Episode 297: COVID modulation by parasitic (helminth) infection?
As you know, there is an ongoing debate since the beginning op de epidemic on the influence of parasitic and more precisely helminth infections on COVID severity. It is a heated debate, because for a long time there was no data. I will try to summarize some of the papers in peer-reviewed journals over the last two years in chronological order and then see if we can already make some conclusions.
Ep 297-1: Richard S. Bradbury opens the debate in June 2020 in Nat Rev Immunol by the observation that helminths induce a Th2 response (IL-4, IL-5, IL-9, IL-13) hence suppress potentially pro-inflammatory Th1 (IFN-g, TNF etc) and produce immunomodulatory proteins that induce IL-10 and regulatory T cells, hence an immune suppressive environment.
Nevertheless, early data on severe COVID indicated that the “cytokine storm” included overproduction of many Th1 and inflammatory cyto/chemokines, but also Th2 cytokines and IL-10.
The author quotes the example of the case of murid herpesvirus 4 (MuHV-4) respiratory infection, prior infection with Schistosoma mansoni reduced disease severity in mice, but he adds that immune responses to pulmonary coronaviruses and MuHV-4 are different and therefore the impact of helminth co- infection may differ also.
Ep 297-2: Russell Hayes in PLoS Negl Trop Dis Aug 2022 proposes an “alternative hypothesis”, based on the fact that most people with severe COVID have underlying metabolic syndrome, obesity, type 2 diabetes, which pre-disposes to the “cytokine storm”.
Recent reports have shown reduced levels of proinflammatory cytokines such as IL-1α, IL-1β, IL-6, IL-12, IL-18, IL-23, IL-27, G-CSF, and GM-CSF in subjects with coexisting helminth infection and T2DM and a partial reversal of this effect following treatment of the worm infection.
Hence: immunomodulatory effects of pre-existing helminth infection could result in a reduced risk of severe COVID, in the context of (metabolic) co-morbidities.
In view of the scarcity of epidemiological studies on the prevalence of severe COVID-19 in societies in which helminth infection are prevalent, they proposed exploring the possible effects of experimental helminth infection in humans on COVID-19 severity in a study setting!
Ep 297-3: Luis Fonte in Frontiers Immunol (Oct 2020) argues, in line with Bradbury, that immune-modulation by helminths could be an explanation for the observed lower lethality of COVID in Africa.
They give the following examples:
- People infected with helminths have a lower risk on severe Plasmodium malaria (e.g. cerebral malaria), which is induced by Th1 and inflammatory cytokines.
- Mice infected by Nippostrongylus brasiliensis showed increased susceptibility to Mycobacterium tuberculosis (which is typically controlled by Th1)
- In mice Trichinella spiralis infection limits inflammatory pulmonary damage induced by influenza virus.
- Mice infection by the rodent roundworm, Heligmosomoides polygyrus, significantly reduce pulmonary lung damage and viral load following intranasal infection with respiratory syncytial virus.
Ep 297-4: Alberto E. Paniz-Mondolfi PLoS Negl Trop Dis (May 2021) is not convinced by the proposed “beneficial immunomodulatory effect of helminths”, because of various observations in the Amazon region, where helminth infestation is very common, while COVID hits very hard:
- Amerindian peoples of the Brazilian Amazon, have a prevalence of soil-transmitted helminths, Ascaris lumbricoides and Ancylostoma sp., 45% to 95% while Amazonas has been most affected by SARS-CoV-2 with a death rate 250% higher than in the rest of Brazil.
- The Colombian Amazon, with intestinal parasitosis 70.5%, similarly has been severely impacted by COVID.
Besides immunomodulation these intestinal parasites have deleterious effects:
- Hookworms Ancylostoma duodenale and Necator americanus cause blood loss, anemia, pica, and wasting.
- Roundworms can also cause malabsorption, compete for nutrients, or cause intestinal or biliary tract obstruction, or in some cases, dysentery or diarrhea
In regions where undernutrition rather than overnutrition is a dominating concern, nutritional and metabolic compromise may present a greater hazard in persons at risk for SARS-CoV-2 infection.
