Influenza B: A Virus Not To Be Underestimated

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While North America is currently dealing with a mostly influenza A/H3N2 flu season, in Asia and in parts of Europe, Influenza B is leading the charge, and as we've seen (see Hong Kong Hospitals Inundated By Flu Cases), causing a good deal of morbidity and mortality.

Until a few years ago, Influenza B was viewed generally as a `less serious' infection than influenza A - affecting mainly children - and producing relatively mild illness in adults.

An example of that belief comes from this 2009 study from Viral Immunology, called Influenza B virus causes milder pathogenesis and weaker inflammatory responses in ferrets than influenza A virus which opens with the statement:

It is unknown why the influenza B virus causes less severe clinical signs than the influenza A virus in humans. Here we show that influenza B virus induces a lower levels of inflammatory cytokines in the lungs of infected ferrets, and causes less pathological damage to their lung tissues than does influenza A virus.

Since then, however, we've seen a growing number of studies that challenge these old ideas, and show the severity of Influenza B infections to being comparable with Influenza A.

In 2012, Lisa Schnirring of CIDRAP News wrote following story on a JID study called Myocardial Injury and Bacterial Pneumonia Contribute to the Pathogenesis of Fatal Influenza B Virus Infection.

Study finds influenza B may be more severe than thought

Lisa Schnirring |
Feb 01, 2012

Feb 1, 2012 (CIDRAP News) – An autopsy study involving influenza B infections revealed how histologically similar the disease is to fatal influenza A and how quickly it can kill, challenging the notion that it is milder than influenza A.

The investigators, from the US Centers for Disease Control and Prevention (CDC), also found a high level of cardiac injury with fatal influenza B infections, especially in younger patients.

The research group said that comprehensive studies of influenza B deaths involving large series of patients and comparing those with and without bacterial pneumonia are lacking. Their findings appeared yesterday in the Journal of Infectious Diseases.

       (Continue . . . .) 
 
Two years later another important study was published, this time in the Clinical Infectious Diseases Journal, that once again challenged the old ideas about influenza B.

Comparing Clinical Characteristics Between Hospitalized Adults With Laboratory-Confirmed Influenza A and B Virus Infection

Su Su Sandra S. Chaves Alejandro Perez Tiffany D'Mello Pam D. Kirley Kimberly Yousey-Hindes Monica M. Farley Meghan Harris Ruta Sharangpani Ruth Lynfield ...

Clinical Infectious Diseases, Volume 59, Issue 2, 15 July 2014, Pages 252–255,

https://doi.org/10.1093/cid/ciu269 Published: 18 April 2014

ABSTRACT

We challenge the notion that influenza B is milder than influenza A by finding similar clinical characteristics between hospitalized adult influenza-cases. Among patients treated with oseltamivir, length of stay and mortality did not differ by type of virus infection.

The CDC, which partnered in this study, published the following summary:

New CDC Study Compares Severity of Illness Caused by Flu A and B Viruses

Influenza B virus infections can be just as severe as influenza A virus infections

As late-season influenza B viruses currently predominate in the United States, a new study published by CDC and partners highlights the comparative severity of illness associated with influenza A versus influenza B virus infections. The results of the study showed that among hospitalized adults, flu B viruses caused equally severe disease outcomes and clinical characteristics as flu A viruses.

This contradicts a common misconception that flu B viruses are associated with milder disease than flu A viruses.

The study looked at the disease characteristics – including the severity of illness – associated with flu A and flu B viruses among hospitalized adults over eight flu seasons (2005-06 through 2012-13). The study identified 21,186 flu A and 3,579 flu B-associated hospitalizations during the study period. Flu A viruses were the predominant flu virus in circulation during all of the seasons studied, particularly during the 2009 H1N1 pandemic.

The study found no significant difference in the overall proportion of hospitalizations with an ICU admission by virus type for each season. Among hospitalized adults with flu A or B infection, length of hospital stay and the proportion of patients admitted into an Intensive Care Unit (ICU) were comparable. Results also showed that flu B virus infections caused a similar proportion of deaths as flu A virus infections among hospitalized adults during the study period.

Study findings prompted the authors to conclude that clinicians should not regard flu B infections as less severe than flu A when considering treatment options.

These findings support CDC’s existing antiviral treatment recommendations for the treatment of all hospitalized and high risk patients with suspected or confirmed flu infection. The type of flu virus infection (A or B) should not influence treatment decisions.

