Co-infection of COVID-19 and parasitic diseases: A systematic review

Co-infection of COVID-19 with other diseases increases the challenges related to its treatment management. COVID-19 co-infection with parasites is studied with low frequency. Here, we systematically reviewed the cases of parasitic disease co-infection with COVID-19. All articles on COVID-19 co-infected with parasites (protozoa, helminths, and ectoparasites), were screened through defined inclusion/exclusion criteria. Of 2190 records, 35 studies remained for data extraction. The majority of studies were about COVID-19 co-infected with malaria, followed by strongyloidiasis, amoebiasis, chagas, filariasis, giardiasis, leishmaniasis, lophomoniasis, myiasis, and toxoplasmosis. No or low manifestation differences were reported between the co-infected cases and naïve COVID-19 or naïve parasitic disease. Although there was a relatively low number of reports on parasitic diseases-COVID-19 co-infection, COVID-19 and some parasitic diseases have overlapping symptoms and also COVID-19 conditions and treatment regimens may cause some parasites re-emergence, relapse, or re-activation. Therefore, more attention should be paid to the on-time diagnosis of COVID-19 and the co-infected parasites.

SARS-CoV-2 in the early stages of infection; thereby increase morbidity and mortality of . It can also suppress the immune responses and mitigate SARSCoV-2 vaccine efficacy (Abdoli, 2020). Co-infection with certain organisms may also make proper illness identification difficult (Gutman et al., 2020). Moreover, regarding the fact that many people infected with SARS-CoV-2 receive immunosuppressive drugs, it is a possible risk factor for severe parasitic infections (Gautam et al., 2021).
Despite some attempts to assess the relationship between COVID-19 and parasitic diseases, the types of co-infected pathogens and the proportion of co-infection in SARS-CoV-2positive patients are unclear (Zhu et al., 2020). Also, many studies in this field are case reports or case series and a limited number of narrative review articles exist in this regard (Cai et al., 2022;Flegr, 2021;Głuchowska et al., 2021;Miguel et al., 2021). There is a demanding need to combine all of the reported parasitic disease-COVID-19 co-infection cases to understand the disease's special conditions and to unlock any possible relationship between them. Therefore, the study aimed to systematically review the cases of co-infection of parasitic disease and COVID-19.
The most co-infected cases were adult (19-59 years) men. The most frequently-used methods for COVID-19 and parasites detection were RT-PCR and microscopic methods, respectively.
None of the included studies reported previous/recurrence COVID-19 infection of the cases. In COVID patients co-infected with strongyloidiasis the most common manifestations were fever, low partial pressure of oxygen (pO2), patchy airspace opacities, leukocytosis, and elevated eosinophils, CRP, ferritin, and D-dimer ( Table 2).

