Viscerotropic leishmaniasis: a systematic review of the case reports to highlight spectrum of the infection in endemic countries

Visceral leishmaniasis is an important neglected parasitic disease that is generally caused by Leishmania infantum , Leishmania donovani and Leishmania chagasi . However, several causative species of cutaneous leishmaniasis (CL) causes an interstitial form of leishmaniasis which known viscerotropic leishmaniasis. The aim of this paper is a systematic review of the cases of viscerotropic leishmaniasis to present the main causative agents, clinical manifestations, treatment and outcomes of the cases. An electronic search (any date to August 2017) without language restrictions was performed using Medline, PubMed, Scopus and Google Scholar. The searches identified 19 articles with total 30 case reports. Of them, old world Leishmania species was reported from 23 (76.7%) cases, including 20 cases of L. tropica and three cases of L. major ; whereas new world Leishmania species were reported in seven (23.4%) cases. The infection was more prevalent in male (24/30, 80%) than female (5/30, 16.7%) patients. Co-morbidity/ co-infection was observed in 13 out of 30 cases (43.4%), which the most of them was HIV/ AIDS (10 out of 13 cases, 76.9%). The results suggested that viscerotropic leishmaniasis should be more attended in the endemic countries of CL and in immunocompromised patients in order to exact discrimination from other endemic infectious diseases.

statement (Moher et al. 2015). The terms and search strategy are described in Table 1. All titles, abstracts and full texts from each of the searches were examined and reviewed. The search was limited to literatures on humans. Moreover, all selected references were hand-searched for other relevant articles or their citations in Google Scholar. Data selection was also performed after removing duplications by Endnote software (Kwon et al. 2015). Articles were considered eligible for inclusion if they involved case reports or case series of patients with VL who infected with one of Leishmania species that regularly causing CL. Also, an article was selected if it reports details of diagnostic tests (e.g. molecular methods or isoenzyme identification) or relevant evidence to confirm the species of Leishmania parasite.

Countries
According to the Table 2, the cases were reported from 10 countries. Leishmania tropica was reported from Iran (five cases) (Alborzi et al. 2006(Alborzi et al. , 2008Jafari et al. 2010), American soldier returned from operation desert storm in Saudi Arabia (eight cases) (Magill et al. 1993), India (four cases) (Sacks et al. 1995), Kenya (two cases) (Mebrahtu et al. 1989) and the Afghan girl who lived in the USA (one case) (Weiss et al. 2009). Leishmania major was reported from Iran (two cases) (Karamian et al. 2007;Shafiei et al. 2014) and Burkina Faso (one case) ( Barro-Traore et al. 2008). Leishmania braziliensis was reported from Brazil (two cases) (Gontijo et al. 2002;Silva et al. 2002) and an Italian man living in Venezuela (one case) (Hernández et al. 1993). Leishmania mexicanawas reported from Colombia (Mestra et al. 2011) (one case) and Mexico (one case) (Ramos-Santos et al. 2000). One case of L. amazonensis was reported from Brazil (Aleixo et al. 2006) and one case of Leishmania variant that shared sequences of L. braziliensis and L. mexicana from Venezuela (Hernández et al. 1995b) (Table 2).

Sex and age of the patients
The infection was higher in male (24/30, 80%) than female (5/30, 16.7%) patients ( Fig. 3 and Tables 3-5). The sex was not reported in a case report as well (Alborzi et al. 2006). From the old world Leishmania-infected patients, L. tropica was detected in 16 (80%) and three (15%) out of 20 cases of male and female patients, respectively (Table 1), but the sex was not reported in an L. tropica-infected patients (Alborzi et al. 2006). All of the three cases of L. major were reported from male patients (Table 4). From the seven cases with the new world Leishmania-infection, five (71.4%) and two (28.6%) cases were reported from male and female, respectively (Table 5).
Among the L. tropica-infected patients (n = 20 cases), seven and six cases were reported from patients with age ranges of 2-15 and 17-50 years old, respectively. The age was not reported in six out of 20 L. tropica-infected patients ( Table 3). All of the three L. major-infected patients were adult with age ranges of 31-53 years (Table 4). Among the seven patients with the new world Leishmania infection, six patients were in the adult aging ranges (19-43 years old) and one case was reported from an 8-year-old L. amazonensis-infected patient (Table 5) The patient died due to complication of the diseases (Continued )

Co-morbidity/co-infection
From the 30 cases, 13 (43.4%) patients had co-morbidity or coinfection ( Fig. 4 and Tables 3-5). The highest co-morbidity/ co-infection rate was reported from patients who infected by the new world Leishmania species (six out of seven cases, 85.7%). While seven out of 20 (35%) cases who infected by the new world Leishmania species had co-morbidity/co-infection. The most co-morbidity/co-infection was HIV/AIDS (10 out of 13 cases, 76.9%), kidney transplant recipient (two out of 13 cases, 15.4%) and renal carcinoma (one out of 13 cases, 7.69%) (Fig. 5). In patients with the new world Leishmania species infection, all three cases of L. braziliensis had co-morbidity/coinfection and were reported from a kidney transplant recipient (Gontijo et al. 2002), an HIV-positive patient (Silva et al. 2002) and an HIV-positive patient with Pneumocystis carinii pneumonia, oropharyngeal candidiasis and pleuro-pericardial tuberculosis (Hernández et al. 1993(Hernández et al. , 1995a (Table 5). Two cases of L. mexicana were reported from a CMV-positive kidney transplant recipient (Mestra et al. 2011) and an HIV-positive patient with P. carinii pneumonia (Ramos-Santos et al. 2000) (Table 5). Also, the patient with mixed L. brazileinsis and L. mexicana infection was HIV positive (Hernández et al. 1993(Hernández et al. , 1995a (Table 5).