For most of the 2013-14 flu season, the 2009 H1N1 virus has been the predominant virus. However, over the past month and a half there has been a late season wave of flu B virus activity. At this time, flu B viruses are the predominant virus, with the highest levels of activity primarily focused in the Northeastern United States. Second waves of influenza B virus activity are not uncommon. About 70% of recent B viruses have been like the B virus component of the trivalent flu vaccine. The remaining flu B viruses have been like the second B vaccine component in the quadrivalent flu vaccine.

This study is available online from the Clinical Infectious Diseases journal website.

Interestingly, in last week's study NEJM: Acute Myocardial Infarction After Laboratory-Confirmed Influenza Infection, it was Influenza B (rather than A) that produced the highest coronary risk, at least among their limited sample size (n=364). 

A finding that harkens back to the 2012 JID study mentioned above.

It is a bit unusual to see influenza B dominated flu seasons in Asia and parts of Europe, since Influenza B generally peaks in the spring, after influenza A begins to wane.  Some have suggested last summer's influenza A surge in Asia may have opened the door to a B-virus season.

This has been an interesting epidemiological twist, and one we'll want to learn more about.

The good news is the flu shot (particularly the quadrivalent version) provides much better protection against influenza B viruses than we've seen in recent years against the A/H3N2 strain. With another 6 to 8 weeks of flu ahead, it isn't too late to get the shot.

Since influenza B viruses have only been found in humans and seals, they tend to evolve slowly, and are not viewed as serious pandemic threats.  Nevertheless, they can spark large epidemics that produce significant morbidity and mortality.

While old ideas about the severity of influenza B still persist, the evidence increasingly shows that influenza B viruses deserve the same respect as their A-list cousins.
 

EID Journal: Novel HPAI A(H5N6) Virus in the Netherlands, December 2017

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By now most are aware that the HPAI H5N6 virus which arrived last November in Japan and South Korea - and turned up in the Netherlands in December - is not the Asian H5N6 virus which has caused at least 18 human infections and a number of deaths in China, but rather a descendant of the HPAI H5N8 virus which sparked last year's record epizootic in Europe.

In late November a report from Japan's Tottori University: Shimane HPAI H5N6 A New Reassortment identified samples collected two weeks earlier in Shimane Prefecture as being similar to a novel reassortment reported in Greece towards the end of last year's European epizootic. 

Essentially a reassortment between HPAI H5N8 and an (as yet) unidentified LPAI HxN6 virus from Europe (see chart below).
  

Over the next couple of weeks additional H5N6 viruses were discovered in South Korea and Taiwan - all described as being `similar' to the sample recovered in Greece the previous March - although genetically distinct variants were reported (see South Korea Reports `Second Strain' Of Newly Reassorted H5N6 Virus).

On December 9th, in Netherlands Bird Flu Identified As Reassorted H5N6, the Wageningen Bioveterinary Research Institute, described recently recovered H5N6 viruses from a Biddinghuizen poultry farm also as being similar to the H5N6 viruses recently detected in Japan and South Korea.

We say `similar' because influenza viruses are constantly changing and evolving through antigenic drift (replication errors) and antigenic shift (reassortment) and so exact matches are rare. There can be dozens of genotypes, and many more minor variants, among viruses of the same subtype. 

Today we have a new analysis of the Netherlands H5N6 virus published this week in the CDC's EID Journal which shows that while similar to the newly reported H5N6 virus in Asia and its predecessor isolated in Greece, it is a genetically distinct reassortment.

A link to, and a few selected excerpts from, yesterday's EID study. But most will want to follow the link to read the report in its entirety. 

Dispatch

Figure 2. Schematic representation of the HPAI H5N6 reassortant virus detected in the Netherlands. Two variants of HPAI H5N8 were detected in 2016; they have different PA gene segments, called PA I and PA II. The novel virus evolved from H5N8 viruses having a PA II gene segment, but obtained both novel NA and PB2 gene segments. The H5N6 viruses detected in Greece, Japan, and Taiwan hahttps://wwwnc.cdc.gov/eid/article/24/4/17-2124-f2ve evolved from H5N8 viruses that have a PA I gene segment and have a N6 segment similar to the virus detected in the Netherlands. HPAI, highly pathogenic avian influenza; PB, polymerase basic; PA, polymerase; HA, hemagglutinin; NP, nucleoprotein; NA, neuraminidase; MP, matrix protein; NS, nonstructural protein.

Novel Highly Pathogenic Avian Influenza A(H5N6) Virus in the Netherlands, December 2017

Nancy Beerens Comments to Author , Guus Koch, Rene Heutink, Frank Harders, D.P. Edwin Vries, Cynthia Ho, Alex Bossers, and Armin Elbers

 Abstract

A novel highly pathogenic avian influenza A(H5N6) virus affecting wild birds and commercial poultry was detected in the Netherlands in December 2017. Phylogenetic analysis demonstrated that the virus is a reassortant of H5N8 clade 2.3.4.4 viruses and not related to the Asian H5N6 viruses that caused human infections.