Frequency of COVID-19-parasitic disease co-infection.
The most frequent manifestations in chagas-COVID-19 co-infected cases were increased blood troponin T, blood glucose alteration, low pO2, leukocytosis, and elevated CRP (Table   2). In two cases of COVID-19 co-infected with amoebiasis, the liver abscess was observed in addition to general symptoms of COVID-19. The clinical manifestations of COVID-19 cases co-infected with other parasites were as reported in Table 2.
3.6. Treatment and outcome of the COVID-19-parasitic disease co-infected cases. The majority of the COVID-19-parasitic disease co-infected cases were healed under appropriate therapeutic management (Table 1). The treatment regimens of the COVID-19-parasitic disease co-infected cases were varying and dependent on the severity of COVID-19 and the co-infected parasite. In all cases, routine therapeutic managements were applied, although only some studies mentioned its details. The most anti-COVID-19 drugs used were oxygen therapy, lopinavir/ritonavir, favipiravir, enoxaparin, hydroxychloroquine, dexamethasone, In the present study, we tried to recover published studies of COVID-19 co-infected with almost all parasitic diseases. However, for many parasites, no co-infection report existed.
Given the existence of chronic parasitic diseases in the world, and with the sheer millions of COVID-19 infections, the number of co-existing infections would be staggering but not reported. Previous studies have shown that some parasitic diseases such as schistosomiasis, malaria, and helminths, may increase the risk of severe COVID-19 infection (Cai et al., 2022;Głuchowska et al., 2021). However, as our systematic review showed, even for those parasites that co-infection with COVID-19 has been reported the number of studies is very low (mainly one or two studies). This issue indicates that co-infection of parasites and COVID-19 is not frequently reported. Also, due to the low number of studies and low sample size of many of them, calculating the prevalence of COVID-19-parasitic diseases co-infection was not applicable.
In comparison to other parasitic diseases, more studies exist on malaria-COVID-19 coinfection. There are some possible reasons for this as follows: 1-Malaria is widely spread around the world (Garcia, 2010), 2-It seems that there is a low prevalence of COVID-19 in malaria-endemic countries (Anyanwu, 2021). The difference in COVID-19 prevalence between malaria-endemic and non-endemic countries may be attributed to several factors like mitigation tools adopted, testing capacity, or cultural habits, although much more theories The co-infection was reported in different parts of the world but mainly in those endemics for the parasites. Even the most reporting cases in non-endemic countries had recently traveled to the parasites' endemic regions. Therefore, it is obvious that the probability of COVID-19parasitic diseases co-infection is higher in parasites' endemic regions. Note that in the literature, other studies than our included articles might also discuss parasite-COVID-19 coinfection, but they were excluded for reasons in the present study. Therefore, the countries presented here are those included in our systematic review and not exclusively the definite countries where co-infected cases have been observed.
Some parasites such as S. stercoralis are opportunistic parasites that may latently live in human bodies and appear after the weakening of the immune system. Since corticosteroids which are immune response suppressants are used to treat COVID-19, latent parasites have the opportunity to emerge and cause disease (Gautam et al., 2021). Therefore, it has been suggested that before initiating immunosuppressive therapy, screening for opportunistic parasites such as S. stercoralis be pursued in COVID-19 patients who originate from endemic regions (Gautam et al., 2021;Lier et al., 2020;Marchese et al., 2021). Furthermore, COVID-19 disease condition and its treatment regimens may cause re-emergence of some previous parasitic diseases as seen for malaria relapse in two co-infected cases (Kishore et al., 2020;Shahid et al., 2021), and giardiasis reactivation in one case (Lupia et al., 2021).
Leishmaniasis is an NTD that has different manifestations from the self-limiting cutaneous type to the fatal visceral type and is caused by several Leishmania species (Maxfield and Crane, 2022;Rostamian and Niknam, 2019). Because cutaneous leishmaniasis has a low life risk, it is neglected, especially in the COVID-19 pandemic era. For this reason, it seems coinfected cases of cutaneous leishmaniasis and COVID-19 may not be sent for publication in scientific journals. Therefore, it is likely that cutaneous leishmaniasis-COVID-19 co-infection is much more common than reported in the current study. On the contrary, its visceral leishmaniasis is clinically valuable due to the possibility of lethality, and for this reason, its co-infection with COVID-19 is more worth reporting. However, there are limited, but increasing cases of this type of co-infection in the information sources (Colomba et al., 2022;Paul and Singh, 2023), although this type has a wide range in the world from Southeast Asia to the Middle East, Africa, and South America (Kone et al., 2019;Rostamian et al., 2021; J o u r n a l P r e -p r o o f Journal Pre-proof Scarpini et al., 2022). As with other neglected parasites, the co-infection of Leishmania with COVID-19 needs further investigation.
