COVID-19 pandemic is still ongoing and the differences in the susceptibility to disease and its severity continue to be a concern. Preexisting chronic diseases may affect the clinical outcome of COVID-19 [1]. Helminthiases are the most common infections with very high prevalences in low- and middle-income countries (LMICs) [2]. Soil-transmitted helminths (STHs) and schistosomiasis are the most frequent helminth infections worldwide [3]. Recent studies show the association between chronic helminth infections and COVID-19 outcome. However, the findings are controversial and potential beneficial and detrimental effects of helminth co-infections on the disease have been reported [4]. Some researchers raise concerns regarding the potential detrimental influence of preexisting helminth infections on COVID-19 since SARS-CoV-2 survival and replication could be enhanced by the Th2-like cytokine response in helminth-infected persons [5,6]. Others acknowledge that preexisting helminth infections may be beneficial by reducing the uncontrolled Th1 pro-inflammatory cytokine response, destructive inflammation, and disease severity [7,8].

The aim of this article is to summarize and analyze the potential effects of helminth co-infections on the clinical outcome of COVID-19 and make some comments.

Studies suggest that there is a complex interaction between parasitic infections, human microbiota and host immunity [9]. Helminths exert systemic immunomodulatory effects characterized by a deviation to a Th2 pattern cytokines through a variety of control mechanisms [4]. The significance of this immune regulation that may affect the severity of COVID-19 is particularly worrisome in helminths endemic areas where SARS-CoV-2 and helminth infections may be component parts of a synergistic epidemic [2].

COVID-19 immune response is expressed by Th1 response. The essential pathophysiology of SARS-CoV-2 infection implies the powerful upregulation of pro-inflammatory cytokines [4]. In the early stages of infection, dendritic cells (DCs) and epithelial cells are activated and produce interleukins (ILs) especially IL-1β, IL-2, IL-6, IL-8, IL-17, interferon (IFN)-γ, tumor necrosis factor (TNF)-α and chemokines that lead to hyperinflammation and the cytokine storm [10] that contribute to the development of disease, multi-organ failure and death [11].

Helminth infections may hamper host immune response through several mechanisms, including suppression of Th1 response by altering the immune system toward Th2 response, control of pattern recognition receptors, activation of T cell regulatory (Treg) cells, and induction of apoptosis in immune cells [12]. Helminths can regulate the immune response due to boosted Th2 response with the production of IL-4, IL-5, IL-10, IL-13, transforming growth factor beta and the stimulation of Treg cells which can affect responses to heterologous infections [6,7]. Helminth-driven immune modulation would hypothetically decrease the uncontrolled Th1 pro-inflammatory cytokine response which is responsible for serious COVID-19 and contribute to the less severe outcome of the disease. However, emerging articles also consider that the evolution of COVID-19 may be aggravated in patients with helminth co-infections [4,6,13,14].

 A helminth co-infection could reduce the host’s ability to combat SARS-CoV-2 by downregulating the immune response against the virus in the early stage of the infection, thereby increasing morbidity and mortality in COVID-19 patients [13]. A helminth/SARS-CoV-2 co-infection could produce a deficient T cell response and low levels of IFN-I. This adjuvant environment for SARS-CoV-2 replication has been observed in cases with severe COVID-19 with low levels of IFN-γ and TNF-α in CD4+ T cells [15]. SARS-CoV-2 survival and reproduction could be augmented by the Th2-like cytokine response in helminth-infected individuals [4,6]. Some authors have attributed the postponement in virus clearance to induction of Th2 response [16]. During helminth infection, IL-10 constrains the activity of cytotoxic T8 cells, CD8+, and Th1 which abolishes the interplay between natural killer cells and DCs, actions that are needed for optimal elimination of pathogens [17]. COVID-19 is known to produce collapse of the immune system, with increasing lymphopenia and reduction of macrophages, monocytes and DCs [18]. Therefore, the contribution of type 2 response in the immunopathology of COVID-19 is worrying when considering the likely consequences of helminth co-infections [6].