Ep 297-5: Amir Abdoli Clin Exp Med (Aug 2021) provides an overview of potential COVID-19 Associated Opportunistic Infections (CAOI):
As can be seen, there is one helminth: Strongyloides Stercoralis, which is know as an opportunist in immune-compromised subjects, e.g. untreated HIV or patients under immune suppressive therapy.
Therefore, patients who received immunosuppressive therapy are considered as a high-risk group and should be screened for S. stercoralis, especially in tropical areas where the infection is prevalent.
Ep 297-6: Dawit Wolday EClinicalMedicine (July 2021) provides real world data in Ethiopia for a beneficial effect of some parasitic infections on COVID severity, including protozoa (Entamoeba cysts) and helminths (Hymenolepis nana, Schistosoma mansoni and Trichuris trichiura)
As can be seen, a beneficial effect was absent for Entamoeba trophoizoites, Gardia Lamblia, Ascaris lumbricoides and Taenia. It was NS in multivariate analysis for hook worms
Ep 297-7: Pengfei Cao Front Immunol (Feb 2022) discusses some helminth-derived proteins that may be in volved in this beneficial effect:
- Schistosoma japonicum cystatin (rSj-Cys);
- Clonorchis sinensis cyclophilin A (CsCyPA);
- Fasciola hepatica fatty acid binding protein (Fh15);
- Trichinella spiralis excretory/secretory products
These have all clinical beneficial effects in mouse sepsis models, with reduced levels of pro-inflammatory cytokines (IL-1, IL-6 and TNF), upregulated levels of IL-10 and TGF-beta) and decreased expression of HMGB1, TLR2 and MyD88 in the lung tissues of the treated mice. So far, human testing has not been performed.
Ep 297-8: Jane Achan Lancet Microbe (Jan 2022) investigates the relation between COVID severity and actual or past malaria in Uganda
Patients with low versus those with high previous P falciparum exposure (as measured with antibodies) had a increased frequency of severe or critical COVID-19 clinical presentation (16 [30%] of 53 patients vs three [5%] of 56 patients; p=0·0010).
However, they had also a higher burden of comorbidities, including diabetes (12 [23%] of 53 patients vs two [4%] of 56 patients; p=0·0010) and heart disease (seven [13%] of 53 patients vs zero [0%] of 56 patients; p=0·0030).
Among patients with no comorbidities, those with low previous P falciparum exposure still had a higher proportion of cases of severe or critical COVID-19 (six [18%] of 33 patients vs one [2%] of 49 patients; p=0·015).
Clearly, the trend of low malaria exposure with severe COVID is there, but is not significant after adjustment.
The only significant factor is age > 60, while diabetes is borderline.
Ep 297-9: Feifan Zhu Pathogens (Oct 2022): Effects of Helminth Infections on Vaccine Efficacy
There is ample evidence that various helminths reduce the antibody production after vaccination in people and animals. Optimal responses to COVID vaccination may require de-worming?
Ep 297-10: Taehee Chang PLoS Negl Trop Dis (Oct 22) investigates the relation between COVID cases (hence confirmed infections) and pre-existing parasitic diseases, using publicly available data and trying to deduce true number of COVID-19 infections based on a function of test positivity rate.
Their conclusion is that lower COVID-19 incidence rates were consistently observed in malaria-endemic
countries, even accounting for potential confounding variables, Gross Domestic Product (GDP) per capita, the population aged 65 and above, and differences in the duration of COVID-19.
However, the other parasitic diseases were not significantly associated with the spread of the pandemic
Remark: Not clear to me how reliable their extrapolation and modeling really are, in view of different quality of publicly available data across the world.
- There is emerging evidence that at least some parasitic infections, including some protozoa (Entamoeba, and maybe malaria) and some helminths (Schistosoma, Hymenolepis, Trichuris) may modulate the severity of COVID, presumably based on mitigation of the inflammatory response. This may explain apparently lower COVID pathogenicity in some parts of sub Saharan Africa.
- Regional differences could be due to the type of endemic parasitic infection e.g. South-American hookworms may not be protective and could be deleterious; Strongyloides may behave as an opportunist etc.
- On the other hand, helminths could weaken the antibody response upon COVID vaccination.
Clearly, well-performed prospective studies are scarce and therefore, strong conclusions cannot be made.
I hope you enjoyed this “atypical” episode
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