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Covid, Africa and Schistosomiasis

January 5, 2021 - 19:55 -- Pierre Lutgen

In an April 10 interview, American philanthropist Melinda Gates expressed her belief that the coronavirus pandemic will have the worst impact in the developing world. She said she foresees bodies lying around in the street of African countries. It is quite surprising to see that although there have been shocking reports of hospitals overwhelmed with patients in the US and in other Western countries, the billionaire philanthropist and others like her still choose to talk about dead bodies in Africa. Gates is not the only one to be predicting total doom in Africa. A report released by the United Nations Economic Commission for Africa (UNECA) in April stated: “….up to 3.3 million African people could lose their lives as a direct result of COVID-19.” And on April 6. Dr Matshidiso Moeti, WHO Regional Director for Africa stated that if we are not able to eradicate this virus in Africa the entire world will collapse.

But the African apocalypse did not happen. Why ? The data are stubbornly telling us that Africa not only has lower death rates than the rest of the world, but also has less confirmed infections In DRCongo with a population of 90 000 000 and 600 Covid fatalities, this is a deathtoll of 0.0007% for the entire country. Efforts have been made, particularly in Africa, to link the low morbi/mortality rates by Covid-19 to many possible influencers, among them, the median young age of the African population, population density variables, climate, etc. All of them do not achieve statistical relevance by any means.

In our weblog « Malaria inhibits Covid » on www.malariaworld.org we discuss the possibility that the overwhelming impact of malaria in Subsaharan Africa might play a role. Both infections generate several immunoglobulins which are synergetic.

In extension to the « hygiene hypothesis », the host immune system is conditioned by lifelong environmental encounters with micro- and macro-organisms, ranging from commensals to pathogens. Co-infections shape the host immune status, thereby influencing the development of inflammatory diseases, which can result in detrimental or beneficial effects.
Helminth parasites have adapted to their hosts during long coevolution processes, which usually result in chronic disease with low mortality and variable morbidity. During this evolutionary coadaptation with their hosts, including vertebrate hosts, parasites have contributed to the modulation of several molecular and physiological host mechanisms, for example, the immune system.

Siles-Lucas M, González-Miguel J, Geller R, Sanjuan R, Pérez-Arévalo J, Martínez-Moreno Á. Potential Influence of Helminth Molecules on COVID-19 Pathology. Trends Parasitol. 2021 Jan;37(1):11-14.

More than 1 million people worldwide are infected by helminths, the highest load in sub Saharan Africa with 700 000 infections. One of the major helminthic diseases is schistosomiasis (bilharzia). The majority of individuals infected with schistosomiasis are asymptomatic, although non-specific signs of infection can include microscopic haematuria and eosinophilia.

Eosinophils are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. They are granulocytes that develop during hematopoiesis in the bone marrow before migrating into blood, after which they are terminally differentiated and do not multiply. They form about 2 to 3% of WBC's. (Wikipedia).

A review paper in 2009 stated that eosinophils are among among the most enigmatic of all cells of the immune system. Some experts even have expressed their concern that a Covid-19 vaccine which increases the eosinophil count could have harmful effects.

Rosenberg HF, Dyer KD, Domachowske JB. Eosinophils and their interactions with respiratory virus pathogens. Immunol Res. 2009;43(1-3):128-137. doi:10.1007/s12026-008-8058-5
Simon H, -U, Karaulov A, V, Bachmann M, F: Strategies to Prevent SARS-CoV-2-Mediated Eosinophilic Disease in Association with COVID-19 Vaccination and Infection. Int Arch Allergy Immunol 2020;181:624-628. doi: 10.1159/0005093

Literature confirms the high eosinophil counts in the general population of helminth prevalent regions, much higher than in the modern urban "dewormed" world.

Ilesanmi A, . O. Olalubi}, Prevalence of latent eosinophilia among occupational gardeners at Babcock University, Nigeria}, Asian Pacific Journal of Tropical Biomedicine},2016, 6, 511-515

An explanation of their action was already described in 1982. Schistosomiasis is characterized clinically by an increase in eosinophil counts in bone marrow and peripheral blood. This eosinophil response is also manifest pathologically by cell accumulation around the invading schistosomula and the parasite ova retained in host tissues. The ability of these cells to destroy multicellular parasites has been shown to be due to highly reactive oxygen reduction products or to release of cationic or major basic proteins from the granules.