Helminths may suppress the fundamental immune response against intracellular pathogens [19]. Warao natives from Venezuela showed Th2 skewed cytokine profiles that promoted Mycobacterium tuberculosis infection in patients with Ascaris lumbricoides [20]. In HIV-infected individuals, Schistosoma infection increased the transmission of the virus, and deworming decreased the viral load and improved the CD4+ counts [2]. A helminth/SARS-CoV-2 co-infection could lead to a defective T cell response and low levels of IFN-I. In addition, Trichinella spiralis elicited the shifting of macrophage type 1 to type 2, as a resilience mechanism [21]. This supportive environment for SARS-CoV-2 replication has been noted in COVID-19 patients with a severe evolution defined by lower levels of IFN-γ and TNF-α in CD4+ T cells [15]. Decreased levels of IFN-γ and higher levels of IL-10 and transforming growth factor beta were observed in individuals co-infected with Plasmodium, A. lumbricoides and hookworm, as compared to those infected only by Plasmodium [22]. Experimental studies on worm and virus co-infection in mice showed that immunomodulation induced by helminths creates a beneficial environment for them by reducing antiviral immunity [23]. Another study reported increased mortality in mice co-infected with Ascaris suum and influenza virus [24]. The development of Treg cells and IL-10 production induced by helminths will impair the host immune response, which in turn enhances host susceptibility to microbial infections [25]. A co-infection with SARS-CoV-2 and Plasmodium can lead to a more serious outcome and may shift the severe COVID-19 age pattern to younger groups [4]. In long term helminth-infected individuals co-infected with SARS-CoV-2, the Th2 pattern cytokines could enhance viral replication of SARS-CoV-2 and severity of COVID-19 [19]. Different immune response profiles were observed in SARS-CoV-2 infection which could be associated with disease severity; patients with serious COVID-19 displayed various type 2 phenotype effectors such as IL-5, IL-13, immunoglobulin E, and eosinophils [26,27]. These findings suggest that induction of the helminth-driven Th2 phenotype could be deleterious instead of favorable.

In Asian and African countries, beneficial effects of helminth co-infections on COVID-19 have been reported. Delhi, India, which has lower prevalences of STHs with respect to Bahir, has had more severe COVID-19 cases [4]. In Sub-Saharan Africa, patients who have intestinal parasitic co-infections are less likely to experience severe COVID-19 [28]. In Ethiopia, patients with preexisting helminth co-infections were less likely to develop severe COVID-19 and non-communicable diseases (NCDs) [29]. According to a study, the lower COVID-19 cases/deaths in parasite-endemic areas could be due to parasite-induced immunomodulation [30].

On the contrary, in some South American countries where parasitic infections are common [31-36] and STHs constitute a serious and persistent public health problem, the pandemic has severely impacted their populations [36]. In Minas Gerais, Brazil, that has a high prevalence of A. lumbricoides and moderate prevalence of hookworm, the fatality rate by COVID-19 was high (25.5%), with respect to Rio de Janeiro (5.8%) where the infection rates of STHs are low [37]. Among the Amazon Amerindians of Brazil where STHs are prevalent, COVID-19 had a high impact with a mortality rate 250% higher than in the rest of the country [36]. Similarly, the Colombian Amazon which has a high infection rate (70.5%) of intestinal parasitic infections, has been markedly impacted by COVID-19 [14]. In Venezuela, persistent high rates of one or more parasitic species up to 92%, and A. lumbricoides and Trichuris trichiura up to 74.6% and 82.8%, respectively, in suburban and rural communities have been estimated [38-41] and this country has been severely impacted by the pandemic, although data referred to fatality are scarce [36].

The available information suggests that Th2-like cytokine response in helminth-infected persons could enhance or inhibit the outcome of COVID-19 [4,6-8]. However, complexity of interactions of several mechanisms in the evolution of COVID-19 and the participation of different factors can cause diverse outcomes of the disease, some of them likely unknown since the interplays between SARS-CoV-2 and helminths are just emerging. Therefore, when characterizing data from helminths endemic areas, other factors must be considered as described below.

