Brazilian MOH: Weekly Microcephaly Report - April 26th

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Brazil has posted their weekly Microcephaly investigation update, and once again we see the number of new cases added over the past week has declined, dropping down into the double digits for the first time since the alarm was raised last fall.

While the cause of this drop is unknown, a few possible factors include:

• Brazil recently adopted a more stringent definition for microcephaly 
• Much of Brazil was still in their winter dry season (Aug-Dec) - with presumably fewer mosquitoes - when this week's birth cohort were in their 1st & early 2nd trimester
• Brazil's mosquito control efforts and mosquito protection awareness efforts were starting to ramp up at that time as well

Overall, only 78 new suspected cases were added last week, a quarter of what we were seeing only a couple of months ago. Meanwhile another 91 have been discarded as not meeting the criteria for microcephaly, while 30 were confirmed.

The total remaining under investigation sits at 3,710. 

While microcephaly is the most visibly striking congenital defect, we've been warned by CDC, NIH, and WHO that maternal Zika infection may produce other, less obvious neurological deficits in developing fetuses. 

It may be some time before we know whether any of these `discarded' cases will go on to display other congenital defects
.

Registration Date: 26/04/2016 17:04:33 the amended 26/04/2016 17:04:31 the

REPORT CARD

Health confirmed 1,198 cases of microcephaly in the country

Of the 7,228 cases reported so far to the Ministry of Health, 3,710 are still under investigation and 2,320 were discarded

Until April 23, it was confirmed 1,198 cases of microcephaly and other nervous system disorders, suggestive of congenital infection, throughout the country. In all, 7,228 suspected cases have been reported since the start of the investigation in October 2015, and 2,320 were discarded. Other 3,710 are under investigation. 

The information is the new epidemiological bulletin of the Ministry of Health, released on Tuesday (26), containing the information passed on by state health departments.

Of the total confirmed cases, 194 had laboratory confirmation to the Zika virus. However, the Ministry of Health points out that this figure does not represent adequately the total number of cases related to the virus. That is, the folder considers that there was infection Zika most of the mothers who had babies with a final diagnosis of microcephaly.

The 1,198 confirmed cases occurred in 435 municipalities located in 22 Brazilian states: Alagoas, Bahia, Ceará, Maranhão, Paraíba, Pernambuco, Piauí, Rio Grande do Norte, Sergipe, Espírito Santo, Minas Gerais, Rio de Janeiro, Amapá, Amazonas , Pará, Rondônia, Distrito Federal, Goiás, Mato Grosso, Mato Grosso do Sul, Parana and Rio Grande do Sul. Already 2,320 cases were discarded because of normal examinations or submit microcefalias and / or changes in the central nervous system causes no infectious.

In the same period, there were 251 suspected deaths of microcephaly and / or alteration of the central nervous system after birth or during pregnancy (miscarriage or stillbirth). Of these, 54 were confirmed to microcephaly and / or alteration of the central nervous system. Other 167 are still under investigation and 30 were discarded.

It should be noted that the Ministry of Health is investigating all cases of microcephaly and other disorders of the central nervous system, informed by the states, and the possible relationship with the Zika virus and other congenital infections. Microcephaly can be caused, many infectious agents, in addition to Zika, as Syphilis, Toxoplasmosis, Other Infectious Agents, Rubella, Cytomegalovirus and Herpes Viral.

The Ministry of Health advises pregnant women to adopt measures to reduce the presence of the mosquito Aedes aegypti , with the elimination of breeding sites , and protect themselves from mosquito exposure, keeping doors and closed or screened windows, wear pants and long-sleeved shirt and use repellents allowed for pregnant women.

OIE Notification: Multiple H5N1 Outbreaks In Iraq

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Officially, Iraq has been free of H5N1 avian flu since the spring of 2006, a time when a handful of poultry outbreaks and 3 human infections were reported.  How good surveillance, testing, and reporting has been over the past decade is an open question,

Over the years we've seen a number of Iraqi media reports suggestive of bird flu. 

