COVID: reinfection after a natural infection

 A recent editorial reviewed several studies regarding SARS-CoV-2 reinfection after a natural infection (see covid reinfection editoral lancet 2021 in dropbox, or doi.org/10.1016/ S0140-6736(21)00662-0 ) 

Editorial Details, along with comments:

-- we do know that many of the coronaviruses do not develop long-lasting immunity, specifically those 4 well-known to be associated with seasonal URIs 

-- we also know that SARS-CoV-2 antibody levels post-Covid infection can be low or undetectable, from several older studies. though antibody levels can also last for more than 6 months

-- they comment on a Brazilian study of healthcare workers, indicating "a relatively high rate of reinfections correlated with the lowest antibody responses", though they do note that do-novo reinfection could not be confirmed (see covid reinfection brazil JInf2021 in dropbox, or doi.org/10.1016/j.jinf.2021.01.020 )

    -- 33 people had recurrent, symptomatic, PCR-positive Covid-19

        -- 30 were healthcare workers: 80% female, 90% healthcare workers, mean age 39

        -- mean time to recurrence of infection was 51 days

        -- higher likelihood of a recurrent infection if blood type A, p=0.002, OR 4.8 [other studies have suggested blood type A is associated with more Covid-19 infections]

        -- all patients had documented Covid-19 by PCR, both initially and on subsequent infection

        -- symptoms of infection were generally quite similar with the 1^st and recurrent infection: 85% had headache, 85% asthenia, 60% myalgia, 35% arthralgia, 50% sneeze or runny nose, 60% odynophagia, 40% dysgeusia

        -- one patient had viral genome sequencing, suggesting reinfection [unclear in the other 32 whether this was reinfection or reemergence from a chronic SARS-CoV-2 reservoir, or a different viral infection but a still-positive PCR and falsely attributed to SARS-CoV-2. and we need more than 1 genomic test to comment/generalize the results]

        -- SARS-CoV-2 antibodies were significantly lower in patients who had "recurrent" disease: their initial Covid-19 titer (2.4), p<0/.0001 and after recurrent infection (6.4), p=0.007 vs higher titers in 62 patients who did not have reinfection

        --might have been helpful in interpreting the data if their PCR testing went from positive to negative and back to positive

    --so, really small study in a large country decimated by SARS-CoV-2 infections. hard to draw firm conclusions....

-- a Danish cohort found that in 4 million people (69% of the total population) getting 10.6 million PCR tests, PCR-positivity was 3.27% in those we who were not infected in the 1^st surge (march-may) but then subsequently infected in the 2nd surge sept to dec) vs 0.65% in those who had a previously positive PCR, suggesting an 80.5% protection rate against reinfection, decreasing to 47.1% in those >65yo. see https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00575-4/fulltext

    -- one limitation of the study is that those who were PCR positive on the 1^st surge may have had a very different behavior from those who were negative, perhaps relaxing their perceived need for masks and distancing, thereby decreasing the "protection" numbers found

    -- no information on whether people were symptomatic or not, just their PCR results. were they reinfected???? no information on what a positive PCR was.  cycle threshold of 40 (where might well be an artifact)?? no information on whether there was live virus culturable in either surges.

    -- could be an asymptomatic reinfection, but not sure their data is sufficient. would be more suggestive if we knew more about the PCR testing done, and if there were PCR negative samples in between the 2 positive ones.

-- A study in Qatar found a potential estimated reinfection rate of 0.2%  (see https://www.medrxiv.org/content/10.1101/2020.08.24.20179457v2 )

    --an interesting study, where 133,266 laboratory-confirmed SARS-CoV-2 cases found that at least 45 days later, 54 patients (0.04%) had a positive PCR swab (median time between PCR-positive tests was 65 days (range 45-129)

        --23 of these 54 cases were symptomatic, others picked up by random testing or contact tracing

            --all of these patients "were asymptomatic or with minimal or mild symptoms"

        -- viral genome sequencing found that 4 of 12 cases were confirmed as reinfection

        -- they suggest risk of reinfection was 0.01% (0.01-0.12%) based on "strong or good evidence of reinfection"

-- one hypothesis of the editorialists is that the SARS-CoV-2 may harbor for a long time in the gut and lead to an infection recrudescence, BUT:

    --their comment that SARS-CoV-2 may persist in the gut, from my search, is not so well documented, other than that the gut can be infected and there are ACE2 receptors in the intestines

    --the editorial cites their reference 7 suggesting that “a minority of individuals can harbor a reservoir of persistent SARS in the gut”, though their cited reference has nothing to do with this. And, by the way, it is pretty common that a comment is made in a study, and when i look for their reference it either does not make the point they made or is a totally irrelevant, random reference. even in the top tier journals.....

