key: cord-1035313-zu6aa5v2
authors: Bamorovat, Mehdi; Sharifi, Iraj; Aflatoonian, Mohammad Reza; Karamoozian, Ali; Tahmouresi, Amirhossein; Jafarzadeh, Abdollah; Heshmatkhah, Amireh; Sharifi, Fatemeh; Salarkia, Ehsan; Khaleghi, Tabandeh; Khosravi, Ahmad; Nooshadokht, Maryam; Zarandi, Mehdi Borhani; Barghi, Maryam
title: Prophylactic effect of cutaneous leishmaniasis against COVID-19: A case-control field assessment
date: 2021-09-24
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.09.050
sha: d1a679d982087c336e8bc54f404b06c2996054dc
doc_id: 1035313
cord_uid: zu6aa5v2

Introduction We assessed the possible relationship between the COVID-19 with laboratory-confirmed CL-registered cases with a history of scar compared with healthy volunteer participants. Methods This case-control retrospective study was conducted in southeastern Iran with a high anthroponotic cutaneous leishmaniasis (ACL) burden. Results Overall, n=1,010 cases of CL consisting of n=479 male and n=531 female were analyzed for probable infection with SARS-CoV-2. Altogether, in the case group, two men and one woman (0.3%) were afflicted with a mild form of COVID-19 disease, and none of them were hospitalized or died. In contrast, out of n=2,020 healthy participants, n=57 (2.9%) contracted laboratory-confirmed COVID-19, including mild (66.7%), hospitalized (26.3%) and critical and death (3.5%, each). There was a strong negative association between CL infection and COVID-19. The burden of COVID-19 in CL-cured participants significantly reduced the morbidity (OR=0.12, CI: 0.03 - 0.30 and P <0.001) and mortality (percentile: -4.10, -0.02). Conclusion Participants with a history of previous CL scar significantly prevented the incidence of COVID-19 morbidity and mortality. The cross-protection mediated by the CL-cured cases would presumably retard COVID-19 in endemic countries. However, further longitudinal studies are needed to explore the potential profile and duration of this protection offered by CL against COVID-19.

Leishmaniasis is a neglected disease caused by protozoan parasites belonging to over 20 human parasitic species of Leishmania. This complex disease is manifested in several clinical and epidemiological presentations and is extensively distributed among one billion at-risk populations in over 100 countries, primarily in the developing world (Bailey et al., 2017; World Health Organization, 2017) . Cutaneous leishmaniasis (CL) is the most abundant form, which causes skin lesions on the naked body with extensive public health problems (Alvar et al., 2012; Bailey et al., 2019; Du et al., 2016) . Cutaneous lesions eventually heal and lead to permanent scars, disfigurement, psychological, social, and economic consequences (Aflatoonian et al., 2019; Bamorovat et al., 2018a) . Leishmania tropica and Leishmania major are the most common causes of CL in semi-arid tropics and subtropics, notably in the Eastern Mediterranean Region (EMR), where 74% of the total cases have been reported (Akhoundi et al., 2016; Bailey et al., 2017; Bamorovat et al., 2018a; World Health Organization, 2017) .

Both innate and adaptive immune systems contribute to the induction of anti-Leishmania immunity, but the effector Th1 cell-mediated immunity plays a more critical role in the protection (Jafarzadeh et al., 2019; Scott and Novais, 2016) . Generally, solid immunity is associated with a cell-mediated immune response, while in the absence of T cell-mediated 5 immunity, non-protective reactions are expressed as a robust humoral response (Jafarzadeh et al., 2019; Scott and Novais, 2016) .

Cytokines such as IL-12 and IFN-γ play a fundamental role in protection against leishmaniasis through inducing the polarization of Th1 cells. Th1 cell-derived cytokines, especially IFN-γ and TNF-α, promote macrophage activation leading to the Leishmania clearance via nitric oxide (NO) and other reactive oxygen species (Jafarzadeh et al., 2019; Scott and Novais, 2016) . The Th2 cell differentiation is driven by IL-4, promoting vulnerability through macrophage inhibition and abrogation of IL-12 expression (Jafarzadeh et al., 2019; Scott and Novais, 2016) . The leishmaniasis progression is related to dominant Th2-and Treg cell-related responses and high IL-4, IL-5, TGF-β, and IL-10 production (Jafarzadeh et al., 2019; Saha et al., 2020; Scott and Novais, 2016) .