Adel A. F. Mahmoud, The Ecology of Eosinophils in Schistosomiasis, The Journal of Infectious Diseases, Volume 145, Issue 5, May 1982, Pages 613–622

Eosinophilia is a common finding in returning travellers and migrants, and in this group it often indicates an underlying helminth infection. Infections are frequently either asymptomatic or associated with non-specific symptoms

Anna M. Checkley, Frances Sanderson. Eosinophilia in returning travellers and migrants from the tropics: Clinical Guidelines of the British Infection Society| Volume 60, ISSUE 1, P1-20, January 01, 2010
Stephan Ehrhardt and Gerd D. Burchard, Eosinophilia in Returning Travelers and Migrants. Dtsch Arztebl Int. 2008 Nov; 105(46): 801–807.

In his study on the effect of Artemisia annua, Artemisia afra and Praziquantel on schistosomiasis infections J Munyangi found that the 3 treatments lowered the eosinophil count by 27 % from day 0 to day 28.

Munyangi, J., Cornet-Vernet, L., Idumbo, M., Lu, C., Lutgen, P., Perronne, C., Ngombe, N., Bianga, J., Mupenda, B., Lalukala, P., Mergeai, G., Mumba, D., Towler, M., & Weathers, P. (2018). Effect of Artemisia annua and Artemisia afra tea infusions on schistosomiasis in a large clinical trial. Phytomedicine : international journal of phytotherapy and phytopharmacology, 51, 233–240.

Helminthic parasites are known to play a protective role. They induce regulatory T and B cells as well as anti-inflammatory cytokines (e.g. IL-10, TGF-β). Although the interaction between helminth infection and viral pneumonia is poorly defined, there is some evidence that helminth infection may moderate the process of pulmonary inflammation in viral infections.

Hays R, Pierce D, Giacomin P, Loukas A, Bourke P, McDermott R (2020) Helminth coinfection and COVID-19: An alternate hypothesis. PLoS Negl Trop Dis 14(8): e0008628

Cotton S, Gonzales Santana B, Dalton JP. Schistosoma mansoni immunomodulatory molecule Sm16/SPO-1/SmSLP is a member of the trematode-specific helminth defence molecules (HDMs). PLoS Negl Trop Dis. 2020 Jul 9;14(7):e0008470

A recent Spanish paper summarizes well the link between helminths and Covid-19. Parasites engineer strategies to maintain the host in an immune "silent" state. Helminths (worms) modify the immune system of their host to avoid immune ejection, a strategy that promotes their long-term survival and results in chronic infection, but that also has a bystander positive effect by protecting both the host and the parasite against the onset of inflammatory disorders.
Helminth infection produces a whole array of effects, which is best described by the so called Th2-IL-10 axis. IL-10 is an anti-inflammatory cytokine abundantly produced by the Th2 CD4+ lymphocytes. During helminth infection, it inhibits the activity of Th1 cells, suppresses the bidirectional crosstalk between NK cells and myeloid dendritic cells, inhibits CD8+ cytotoxic T cell function and directs macrophage polarization to an immunosuppressive phenotype.
It is now generally accepted, that what leads to the Acute Respiratory Failure in the Covid-19 disease is not the viral infection (i.e. the viral load) itself, but the extremely intense and seemingly uncontrolled inflammatory reaction as seen in the lungs of these patients.
To sum, the Spanish authors believe that chronic helminth infection provides infected people with an unexpected wealth of protective mechanisms against the Covid-19 disease and its lethal complications. This protective mechanism is based on two legs : eosinophils and the Th2-IL-10 system.

Rodriguez, Carlos. The global helminth belt and Covid-19: the new eosinophilic link, Journal Qeios, 2020/05/28 DO - 10.32388/IWKQH9.2

Coming back to studies in the « dewormed » Northern hemisphere, it was found that in the elderly IL-10(+) B cells generally decline. IL-10 is an essential cytokine, mainly produced by macrophages, and is responsible for suppressing proinflammatory response in various tissues. In elderly women, an increased Th1/Th2 ratio was found, due to a higher response of Th1 cells and lower response of Th2 cells.

Kroesen BJ, Brouwer E, Boots AM. Aging-dependent decline of IL-10 producing B cells. 2016 Mar; 75:24-9.
Dagdeviren S, Jung DY, Friedline RH, et al. IL-10 prevents aging-associated inflammation and insulin resistance in skeletal muscle. FASEB J. 2017;31(2):701-710. doi:10.1096/fj.201600832R

Eosinopenia is often used as predictor of infection. In a Spanish study on 99 patients admitted for acute respiratory failure related to SARS-CoV-2 pneumonia 88% had eosinopenia at ICU admission and 33% developed eosinophilia during ICU stay. A French team noticed that the early phase of SARS-CoV-2 infection seems to be accompanied by eosinopenia. Conversely, several of the critically ill COVID-19 patients developed unexpected and unexplained eosinophilia.