• In 2008 we saw Iraq: H9 Bird Flu Detected In Duhok, Reports Of Extensive Bird Culling In Iraq, and KUNA: Bird Flu Detected In Iraqi Birds.   
• In 2011,we saw Iraq: Media Report Of Numerous Poultry Deaths, while in the spring of 2015, we saw Voice Of Iraq: H5N1 Reported in Sulaimaniya Poultry

None of these reports were ever confirmed by the OIE, and so today's report from the OIE of six, widely scattered H5N1 outbreaks (Dec 2015 - Feb 2016), is the first confirmation of H5N1 in Iraq in more than a decade.

Last week, we saw the first outbreak of H5N1 in Lebanon: Minister of Agriculture followed by an FAO confirmation, while earlier this morning Sharon Sanders of FluTrackers  picked up a recent report of fresh poultry die offs in Iraq.

Iraq - Unknown disease killed at least 60,000 poultry causing price rise in several provinces including Muthanna - April 17, 2016

We'll have to wait to see if this latest die off is linked to H5N1.

Dengue & Zika: Does What Goes Around, Come Around?

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More than two years ago, in Zika, Dengue & Unusual Rates Of Guillain Barre Syndrome In French Polynesia, we looked at the first reports of serious illness linked to the Zika virus, and speculation that it might be due to concurrent or prior infection with Dengue.

A few weeks later, in a Eurosurveillance report (see Zika Virus Infection Complicated By Guillain-Barré Syndrome), the authors wrote:

Our patient, like part of others who also presented a GBS, harboured serological markers of resolute dengue and recent ZIKA infections. This raises the hypothesis of a sequential arboviral immune stimulation responsible for such unusual clustering of GBS cases during concurrent circulation of ZIKA and two dengue serotypes. The risk of developing GBS would be consequently underlain by a specific sequence of DENV and ZIKA infections.

It is not so far-fetched an idea, as we see it sometimes in sequential dengue infections, in a phenomenon called ADE (Antibody Dependent Enhancement).

There are 4 distinct, but closely related, serotypes of the Dengue virus, and the first infection of any serotype is usually mild. The patient recovers with lifetime immunity, but remains susceptible to the other three serotypes.

When infected a second time,the host’s immune system - which already has neutralizing antibodies against the first DENV infection - misidentifies the second DENV infection as the first strain.

Rather than creating new neutralizing antibodies to fight the infection, it deploys its existing cross reactive, but non-neutralizing (read: ineffective) antibodies to the field of battle.

When congenital birth defects began cropping up in Brazil last fall, the ADE theory was immediately suggested as a possible contributing factor, since Zika is genetically very similar to Dengue. 

You'll find a January discussion here, and in February Helen Branswell wrote Dengue could be the surprise culprit making Zika worse, researchers say.

While this is all still an unproven theory, if true, it offers hope that the risks of seeing severe fetal outcomes, or neuroinvasive disease, are less in regions where other flaviviruses are not endemic. 

Adding a bit more fuel to this hypothesis, we have a new paper - that while not yet published in a peer-reviewed journal - has been offered as a preview on the BioRxiv (Bio Archive) site, called:

Dengue Virus Antibodies Enhance Zika Virus Infection,m 

Lauren M Paul, Eric R Carlin, Meagan M Jenkins, Amanda L Tan, Carolyn M Barcellona, Cindo O Nicholson, Lydie Trautmann, Scott F Michael, Sharon Isern

doi: http://dx.doi.org/10.1101/050112

Abstract

Background For decades, human infections with Zika virus (ZIKV), a mosquito-transmitted flavivirus, were sporadic, associated with mild disease, and went underreported since symptoms were similar to other acute febrile diseases endemic in the same regions. Recent reports of severe disease associated with ZIKV, including Guillain-Barre syndrome and severe fetal abnormalities, have greatly heightened awareness. Given its recent history of rapid spread in immune naive populations, it is anticipated that ZIKV will continue to spread in the Americas and globally in regions where competent Aedes mosquito vectors are found. 