(SNIP)

Since 2013, HPAI H5N6 viruses have emerged in poultry and caused sporadic infections in humans in Asia, raising global concerns regarding their potential as human pandemic threats. H5N6 viruses constitute >34 distinct genotypes, of which 4 were detected in humans (9). 

To genetically characterize the novel H5N6 subtype influenza virus detected in the Netherlands, we sequenced the full genome of the viruses found at the duck farm, and in the 2 mute swans and the tufted duck (GISAID [http://platform.gisaid.org] accession nos. EPI ISL 287907, EPI ISL 288409, EPI ISL 288410, and EPI ISL 288412), as described previously (4).

Database searches (GISAID and GenBank) showed that these viruses are highly similar to the HPAI H5N8 clade 2.3.4.4 viruses, which were detected previously in wild birds at the Russia–Mongolia border in May 2016 (10), for the gene segments polymerase basic 1 (PB1), polymerase acidic (PA), HA, nucleoprotein (NP), matrix protein (MP), and nonstructural protein (NS) (Table). The polymerase basic 2 (PB2) and NA segments shared sequence similarity with Eurasian low pathogenicity avian influenza (LPAI) viruses.

Moreover, the N6 gene of the H5N6 viruses found in the Netherlands showed high homology to those detected in Greece in February and in Japan and Taiwan in November–December 2017.

(SNIP)

Of note, the N6 segment of the virus in the Netherlands is closely related to, but distinct from, that of the H5N6 viruses detected in Greece, Japan, and Taiwan in 2017. Furthermore, the virus in the Netherlands has PB2 and PA segments that are distinct from those found in the viruses from Greece, Japan, and Taiwan (Figure 2). These results indicate that H5N6 virus in the Netherlands is a reassortant of HPAI H5N8 subtype that obtained novel PB2 and NA segments.

(SNIP)

Finally, we analyzed the genome of the novel H5N6 virus for potential zoonotic signatures associated with increased human risk (Technical Appendix[PDF - 2.73 MB - 12 pages] Table 2). We found that the virus has a typical avian receptor specificity and identified no sequence signatures associated with increased airborne transmission.

In the MP and NS genes, we identified mutations that were associated with increased virulence, but similar mutations have been found in other H5 clade 2.3.4.4 viruses. Our analysis demonstrated that the virus may have reduced sensitivity to treatment with the antiviral drug oseltamivir.

Conclusions

A novel reassortant HPAI H5N6 virus affected wild birds and commercial poultry in the Netherlands in December 2017. Phylogenetic analysis demonstrated that the virus is related to the HPAI H5N8 clade 2.3.4.4 viruses but contains novel PB2 and NA segments derived from Eurasian LPAI viruses.

The N6 gene segment is related to that of HPAI H5N6 viruses found in Greece, Japan, and Taiwan, for which a common ancestor was estimated around November 2015. In addition, the H5N6 virus in the Netherlands differs from that in Greece by the PA and PB2 gene segments. This suggests that the H5N6 virus in the Netherlands did not result from continued circulation of the virus in Greece (or Europe) that was detected in February 2017 but likely represents a separate introduction related to wild bird migration in fall 2017.

The reassortment events may have occurred on breeding grounds in Siberia, where large numbers of wild birds congregate, and the virus may have spread by long-distance flights of infected migratory birds (6).

Phylogenetic analysis demonstrated that the virus is not related to the zoonotic Asian H5N6 strains that cause infections in humans. Furthermore, genetic analysis identified no sequence features related to increased human risk. There are no indications that mammals (such as humans) can be infected by the novel reassortant HPAI H5N6 viruses detected in the Netherlands, Greece, Japan, and Taiwan. We recommend further studies in mammals (ferrets or mice) to provide experimental data on the virulence for mammals.

Dr. Beerens is a senior scientist and head of the National Reference Laboratory for Avian Influenza and Newcastle Disease in the Netherlands. Her research interests focus on molecular virology, genetics, and virus evolution.

 For more on the growing diversity of these recently emerged HPAI H5N6 viruses you may wish to revisit:

Japan: Kagawa H5N6 Outbreak Genetically Distinct From Shimane Isolate

South Korea: Pathogenicity Testing Of Gochang Reassorted H5N6 Virus

OIE: Taiwan H5N6 Identified As Similar To New Reassortant Reported In Japan

Hong Kong Hospitals Inundated By Flu Cases

WEEK 3 Severe Flu - Credit HK Flu Express

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Although we won't get another Hong Kong Flu Express report for another two days, already we're seeing indications in the media, and through HK CHP reports, that Hong Kong is - for the second time in 6 months - battling a severe flu season.

