article: Tegumentary leishmaniasis (TL) is a disease of skin and/or mucosal tissues caused by Leishmania parasites. TL patients may concurrently carry other pathogens, which may influence the clinical outcome of TL. This review focuses on the frequency of TL coinfections in human populations, interactions between Leishmania and other pathogens in animal models and human subjects, and implications of TL coinfections for clinical practice. For the purpose of this review, TL is defined as all forms of cutaneous (localised, disseminated, or diffuse) and mucocutaneous leishmaniasis. Human immunodeficiency virus (HIV) coinfection, superinfection with skin bacteria, and skin manifestations of visceral leishmaniasis are not included. We searched MEDLINE and other databases and included 73 records: 21 experimental studies in animals and 52 studies about human subjects (mainly cross-sectional and case studies). Several reports describe the frequency of Trypanosoma cruzi coinfection in TL patients in Argentina (about 41%) and the frequency of helminthiasis in TL patients in Brazil (15% to 88%). Different hypotheses have been explored about mechanisms of interaction between different microorganisms, but no clear answers emerge. Such interactions may involve innate immunity coupled with regulatory networks that affect quality and quantity of acquired immune responses. Diagnostic problems may occur when concurrent infections cause similar lesions (e. g. , TL and leprosy), when different pathogens are present in the same lesions (e. g. , Leishmania and Sporothrix schenckii), or when similarities between phylogenetically close pathogens affect accuracy of diagnostic tests (e. g. , serology for leishmaniasis and Chagas disease). Some coinfections (e. g. , helminthiasis) appear to reduce the effectiveness of antileishmanial treatment, and drug combinations may cause cumulative adverse effects. In patients with TL, coinfection is frequent, it can lead to diagnostic errors and delays, and it can influence the effectiveness and safety of treatment. More research is needed to unravel how coinfections interfere with the pathogenesis of TL.
  Tegumentary leishmaniasis (TL) is a disease of the skin and mucosal tissues caused by several species of the genus Leishmania (Protozoa, Trypanosomatida, Trypanosomatidae) that are transmitted by the bite of phlebotomine sandflies [1]. Parasites belonging to the subgenus Leishmania are found in the Old and the New World, whereas those of the subgenus Viannia are restricted to the New World [1–3]. Leishmania parasites produce a wide spectrum of clinical manifestations in humans and other mammals, ranging from asymptomatic infection to life-threatening disease [1–3]. Yearly, an estimated 1 million people develop TL, mainly in Bolivia, Brazil, Colombia, Peru, Algeria, Tunisia, Saudi Arabia, Syria, Iran, Afghanistan, and Pakistan [4]. The overlapping geographical distribution of TL with many highly prevalent (e. g. , helminthiasis) [5] and some less common (e. g. , leprosy) [6] infectious diseases, as well as experimental studies [7], together indicate the importance of understanding how coinfections may alter the outcome of TL and vice versa. Indeed, several infectious diseases linked to poverty, housing conditions, hygiene, or to vectors that thrive in similar circumstances tend to affect the same populations [8–12]. It is therefore likely that in the tropical and temperate regions where TL occurs, many people carry more than one pathogen at once, although the epidemiology of such coinfections is not well known. Furthermore, the clinical outcome of Leishmania infection depends on characteristics of both the Leishmania parasite and the human host immune response [13–16]. Pathogens other than Leishmania may modulate this host immune response and consequently influence the natural history of TL as well as the response to antileishmanial treatment [12,16]. The most frequently studied coinfection is that between Leishmania and human immunodeficiency virus (HIV), in that the natural history of each of the two infections is modified by the presence of the other [17]. HIV increases the risk of severe and disseminated TL, and some HIV-infected patients develop visceral leishmaniasis in the presence of Leishmania species that are usually only dermotropic [17–19]. HIV also increases the risk of TL recurrence and treatment failure [18,19]. On the other hand, leishmaniasis interferes with monocyte and macrophage function in such a way that it facilitates HIV progression [20]. Interactions between TL and infections other than HIV have not been comprehensively reviewed before. The objectives of the present review are to summarise the evidence about the (i) frequency of TL and coinfections other than HIV in human populations, (ii) interactions between Leishmania and other pathogens in animal models and human subjects, and (iii) implications of TL coinfections for clinical practice.
