Archiv der Kategorie: Noteworthy

Covid-19 genetics – Any role of MIP1B?

The first GWAS of severe COVID-19 infection was published in the NEJM with the main hit at rs11385942 at locus 3p21.31, a region linked by the authors to LZTFL1. The GWAS catalogue points to MIP1B ( Macrophage Inflammatory Protein 1 beta, MIP-1b, CCL4) level that has been mapped there as well.

https://www.ebi.ac.uk/gwas/genes/LZTFL1
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223028/

MIP-1B seems to be increased in patients with COVID-19 as a study showed that levels of various CCGFs, including PDGF-BB, CCL5/RANTES, CCL4/MIP-1β, IL-9, and TNF-β were upregulated in COVID-19 patients but negatively correlated to disease severity.

Supplement https://www.nature.com/articles/s41392-020-0211-1

Another study measured also MIP-1B but no major effect

Supplement https://insight.jci.org/articles/view/139834/sd/1

A recent Frontiers review discusses the relationship to the cytokine storm in fatal COVID-19 infection but again no isolated effect. Nevertheless I have a gut feeling from a 1995 Science paper that it could be relevant as it was identified as the major HIV-SF produced by CD8+ T cells (which are so important also in COVID-19 recovery).

Corona – die wichtigsten Videos der Woche

Beginnen wir mit dem Appell der Bundeskanzlerin “Bitte bleiben Sie, wenn immer möglich, zu Hause”.

 

Dann der wichtigste Corona Experte in Deutschland “So etwas wie eine Meinung gibt es eigentlich in der Wissenschaft nicht“.

 

Ein aktueller Blick in die Schweiz (Zahlen hier) mit einem wunderbaren Musical.

 

Damit zu den Folgen im Spital Schwyz mit Prof. Reto Nüesch (Nachfolger des legendären Paul Vogt Appell).

Masks are working!

CDC recommends them, RKI also while there are still some people who raise doubts, people who are wearing either pseudo-masks or face shields.

So here is another argument by the most contagious airborne disease – measles has a secondary attack rate of >90%. Using masks should have reduced the incidence. And it did – as shown by a recent eurosurveillance.org paper

Average number of measles cases in 2010–2019 and number of measles cases in 2020 reported to TESS (ECDC) by month of statistics during the January to May measles season peaks, EU/EEA and the UK and selected countries. https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.31.2001390#abstract_content

This is fully backed by live European data http://atlas.ecdc.europa.eu

http://atlas.ecdc.europa.eu/public/index.aspx 28Sept20

Corona Infektionsprophylaxe und HEPA Raumluftfilter

(eigene Stellungnahme vom 23.9.2020)

Schwebstofffilter (HEPA = High-Efficiency Particulate Air Filter) sind Hochleistungs-Partikelfilter zur Trennung von Schwebstoffen aus der Luft. Sie zählen zu den Tiefenfiltern, die in der Tiefe des Filtermediums trennen und Partikel mit einem aerodynamischen Durchmesser <1 µm eliminieren wie Bakterien und Viren, Pollen, Milbeneier, -kot , Stäube, Aerosole und Rauchpartikel. Als Filter können sowohl Einmalfilter, als auch wiederverwendbare Filter eingesetzt werden. Verwendet werden HEPA Filter in hochwertigen Staubsaugern wobei der Haupteinsatz aber spezielle Luftreiniger sind, die überall dort eingesetzt werden, wo die Luft von kleinsten Schwebeteilchen gereinigt werden soll. Man findet sie fest eingebaut in Operationssälen, Intensivstationen, Reinräumen zur Chipherstellung ebenso wie in mobilen Geräten. Corona Infektionsprophylaxe und HEPA Raumluftfilter weiterlesen

Translationale Forschung

Im aktuellen Laborjournal steht ein phänomenal guter Artikel zur translationalen Forschung “Von Maus zu Mensch durch das Tal des Todes

Die Translation von Ergebnissen der Grundlagenforschung in die klinische Anwendung klappt nicht besonders gut. Dabei ließen sich einige schwache Glieder der Translationskette sehr leicht ersetzen. Dumm nur, dass die neuen Glieder leider nicht so recht in unser akademisches Karriere- und Fördersystem passen würden.

Tolle, lege!