Five days ago, in Hong Kong Flu Express Week 3: Flu has Increased Markedly, the CHP reported  `92 severe influenza cases among all ages have been reported, including 47 deaths'  since the start of Epi Week 2.

Since then, the numbers have, according to a report today in the SCMP, jumped to `144 severe flu cases were reported for patients of all ages, including 77 deaths' as of Monday.

Last Friday, the CHP announced they had ordered additional doses of flu vaccine (see DH procures additional seasonal influenza vaccines from vaccine suppliers) which are `. . . .expected to arrive in Hong Kong in early February at the earliest.'

Today the Hong Kong Hospital Authority has announced an emergency infusion of 500 Million HKD ($64 Million USD) in order to cope with what they call  `. . .  stringent challenges facing public hospitals at the moment'.

HA responds to media enquiries on additional allocation of $500 million for coping with winter surge

The following is issued on behalf of the Hospital Authority:

     In response to media enquiries following the announcement by the Chief Executive, Mrs Carrie Lam, today (January 30) of an additional $500 million allocation to the Hospital Authority (HA) for coping with the demand caused by the winter surge, the HA spokesperson gave the following reply:

     The HA welcomes the one-off additional allocation of $500 million from the Government for timely implementation of a series of short-term measures to help relieve the heavy work pressure facing front-line healthcare staff under the current winter surge.

     While expressing gratitude for the Government's additional allocation, the HA will deploy the resources to implement various targeted measures including the increase of healthcare manpower. The funding will be used to hire more clerical staff and clerical assistants to assist nurses in handling clerical as well as patient care duties. With the further extension of the Special Honorarium Scheme to cover ward clerks, the administrative work of front-line nurses will be further relieved.

     Furthermore, the HA will expedite the process of abolishing the policy on incremental pay freeze for the first two years of newly recruited nurses. The HA will discuss the implementation details in close collaboration with nurses groups with a view to boosting the morale of front-line staff. 

     The HA recognises the stringent challenges facing public hospitals at the moment and thus has deployed all available manpower and resources to cope. We also deeply appreciate our front-line staff for their professionalism and dedication in taking care of the patients. 

     As at January 28, the HA had additionally recruited 1 248 temporary nurses to meet with the upsurge in demand and additional workload. The HA will continue to actively recruit more manpower to meet demand.

     For 2017-18, the HA was committed to recruiting 2 130 full-time nurses. As at December 2017, a total of 1 842 nurses were in place, accounting for 86 per cent of the planned total. In the coming year (2018-19), we plan to recruit 2 230 full-time nurses.

Ends/Tuesday, January 30, 2018

Issued at HKT 19:05

The latest Hospital Occupancy Statistics (as of Jan 28th) show an average of 111% occupancy, with United Christian Hospital in Kwun Tong topping the list at 127%.

 
Meanwhile the daily HK CHP press releases this week continue to feature outbreaks, and severe cases, of (primarily) Influenza B, followed by H1N1 and then H3N2.

• CHP investigates a case of severe paediatric influenza B infection and two influenza outbreaks at schools
• CHP investigates outbreak of upper respiratory tract infection at primary school in Sai Kung District
• CHP investigates two influenza outbreaks at primary schools 

Iranian MOA Reports 21 Million Birds Lost To H5N8

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Officially, Iran hasn't notified the OIE of any new H5N8 outbreaks in nearly a year, having last reported 30 outbreaks between November 2016-January 2017 (see OIE report) involving the loss of just over 1 million birds.

Despite this silence, we've continued to see sporadic media reports - and occasional admissions by their Ministry of Agriculture - that large outbreaks of avian flu have continued around the county. 

In early February of last year, in H5N8 & H5N1: Murmurs From The Middle East, we saw media reports (via IRNA the official news agency of the Islamic Republic of Iran) reporting their losses had reached 6 million birds.

A few weeks later, in Iran: Media Reports Of H5N8's Spread, we saw warnings (via Iran's Press TV) going out to the public to avoid contact with wild birds or migratory birds (living or dead), to stop using local poultry products “until further notice.”, and to only consume chickens and eggs that have certification from the Iran Veterinary Organization or the Ministry of Agriculture.

Just over a month ago, in Iran's Hidden Bird Flu Burden, we looked at a brief report from the FARS news agency that (along with excerpts from an MOA statement) that indicated between 21 March  - December 24, 2017 poultry losses in the country had jumped to over 12 million birds. 

Which, when combined with the reports prior to March 31st, would put their losses over the past year somewhere around 18 million birds.