Globally, dengue virus (DENV) is the most common mosquito-transmitted human flavivirus and is both well-established and the source of outbreaks in areas of recent ZIKV introduction. DENV and ZIKV are closely related, resulting in substantial antigenic overlap. Through a mechanism known as antibody-dependent enhancement (ADE), anti-DENV antibodies can enhance the infectivity of DENV for certain classes of immune cells, causing increased viral production that correlates with severe disease outcomes. 

Similarly, ZIKV has been shown to undergo ADE in response to antibodies generated by other flaviviruses. However, response to DENV antibodies has not yet been investigated. 

Methodology / Principal Findings We tested the neutralizing and enhancing potential of well-characterized broadly neutralizing human anti-DENV monoclonal antibodies (HMAbs) and human DENV immune sera against ZIKV using neutralization and ADE assays. We show that anti-DENV HMAbs, cross-react, do not neutralize, and greatly enhance ZIKV infection in vitro. DENV immune sera had varying degrees of neutralization against ZIKV and similarly enhanced ZIKV infection. 

Conclusions / Significance Our results suggest that pre-existing DENV immunity will enhance ZIKV infection in vivo and may increase disease severity. A clear understanding of the interplay between ZIKV and DENV will be critical in informing public health responses in regions where these viruses co-circulate and will be particularly valuable for ZIKV and DENV vaccine design and implementation strategies.

Follow the above link to read the full PDF of the study.

Vaccine: Taking Your Best Shot

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The effectiveness of the flu jab can vary widely from one person to the next, and over the years we've seen a number of theories as to why this might be. The usual suspects - age (over 65), or a less than robust immune system - are often cited as likely factors, but other theories include:

• Taking antipyretic medications – like acetaminophen, Aspirin, or other NSAIDs - see A Few Inflammatory Remarks
• Similar concerns have been voiced over statins (see JID: Statins & Flu Vaccine Effectiveness)

Overnight a new study, published overnight in the Journal Vaccine, has been making headlines with a new possibility: that the time of day you are vaccinated may make a difference in your body's immune response.


The cluster-randomized trial followed 276 adults (over 65) across 24 GP practices in the West Midlands, UK who - between 2011 and 2013 - were assigned to receive their flu shots either in the morning or afternoon.

Follow up blood work showed substantially higher antibodies against H1N1 and Influenza B (but not H3N2) in the morning vaccination cohort. 

The poor performance of H3N2 vaccines over the past few years may have contributed to the less than stellar improvement for that strain (see Branswell: H3N2 Remains the `Weak Link’ In The Flu Vaccine). 


While the results suggest morning vaccination may increase vaccine effectiveness, this study (like all studies) is subject to some limitations, and confirmatory studies are needed. Follow the link below to read it in its entirety.

Morning vaccination enhances antibody response over afternoon vaccination: A cluster-randomised trial

Joanna E. Long^a, Mark T. Drayson^b,Angela E. Taylor^d, Kai M. Toellner^b, Janet M. Lord^{c, 1}, Anna C. Phillips^{a, 1, ,}

doi:10.1016/j.vaccine.2016.04.032Get rights and content

Open Access funded by Medical Research Council

Under a Creative Commons license

Highlights

• Early small studies provide mixed evidence for effects of time of vaccination on antibody response.
• This is the first large scale randomised trial of different times of vaccination.
•  Morning vaccination enhances the antibody response to the influenza vaccine.
•  This simple manipulation is cost neutral and may improve protection from influenza in older adults.

         ABSTRACT (Excerpts)

Design

We utilised a cluster-randomised trial design.

Setting

24 General Practices (GPs) across the West Midlands, UK who were assigned to morning (9–11 am; 15 surgeries) or afternoon (3–5 pm; 9 surgeries) vaccination times for the annual UK influenza vaccination programme.

Participants

276 adults (aged 65+ years and without a current infection or immune disorder or taking immunosuppressant medication).
Interventions

Participants were vaccinated in the morning or afternoon between 2011 and 2013.