Hygiene conspiracy theorists argue at trumplevel

It is quite interesting to see how the proponents of the hygiene hypothesis are reacting to the Covid-19 pandemic, citing only selected BCG and polio studies and are advising (no disinfectant of course :-) but galectin

The fact that trained immunity can be induced raises the prospect of its exploitation to raise the threshold of resistance to COVID-19 infection … Some studies have already shown that communities that still use Bacillus Calmette–Guérin (BCG) as a vaccine against tuberculosis may have lesser instances of severe COVID-19 infection than those countries that do not use BCG. This notion has been complemented by advocating the use of BCG to vaccinate persons in an attempt to protect them against COVID-19. A recent letter by HIV pioneer Bob Gallo advocated using oral polio vaccine for a similar effect. We consider that administration of galectin molecules, some of which can activate the innate immune system might also represent an approach to reduce the consequences of COVID-19 infection. It is also worth noting that galectin therapy also has the potential to reduce the severity of COVID-19 once infected.

NIH grants EY05093 and AI142862. “Microbes & Infection” has an impact factor 2,3. Published by Institute Pasteur.

Why doesn’t the NEJM retract?

In contrast to what the NYT wrote and in contrast to what the SPIEGEL reiterates today – the NEJM letter form Munich wasn’t the first description of an asymptomatic patient – this was already published one week earlier on January 24, 2020.

…one asymptomatic child (aged 10 years) had radiological ground-glass lung opacities.

The wording of the letter was immediately criticized by Kai Kupferschmidt in Science

But now, it turns out that information was wrong. The Robert Koch Institute (RKI), the German government’s public health agency, has written a letter to NEJM to set the record straight, even though it was not involved in the paper.

The NEJM tried to rescue the letter with an online supplement giving more details from another phone call to the Chinese lady, making clear that she already had symptoms taking acetaminophen. But also Drosten did not want to retract according to a transcript of the press conference.

https://www.sciencemediacenter.de/fileadmin/user_upload/Press_Briefing_Zubehoer/Transkript_Coronavirus_PressBriefing_13022020.pdf

Maybe it was a somewhat unclear situation if the index case could not be interviewed (which should have been done when writing a case report)… Clearly this wasn’t a dysfunctional social media discussion but a basic scientific question as the following RKI report in the Lancet corrected numerous details. Differences of the two reports

The NEJM Article missed patient #13 who accompanied index #0.
#0 had been well with no signs or symptoms of infection” was wrong already at time of submission.
#0 had no business meeting on 19th (also wrong according to the online supplement).
#1 symptoms on 23rd not 24th.
#2 symptoms on 25th not 24th, meeting also on 20th.
#3 symptoms on 25th not 26th, contacts with #1 only 24th.
#4 symptoms 24th not 26th, met #0 not #1.

And again the Rothe version 0:32 tells version of #1…

Corona Mortalität- und Case Fatality Verlauf in den Bundesländern

Hier kommt ein Plot der Case Fatality Ratio nach Bundesländern.

Warum sinkt eigentlich die CFR, wo der Virus vermeintlich immer gleich tödlich ist?

Case Fatality Ratio (CFR, rot) definiert als kumulative Sterblichkeit innerhalb eines 7 Tage Zeitfensters das 14 Tage auf das symmetrische 7 Tagesfenster um den Indextag folgt. Fallzahlen hinterlegt in grau für den jeweiligen Indextag. Sliding Window mit Loess Smoother span=0.5. Für Definitionen siehe https://www.heise.de/newsticker/meldung/Zahlen-bitte-3-4-Coronavirus-Fallsterblichkeit-False-Number-4679338.html bzw https://www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/Steckbrief.html Datenstand: RKI 4.6.2020

 

Am Anfang der Pandemie waren die bestätigten Fälle selten, da nur begrenzt PCR Tests zur Verfügung standen, die CFR wird also massiv überschätzt. Dann steigt die Zahl der durchgeführten Tests, die Case Fatality Rate sinkt auf dem Höhepunkt der Pandemie auf Werte diesich mehr der Infection Fatality Rate annähert also der Zahl der Todesfälle pro Infektionen. Am Ende der Epidemie geht die CFR gegen Null, da es immer weniger Tote gibt. Insgesamt unterschätzt diese Rechnung die CFR, da Todesfälle auch noch nach dem Intervall auftreten können.

In dem Verlauf zwischen dem 15.3. und 15.4. könnten allerdings auch inhaltliche Aspekte eine Rolle spielen, etwa eine Lernkurve in den Kliniken, dass die Patienten besser behandelt werden. Es könnte aber auch ein positiver Effekt durch Mundnasenschutz sein, dass zum Beispiel Infektionen mit geringeren Virusmengen weniger tödlich verlaufen. Oder ein weiterer positiver Effekt, dass durch Kontaktbeschränkung weniger Gefahr durch Super Spreader droht.

