection in Cambodia. The two victims, a 15-year-old girl and a 35-year-old man, passed away after preparing infected chicken. In addition the agency reported the existence of a pediatric case earlier in the month, but that patient later recovered. In total, there have been 24 reported cases of HIV in one in Cambodia since 2003 and all but three of the cases were fatal.

 

The WHO has reported that, worldwide as of 16Jan13, there have been a total of 610 laboratory-confirmed human cases of influenza A(H5N1) virus infection from 15 countries, of which 360 died. This latest assessment also notes that...  “Recent poultry outbreaks in Indonesia have been attributed to influenza virus A (H5N1) clade 2.3.2.1. This clade has not been previously detected in Indonesia, although it has been circulating for some years in poultry and has been isolated from a few human cases with H5N1 infection in other countries.”