In early January, in Iranian MOA: 14 Million Birds Lost To Avian Flu, we saw another admission from the MOA that the losses (again, presumably since March 31st) had climbed by another 2 million birds.

Avian flu losses have been so great this year, and have driven poultry and egg prices up so high, that it has even been cited as at least one of the reasons behind the citizen protests that sprang up across the country in late December (see Iran: Bird Flu, Food Insecurity & Civil Unrest).

Fast forward a little over 3 weeks and today we have a statement by the MOA - which appears about halfway through a list of agenda items being discussed - indicating the number of birds lost has now reached 21 million.

A translation of the excerpt follows:

According to the latest reports, more than 21 million chicken poultry have been eliminated from the infectious disease of the H5N8 avian influenza virus in order to prevent the outbreak of the disease, the head of the country's veterinary organization said. .

He said: Of the total poultry affected by the disease, 73% of it was related to laying hens.

Rafieeipour said that more than 16 provinces of the country have been involved in the suprapubic disease of birds, said that 421 cases of this disease have been identified in the provinces, 114 of which are in Qom province.

He continued: there is a possibility of an outbreak of this disease in the provinces of Qom, Isfahan and Yazd.

Although no time span is explicitly stated in today's report, in  December the totals were stated as coming between March 31st - December 24th. If you add in the 6 million birds supposedly lost between November 2016-March 2017, Iran may have lost as many as 27 million birds in the past 14 months.

Despite international agreements mandating the prompt reporting of certain animal diseases (including H5 & H7 avian flu)  to the OIE, and specific human diseases (and outbreaks) to the World Health Organization, these regulations are notoriously lacking in `teeth’.

Nations agree to abide, but there is little recourse if they don’t follow through - a topic we looked at in depth in 2015 in Adding Accountability To The IHR.

While for some countries this can be attributed to a lack of money, or surveillance and reporting infrastructure . . .  sometimes it seems to simply boil down to policy (see 2008's  WHO: Indonesia Agrees To Resume Bird Flu Notifications). 

A reminder that when it comes to infectious disease threats - while it may sometimes be comforting -  no news isn't always good news.

An IFRC H1N1 Flu Report From North Korea

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Although we rarely get reports out of North Korea, with multiple influenza subtypes (H3N2, H1N1, Influenza B) raging across the Northern Hemisphere this winter, it shouldn't come as a surprise that the DPRK is being battered as well. 

What is a bit surprising is that they are apparently being hit by H1N1, while the rest of Asia has been reporting primarily Influenza B this winter. 

According to the Latest report from the South Korean CDC, H1N1 has only made up about 5% of their flu cases this winter.  Influenza B leads with 54%, followed by H3N2 with 39%.  This last report (issued Jan 19th) indicated flu was beginning to decline across the country.

We get details about the North Korean outbreak from the following bulletin issued by the International Foundation of Red Cross and Red Crescent Societies.

Information bulletin

DPR Korea: Influenza A Outbreak

This bulletin is being issued for information only and reflects the current situation and details available at this time. The Democratic People’s Republic of Korea Red Cross Society (DPRK RCS), with the support of the International Federation of Red Cross and Red Crescent Societies (IFRC), has determined that available information points toward significant humanitarian needs that may require support from the IFRC Disaster Relief Emergency Fund.

The situation
 
On 19 January 2018 the Vice Minister of Public Health (MoPH) officially informed the World Health Organization (WHO) Country Office in Pyongyang of an outbreak of Influenza A (H1N1) stating that between 1 December 2017 and 16 January 2018 there was a total of 126,574 suspected influenza cases – individuals presenting with influenza-like illness.

Of these, 81,640 cases were confirmed as Influenza A (H1N1) and as per the Ministry communication there had been four deaths – three children and one adult. 

According to the Ministry, 24.5 per cent of suspected influenza cases (numbering 31,010) were among children aged 0-7 years, 22.8 per cent (n= 28,858) were among children 8-16 years and the rest 52.7 per cent (n= 66,706), were among those who were above 17 years. The outbreak has become generalized throughout the country with 28.7 per cent of cases in the capital city – Pyongyang. 

The government has requested support for influenza vaccination targeting high-risk individuals with the MoPH specifically requesting 30,000 Oseltamivir tablets for healthcare workers. WHO has so far dispatched 5,000 tablets with 30,000 in the pipeline to distribute to frontline healthcare workers and vulnerable groups.

There is a request to strengthen the non-pharmaceutical aspect of the operation with an emphasis on public health including surveillance and preventive activities with all agencies (WHO, UNICEF) requested to support with conducting an effective communication programme. 