    -- the best evidence i could find was https://www.tigejournal.org/action/showPdf?pii=S2590-0307%2821%2900020-9 , which described the many GI manifestations of Covid-19, noting:

        --there can be persistent fecal RNA shedding (ie: positivity) after a negative nasopharyngeal swab. but does this mean anything??? does this positive PCR reflect viable virus or inactive viral remnants?? (we do know that people can remain PCR-positive from respiratory samples for >3 months, though viral culture is positive for only around 10 days or so)

        --one study that actually looked at viable virus detected in stool found that out of 153 stool specimens, 44 (29%) were PCR-positive and replicating virus was detected in 2 of 4 specimens. in some cases there were positive stool PCRs (Ct of 31.4 with range 22.3 to 38.4) in patients without diarrhea. though this study did not comment on length of PCR-positivity or even how long after SARS-CoV-2 infection that the viral cultures were positive (see https://jamanetwork.com/journals/jama/fullarticle/2762997 )

        --another study found "prolonged presence of SARS-CoV-2 viral RNA in fecal samples" (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158584/ ), though only for a mean of 27.9 days after the first symptom onset, 11.2 days longer than respiratory samples, with one person testing positive for 47 days. but no test of viral viability. again, perhaps non-infectious viral remnants picked up by PCR?? 

    --so, SARS-CoV-2 may in fact harbor in a dormant form in the body (as with another sneaky virus: HIV), but these data that i can found are not particularly conclusive

Commentary: 

-- i'm not sure this editorial added much to this important discussion

-- it is very hard for us to know what the true level of reinfection is, since the only reasonably definitive way to know is to have a genetic analysis showing that the 2^nd viral strain is so different from the 1^st one that it is unlikely to be internal mutations from a virus that is been hanging on in an individual (ie, we know roughly how frequently the virus mutates, so comparing the numbers of mutations found vs the predicted mutation rate helps differentiate the source of the virus: if too many mutations over the predicted mutation rate, then highly likely to be a new infection from a different viral source: see covid reinfection LancetID2020 or doi.org/10.1016/S1473-3099(20)30764-7), or see blog http://gmodestmedblogs.blogspot.com/2020/10/covid-us-case-of-reinfection.html . 

-- And, reinfections are not routinely analyzed in non-hospitalized people (the vast majority of Covid infections). Hence reports of reinfection likely reflects significant underreporting (eg, at our small health center we have had a couple of cases of documented Covid-19, clearing infection within a couple of weeks, then PCR-positive infection consistent with Covid-19 three months later. But, there was no trigger in the lab to do genetic analyses of the first and second positive PCRs...

-- we do know that neutralizing antibody titers do vary post-Covid, and are usually higher with more severe cases

    -- and, by the way, we do know that these titers are way higher after vaccination (likely a really good thing, and perhaps explaining the shockingly good effectiveness of the vaccines)

        --in those with a prior Covid-19 infection, there is a dramatic booster effect, with sky-rocketing antibody levels, even after one vaccine dose: see http://gmodestmedblogs.blogspot.com/2021/02/covid-single-dose-vaccine-post.html 

-- the above studies cited in the editorial are problematic, especially since relying on a positive PCR does not necessarily implicate reinfection. the best lab-based test, i think, would be viral cultures (suggesting viable virus), which were not often done, and, when done, were not clearly done well after the initial infection. and suspected reinfections should really be assessed by genomic analysis, to really assess reinfection rates. that way, we would have a better understanding of the real numbers of reinfections: this might help guide our understanding of if/when booster vaccines will be needed.....

    -- and, overall, we do not really know the relationship between antibody titers and clinical protection (the antibody titers are a laboratory determination, and even undetectable levels may be still associated with clinical protection since there may be a small number of memory cells, perhaps hiding elsewhere in the body than the blood, so they are undetectable by our standard blood analysis)

 

so, my sense of all of this is:

--there are no rigorous data that i have seen looking at community-based reinfections.

    --community-based infections are way more likely to lead to reinfections, given the disproportionate numbers of asymptomatic or mild-moderately symptomatic SARS-CoV-2 infections (ie, we need to look beyond the small percent of patients who are hospitalized with Covid-19)

    --community-based infections also are more likely to elicit lower antibody responses, and decrease much more rapidly, see http://gmodestmedblogs.blogspot.com/2020/12/covid-waning-antibodies-but-does-it.html

--but, that all being said, it seems quite likely that reinfection rates are low, at least for the first year of this scourge.

    --though, it is pretty clear that reinfections do happen: eg see http://gmodestmedblogs.blogspot.com/2020/10/covid-us-case-of-reinfection.html .

--however, knowing reinfection rates are really important in understanding this virus' epidemiology better, and the various public health concerns we need to address: need for continued personal protection/mitigation strategies, need for booster vaccines...

 

--and, unfortunately, we seem to be creating the groundwork for more reinfections: there seems to be a general approach in many countries to decreasing lockdowns and personal protection, with the US playing a leadership role. In the US the number of infections is increasing (4th surge), especially in people under 30 years old. The apparent default now seems to be having enough infections that there is herd immunity. However, especially in light of the new SARS-CoV-2 variants with their known increased virus transmissibility, there will have to be even more people either infected or getting the vaccine to achieve herd immunity (ie, the R₀ increases as the viral transmissibility increases) 

geoff

 

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