Main outcome measures

The primary outcome was the change in antibody titres to the three vaccine influenza strains from pre-vaccination to one month post-vaccination. Secondary outcomes of serum cytokines and steroid hormone concentrations were analysed at baseline to identify relationships with antibody responses.

Results

The increase in antibody levels due to vaccination differed between morning and afternoon administration; mean difference (95% CI) for H1N1 A-strain, 293.3 (30.97–555.66) p = .03, B-strain, 15.89 (3.42–28.36) p = .01, but not H3N2 A-strain, 47.0 (−52.43 to 146.46) p = .35; those vaccinated in the morning had a greater antibody response. Cytokines and steroid hormones were not related to antibody responses. No adverse events were reported. 

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 From the University of Birmingham press release:

Vaccinations are more effective when administered in the morning 
 

Posted on 26 Apr 2016

New research from the University of Birmingham has shown that flu vaccinations are more effective when administered in the morning.

The findings, published in the journal Vaccine, suggest administering vaccinations in the morning, rather than the afternoon, could induce greater, and thus more protective, antibody responses.

(SNIP)

Dr Anna Phillips, the Principal Investigator of the study from the School of Sport, Exercise and Rehabilitation Sciences at the University of Birmingham explained, “We know that there are fluctuations in immune responses throughout the day and wanted to examine whether this would extend to the antibody response to vaccination. Being able to see that morning vaccinations yield a more efficient response will not only help in strategies for flu vaccination, but might provide clues to improve vaccination strategies more generally.”

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UK Resistance Alert: Expansion Of Azithromycin Resistant Gonorrhea Outbreak

Credit CDC PHIL

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In the 75 year history of antibiotics, one truth has been apparent from almost the beginning; over time, and particularly with repeated exposure, bacteria can become resistant to antimicrobials.    

Even before penicillin could be rolled out for clinical use, a β-lactamase (Penicillinase) was identified by researchers Abraham and Chain in a sample of Gram-negative E. coli in 1940 (cite).

Over the next two decades penicillinase resistance spread to other bacteria, which required the creation of newer generations of the drug (such as Methicillin in 1959), that were resistant to these enzymes.

Methicillin resistance emerged in the UK only 2 years later, and while it is no longer used, we retain its name in the term MRSA (Methicillin-resistant Staphylococcus aureus) (cite).

One of the earliest, and most important uses for penicillin was in curing gonorrhea. But by the 1970s penicillin/tetracycline resistant forms of Neisseria gonorrhoeae began to appear in the United States, and eventually cephalosporins  replaced them as the first-line treatment for gonorrhea.

In 1993, the CDC also recommended the use of fluoroquinolones (i.e., ciprofloxacin, ofloxacin, or levofloxacin) to treat gonorrhea, as they were relatively cheap, effective, and allowed for a 1 dose treatment.

But in less than a decade, fluoroquinolone-resistant N. gonorrhoeae (QRNG) emerged out of Asia and began showing up in Hawaii and then California (see MMWR Increases in Fluoroquinolone-Resistant Neisseria gonorrhoeae --- Hawaii and California, 2001).

 
In 2007, the CDC announced Fluoroquinolones No Longer Recommended for Treatment of Gonococcal Infections, leaving just one class of antibiotics - the cephalosporins - still recommended and available for the treatment of gonorrhea.

Today, a combination therapy of a cephalosporin (cefixime or ceftriaxone), along with a macrolide antibiotic (preferably azithromycin) are the only recommended treatments that remain for Gonorrhea.

 
But given the above history, it no surprise that we are beginning to see cracks in this last line of defense.   A few past blogs include: 

Gonorrhea: The Path Of Increased Resistance

Referral: McKenna On Almost-Untreatable Gonorrhea

ECDC Response Plan To Multi-Drug Resistant Gonorrhea

 

Last December following an outbreak of  an outbreak of `super gonorrhea' in Leeds, England  (cite BBC report), Dame Sally Davies - England's Chief Public Health Officer - issued a dire warning that: Gonorrhoea 'could become untreatable'.