• The clinical resolution of co-infected patients can be affected by factors dependent on the virus, helminths, and the host, including their immunogenetic profiles [4,19]. Multiparasitism is quite common in LMICs [36,38-41] and the overall impact on the host depends on the sequence and burden of each infection [4]. Thus, co-infection with parasitic neglected tropical diseases could result in severity of SARS-CoV-2 infection.
• Elderly and comorbidities may contribute to the interplay between helminths and SARS-CoV-2, affecting COVID-19 severity and mortality rate. Aging can increase vulnerability and severity of the disease [42]; the possibility of dying from COVID-19 varies considerably with age [43]. Aging also plays a crucial role in patients with chronic diseases. Comorbidities such as obesity, diabetes, metabolic syndrome, liver or kidney diseases and cardiovascular diseases increase the risk of severe COVID-19 [42,44].

• The influence of the human microbiome on the immune response to new infections may also be a significant factor in response to SARS-CoV-2. Helminth infections can alter the gut microbiome by increasing bacterial richness and diversity; in this regard, diet, living in urban or rural areas, the circadian rhythms and the use of antibiotics must be considered [45]. It is not well defined if the interplay between helminths and microbiota will promote susceptibility or protection. However, the generation of an anti-inflammatory environment could produce less immune response and more susceptibility to co-infections [46].
• Intestinal helminths can cause multiple adverse effects. Different helminths and stages of infection may have diverse effects on the host, given that they occupy distinct compartments and promote a range of immunological effects that could be local or systemic [19,43]. During the adult stage, heavy helminth infections can lead to childhood malnutrition, growth restriction and neurocognitive effects [47]; undernutrition may present a greater hazard in persons at risk for SARS-CoV-2 infection. Anemia is frequent in children with ascariasis [48] and biliary strictures, cirrhosis and liver atrophy can develop by migration of adult worms [49]. Children with excessive burden of T. trichiura can suffer from dysenteric colitis [50] and iron-deficiency anemia [51]. Hookworm infection can also cause this type of anemia [52]. A. lumbricoides and Toxocara larval migration through the lungs can cause asthma and chronic disease [49,53]. Neurotoxocariasis can produce eosinophilic meningoencephalitis, myelitis, cerebral vasculitis, or seizures [54].
• The pandemic has increased the immunosuppressed population which is vulnerable to opportunistic parasitic infections due to the disease pathophysiology and ample use of corticosteroids [55-59]. Consequently, the risk of these opportunistic pathogens has increased and could modify the evolution of COVID-19. Strongyloides stercolaris is usually asymptomatic. However, systemic strongyloidiasis usually occurs in patients treated with steroids. The clinical picture is variable and is mainly characterized by gastrointestinal and respiratory symptoms; paralytic ileus and acute respiratory failure may be prominent, and sepsis and meningitis are common [60,61]. Due to the pathologies and sequelae caused by helminths, they play a potential role in driving NCDs, including intestinal, pulmonary, cardiovascular, and neuropsychiatric diseases [43].
• The complex epidemiological, poverty and sanitary picture in LMICs combined with the potent spread of SARS-CoV-2 and eventual severity of the infection indicate the high risk of such populations having a more disastrous impact of COVID-19. According to family wealth, education and ethnic group, appreciable differences in the prevalence of the disease have been observed in developing and developed countries; COVID-19 pandemic has greatly impacted the poorest groups [62,63]. The immune balance status inferable to the immune interaction between host and pathogens must be defined in this scenario.
• In LMICs, the competence of the health infrastructure and system of collecting cases by official authorities play a main role in the reliability of the registered information. A study from Africa reported that severe COVID-19 is less likely to occur in patients co-infected with intestinal parasites [28]. However, prospective studies in the area suggest that the number of COVID-19 cases is underreported [64].

 According to these observations, the high prevalence of STHs in LMICs appears to be more detrimental than beneficial in relation to COVID-19 morbidity and mortality. Undernutrition associated with helminths, common in these localities, may be a greater risk for individuals with COVID-19. Preexisting helminth infections may impair the host’s ability to combat SARS-CoV-2 which could increase COVID-19 morbidity and mortality [13].