Both lines have a similar signaling pathway utilizing IL-4 receptor alpha, IL-13, and share several features with IL-4 (Matthews et al., 2000) . Interleukin-13 has disease-promoting properties and operates independently of IL-4 (Belkaid et al., 2001) , suggesting that IL-13 and IL-4 have additive effects. Prevention of IL-12 generation by macrophages and high levels of IL-13 inhibits the Th1 cell-mediated responses, causing a skewing of harmful Th2 cells. The clinical outcome of infection with Leishmania correlates with the cytokine development profile and timing. Many immune cells are expressed, predominantly by CD4 + T cells (such as Th1 and Th2 cells), but also by CD8 + T cells and CD4-CD8 double-negative T cells (Liese et al., 2008) , including dendritic cells, macrophages, NK cells (Ronet et al., 2010) , and B cells (Gessner et al., 1993) .

On the other hand, the recent emergence and rapid global spread of coronavirus 2 (SARS-CoV-2) severe acute respiratory syndrome and the subsequent 2019 coronavirus disease 6 (COVID-19) is an ongoing health pandemic with devastating consequences. In addition to nonstructural proteins, SARS-COV-2has several types of structural proteins (Shang et al., 2020) . A wide range of mechanisms such as hyper-inflammatory reactions, immune imbalances, cytokine storm, massive replication of SARS-CoV-2, extensive cell death, lymphopenia, and coagulopathy contribute to the COVID-19 pathogenesis leading to multi-organ failure, especially acute respiratory distress syndrome (ARDS) (Jafarzadeh et al., 2020a; Li et al., 2020; Lingeswaran et al., 2020; Zou et al., 2020) .

Innate immunity interferons (IFNs) provide the first border of defense against viral infections as timely production of proper amounts of IFNs can limit a viral infection (Jafarzadeh et al., 2020b) . During the incubation period or early phases of COVID-19 infection, appropriate local type III and type I IFN responses can eliminate SARS-CoV-2or limit its replication, preventing disease progression to moderate and severe stages (Jafarzadeh et al., 2020b) .

However, if the early IFN responses fail to control SARS-CoV-2, the virus replicates in the lungs, enters the circulation, and leads to massive tissue destruction as its receptor is expressed by many cell types (Jafarzadeh et al., 2020b) .

In adaptive immunity, effector Th1 cell-derived cytokines, especially IL-2 and IFN-γ, activate CD8 + cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells to reduce viral load through killing virus-infected-cells (Frank and Paust, 2020; Miyauchi, 2017) . Moreover, The Th2 cell-derived cytokines induce B cells to secrete anti-viral antibodies. The specific antibodies against surface viral antigens bind to the free virus to prevent virus attachment to target cells (Jafarzadeh et al., 2008) .

We assessed the potential relationship between the SARS-CoV-2infection with laboratoryconfirmed CL-registered cases with a history of scar in Kerman County compared with healthy 7 volunteer participants. We hypothesized that possibly some infectious diseases such as CL with the immunological memory cells could prevent the incidence and severity of the COVID-19 disease. To date, there is no epidemiological study to indicate that CL may offer protection against SARS-COV-2. To our knowledge, this longitudinal observation is the first evidencebased field assessment suggesting that CL may be associated with a lower risk of COVID-19.

The current study was given ethical approval by the Joint Ethics Committees of the 

This study was carried out between July 2020 and December 2020 as a case-control retrospective study from the high-risk areas and endemic to ACL caused by L. tropica in Kerman county, southeastern Iran. In the southeast and about 1,000 km away from Tehran, Kerman is the largest province in Iran. This province falls into the hot and dry zones and suffers from water shortages. In Kerman, average annual precipitation is low (140-150 mm), and maximum rain falls in winter. One of Iran's well-known ACL focal points is Kerman's county (Aflatoonian et al., 2019; Bamorovat et al., 2019b Bamorovat et al., , 2019a Bamorovat et al., 2018b Bamorovat et al., , 2018a Sharifi et al., 2015) ( Fig. 1 ).

The current study was conducted at the Dadbin Health Center, the primary referral clinic for CL care and control operations. The clinic is directly connected to the Kerman Leishmaniasis Research Center in Kerman and the Afzalipour School of Medicine. The clinic is responsible for 8 CL patients that have been referred from various localities within the county. Each CL patient has a case report form (CRF) recording demographic and clinical status and underlying diseases.

In the case group (confirmed CL-cured volunteer participants who had a history of a scar), the subjects or their guardians were fully informed about this investigation's purpose.