Last October a National Resistance Alert was issued in the UK ordering all gonococcal samples tested for azithromycin resistance and that resistant isolates be referred to PHE’s Sexually Transmitted Bacteria Reference Unit (STBRU).

Fast forward to mid-April, and the UK's PHE  published a new report (Outbreak of high level azithromycin resistant gonorrhoea in England) detailing the spread of their `super gonorrhea outbreak' well beyond Leeds (excerpts below).

Volume 10 Number 15 Published on: 15 April 2016


Outbreak of high level azithromycin resistant gonorrhoea in England

There have been 34 cases of high level azithromycin resistant gonorrhoea (HL-AziR) (MIC >256 mg/L) diagnosed amongst residents of England between November 2014 and April 2016 (see figure). HL-AziR has previously been observed only sporadically in the UK and elsewhere. 


Cases of highly azithromycin-resistant Neisseria gonorrhoeae 2014 to February2016

The outbreak first emerged in residents of Leeds and the north of England [1]. The outbreak has since spread to the West Midlands and south of England, including London. Initial cases were among heterosexuals but more recent evidence suggests HL-AziR is now spreading among men who have sex with men. Partner notification has been of limited success: of 50 partners thus far reported, only 22 (44%) were successfully contacted, 18 (82%) of which were tested; 17 (94%) tested positive for gonorrhoea. Whole genome sequencing of a subset of the isolates indicates that many of the isolates were clonal, consistent with recent transmission, and the remainder are closely related and share a more distant common ancestor.  

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This continuing geographic expansion of resistant gonorrhea in England has prompted PHE to issue a fresh Resistance alert: high-level azithromycin resistance in Neisseria gonorrhoeae dated May 2016. 

 

Resistant gonorrhea is just one prong of our growing antibiotic resistance problem, something which author, blogger, and journalist Maryn Mckenna has been writing and talking about for more than a decade.


If you haven't already seen it, I highly recommend you view:

Maryn McKenna’s TED Talk - What do we do when antibiotics don’t work any more?

WHO MERS-CoV Update - Bahrain

 

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Earlier this month there were reports of an imported (from Saudi Arabia) MERS case in the island Kingdom of Bahrain (see CIDRAP Bahrain, Saudi MERS detections tied to camel contact). Despite their close proximity to KSA, this is first case reported by the Kingdom.

Bahrain is connected to Saudi Arabia by the 24 km King Fahd Causeway, which accommodates more than 50 thousand travelers each day.  

Today, the World Health Organization has published the following update, which elaborates on, and confirms many of the previously known details. 

Middle East respiratory syndrome coronavirus (MERS-CoV) – Bahrain

Disease outbreak news
25 April 2016

 
On 10 April 2016, the National IHR Focal Point of Bahrain notified WHO of a fatal case of Middle East respiratory syndrome coronavirus (MERS-CoV). This is the first case reported in Bahrain.

Details of the case

A 61-year-old, Saudi male was admitted on 29 March to a health care facility in Bahrain for an unrelated medical condition. He was screened for MERS-CoV, a routine procedure for those coming from Saudi Arabia, and tested negative for the infection. On 4 April, and while hospitalized, he developed symptoms. On 9 April, the patient tested positive for MERS-CoV. The patient had comorbidities. He owned a dromedary barn in Saudi Arabia and had a history of frequent contact with them and consumption of their raw milk. He had no history of exposure to the other known risk factors in the 14 days prior to the onset of symptoms. On 12 April, he was transferred to a hospital in Dammam city, Saudi Arabia but passed away on the same day.

The National IHR Focal Point for the Kingdom of Saudi Arabia has been notified. Contact tracing of household and healthcare contacts is ongoing for this case. The Ministry of Agriculture was notified and investigation of dromedaries is also ongoing.

Globally, since September 2012, WHO has been notified of 1,725 laboratory-confirmed cases of infection with MERS-CoV, including at least 624 related deaths.

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