  We searched the medical literature to identify publications about TL and coinfections. For the purpose of this review, we defined TL as all forms of cutaneous (localised, disseminated, or diffuse) and mucocutaneous leishmaniasis. Records about the skin manifestations caused by L. donovani and L. infantum/L. chagasi (such as post–kala-azar dermal leishmaniasis) were not included because the main clinical outcome of these infections is visceral leishmaniasis, which is outside the scope of this review. Records about HIV/AIDS and TL were not included because this topic has already been extensively reviewed elsewhere [17–19]. Records about the contamination or superinfection of TL lesions with gram-positive or gram-negative bacteria of the skin such as Staphylococcus aureus or Streptococcus pyogenes were also excluded. Review papers were not included. We did not restrict the search by geographical region, study design, language of publication, or publication date. The databases MEDLINE, Embase, LILACS, Scielo, Cochrane, and African Index Medicus as well as local library databases, searched in August 2017, were the information sources for this review. We used search terms indicating (groups of) infections, pathogens, and diseases caused by these pathogens. The detailed search strategy for MEDLINE is given in S1 File. We also reviewed the reference lists of selected articles. Two reviewers extracted the data from the included records; any doubts and discordances were resolved through discussion. Specific points of interest while reading and summarising the articles were (i) frequency of coinfection in humans, (ii) mechanisms of interaction and effect of coinfection on TL progression, and (iii) potential implications for clinical management. We described the information the same way the authors of the original publications did, using mainly counts, proportions, and medians. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [21] to prepare this review, but it was not possible to follow all the recommendations because PRISMA mainly focuses on the evaluation of healthcare interventions and our focus was broader than that. The PRISMA checklist is given in S1 List.
  The MEDLINE search retrieved 669 records, and searching other databases yielded 348 additional records. After reading titles or abstracts or both, we removed 79 duplicates and discarded 841 records because they were not relevant (Fig 1). The most frequent reason for dropping records was that, while leishmaniasis and another infection were mentioned in the same text, the publication was not about coinfection (e. g. , a paper about different infections occurring in the same region but not affecting the same persons). We assessed the remaining 97 full-text records for eligibility and retained 73 for the present review (Fig 1). The 73 articles included in this review had different study designs (Table 1). There were 21 original research papers about experimental studies of coinfection in animal models and 52 original research papers about coinfection in human patients. The 52 studies about human subjects included 1 clinical trial, 2 cohort studies, 13 cross-sectional or prevalence studies, 7 studies on the development or performance of diagnostic tests, 24 case series or case reports with a clinical focus, and 5 case series or reports with an immunological focus. The coinfecting pathogens for which we found the highest number of records were Trypanosoma cruzi (n = 18), Mycobacterium leprae (n = 14), helminths (n = 12), and M. tuberculosis (n = 9). Two records addressed coinfection of Leishmania with more than one pathogen (Table 1). The studies providing information about the frequency of coinfection in human populations are summarised below and in Table 1.
  This is the first comprehensive review of the literature about TL and coinfections other than HIV. Coinfection adds to the complexity of TL: the outcome of a single Leishmania infection in humans is difficult to predict, and the impact of coinfection on the course of TL is even more puzzling. Nevertheless, coinfection is clinically relevant because it is frequent, it can lead to diagnostic errors and delays, and it can influence the effectiveness of treatment and drug side effects. Therefore, it is crucial to gain a better understanding of the interaction between TL and other infectious diseases. The frequency of coinfections has been studied mostly in Latin America so far. There is relatively good evidence about T. cruzi infection in Argentina (an estimated 41% of TL patients also carry T. cruzi) [36] and about helminthiasis in Brazil (an estimated 15% to 88% of TL patients also carry helminths) [5,12]. Several hypotheses have been explored about the mechanisms of interaction between the different microorganisms, but no clear answers have emerged so far from a literature that is scattered and still developing. Such interactions may involve one or all components of innate immunity coupled with the complexity of regulatory networks that affect the quality and quantity of the acquired immune responses (e. g. , T-cell subset bias or regulatory cytokine production). Given that TL pathology is fundamentally an immunopathology reaction, coinfections could paradoxically lead to exacerbated TL disease by enhancing immune responses against Leishmania parasites in lesions. The impact of Plasmodium coinfection on TL in animal models is clearly detrimental; the impact of all other coinfections in animal models or human studies is less clear or less consistent. Diagnostic problems occur when concurrent infections cause similar lesions (e. g. , TL and leprosy), when different pathogens are present in the same lesions (e. g. , Leishmania and S. schenckii), or when cross-reactions induced by phylogenetically close pathogens affect the accuracy of diagnostic tests (e. g. , serology for leishmaniasis and Chagas disease). Regarding treatment, some coinfections seem to reduce the efficacy of antileishmanial drugs (i. e. , helminthiasis), and there may be cumulative adverse effects caused by drugs or drug combinations (e. g. , antimonial treatment in patients with chagasic cardiomyopathy, and combinations of antileishmanial and antimycobacterial drugs). The strengths of this review are the broad search of the literature and the fact that the reporting follows PRISMA guidelines [21]. On the other hand, because the search strategy had few restrictions, we retrieved information in heterogeneous formats. As a consequence, we could