Silva JM, Costa AM, Tuna C, Ascensão M. Eosinopenia as predictor of infection in patients admitted to an internal medicine ward: a cross-sectional study. Porto Biomed J. 2020 Nov 11;5(6):e084.

Mateos Gonzalez M, Sierra Gonzalo E, Casado Lopez I, Arnalich Fernandez F, Beato Perez JL, Monge Monge D, et al. The prognostic value of eosinophil recovery in COVID-19: a multicentre, retrospective cohort study on patients hospitalised in Spanish hospitals. medRxiv. 2020;2020.08.18.20172874.

Fraissé, M., Logre, E., Mentec, H. et al. Eosinophilia in critically ill COVID-19 patients: a French monocenter retrospective study. Crit Care 24, 635 (2020)

Comments

Submitted by Pierre Lutgen on

In our reccent weblog "Covid, Africa and Schistosomiasis" we documented that eosinopenia is common in helminthic diseases and in malaria.

WUHAN STUDIES ON COVID AND EOSINOPENIA

Early in 2020, a detailed clinical investigation of 140 hospitalized COVID-19 cases in Wuhan suggested eosinopenia together with lymphopenia as a potential indicator.

Zhang JJ, Dong X, Cao YY, Yuan YD, Yang YB, Yan YQ, Akdis CA, Gao YD. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy. 2020 Jul;75(7):1730-1741. doi: 10.1111/all.14238. Epub 2020 Feb 27. PMID: 32077115.

This was confirmed a few months later by another Chinese team.

Zhao, L., Zhang, Y.‐p., Yang, X. and Liu, X. (2021), Eosinopenia is associated with greater severity in patients with coronavirus disease 2019. Allergy. https://doi.org/10.1111/all.14455

In a study on the clinical features of 85 fatal cases of Covid 19 in Wuhan, 81.2% of the patients had very low eosinophil counts

Yingzhen Du , Lei Tu, Pingjun Zhu , Clinical Features of 85 Fatal Cases of COVID-19 from Wuhan. A Retrospective Observational Study American Journal of Respiratory and Critical Care Medicine, 2020, 201, 1372-79

In addition to other markers eosinopenia appeared in the majority of patients with COVID-19

Li Q, Ding X, Xia G, Chen HG, Chen F, Geng Z, Xu L, Lei S, Pan A, Wang L, Wang Z. Eosinopenia and elevated C-reactive protein facilitate triage of COVID-19 patients in fever clinic: A retrospective case-control study. EClinicalMedicine. 2020 May 3;23:100375.

A survey in the US confirmed these findings : eosinopenia is not unique to COVID-19, but it is more prevalent in COVID-19 than it is in influenza infection. For a cohort of 50 patients the authors found an absence of eosinophils in 88 % of the COVID-19 patients and only 16 % in the influenza group.

Fahmina Tanni, DO; Eleonora Akker, DO Eosinopenia and COVID-19. The Journal of the American Osteopathic Association, August 2020, Vol. 120, 504-508

THE DETRIMENTAL EFFECT OF EOSINOPENIA IS KNOWN SINCE YEARS

Already in 2004 a paper reported that nearly 90% of SARS-CoV patients had eosinopenia

Yao X., Zeng Y., Tong Y., Tang X., Yin Z. Determination and analysis of blood eosinophil in 200 severe acute respiratory syndrome patients. Lab Med. 2004;5(19):444–445

In 2007 it was found that contrary to the dogma that eosinophils have adverse roles in inflamed lungs they dampen airway hyperresponsiveness caused by viral infections

Stevens JM, Syndercombe-Court D, Oakervee HE, et al. Development of original donor cell leukemia after successful engraftment from a second donor. Blood. 2007;110(13):4621-4622. doi:10.1182/blood-2007-07-104240

The eosinophil count might be a useful marker of severity. As it is routinely given in the full blood count in all patients admitted to hospital, there is no extra cost for this beneficial test.

Holland M, Alkhalil M, Chandromouli S, Janjua A, Babores M. Eosinopenia as a marker of mortality and length of stay in patients admitted with exacerbations of chronic obstructive pulmonary disease. Respirology. 2010 Jan;15(1):165-7.