So far, the outbreak has not been graded as WHO is awaiting further epidemiological information from the MoPH including the age break down of suspected and confirmed cases, number of pregnant women affected and confirmation of the type of influenza.

(Continue . . . )

While there is no indication that there is anything unusual about this (presumably) seasonal H1N1 outbreak - with North Korean athletes now set to compete in the Winter Olympics in two weeks time - this is something we'll definitely want to keep an eye on.
 
I was led to this IFRC report by an amazing bit of reportage this morning from VOA news, (see North and South Korea Hit by Bird Flu Outbreaks Ahead of Olympics) which initially claimed that H1N1 was `avian or bird flu'.

Someone must have clued them in, as an hour later they changed the headline to North, South Korea Hit by Flu Outbreaks Ahead of Olympics and `corrected' their story to read:

North Korea’s Ministry of Public Health reported over 80,000 confirmed cases of the influenza strain H1N1 that is endemic in pigs, known as swine flu, between December 1, 2017 and January 16, 2018, according to a bulletin issued by the International Foundation of Red Cross and Red Crescent Societies.

Closer, but still no cigar. The H1N1 virus that is endemic in pigs is not the same virus as seasonal H1N1. Still, it is an improvement.  Of sorts.

WHO: First Global Antimicrobial Surveillance System (GLASS) Report

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While pandemics and outbreaks of novel diseases like avian flu, MERS, and Ebola, and pneumonic plague make the immediate headlines, in terms of medium-to-long term threats, there is little that can match the threat we face from the rise of antimicrobial resistant (AMR) bacteria.

Despite decades of warnings, this threat is largely under appreciated by the public because its progression has been gradual, the loss of antibiotics incremental, and so far at least . . . there have always been replacement drugs available when an antibiotic has failed.

But the number of new antibiotics in the pipeline are desperately few (see WHO: The World Is Running Out Of Antibiotics), and new and improved antimicrobial resistant threats keep emerging.

Five months ago CIDRAP reported on a Hypervirulent, highly resistant Klebsiella identified in China, one which a week later was described as New Klebsiella strains 'worst-case scenario,' experts say.

A press release from The Hong Kong Polytechnic University described this emerging threat. 

Furthermore, these CRKP strains are also hypervirulent and belong to ST11 type of CRKP, the most prevalent and transmissible CRKP strains in Asia. As these strains simultaneously exhibit the features of hyper-resistance, hypervirulence and high transmissibility, they can be considered a real superbug known as ST11 CR-HvKP (ST11 carbapenem-resistant hypervirulent K. pneumoniae).

It would be bad enough if this were the only significant antibiotic resistant threat we face, but below you'll find some of my blogs on a few (of dozens) of other unwelcome antimicrobial resistant milestones reported in the past couple of years:

Eurosurveillance: Mcr-One, Two, Three And Counting

MMWR: Fatal Pan-Drug Resistant CRE - Nevada 2016

mBio: 1st Colistin & Carbapenem Resistant E. Coli Infection In A U.S. Patient

Eurosurveillance: Identification Of A Novel Colistin-Resistant MRC-2 Gene In E Coli - Belgium, 2016

CDC HAN: Alerting Healthcare Facilities Of 1st MCR-1 Gene Detection In US Patient

For years we've been warned the world is barrelling towards a `post-antibiotic era' (see  Chan: World Faces A `Post-Antibiotic Era’). One where simple, once-treatable infections can kill, and where routine surgeries become increasingly dangerous.

While we aren't there yet, today the World Health Organization has released a  survey of antibiotic resistance around the world, gathered from 52 nations (25 high-income, 20 middle-income and 7 low-income countries) who are enrolled in the Global Antimicrobial Surveillance System (GLASS). 

While this first look is far from complete, as is explained in the summary (excerpt below), it is a start :

In this data call, countries provided AMR data primarily for pathogens isolated from blood specimens, followed  by  urine, stool, cervical and urethral ones. The  total  number  of  isolates  with  submitted  AST results varied considerably,  from  a  minimum  of  72  isolates  per  country  to  a  maximum  of  167,331  (for  countries  combined  total  of  507,746  isolates).  Only  one  country  submitted  data  on  all  selected pathogens.

First some excerpts from the press release, and then a link to the 164 page report. 

 
High levels of antibiotic resistance found worldwide, new data shows

News release
 

29 January 2018 | BANGKOK - WHO’s first release of surveillance data on antibiotic resistance reveals high levels of resistance to a number of serious bacterial infections in both high- and low-income countries.

WHO’s new Global Antimicrobial Surveillance System (GLASS) reveals widespread occurrence of antibiotic resistance among 500 000 people with suspected bacterial infections across 22 countries.

