24 Sept 2021 Episode 176 : COVID and the genital/reproductive system

Dear colleagues,

This time, my starting point is a recent comment in Nature on potentially persistent EBOLA in the male reproductive tract and from there I was searching the literature for similar evidence in COVID….

Episode 176-1: An analysis of EBOLA genomes from a recent small outbreak (23 cases, 12 deaths) in Guinea and a similar outbreak in the DRC (12 cases, 6 deaths) suggested that it was due to (very) late transmission from a “human reservoir”: people who were infected in the previous outbreaks (6 and 3 years ago), survived and kept the virus slowly replicating in a immune-privileged “sanctuary”.  This deduction is made, because the active replication in the usually suspected bat reservoir is faster, hence more mutations (faster evolution) would be present than observed (see Figure). Suspected reservoirs are testes, eyes and central nervous system. 

Ep 176-2 A: One of several reports, where amongst 5 cases late recrudescence of EBOLA in Guinea, three were linked by continued shedding of virus in the semen approx. half a year after the transmitter was “cured”.

Ep 176-2 B: Another intriguing (and frightening) case report in NEJM reports on a relapse (or breakthrough?) after vaccination with the Merck vaccine (recombinant EBOLA / vesiculo-stomatitis- virus) in Kivu.  This patient was at the basis of 98 cases in 6 health zones over 4 months.  Despite various treatments, he ultimately died.

Ep 176-3 A: Also ZIKA virus is known to be spread via sexual route long after the onset of symptoms. Recent studies have shown the TAM (TYRO3, AXL, and MERTK)-family receptor tyrosine

kinase AXL to be the primary ZIKV entry cofactor. AXL is highly expressed in Sertoli cells (SCs), a major component of the blood-testis barrier (BTB) which provides protection from the entry of pathogens into the seminiferous tubules

Ep 176-3 B: The receptor for EBOLA is TIM-1 (T cell immunoglobulin mucin domain-1).  Unfortunately, I could not find studies on tissue distribution in the reproductive tract.

I was wondering to what extent “latency” over weeks or months has been documented in COVID, but that search did not satisfy me.  I’ll take it up later.

On the other hand, I did find some literature on the implication of the genital tract in the SARS-CoV-2 infection and I’ll elaborate on the clinical consequences with regard to fertility and pregnancy    

Presence of SARS-CoV-2 in genital tract

Ep 176-4 A: An early Chinese study in Fertility and Sterility (June 2020) on semen samples from 36 men with confirmed COVID, taken about a month after symptoms onset were all negative, despite the fact that 19 patients had clinical evidence of orchitis (inflammation of testes).  Also no evidence of co-expression of the ACE-2 receptor and the SARS-CoV-2 S activating human enzyme TMPRSS2 in various testicular cells.

Ep 176-4 B:   A study on 43 male COVID patients, after negative nasopharyngeal swabs were investigated for

• Abnormalities in sperm (oligo- or azoospermia) in 11 (25 %): clearly higher than in general population (4%) and related to COVID severity
• Evidence of inflammation (raised IL-8) in 33 (76 %)
• Only 1 patient positive semen PCR (in addition also 1 positive saliva; 1  post-ejaculation urine).

Ep 176-4C: The study by Li et al in JAMA Open provides a rather high percentage of positive semen samples. Of the 6/38 positive samples 4 were in the 15 patients in the acute phase and 2 in the 23 patients in the recovery phase. No clear-cut clinical distinctions between positive and negative patients were noted.

Ep 176-4 C:   A more recent review by Spike et al. summarizes 9 studies on 6-38 patients per study, some in acute phase, most later on.  Only very few PCR positive results were found

Clearly, the study by Li et al. is the exception: a positive PCR in semen is uncommon and certainly so in the recovery phase, which is more important in the context of sexual transmissio .

Ep 176-5 A: Stanley at al confirm that (co) expression of ACE-2 and TMPRSS-2 In male and female reproductive tissue is low or absent.

Ep 176-5 B: On the contrary, Ren et al claim that In the testis, ACE2 is predominantly expressed in gametocytes, Sertoli cells, and spermatogonial stem cells.  Also TMPRSS2 is said to be expressed, but whether there is really co-expression is not clear to me.