Although hypertension and diabetes were the most frequent underlying diseases observed in the co-infected cases and could be assumed as risk factors, the number of reports is low and more studies are needed to confirm it. It is noteworthy that hypertension and diabetes are two main risk factors of COVID-19 severity (de Almeida-Pititto et al., 2020). Therefore, it seems logical that co-infection with parasites, parallel to COVID-19 severity, be more prevalent in individuals with hypertension and diabetes.
Clinical manifestation of COVID-19-parasitic disease co-infected cases dependent on the parasitic diseases. These manifestations seem to be no different from routine COVID-19 or parasitic diseases, separately, although only some studies mentioned this issue (Mahajan et al., 2020). However, two studies on malaria-COVID-19 co-infection showed a somewhat different manifestation of co-infected cases in comparison to COVID-19 naive. In one study, severe thrombocytopenia (23,000/µL) and CRP of 1000 mg/L were observed in the coinfected cases that were considered atypical for a clinically mild case of COVID-19 (Jochum et al., 2021). Another study reported decreased alpha-tocopherol values and a significant increase of 8-iso-prostaglandin F2α (8-iso-PGF2α) among co-infected cases compared to COVID-19 naïve (Muhammad et al., 2020). It is also noteworthy that due to some overlapping symptoms and more frequent cases of COVID-19 in the pandemic era, most coinfected cases have been initially diagnosed as COVID-19 and later the parasitic infection has been found as an incidental finding.
The standard common treatments for COVID-19 and parasitic diseases seem to be effective since the majority of co-infected cases healed and only those who were old and had severe forms of COVID-19 died. The challenging issue for the treatment of co-infected patients is their accurate and on-time diagnosis because COVID-19 and some parasitic diseases such as malaria have many overlapping symptoms that make their diagnosis difficult (Di Gennaro et al., 2020;Shahid et al., 2021).
Altogether, here we compiled reporting cases of parasitic diseases-COVID-19 co-infections and found out that: 1-There are a relatively lower number of reports on parasitic diseases-COVID-19 co-infections in the world compared to co-infection with other microorganisms, 2- The most co-infected cases are adult men who resident of or travel to parasite-endemic J o u r n a l P r e -p r o o f Journal Pre-proof countries, 3-No or low manifestation differences exist between the co-infected cases and naïve COVID-19 or naïve parasitic disease, 4-COVID-19 conditions and treatment regimens may cause parasites re-emergence, relapse, and re-activation, 5-If the parasitic disease and COVID-19 diagnosed accurately and on-time, the patients will be treated faster and more efficiently. It should be noted that since diagnostic strategies for acute COVID-19 infection are considerably variable and diagnostic test positivity does not always confirm active infection (Vandenberg et al., 2020), the meaning of co-infection should be considered carefully. We also suggest that more accurate studies on general populations of endemic regions with larger sample sizes be conducted to find any relationship between parasitic diseases and COVID-19.
The present study faces some limitations as follows: 1-We excluded reviews, comments, letters, and conferences, consequently the data gathered here may not represent all the existing data in the field, 2-The cases that had the latent type of parasitic diseases (such as latent toxoplasmosis) and were later infected with COVID-19 were excluded from the study, and 3-An article on Chagas-COVID-19 co-infection (Molina et al., 2021), was excluded because it selected the co-infected cases and compared them with non-co-infected cases. Since this strategy does not show the real number of co-infected cases it was excluded, however, its data may be also valuable in this case.

Conclusion
Although there was a relatively low number of reports on parasitic diseases-COVID-19 coinfection, COVID-19 and some parasitic diseases have overlapping symptoms and also COVID-19 conditions and treatment regimens may cause some parasites re-emergence, relapse, or re-activation. Therefore, more attention should be paid to the on-time diagnosis of COVID-19 and the co-infected parasites.    (2) Antimalarial selfmedication N/A Co-infected cases had a higher parasitaemia, a higher temperature,and were mostly infected with non-falciparum malaria.
Only one had severe anemia.
Steroids, supplemental oxygen, thrombosis prophylaxis, anti-malarial treatment 0 to 17 The study documented a high proportion of adverse outcomes (for both mother and fetus) among pregnant women with malaria-COVID-19 co-infection.

S1
Fever and diarrhea (4  days *-A code was used for each study (if an article described more than one case or case series, each one was specified with a unique code). These codes are concordant in codes used in Table 1 so their references could be find in Table 1.
**-Only those parameters that were outside of the normal ranges are given. Parasitaemia have been reported only in some studies, although all have confirmed the J o u r n a l P r e -p r o o f Journal Pre-proof