Main clinical manifestations
In most of the patients, there were major symptoms of VL including fever, weight loss, hepatosplenomegaly, anaemia and leucopenia, but some patients had non-specific symptoms such as malaise, headache, cough or no symptoms (Tables 3-5). However, it seems that complication of the disease might be involved in the immunity of the patients so that more severe infections alongside with more non-specific symptoms had reported from patients with co-infection/co-morbidity. Duration of the disease is ambiguous because it not reported in the most of the cases. In addition, some cases had several co-morbidity/ co-infection that might impact on the duration of infection (Tables 3-5).
Cutaneous lesions were reported in nine out of 30 cases (30.0%), among them, seven and one patients infected with old and new world Leishmania species, respectively. In patients who infected with the old world Leishmania species, cutaneous lesions were detected in five out of 20 patients with L. tropica infection (two patients had co-infection with HIV/AIDS) and (Alborzi et al. 2008;Weiss et al. 2009;Jafari et al. 2010;Mohebali et al. 2011), two out of three L. major-infected patients (both cases had co-infection with HIV/AIDS) (Karamian et al. 2007;Barro-Traore et al. 2008). Among the patients with the new world Leishmania species infection, cutaneous lesions were reported in two cases of L. braziliensis infection who was a kidney transplant recipient patient (Gontijo et al. 2002) and an HIV-positive patient (Hernández et al. 1993(Hernández et al. , 1995a (Tables 3-5).

Diagnostic tests
Diagnosis of the infection was conducted by one or more diagnostic tests according to the symptoms of the patients (Tables 3-5).

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Treatment Patients had mainly been treated with antimonial compounds so that the disease symptoms improved and liver and spleen size decreased or returned to normal size after treatment among the majority of the cases (Tables 3-5). However, five patients with L. tropica (Mebrahtu et al. 1989;Magill et al. 1993;Sacks et al. 1995;Alborzi et al. 2008) and one patient with L. major (Karamian et al. 2007) showed refractory to antimonial compounds and treated with other drugs (such as amphotericin B, pentamidine, miltefosine, etc.) (Tables 3 and 4). Also, one patient with L. tropica was resistant to amphotericin B (Alborzi et al. 2008) (Table 3). Some HIV-positive patients had also been received anti-retroviral therapy (Hernández et al. 1993(Hernández et al. 1995aMagill et al. 1993;Ramos-Santos et al. 2000;Silva et al. 2002;Karamian et al. 2007;Barro-Traore et al. 2008;Jafari et al. 2010;Shafiei et al. 2014) (Tables 3 and 5).

Outcome
Although most of the patients had healed following common anti-leishmanial therapy alone or in combination with other drugs (Tables 3-5), mortality had occurred in two kidney transplant recipients that infected with L. braziliensis (Gontijo et al. 2002) and L. Mexicana (Mestra et al. 2011) and one HIV-positive patient with mixed L. brazileinsis and L. mexicana infection (Hernández et al. 1995b) (Table 5).

Discussion
Viscerotropic leishmaniasis is an interstitial form of leishmaniasis with some non-specific symptoms. These non-specific symptoms may be considered in endemic regions of CL, and also in immunocompromised patients to help differential diagnosis from other endemic diseases. CL is more distributed than VL worldwide, while the most cases of CL have been reported from Afghanistan, Algeria, Colombia, Brazil, Iran, Syria, Ethiopia, North Sudan, Costa Rica and Peru. The results revealed that the main causative agent of viscerotropic leishmaniasis is L. tropica. In some regions, such as east and southeast of Iran (Sharifi et al. 2015;Karamian et al. 2016
Leishmania species. In these regions, the viscerotropic manifestations of L. tropica should be considered more seriously. Studies have shown that co-infection of leishmaniasis and HIV/AIDS is an important public health problem in different parts of the world (World Health Organization 2000; Monge-Maillo et al. 2014;Singh, 2014) as well as Iran (Shafiei et al. 2014). Co-morbidity with these two pathogens leads to rapid progression of the disease, development of more severe disease and a poor response to treatment (Singh, 2014). Several atypical presentations have been reported from of CL patients, which most of them detected from HIV-infected individuals (Meireles et al. 2017). The results have shown that the majority of patients who infected with the new world Leishmania species and L. major had co-infection/co-morbidity such as HIV/AIDS (Figs 3  and 4). Therefore, viscerotropic leishmaniasis should be considered in patients with immunocompromising conditions.
Several studies have shown that higher prevalence of VL in male than female individuals (Guerin et al. 2002;Rodríguez et al. 2018), while a similar proportion in males and females had reported from CL patients (Karimkhani et al. 2016). We also found that higher prevalence of viscerotropic leishmaniasis in male than female cases (80% vs 167%). It is well documented that VL due to L. donovani infects all age groups, whereas L. infantum infects mostly children and immunosuppressed individuals (Chappuis et al. 2007). Also the majority of cases of American VL caused by L. chagasi occur in children (Evans et al. 1992;Pearson and de Queiroz Sousa, 1996;D'Oliveira Júnior et al. 1997). The results showed that the majority of the cases of viscerotropic leishmaniasis due to L. major and new world Leishmania species were reported from adults. In L. tropica, seven out of 20 cases were reported in patients under 15 years and the remaining cases were reported in adults (Table 3).
In conclusion, the results provide information regarding the species and clinical spectrum of viscerotropic leishmaniasis. Therefore, viscerotropic manifestations of CL in native people who live in endemic regions of CL should be considered for exact discrimination from other endemic infectious diseases. In patients who infected with L. tropica, a viscerotropic form of leishmaniasis should be more attended. Furthermore, viscerotropic leishmaniasis in patients with immunocompromising conditions and in non-native people who travel to the endemic regions of CL should be a greater consideration.