Was davon stimmt, kann nur über neue Studien herausgefunden werden. Der Zeitverlauf zeigt jedenfalls, dass man die CFR sinnvollerweise nur am Ende einer Pandemie bestimmt.

Schauen wir uns noch einen Plot der Mortalität nach Landkreisen an.

Mortalitätskurven (rot) definiert als kumulative Sterblichkeit innerhalb eines 7 Tage Zeitfensters um den Indextag bezogen auf 1000 Einwohner des jeweiligen Land-/Stadtkreises. 412 Kreise wurden dafür ausgewertet. Rot zeigt die jeweiligen Spitzenreiter des Bundeslandes an. Datenstand: RKI 4.6.2020.

Am stärksten betroffen sind Baden-Württemberg, Bayern und Nordrhein Westfalen, wobei bei den einzelnen Landkreisen aber nicht Gangelt/Heinsberg sondern Mitterteich/Tirschenreuth den Spitzenplatz einnimmt. Details dazu in dem nächsten Post.

Spät-Intubation

In Deutschland gibt es zwei Wissenschaftler, die den Verlauf der Corona Pandemie massgeblich beeinflusst haben.

Der eine ist sehr bekannt, hat massgeblich die Strategie der Bundesregierung beeinflusst. Der zweite ist eher unbekannt, dafür verdankt ihm Deutschland die niedrige Mortalitätsrate: Dr. Thomas Voshaar.

Hier die Erklärung im O-Ton, warum die Mortalität hierzulande so viel geringer ist als in anderen Ländern.

Das Thema wurde auch in der Tagesschau und Monitor aufgegriffen und – logisch – von Anästhesisten kritisiert. Pathophysiologie und Mortalität in England und USA sprechen aber eindeutig gegen die Einwände.

Heinsberg und Tirschenreuth aus den Schlagzeilen, dafür Greiz, Coesfeld, Steinburg und Neuburg

Heute verschwindet Heinsberg und Tirschenreuth von der Corona Karte, wenn man die neue Definition “Neuinfektionen der letzten 7 Tage” nimmt. Ein grosser Erfolg der Massnahmen vor Ort.

Neu im Club dafür sind Greiz (Familienfeiern), die drei Schlachtereien Pforzheim Müller Fleisch, Coesfeld Westfleisch und Bad Bramstedt Vion, Esslingen war es eine Beerdigung, Neuburg eine Asylunterkunft, Rosenheim und Traunstein sind Altfälle von den Starkbierfesten.

RKI Situationsbericht von heute

The Gangelt Study

The Gangelt study that surfaced this morning is interesting as it includes now more sound statistics using GEE models to account for household clustering (in a previous interview the lead author denied the value of statistical models). The PDF is only available an internal university server without any doi number and timestamp – not even a “preprint” at all.

Maybe I am a bit disappointed as it remains basically a cross-sectional analysis, without any virus phylogeny and without any description if and how containment measurements were followed under lock-down conditions. At first glance, although being performed at a hotspot, PCR results are not particular exciting. 439/12597=3.4% as measured by official surveillance and 33/919=3.6% as measured by the authors.

The claim to fame (besides some annoying reports about the accompanying PR campaign that made it even into Science magazine) are those 15% antibody positive results. Everything in this paper depends on the IgG antibody specificity to Sars-Cov2. It is reported

as of April 7, 2020, validated in cooperation with the Institute of Virology of the Charité in Berlin, and the Erasmus MC in Rotterdam, Euroimmun, Lübeck, Germany). The data sheet (April 7, 2020) reports cross-reactivities with anti-SARS-CoV-1-IgG-antibodies, but not with MERS-CoV-, HCoV-229E-, HCoV-NL63-, HCoV-HKU1- or HCoV-OC43-IgG antibodies.

Interestingly this data sheet was produced only after the examination. I could neither obtain it per email nor is it available on the manufacturer’s website.  I also do not understand why Drosten criticized Streeck for this assay. Wasn’t he involved in the validation?

Here is how the authors checked their own methods

which is a bit weak regarding current pre-test standards, neither in terms of selection of samples, numbers and reporting. The press briefing even adds more confusion

as this reference is not cited in the preprint. I assume it is the  Lassaunière comparison (medRxiv preprint) that showed a specificity of 96% only which is n o t  s o good with the low prevalence expected.

posted April 10 (downloaded May 5) https://www.medrxiv.org/content/10.1101/2020.04.09.20056325v1

A further study on medRxiv reported a specificity of 99% using a “well-defined specificity panel of 147 serum and plasma samples” without any further description. Seroconversion data would also been helpful from Gangelt – why are those N=9 in the figure below not being retested after 2 weeks?