Throughout the interview, the evaluators warranted that the questions were well-understood by the participants or their guardians. Before the study began, several face-to-face meetings and interviews were held with the participants and community health authorities to describe the purpose, procedure, and possible benefits. In the research, CL-cured patients participated voluntarily. A written informed consent form was completed for each patient or guardian "on behalf" of all the children. All the data was kept confidential. Figure 2 shows CL patients with lesions in different locations of the body from the study areas.

All CL cases who participated in the present study had a history of the previous scar and were laboratory-confirmed by standard Giemsa and polymerase chain reaction (PCR) (Aflatoonian et al., 2019; Bamorovat et al., 2018; Bamorovat et al., 2018a) . Referred subjects from various health clinics within the Kerman county suspected of being infected with CL were diagnosed by the direct microscopic examination at the registry center (Dadbin Heath Clinic diagnostic laboratory). Tissue smear preparations were obtained from the edge of the lesions, dried, fixed, stained by routine Giemsa, and visualized under an optical microscope for the presence of Leishman bodies (amastigotes). CL-cured subjects were prospectively evaluated for COVID-19.

Suspected COVID-19 patients referred to the Kerman University of Medical Sciences hospitals were identified by Multiple One-Step quantitative real-time PCR method using the COVITECH kit. The demographical and clinical data in the control group (healthy individuals with no history of CL who contracted COVID-19) were obtained in collaboration with the Statistics Center of Kerman University of Medical Sciences. Both groups (controls and cases) were closely related residents, regarding the age, gender, and socioeconomic backgrounds, selected from the same endemic communities within Kerman County, Kerman province. Therefore, they are similarly exposed to the infection.

In order to analyze the data, statistical software R 4.0.2 was performed. Firth's biasreduced penalized-likelihood logistic regression was used to affect the CL and COVID-19 variables in the studied dataset. This model is the Bayesian logistic regression with noninformative Jeffrey's Prior. In this model, instead of using the maximum likelihood method to minimize the bias caused by the rare event in the dataset, the penalized maximum likelihood approach was used to estimate the parameters and regression coefficients. There is no need to concern about accurate coefficient estimation in this model, despite the rare event data in the studied dataset. In addition to the p-value, the regression coefficient and odds ratio (OR) were also assessed.

Furthermore, Bayesian inference in ordinal logistic regression was used to analyze the severity of COVID-19 in the case and the control groups. Due to the incidence of the event being relatively low at some levels, standard statistical methods to analyze this dataset may have 10 undesirable and inaccurate outcomes. Normal distribution was used as the prior distribution.

Finally, the arm and logistic packages were used for this analysis in R software.

Overall, n=1,010 laboratory-confirmed cases with a history of CL scar consisting of n=479 male and n=531 female were explored and precisely analyzed for possible infection with coronavirus. Altogether, in the case group, two men and one woman (0.3%) were afflicted with a mild form of coronavirus disease, and none of them neither hospitalized nor died. In contrast, n=2,020 healthy participants were sequentially selected as a control group, including n=998 men and n=1,022 women. In total, n=57 (2.9%) consisting of n=28 men and n=29 women contracted laboratory-confirmed COVID-19, including mild (66.7%), hospitalized (26.3%) and critical and death (3.5%, each). The findings indicated that there was a strong negative association between CL-cured infection and COVID-19. Based on Firth's Bias-Reduced logistic regression analysis, the burden of the COVID-19 disease in CL-cured participants was significantly reduced in terms of morbidity (OR=0.12, CI: 0.03 -0.30 and P <0.001) and mortality (percentile: -4.10, -0.02) compared with that in the healthy non-CL control group (Tables 1 and 2 ).

According to Table 2 , converge probability did not include the value of zero, which showed a significant relationship between the two variables (percentile = -4.10, -0.02). On the other hand, considering the negative sign of the estimated parameter, it can be argued that the chance of severity of COVID-19 in participants with healed CL was lower than that in patients with no CL.

The present study showed that participants with a history of CL significantly prevented the incidence of COVID-19 and lowered the severity of the disease more significantly than the healthy non-CL control group. This observation does not clearly show whether the protection against the COVID-19 disease is temporary or long-lasting, although the cured CL cases recruited in this study indicated a long history of the CL scar between 2013 and 2020.

Furthermore, clinical records show that the severity of COVID-19 was significantly lower in healed CL cases than in healthy participants. This observation indicates that the protection still exists in numerous of the cured CL participants with previous scars, suggesting that the crossprotective effect of CL can be long-lasting. Our understanding of extensive immune protection facilitated via memory cells and the current epidemiological evidence from coronavirus following the CL infection offer a rational immunological basis for CL's potential prophylactic effect against severe COVID-19. Figure 3 illustrates the proposed model for the role of leishmanial-mediated concomitant immunity in promoting the anti-SARS-CoV-2immune responses.