Also in 2014 eosinopenia was found to be common in people infected by the H1N1 virus. In a cohort of 198 patients, mean age 74 years, mortality was higher for patients with eosinopenia

H. Flick, M. Drescher, J. Prattes, K. Tovilo, H.H. Kessler, K. Vander, K. Seeber, M. Palfner, R.B. Raggam, A. Avian, R. Krause, M. Hoenigl, Predictors of H1N1 influenza in the emergency department: proposition for a modified H1N1 case definition, Clinical Microbiology and Infection, 2014, 20, 2.

Blood eosinopenia is a strong predictor of 30 day mortality in patients with pneumonia.

Carlos Echevarria, Tom Hartley, Thapas Nagarajan 30 day mortality and eosinopenia in patients with pneumonia. European Respiratory Journal Sep 2014, 44 (Suppl 58) P2550;

CONCLUSION

The pathophysiology for eosinopenia in COVID-19 remains unclear, but it may be multifactorial. Mechanisms may include inhibition of eosinophil egress from the bone marrow, blockade of eosinophilopoiesis, reduced expression of chemokine receptors/adhesion factors, and/or direct eosinophil apoptosis induced by type 1 interferons released during the acute infection.
Eosinopenia develops promptly after the administration of corticosteroids. However, β-blockers apparently inhibit eosinopenia and favor an increase in the number of circulating eosinophils.

G Zini, Abnormalities in leukocyte morphology and number. Blood and Bone Marrow Pathology (Second Edition), 2011

Szczeklik A, Podolec Z. Central regulation of blood eosinophilia by the beta-adrenergic system in rats. Int Arch Allergy Appl Immunol. 1976;50(3):328-40. PMID: 2558.

Submitted by Pierre Lutgen on

M Markus, J Fincham et al., already 20 years ago discussed the link between deworming, virus infection and eosinopenia.

M B Markus, J E Fincham. Worms and pediatric human immunodeficiency virus infection and tuberculosis. J Infect Dis. 2000 May;181(5):1873.
M B Markus. Worms and allergy Trends Immunol. 2001 Nov;22(11):598-9.

J.E.Fincham, M.B. Markus et al., count. Association of deworming with reduced eosiphilia. South African Journal of Science, 2003,99, 182-184

Ivermectin also causes eosinophil sequestration which might have a detrimental effect in the case of viral infection.
P J Cooper, K Awadzi, Eosinophil sequestration and activation are associated with the onset and severity of systemic adverse reactions following the treatment of onchocerciasis with ivermectin Ivermectin Clinical Trial J Infect Dis. 1999 Mar; 179(3):738-42

Eosinophils are considered blood cells, but they also reside in various tissues : in the gastrointestinal tract and the lung. Preclinical studies (mainly in mice) have shown that eosinophils are equipped with an assortment of molecular tools that enable them to recognize, respond, and orchestrate antiviral responses to respiratory viruses. It is often found that eosinophil levels improve in Covid patients before discharge, suggesting that resolution of eosinopenia may be an indicator of improving clinical status.

Lindsley AW, Schwartz JT, Rothenberg ME. Eosinophil responses during COVID-19 infections and coronavirus vaccination. J Allergy Clin Immunol. 2020 Jul;146(1):1-7.

Plasmodium falciparum infections induce eosinophilia. Acute malaria in adults with no or limited previous exposure toPlasmodium infection is usually associated with low eosinophil counts (eosinopenia), followed by persistent eosinophilia in a proportion of patients after cure.

Asymptomatic malaria infected patients have a higher eosinophil count. These eosinophils may contribute to immunity by killing parasites generated by a new infection.

Kurtzhals JA, Reimert CM, Tette E, et al. Increased eosinophil activity in acute Plasmodium falciparum infection--association with cerebral malaria. Clin Exp Immunol. 1998;112(2):303-307.

Waters LS, Taverne J, Tai PC, Spry CJ, Targett GA, Playfair JH. Killing of Plasmodium falciparum by eosinophil secretory products. Infect Immun. 1987; 55(4):877-881.

Submitted by Pierre Lutgen on

Daniel Parsons in a blog of Feb 5 in the Malaria Journal asks the valid question if the low incidence of COVID-19 in Africa is due to prior infections with Plasmodium falciparum ?
He proposes the following hypothesis:"Evidence of shared immunodominance between Plasmodium falciparum and SARS-CoV-2 may explain low COVID-19 incidence in the malaria-endemic belt of Africa, and could highlight SARS-CoV-2’s ability to infect red blood cells.
In our weblog Covid, Africa and Schistosomiasis on www.malariaworld.org we had come to the conclusion that the immunity of Africans against Covid is probably due to a larger extent to helminthic diseases than to malaria.
The debate is open!