In the absence of any hard data the results remains questionable although it shouldn’t be impossible to design and validate a reliable test where even ultra-sensitive assays have been already published.
Why haven’t the neutralisation tests been incorporated?

Lets step into the results.

PCRreported overlaps with PCRnew as expected while I would like to see also the match of PCRnew with PCRreported negative results.

4.5.2020 downloaded from https://www.ukbonn.de/C12582D3002FD21D/vwLookupDownloads/Streeck_et_al_Infection_fatality_rate_of_SARS_CoV_2_infection2.pdf
Unfortunately all consecutive plots stratify for infection rate only (combining IgG+ and PCR+) but do not show if the significant difference between carnival / no carnival is due to IgG+. Did IgG+ probands suffer from more symptoms? Why do the co-morbidities not show up here as in many other studies? Why is there such a low household secondary infection rate although the initial transmission is so high?
The contact persons outside of the household are ignored. Unfortunately, the paper also does not show the data promised in a previous interview, for example data on drug use, seating arrangement at the festival, infection chain and association with school closing at the end of January. Will that be published only as salami sliced?
Compared to the April 9 report, based on 500 study participants there are also major discrepancies
– the number of inhabitants in Gangelt increased by 68 for whatever reason
– Forsa is no more mentioned in the acknowledgment
the percentage of PCR+ individuals was previously given as 2% but is now reported to be 3.6%. Either the first figure was completely wrong, or the additional 419 individuals must have contributed a phenomenal 5,5% PCR+ rate.

– the preliminary case fatality CFR was 0.37% based on 7 individuals. This figure remained unchanged even when moving to infection fatality IFR that should be lower as the denominator increased with more infections. Patients also continued to die after the end of the observation period, making the IFR estimate unreliable if not expanded by the 14-21 day usual symptom to death interval.

I tried to validate those 7 deaths reported in the manuscript for Gangelt until March 30. RKI reports 55 in the district Heinsberg until March 30. Did most of them really happen outside Gangelt?

According to the official statistics of the state department we may expect 11 deaths per month in Gangelt. So with the 7 reported cases we should find 18 cases by the end of March. According to the website https://www.aachen-gedenkt.de there are, however, 21 obituaries found in Gangelt eg 3 more than expected. Maybe there are some errors in my re-analysis as the obituaries do not always give the last address or not each death results in an obituary but we can assume that there was at least an excess of 10 and not only of 7 cases until March 30. For a final estimate we need to add at least 1 more case who died after the end of study. My estimate therefore is at least 11 and not just 7 cases.
– Why have the death certificates not been verified in a paper that has even “infection fatality rate” in the title?
– Why are there no virus tests in the victims?

There are few more but less important issues
– it does not make sense in Figure 5 for 1 person to be infected by 1 person
– the prevalence of 107 lung diseases in table 1 is wrong with the given percentage
– the “officially reported cases for this community 3.1%” in the abstract contradicts Fig 1A which gives 439/12597 or 3.5%
– a non responder survey is missing in particular as previously PCR+ individuals were underrepresented. Although not directly reported in the paper, I calculate the response to 407/600=67.8% which is acceptable but not top class.
Taken together, it seems that the study leaves us with a lot of open questions. What is the functional relevance of this particular Ig G+? Is there any Ig G+ reinfection? What do the N=20 in the diagram 2C mean – chronic carrier, false positives, re-infected patients?
The new FAZ headline published in parallel is clearly unwarranted as hotspot data can not be extrapolated.
15% of 81 Million infected? Only now I get the argument: the authors increase their infection rate from 15% to 20% due to some non-participation, then use the IFR based on 7 cases, relate it to the number of German inhabitants to obtain the number of infected ones in Germany. Breathtaking!
Commentary: While I think, it is fine to post a preprint ahead of a publication, this is not even a preprint, it is just a copy of a manuscript on a university server. Using this copy to legitimate a FAZ headline, means that the information released here can no more retracted. It will influence politics, it will influence the live of millions of people. It also means: peer opinion is not relevant for somebody who talks to the press without any peer comment. Streeck hat been warned after publishing the interim report while circumventing again standard procedures in science, means this is a misuse of science as pretext.