Brazil's microcephaly and CNS disorder (M&CD) monitoring: Report No. 23, 2016-Week No. 16...

These graphs are made using data obtained from Week 16's Brazil Ministry of Health microcephaly and foetal and infant microcephaly and central nervous system (CNS) disorders (M&CD) report [1] and media report.[2]

Suspected M&CD cases...

The total number of suspected M&CD cases increased by 78 to 7,228 this week - the smallest rise reported by Brazil to date. This should not be confused with comments in the latest World Health Organization's Zika virus (ZIKV) situation report which states...

 "At this stage, based on the evidence available, WHO does not see an overall decline in the outbreak." 

That statement refers to current data whereas Brazil's M&CD report #23 is describing events that may have occurred approximately 20 to 40 weeks ago.[3] I picked that range because foetal disorders with preceding ZIKV detection have been reported to occur very rapidly, between 17 and 20 weeks in one case study.[4]

The chart above reports the number of newly suspected M&CD diagnoses in Brazil up to 23-April-2016. The cumulative curve (yellow dots; left hand axis) is steady and growing, but slowly steadily. This was the lowest weekly rise (orange bars; right-hand axis) on record.

Confirmed and discarded M&CD diagnoses...

M&CD cases under investigation decreased by 31 to 3,710 this week - the fifth consecutive decrease.

In the graph above, we can see that 79 (blue bars; right hand axis) suspected M&CD diagnoses were discarded upon closer investigation.The rate of these resolved diagnoses (line with blue dots, left-hand axis) is slowing but still seems to be outpacing the rate of confirmed M&CD diagnoses (red dots, left-hand axis). The cumulative number of M&CD diagnoses does continue its climb this week (+30), but this is the smallest addition of new diagnoses on record (red bars; right-hand axis).

The number of these M&CD diagnoses to be confirmed with a ZIKV infection also grows (green dots; left-hand axis) but by just 2 new detections to 194 this week (green bars; right-hand axis). That's the smallest rise on record. Those confirmed ZIKV infections represent 16% of all confirmed diagnoses and 3% of all suspect M&CD cases - but these are not fair comparisons for a range of reasons I won't go on about here.

Why are M&CD diagnoses slowing...?

It's not precisely known why the numbers of M&CD diagnoses are slowing in Brazil. Whatever their cause(s), the trigger(s) for the anomalies occurred in the past - as far as 9 months or as close as perhaps 20 weeks. One suggestion which ties in with the timing of arbovirus epidemics in Brazil, is the weather and its impact on the mosquito breeding cycle. (Thanks Luis F. B. Correia) Mosquitoes are assumed to be the major vector for transmitting ZIKV, wherever in the world it may be. That's a safe bet as far as we know. Undoubtedly, reporting on mosquito detections is not a priority. Only Mexico has reported infected wild-caught mosquitoes to date.[5] There have been more monkeys identified as ZIKV-infected than mosquitoes![5,6] For now at least.

The rainy season begins in the north-east (where M&CD has mostly been diagnosed) in May. Infections are likely to pick up from then - if we crudely add 6-9 months to May 2015 we get to October-2015 - January-2016. 

August saw a rise in microcephaly diagnoses in Pernambuco State in the north-east.[6] 

November is when the Brazil ministry declared a link between M&CD and ZIKV.[7] 

It all kinda fits. 

None of these numbers are precise though because when and where ZIKV was becoming established in Brazil is not known. It is predicted to have been as early as May-December 2013 based on analysis of viral genome sequences to hand,[9] but local transmission was not detected (looked for?) until April/May 2015.[9,10] It may have been there earlier.

Solid data and answers continue to evade trapping. As do ZIKV positive mosquitoes apparently.

References...