Helminths can alter the immune system leading to reducing the primary immune responses against pathogens and can produce several negative effects, increasing susceptibility and severity of infectious diseases [2,4,65]. The outcome of COVID-19 may be aggravated in individuals with helminth co-infections [2,6,13,14]. Besides, patients with underlying illnesses or under immunosuppressive therapy have a higher risk of opportunistic infections, including helminthiases such as strongyloidiasis [61,62]. At least, 22 cases of this infection have been identified in COVID-19 patients, of which 7 had Strongyloides hyperinfection [66]. Therefore, the integrated management of COVID-19 and helminth co-infections in endemic areas should be considered.

There are several treatment implications arising from embracing the complexity of physiological mechanisms involved in the interactions between SARS-CoV-2 and helminths. In our opinion, strategies for screening and early diagnosis, prophylaxis and treatment of helminthiases could decrease the morbidity and mortality of COVID-19 co-infected patients. Mass deworming, as recommended for endemic areas [67] would be beneficial; it is a therapeutic mediation that could improve COVID-19 outcome in patients co-infected with helminths. Few reports show the benefit of deworming in COVID-19 patients as it may reduce SARS-CoV-2 viral load and improve CD8+ T cells in the lung microenvironment [68]. However, it is interesting that Schistosoma infection in HIV-infected individuals is associated with enhanced spread of the virus and deworming reduces viral load and increases CD4+ counts [2].

Melatonin (MEL), a multifunctional natural molecule, is a potent anti-inflammatory, antioxidant, immunoregulator and a suppressor of apoptosis, with therapeutic effects in diverse pathologies, including viral and parasitic diseases [69-72]. Notably, its efficacy as an adjuvant or therapeutic weapon against COVID-19 has been demonstrated, reducing the severity and mortality of the patients [69,70]. In addition, given the recognized beneficial effects of MEL in helminth infections [71,72], it is plausible that this molecule exerts a therapeutic role in improving the symptomatology and mortality associated with these co-infections. Therefore, MEL should be evaluated in patients with COVID-19/helminths co-infections.

On a global level, little is known regarding the relationship between helminth infections and COVID-19 outcome. There is scarce documentation in the literature. Data on preexisting helminths and SARS-CoV-2 infection are just emerging and the implications of their complex interactions remain ill-defined. The majority of articles are reviews where the authors argue and conjecture that helminths could have a beneficial or detrimental effect on COVID-19 outcome and both assumptions look persuasive. To the best of our knowledge, a report from Ethiopia [29] appears to be the first and unique study to demonstrate that co-infection with enteric parasites is associated with the evolution of COVID-19. Currently, a clear knowledge of the impact of helminth infections on COVID-19 outcome in different areas is lacking.

The gaps in current knowledge on this matter underscore the current deficiencies in properly comprehending the correlation between SARS-CoV-2 and helminths. There is a critical need for further research to demonstrate the interaction between helminths and SARS-CoV-2 infection. In vitro and in vivo studies are required to unravel underlying immunology and consequences for COVID-19 in co-infected individuals and whether the outcome of the disease is different and if this harms or protects patients from helminths. Unraveling the parasite-modulated mechanisms underlying severe COVID-19 offers new avenues for novel preventive and therapeutic interventions. Large-scale prospective epidemiological studies regarding COVID-19/helminths co-infection prevalence to address their combined impact in different geographic settings and populations are needed.

Intestinal helminths may alter the host’s immune response to SARS-CoV-2 with potential beneficial or detrimental effects. However, given the multiple adverse effects that these parasites may have on human hosts, it seems that they are more harmful than favorable on SARS-CoV-2 morbidity and mortality. The complex role of helminth co-infections on the progress of COVID-19 is just emerging and is still elusive and controversial. Therefore, large-scale prospective epidemiological studies are needed to clarify their role on COVID-19 outcome. These studies would be crucial to determine the management of COVID-19 in areas where helminth infections are co-endemic. This pandemic has highlighted the need for a holistic perspective when assessing the impact of infectious diseases on the global population. The control of coexisting helminth infections should be included in the management of the ongoing pandemic. Strategies for screening and treating helminthiases could improve the outcome of COVID-19 co-infected patients. Mass deworming could be beneficial.

There is no conflict of interest in this study.