The most commonly reported resistant bacteria were Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, and Streptococcus pneumoniae, followed by Salmonella spp. The system does not include data on resistance of Mycobacterium tuberculosis, which causes tuberculosis (TB), as WHO has been tracking it since 1994 and providing annual updates in the Global tuberculosis report. 

Among patients with suspected bloodstream infection, the proportion that had bacteria resistant to at least one of the most commonly used antibiotics ranged tremendously between different countries – from zero to 82%. Resistance to penicillin – the medicine used for decades worldwide to treat pneumonia – ranged from zero to 51% among reporting countries. And between 8% to 65% of E. coli associated with urinary tract infections presented resistance to ciprofloxacin, an antibiotic commonly used to treat this condition. 

“The report confirms the serious situation of antibiotic resistance worldwide,” says Dr Marc Sprenger, director of WHO’s Antimicrobial Resistance Secretariat. 

“Some of the world’s most common – and potentially most dangerous – infections are proving drug-resistant,” adds Sprenger. “And most worrying of all, pathogens don’t respect national borders. That’s why WHO is encouraging all countries to set up good surveillance systems for detecting drug resistance that can provide data to this global system.” 

To date, 52 countries (25 high-income, 20 middle-income and 7 low-income countries) are enrolled in WHO’s Global Antimicrobial Surveillance System. For the first report, 40 countries provided information about their national surveillance systems and 22 countries also provided data on levels of antibiotic resistance.

(Continue . . . )

Global antimicrobial resistance surveillance system (GLASS) report
Early implementation 2016-2017

Authors: WHO
Publication details

Number of pages: 164
Publication date: 29 January 2018
Languages: English
ISBN: 978-92-4-151344-9
Downloads

Global antimicrobial resistance surveillance system (GLASS) report

Supplementary materials

• Supplementary electronic material
• GLASS data visualization from Global Health Observatory
• GLASS country profiles

Overview

The Global Antimicrobial Resistance Surveillance System (GLASS) Report: Early Implementation 2016-17 draws information from GLASS enrolled countries on the status of their AMR surveillance systems, and reports official national AMR data for selected bacteria that cause infections in humans: Acinetobacter spp., Escherichia coli, Klebsiella pneumoniae, Neisseria gonorrhoeae, Salmonella spp., Shigella spp., Staphylococcus aureus, and Streptococcus pneumoniae.

By the end of the first GLASS data call on 8 July 2017, 42 countries were enrolled in GLASS, of which 40 countries provided information on their AMR surveillance systems, and 22 provided 2016 AMR data. The aim of the report is to document participation efforts and outcomes across countries, and highlight differences and constraints identified to date. In this first GLASS report data vary considerably in terms of completeness, so no attempt was made to compare AMR status at a regional or global level. However, as GLASS and country participation evolves, the data reported will help understand surveillance capacities and mechanisms of reporting across countries in all regions, and will inform further GLASS development.

Related links

Antimicrobial Resistance: global report on surveillance (2014)
GLASS resource centre

Saudi MOH Announces 4 New MERS-CoV Cases

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After several days of silence the Saudi MOH has published three days of MERS activity reports (25th, 26th, 27th) overnight, adding 4 more cases, including 1 secondary household contact of a primary case reported on the 24th from Hail.  

Today's report raises January's reported totals to 22 cases and 12 deaths, a  marked increase over the 8 cases reported in December.

Of the 22 cases we are aware of in 2018, 5 have been linked to recent camel exposure, 15 are primary (community acquired), 1 was a secondary HCW exposure and 1 is a secondary household contact.

From the 27th:

The 26th:

And the 25th: 

Why Flu Fatality Numbers Are So Hard To Determine

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Now that the effects of this winter's severe flu season are being felt across the country - in the form of school closures, employee absenteeism, long ER waits & Tamiflu shortages - I'm beginning to see social media posts suggesting the CDC is deliberately `downplaying' the true severity of this year's outbreak.

While it is true that the numbers provided by the CDC each week in their FluView reports under represent the true burden of flu in the country, the CDC  has always been up front about the limitations of influenza surveillance and reporting.

Unfortunately, most reporters only see the weekly numbers - and report them as if they are  `facts' - rather than explain why these numbers are only representative of the relative severity of the flu season, not a true accounting of the impact.

In Friday's CDC press conference, Dr. Dan Jernigan once again addressed the problem of getting a handle on the number of flu fatalities (underlining mine).

DAN JERNIGAN:
(excerpt) 

So with pediatric deaths, these that are in the graphs and the ones we report again, probably also are an underestimation of the actual deaths that are out there. There may even be as much as twice than the number we have.