1. http://portalsaude.saude.gov.br/images/pdf/2016/abril/27/COES-Microcefalias---Informe-Epidemiol--gico-23--SE-16-2016--25abril2016-20h07.pdf
2. http://portalsaude.saude.gov.br/index.php/cidadao/principal/agencia-saude/23386-saude-confirma-1-198-casos-de-microcefalia-no-pais
3. http://apps.who.int/iris/bitstream/10665/205686/1/WHOsitrep_28Apr2016_eng.pdf?ua=1
4. http://www.nejm.org/doi/full/10.1056/NEJMoa1601824?query=featured_zika
5. http://virologydownunder.blogspot.com.au/2016/04/biting-assumptions.html
6. http://virologydownunder.blogspot.com.au/2016/04/three-monkey-species-and-some-labs.html
7. http://www.theguardian.com/global-development/2016/jan/25/zika-virus-mosquitoes-countries-affected-pregnant-women-children-microcephaly
8. http://wwwnc.cdc.gov/eid/article/22/6/16-0062_article
9. http://portalsaude.saude.gov.br/index.php/cidadao/principal/agencia-saude/23384-saude-divulga-primeiro-balanco-com-casos-de-zika-no-pais
10. http://science.sciencemag.org/lookup/doi/10.1126/science.aaf5036

The season of the MERS...is mainly whenever the infection control fails

I still only see a "seasonality" to MERS and human MERS-CoV detections that is made up of the times when hospital outbreaks spread cases due to missed opportunity to control and prevent infection wihtin their walls. In other words - no real season at all. 

MERS-CoV is an opportunistic virus - which includes making the most of the frequent opportunities we humans provide for it to spread.

Data from public sources up until December 3rd 2015.
Click on image to enlarge.

Any true seasonality is in that small percentage of cases that are the result of a primary, sporadic infection from an infected and infectious camel. Those cases may be related to times of camel calf weaning when young camels acquire their first infection, or it might just be whenever a particular herd has MERS-CoV raging though it.

H7N9 age with time: is a younger adult demographic emerging this time around?

This is a big graphic - sorry for that - but I thought it best to show the distribution of age bands (this is updated from the paper I co-authored recently with Joseph Dudley) alongside the shifting age in total numbers and proportion of cases each week. The data are all publicly sourced and verified against the WHO and scientific literature whenever possible and of course, against FluTrackers excellent case list.

1 case is lacking age data.

The chart below (click on it to enlarge and see much more clearly) then some comments underneath. Keep the previous sex/week chart in mind (it's trend has not changed much with the latest cases; these charts also result from a question from CIDRAP's Lisa Schnirring last Saturday) when looking at this. Is any effect seen below due to the increased female representation?

Click on image to enlarge.
It's probably more technically correct to use a line graph for (c) 
since a linked line implies that we know what happens in between 
each data point, but bars just don't show up clearly enough.

1. The median age of all H7N9 cases (surviving and fatal) is currently at 59-years; the mode is at 54-years.
2. The median age since Week 33 (see earlier post for why this number) is 54-years whereas from Week #1 to Week #32 it was 60-years. Is this a significant lowering of the median age in wave 2 or just because we're coming into Marc-April, where things may even out?
3. 74% of all cases are aged 40-years or older (M:F 1:2.36); 48% are 60-years of older (M:F 1:2.23); 6% are 20-years or younger (M:F 9:1)
4. The age band graph (a) looks very similar to that which we published in late 2013 using 136 avian influenza A(H7N9) virus cases (not at 175 cases)
5. The total numbers in graph (b) show that patients 20-years of age or younger have not yet shown up among the new wave of H7N9 cases, and if we look at the proportion of each age band each week (c), we can see that a younger than 60-year old demographic is predominating from December, as it did back in March and April 2013.

The case against over-interpreting MERS-CoV detection by month...

Click to enlarge. MERS-CoV cases plotted by month of
detection (global data; combining 2012 and
2013 confirmed detections).