not systematically assess the risk of bias in the individual records and decided to include all the available information. Most animal studies predate the introduction of the Animals in Research: Reporting In Vivo Experiments (ARRIVE) guidelines for reporting animal research [102]; therefore, issues related to experimental design and the avoidance of bias may not have been explicitly recorded in the publications reviewed. Despite the broad search including several databases other than MEDLINE, the retrieved information was fragmented, and the evidence was insufficient to give firm answers to all the review questions. For example, all the evidence about TL and malaria came from animal studies without validation in humans. By contrast, all the information about tuberculosis came from human case reports with limited information about pathogenesis. In total, only 3 out of the 73 included records were cohort studies or clinical trials specifically designed to investigate the impact of coinfection on the course of TL in humans. Furthermore, there was not enough information available to look into the effect of coinfections on different clinical forms of TL (i. e. , localised, diffuse, disseminated, and mucosal) separately. This is an important limitation because the host immune responses underlying these different forms of TL are contrasting and may be differentially modified by coinfections. For example, coinfections that induce a strong proinflammatory response could be beneficial in early cutaneous but detrimental in mucosal leishmaniasis. Finally, there was almost no information about coinfection in human subjects from Africa or Asia. Several factors may have contributed to the lack of evidence about coinfections. First, coinfections tend to get less attention than single infections. Second, TL and many of the relevant coinfections are neglected diseases that affect poor populations and are typically under-researched and underreported. Finally, the complexity of TL together with other infections may lead to negative results or findings that are difficult to explain, which may reduce the chance of publication. From a clinical point of view, several questions remain to be resolved. Even if the interactions between pathogens are complex, these clinical questions are fairly straightforward. For each of the coinfecting microorganisms, we need to better document (i) how frequent it is among patients with TL in different settings, (ii) whether TL patients with the coinfection fare better or worse than patients without it, (iii) whether the presence of the coinfection affects the accuracy of diagnostic tests, and (iv) what the best way to treat the coinfected patient is. With advances in the development of vaccines for leishmaniasis, including TL, an understanding of how vaccine responses might be modulated due to coinfection also becomes a question of some significance. With regard to the interaction between pathogens, additional mechanisms, unexplored in the literature to date in relation to TL, are worthy of consideration. First, metabolic disturbances resulting from coinfection may alter the capacity of the immune system to appropriately respond during TL or vice versa [103,104]. Second, coinfections, in particular with helminths, may lead to a dysbiosis (i. e. , alterations in the development or composition of the microbiota) that consequently impacts immune health [97,104,105]. Therefore, the answer to how the clinical outcome differs between single- and coinfected patients may not lie in understanding how two specific sets of immune responses interact but rather in how these responses are linked via complex regulatory circuits established and maintained by our commensal microbiota. Several elements of the design of future experimental research deserve consideration. First, it is important to clarify what the outcomes of interest are, i. e. , the risk of symptomatic disease, the time between infection and lesion appearance, the size of the lesion, time to healing, response to treatment, or risk of metastasis and comorbidities. The impact of coinfections on these different clinical outcomes may vary. Second, the species, the infective doses, and the timing of Leishmania and coinfection may also matter. Finally, animal models differ from each other, and they do not always represent what happens in human coinfection.
  In patients with TL, coinfection with other pathogens may be the rule rather than the exception. More research is needed to unravel how other infections interfere with the pathogenesis of TL. It is important that clinicians bear in mind the possibility of coinfection because this can complicate diagnosis and treatment.
summary: Infectious diseases are often studied one by one, but people can have more than one infection at the same time. This is likely to happen when different microorganisms are linked to specific geographical regions or living conditions. In this paper, we summarise the literature about infections occurring together with tegumentary leishmaniasis (TL), a disease of skin and mucosal tissues that is caused by Leishmania parasites. We found that in Latin America, patients with TL are often also infected with helminths or with Trypanosoma cruzi (the parasite that causes Chagas disease). Information from other parts of the world is scarce. Animal studies and observations in humans show that one infection can change the course of another infection, but how this happens is not well understood. When different infections affect the same patient at the same time, the diagnosis can be difficult, especially when different microorganisms are biologically similar, when they cause similar lesions, or when they are present in the same lesions. Treatment can also be difficult because some coinfections reduce the efficacy of the treatment against Leishmania and because some drug combinations can lead to cumulative adverse effects.
keywords: invertebrates
  medicine and health sciences
  pathology and laboratory medicine
  helminths
  tropical diseases
  parasitic diseases
  parasitic protozoans
  animals
  bacterial diseases
  review
  protozoans
  signs and symptoms
  leishmania
  neglected tropical diseases
  infectious diseases
  zoonoses
  lesions
  protozoan infections
  trypanosoma cruzi
  helminth infections
  trypanosoma
  eukaryota
  diagnostic medicine
  leishmaniasis
  co-infections
  biology and life sciences
  leprosy
  organisms
title: Tegumentary leishmaniasis and coinfections other than HIV