The cross-protection arbitrated by CL would significantly advantage most developing countries, notably the Mediterranean region, where approximately 74% of the global CL cases belong to these areas. The lower burden of COVID-19 regarding the incidence and case-fatality rate during the pandemic has been repeatedly documented in tropical and subtropical areas (World Health Organization, 2020a). The above finding caused by cured CL participants is aside from the partial protective effect of a robust BCG vaccination policy routinely implemented in these countries and further contributes to lowering the morbidity and mortality profiles of COVID-19.

At present, no direct evidence exists to exhibit that the Bacillus Calmette-Guérin vaccine (BCG) protects people against the coronavirus. Hopefully, two clinical trials addressing this issue are proceeding, and WHO will assess the proof when it is available (World Health Organization, 2020b). However, since the emergence of SARS-CoV-2, a growing body of evidence has been compiled, indicating BCG's ability to induce a range of general immunological effects harmful to other conditions (Curtis et al., 2020; Escobar et al., 2020 ). There appears that CL has the potential to train the innate and adaptive immune systems to produce active memory cells and associated components against COVID-19, a process also called trained immunity" (Arts et al., 2018; Kleinnijenhuis et al., 2014) .

There have been many interactions between parasites and other parasitic and microbial infections. Concomitant infections are a common phenomenon in nature and are frequently associated with parasites. Many examples of the interactions resulting in susceptibility or resistance between parasites, viral, and bacterial infections have been described. In concomitant infections, several modalities of parasites' burden on the immune system are well documented, including immunosuppression and immunopotentiation (Cox, 2001; Griffiths et al., 2014) . T lymphocytes' polarization towards cell-mediated or antibody-mediated responses depends on the quantity and quality of antigens produced by the parasite. What is essential in these interactions is that the cytokines and also the effector molecules act non-specifically. Therefore, any microbial organisms can be caught up in the cytokine network concurrently or subsequently.

Concomitant agents are precisely characterized as being inherently heterologous, a mechanism that is not yet well-documented. One of the reasons why little consideration has been paid to concomitant infections is that the interactions involved are difficult and complex to understand (Cox, 2001; Shen et al., 2019; Wait et al., 2020) . The best-studied molecules are generated by trypanosomes that produce lymphocyte activating factors to produce IFN-γ and a cascade of immunological molecules to stimulate macrophage activity and IL-12 production 13 (Cox, 2001) . The exact role of these components and effector cells induced by the leishmanial agents is not well clear but what is important here is that these Leishmania-derived molecules can interact with the other elements of the immune system and may be involved in a long-lasting enhancement in immune surveillance to COVID-19.

In addition to concomitant immunity, the antigenic similarities between some Leishmania species and SARS-CoV-2 need more investigation. If the presence of antigenic similarities is proved, then the Leishmaina-mediated cross-immunity can protect SARS-CoV-2in cured individuals due to the induction of long-lasting memory cells. Accordingly, vaccination with whole Leishmania vaccines may confer protection against COVID-19.

CL typically produces skin ulcers on the arms, legs, and particularly the body's face (World Health Organization, 2014) . In three to 18 months, over 90% of cases of CL recover spontaneously (Davies et al., 2003) . At the sandfly bite site, the disease starts as a slight red swelling (papule). The papule improves in size and becomes a nodule that ulcerates and finally crusts over. Eventually, most CL sores can heal naturally, although it is impossible to predict this phase's length in an individual case. For primary sores, topical or systemic treatment approaches such as chemicals and freezing are used (Ejov and Dagne, 2014) . Meglumine antimoniate (Aflatoonian et al., 2019; Karamian et al., 2015; World Health Organization, 2014) is the conventional treatment for CL. Individuals are usually resistant to reinfection from the same species after healing, and a lifelong immunity will often be produced.

One of the few parasitic diseases likely to be controllable by vaccination is leishmaniasis.