Ep 176-6: A comprehensive meta-analysis on the distribution in various bodily fluids of the three most pathogenic human Sarbecoviruses (SARS, MERS and SARS-CoV-2) outside the nasopharynx , shows that presence of SARS-CoV-2 was  common in saliva (57.5 %) and stool (54.9 %), it was 23.7 % in blood and 21.2 % in vaginal swabs, but only 9.8 % in semen and 2.2 % in urine.  

Clinical complications

Ep 176-7 A and B:

Possible clinical complications for male genital system:

• Orchitis and orchi-epididimytis (inflammation of testes and surroundings) have been documented
• Also rarely thrombotic complications with priapism’s
• Decreased quality of sperm: numbers, motility, viability
• Hormonal disturbances: “risk of hypogonadism”: decreased testosterone to Luteininzin Hormone ratio

Possible explanations:

• Inflammatory damage, oxidative stress
• Disturbances in ACE-2 activity with ensuing pro-inflammatory changes

Possible complications for female fertility:  at present still more speculative

• Whereas COVID-19 has not yet been reported to damage female fertility, its potential detrimental effects cannot be ignored.
• ACE2 is ubiquitous in the female reproductive system, it is found mostly in the ovaries
• The downregulation of ACE2 by SARS-CoV-2 may cause alterations in normal ovarian physiology, such as follicular development and oocyte maturation, impacting oocyte quality and fertility.

The implications for sperm donation and assisted reproduction are well covered in Ep 176-6 B. 

Pregnancy

Ep 176-8 A:  A very nice, comprehensive and recent review by Jamieson in AJOG about SARS-CoV-2 and pregnancy

Infection, severity and complications

• Infection risk in pregnancy may be higher (but not sure).  Risk factors comparable to non-pregnant: lower socio-economic status
• Risk of severe disease clearly higher than in non-pregnant women (see Figure below).
• Risk factor for severity also largely similar: overweight, older age, hypertension (pre-eclampsia), pre-gestational diabetes, asthma and COPD.

• Clearly increased risk on pre-eclampsia, preterm birth and stillbirth, especially with severe COVID: average Odd’s ratios between 2 and 4 (See Ep 176-8 B for a nice systematic review);

In general, COVID is not an indication for delivery and should not alter the timing nor mode of

delivery. However, in some cases where delivery is not medically indicated, delivery may be

delayed until the mother tests negative for COVID to decrease the likelihood of transmission to the neonate

Implications for infant

• Intra-uterine transmission is rare: SARS-CoV-2 has no high viremia and low co-expression of ACE-2 and TMPRSS2 (the latter remains controversial).
• Neonatal transmission can occur and the risk for the neonate to develop serious respiratory, gastro-intestinal, neurological problems is real.  See review Ep 176-8 C with a discussion on guidelines and advantages/drawbacks of early mother-child separation.
• No risk of transmission via breastmilk (contains no replication-competent virus), if mother takes precautions: face mask, hygiene, breast cleansing

Treatment of pregnant COVID: similar as non-pregnant: Remdesivir, monoclonal antibodies (to block the virus), dexamethasone;  prophylactic anti-coagulation according to clinical indications

Vaccination: obviously indicated

• mRNA vaccines preferred: similar side effects as non-pregant
• Additional advantage of passive transfer of IgG and IgA antibodies via breastmilk to the infant.

Ep 176-9: A nice review that puts SARS-CoV-2 in the context of other viruses and pathogens,  with a more established role in mother-to-child transmission.  

Some conclusions

1. Sexual transmission of SARS-CoV-2 through semen or vaginal fluid seems not impossible but rather unlikely as a major route of transmission (also because mostly in acute phase, where sexual activity maybe low).
2. COVID in men may lead to orchitis, thrombosis and potentially fertility issues
3. Whether COVID in women influences fertility is uncertain (but not excluded)
4. Pregnancy may increase susceptibility to SARS-CoV-2 infection, but certainly increases the risk on severe COVID.
5. COVID increases the risk on preterm delivery and stillbirth. There is a (small) risk on mother-to-child transmission, but breastfeeding is safe, provided precautions are taken.
6. mRNA vaccination of pregnant women is strongly indicated and may also help to protect the newborn via breastfeeding

Obviously, it is quite possible that SARS-CoV-2 could lead to sexual dysfunction and fertility issues during the acute phase, but that is probably the case for many (systemic) viral infections.

An important research question, however, is whether sexual dysfunction and/or fertility issues are part of the “long COVD syndrome.  

I hope I provided some insight…  

Best wishes,

Guido