For the adults, curves that we have in the graphs from the pneumonia and influenza morality reporting system, that data comes from death certificates. You can look and see that the rapid rise that we have in this past couple of weeks, really looks very similar to what happened in 2014-15. With that, it’s possible it may go a little above it. It may peak at the same time. We don’t know right now, but again that information has some of the same lags because of information getting into the death certificates as well.

ROB STEIN: Do you have a total number of deaths?

DAN JERNIGAN: We don’t, partly because the systems that we collect those numbers from only are representative of parts of the U.S. So what we do then is look at the rates, so we can have trends over time.

In years where there is an H3N2 that is at that higher level of severity, we have estimated that at the end of the year there were 56,000 deaths. So the H3N2 years are the ones that have the higher number of deaths and that upper level is about 56,000 for the total year.

Unlike adult fatalities, pediatric flu deaths are required to be reported to the CDC. Even with this reporting requirement, many pediatric deaths are missed. Often because not all child deaths at home are tested for influenza, particularly when there are other comorbidities.

In October 2010's Lancet: Pediatric Mortality Related To Pandemic H1N1, we looked at the retrospective accounting by the CDC of adult and pediatric deaths during the pandemic.  Officially, there were roughly 280 pediatric fatalities reported across the country.

As bad as these numbers were, the CDC actually estimated that only about 25% of pediatric influenza deaths were identified – and put the `real’ number at closer to 1300.

With adults - particularly older adults - influenza deaths are even harder to quantify. 

Take it from a former paramedic, thousands of people die at home every day, and unless there is something suspicious or unexpected about a death, the patient's physician will generally sign the death certificate and no tests or autopsy are performed.  

If the patient had cancer, or heart problems, was of advanced age, or had any other significant comorbidity - that, not influenza or pneumonia - is usually listed as the primary cause of death.

Just four days ago we looked at another study that found the risks of a heart attack go up significantly in the first week after an influenza infection (see NEJM: Acute Myocardial Infarction After Laboratory-Confirmed Influenza Infection).
 

Only rarely would one of these heart attack victims be charted as a `flu fatality'.  And without that on the death certificate, it never makes it into the flu statistics.

Globally, it has been estimated that seasonal flu kills between 291,000 and 646,000 people each year (see The Lancet: Estimates Of Global Seasonal Flu Respiratory Mortality).

But even these recently revised numbers likely understate the burden of influenza, since they are based strictly on respiratory-mortality, and ignores other influenza-associated causes of death (heart attack, stroke, etc.).

Closer to home, the CDC explains how they derive their flu numbers:

Disease Burden of Influenza

The severity of influenza disease in the United States can vary widely and is determined by a number of things including the characteristics of circulating viruses, the timing of the season, how well the vaccine is working to protect against illness, and how many people got vaccinated. 

CDC tracks severity principally through its national Influenza Surveillance System that monitors key indicators like the percentage of deaths resulting from pneumonia or influenza, rates of influenza-associated hospitalizations, pediatric deaths and the percentage of visits to outpatient clinics for influenza-like illness.

In addition to using surveillance data, CDC uses mathematical models to fill in the picture of the disease burden and the impact of influenza immunization programs. Models are used to augment surveillance because most of the surveillance systems only look at portions of the U.S. population and in some cases there can be significant under-reporting of influenza deaths and hospitalizations. This page includes links to key resources on the burden of influenza.

https://www.cdc.gov/flu/about/disease/burden.htm

While it would be great if we had a way to definitively say how many flu deaths occur each year, there is simply no practical way to do so.  The same holds true in the United States, and around the world, for just about every cause of death.

But what we can say is this influenza season is particularly severe, and that tens of thousands of lives will be lost across the country this winter either due directly or indirectly to influenza infection.

The severity of this year's flu season isn't exactly a surprise. In late December the  CDC issued a HAN Advisory warning of an aggressive H3N2 season ahead, reduced vaccine effectiveness, and stressed the importance of early and aggressive treatment of severe influenza - particularly for `high-risk' patients - with antivirals. 

A month ago in Yes, We Have No Pandemic . . . But Line Up A Flu Buddy Anyway, I urged my readers to have, and to become, flu buddies - particularly to those who live alone. 

Hopefully we'll see a peak in the flu season soon, but even so, we've probably got another two months of flu ahead.  We might even see a second `surge' of H1N1 or Influenza B as H3N2 begins to wane in the spring.

As rough as this flu season turns out to be, it will pale compared to the next influenza pandemic.  Hopefully the lessons we learn from this winter will be taken to heart, and acted on, rather than simply fading away with the arrival of summer.

After all, we can only expect to get so many warnings.