There are a number of reasons why I started my post yesterday (my time) with "I'm the first one to say its way to early to be talking about the seasonal distribution". Let's look at some of those reasons today:

1. Where there are few positives in the chart, there has also been very little testing done. The first validated PCR assay was published in 27th September 2012. So Sept-Dec 2012 cases are few and far between for this reason.
2. We are not yet 12-months beyond the announcement of the discovery of MERS-CoV (then nCoV and subsequently HCoV-EMC/2012). It was announced via ProMED on the 20th of Sept and the first genome and clinical study went online 17th October 2012. So no real screening had been done before that time. Cases shown prior to Sept 2012 that identified were retrospectively and not the result of systematic screening
3. As far as I know, screening is still mostly done on a case by case (and contacts thereof) basis. We don't know whether MERS-CoV is circulating endemically in the KSA or any other peninsula country. This is an important data gap since it may be humans that are acting as the reservoir - for all we know
4.  If we look at my post prior to the seasonality chart last night, we can see that cases are climbing steadily - have been since April, and there is no real sign that there is a change in that climb by month. Some reduction of numbers July & August but September is shaping up to be a big month.
5. The spike in cases starting in April was related to a hospital outbreak (the Al-Hasa cluster). And things have rolled on since then. What triggered that outbreak or how the first case(s) acquired the infection remains unknown

So why draw the chart if it is not an accurate representation of true seasonality? Because it gives us an idea of how all the cases officially announced so far are falling out over time, based on the data we have. 

But it should not be over-interpreted. 

We'd need a much greater number of cases and probably a couple of years of surveillance (including community screening) before we could accurately define whether MERS-CoV appears with any seasonal recurrence. Nonetheless, the seasons, or events that happen with seasonal regularity, may influence the risk of exposure and spillover. Also, most of the other seasonal human CoVs occur at their peak every couple of years, and even then, some occur in very low proportions of specimens from people with acute respiratory tract infections. That may be irrelevant to an emerging CoV, or not, so it may take even longer before we can speculate on any seasonal regularity to MERS-CoV infections; if we don't first stamp out the virus altogether as we did with the human SARS-CoV.

So to conclude, before I have to find something and PCR it, given the small amount of data we have, and hints that it might be only the tip of that well referred to iceberg, the more we can extract from what we have the better our chances of finding some clues to the host and some risks for acquiring infection.

Can MERS-CoV seasonality tell us anything about acquisition of MERS?

Click to enlarge. Combined MERS-CoV cases for 2012 & 2013.

I'm the first one to say its way to early to be talking about the seasonal distribution of a new or emerging virus when there are only 124 cases worldwide. 

Right. 

Having said that, I thought I'd plot the cases by date of illness onset or (less satisfactorily) date they were first reported (even if that first was the report of a death). 

When combining the 15-months worth of case data for 2012 and 2013, the graph revealed a single "season" or at least larger numbers around summer in the Kingdom of Saudi Arabia (KSA). Because >80% of cases have occurred in the KSA, I have also listed a few festivals (some of which are frequented by camels) as well as the peak temperature variations and dust storm activity.¹ 

While I have no idea whether weather could be kicking up clouds of infectious CoV, it is an interesting co-occurrence, as are the presence of a number of festivals before case numbers spike. The Saudi Gazette commented that the risk of [acquiring?] bacterial and viral infections increases during dust storm season as do complication due to allergen exposure.

Of course we also know that some large clusters of cases have originated form hospital outbreaks and so environmental factors may play very little role at all. Or they might. Its impossible to say. But it is worth considering what could be happening up 2-weeks prior to a sharp rise in cases - if only to identify 1 index case that then ended up triggering a hospital outbreak.

1. Dust Storms in the Middle East: Sources of Origin and Their Temporal Characteristics. http://ibe.sagepub.com/content/12/6/419.short
2. http://www.magazine.noaa.gov/stories/mag86.htm
3. http://www.saudiaramcoworld.com/issue/200803/heads.high.htm

Flu season isn't the only season.

Its worth noting that when we talk about flu season we are talking about that time of year when flu cases peak. Its not flu season in the US now but there are still cases of influenzavirus spreading among humans. Its just not at epidemic levels (case numbers significantly above the norm).We are entering normal flu season in other parts of the world though, like down here in Aus, although cases are currently sparse. Cases of seasonal flu in one country can be easily spread to other countries by global travel. This is not just the case for influenza viruses of course. Any human respiratory virus ticks over at baseline levels outside of its main "season". Most of the time these infection come and go quickly and with relatively little illness.
Remember, viruses don't know the temperature outside, or the cloudiness - it's the hosts of infection that play the biggest role in virus activity.