Efforts to produce approved and efficacious vaccines have so far been inconclusive, although numerous clinical and field trials of killed and live vaccines have been conducted around the world (Khamesipour et al., 2005) . One live prophylactic vaccine is a mixture of Uzbekistan-registered live virulent L. major combined with a killed Leishmania parasite (Khamesipour et al., 2005) . In hyper-endemic Asian countries, it is commonly recognized that after recovery from CL, they are typically protected against further reinfection. Therefore, an active lesion exudate has been used to inoculate young children, particularly girls, on their buttocks for centuries. This approach would develop a self-healing lesion and shield the face and other exposed body parts against lesions (Modabber, 1989; Nadim et al., 1983) . It became known as leishmanization (LZ) inoculation of live virulent Leishmania. Leishmanization has been used in many countries for over 60 years (Khamesipour et al., 2005) . The problem with live metacyclic promastigotes is that approximately 1-3% of the patients develop non-healing forms after inoculation. Nevertheless, a population of over 2 million Iranian people who voluntarily participated in the Iran-Iraq war was vaccinated against zoonotic CL caused by L. major (Khamesipour et al., 2005; Nadim et al., 1983) .

Similarly, the BCG vaccine is generally used in infancy as a prevention against tuberculosis (TB). Many studies suggest that the BCG vaccine protects against infant mortality through nonspecific heterologous protection to other infectious diseases (Shann, 2013) , possibly, through innate immune epigenetic mechanisms (Moorlag et al., 2019; Shann, 2013) . Exposure to the BCG vaccine may reduce the severity of COVID-19 and lower mortality, and thus, it possibly help develop therapeutic or preventive strategies that can impact SARS-CoV-2infections (Escobar et al., 2020; Malik et al., 2020; Mohapatra et al., 2020) . A vaccine against TB is considered an alternative therapeutic modality. BCG vaccine is known to induce both innate and adaptive immunities, thereby activating both nonspecific and cross-reactive immune responses; when combined, it could effectively resist other pathogens, including SARS-CoV-2 (Malik et al., 2020) .

A current study showed that malaria caused by Plasmodium falciparum in endemic areas substantially lower the incidence of the COVID-19 disease. The authors detected possible common targets for an immune response to SARS-CoV-2by immune determinants' shared characters. Possible cross-reactivity was proposed via HLA-A*02:01 and consequent CD8+ Tcell stimulation. They concluded that immunodominant epitope conservation between coronavirus and P. falciparum thrombospondin-related anonymous protein might motivate the low COVID-19 incidence in malaria-affected areas by offering immunity against coronavirus patients that were previously infected with malaria (Iesa et al., 2020) .

As mentioned, the SARS-CoV-2is an emerging disease, and probably other emerging diseases are also to occur in the future; perhaps some infectious diseases such as CL with the immunological memory they create in the body can retard and prevent the severity of emerging diseases that they have like immune response similar to the coronavirus pathway. Further clinical trials should be conducted to provide scientific data to investigate our hypothesis of whether the LZ effectively reduces the COVID-19 incidence and severity.

The present findings indicated that overall, three CL-cured participants contracted a mild form of COVID-19 compared to n=53 cases in healthy non-CL afflicted participants with a spectrum of disease severities, including mild, hospitalized, critical, and death. In the world's vast CL endemic countries, COVID-19 is possibly prevented due to various prophylactic vaccines and previous infectious conditions such as CL. However, further longitudinal studies are needed to explore the potential profile and duration of CL's protection against COVID-19.

Furthermore, exploring the precise association between all forms of leishmaniasis and COVID-19 in multi-central approaches helps design more effective prophylactic and therapeutic measures for planning future control strategies.

This study was funded by the Vice-Chancellor of Research, Kerman University of Medical Sciences Kerman, Iran (grant number 99000242).

We declare no conflict of interest.

The current study was given ethical approval by the Joint Ethics Committees of the Kerman University of Medical Sciences and Kerman Leishmaniasis Research Center (Ethics no.

IR.KMU.REC. 1399.210, contract no. 99000242).

All participants received written and oral information on the study and signed a non-opposition statement.

All participants signed a non-opposition statement. Data were anonymised for publication.

Data are available to any reader directly upon reasonable request.

Not applicable. type cytokines inhibit viral replication and activate the local NK cells and CD8 + CTLs, eliminating virus-infected cells to limit viral load in the lungs (Right). In the absence of Leishmania-mediated Th1 cell concomitant immunity, SARS-CoV-2-infected epithelial cells can produce type I IFN-γ, which can control The COVID-19 replication. If SARS-CoV-2 evades the type I IFN-γ-mediated response, it then enters the blood and causes blood viremia and subsequent consequences after that.

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We would like to thank the patients for their cooperation and the health personnel and staff at Dadbin Health Clinic, County Health Surveillance Systems, to perform this study.