This is the first multicenter retrospective survey ever undertaken in the field of VL-malaria co-infections. The study describes the epidemiology of concomitant malaria among VL in-patients from Gedarif Teaching Hospital, Tabarakallah Hospital and Al`Azaza kala-azar Clinic, eastern Sudan (2005-2010) and confirms its clinical relevance by comparing prevalence and mortality rates with an antecedent (1998), independently collected dataset from the same region (Um-el-Kher and Kassab Hospitals). Not only the risk of co-acquiring VL and malaria appears to be substantial in these areas, with a significant geographical variation, but the clinical implications deriving from being co-infected provide the evidence for a public health concern. Exacerbated clinical pictures and increased mortality risk, possibly due to inadequate antimalarial treatment, were highlighted by this survey, suggesting that prompt diagnosis and effective therapy of concomitant malaria is needed to ensure positive resolution of the VL-malaria co-infection.
Ranging from 3.8 to 60.8% and with a median of 26.2%, the prevalence of malaria co-infection among VL surveyed patients (2005-2010) confirms the frequent superimposing of the two diseases in rural areas of Gedarif and Sennar States. Although these estimates may be higher than expected, based on the local malaria transmission rates, similar figures have been found in the MSF’s dataset from Um-el-Kher and Kassab Hospitals, where 19.7% and 11.3%, respectively, of the VL patients enrolled in the clinical trial (1998) were positive for malaria. Again at Um-el-Kher Hospital, clinical studies conducted between January 2004 and early 2005 revealed that 15% of pregnant VL women enrolled in the trial  and 31% of Ambisome-treated VL patients  were co-diagnosed with malaria, while a 4.8% rate was found in Kassab (2005-2006) , where the malaria prevalence is notoriously lower. In agreement with previous observations performed at Amudat Hospital, Uganda (2000-2006) , where a co-infection rate of 19% was reported using the same criteria as here, the frequent co-occurrence of malaria in VL patients suggests that these patients may have increased susceptibility towards the malarial infection, possibly due to a VL-promoted impairment of the immune system. The clustering of most co-infection diagnoses in Al`Azaza kala-azar Clinic (74.8%), however, followed by Tabarakallah Hospital (20.8%) and Gedarif Teaching Hospital (4.4%) is rather unexpected. In Gedarif Teaching Hospital, only 3.8% of the VL-confirmed patients were co-diagnosed with malaria, a figure which may be explained by its function as Regional Reference Hospital, besides the low malaria burden found in this urban area. Difficult cases encountered in rural hospitals and referred to Gedarif Teaching Hospital, usually received, prior to admission to the Regional Hospital, a full course of anti-malarial treatment to exclude malaria as a possible complication. This may therefore have resulted in a lower percentage of VL patients having malaria on hospital admission. The longer disease duration described among VL patients hospitalized in Gedarif Teaching Hospital compared to the other two study sites, and their villages of origin, seem to confirm that a large number of these patients may not have presented to this hospital as a first-line action. If, therefore, a higher malaria-VL co-infection rate is to be expected in rural hospitals of Gedarif and Sennar State, the figure obtained in Al`Azaza kala-azar Clinic (60.8%), appears to somehow overestimate the burden posed by this co-morbidity. Given that higher malaria rates, favored by the proximity with the river and natural reserve, might have locally occurred, poor quality of malaria diagnosis in Al`Azaza kala-azar Clinic cannot be excluded.
Concomitant malaria partly exacerbated the clinical picture of VL patients, who presented with more frequent emaciation, icterus and moderate anemia. Two scenarios may be postulated: co-infected patients may either have suffered from malaria-associated symptoms which, in addition to the VL ones, have caused deterioration of their clinical condition and/or have run an exacerbated course of VL due to concomitant malaria, in which case symptoms may be related to VL rather than to malaria. If this latter hypothesis may find its rationale in the increased number of Leishmania parasites observed in aspirates of co-infected patients, the first speculation may be supported by the peculiar symptom pattern. Jaundice, in fact, is rarely described among VL patients, while it is not uncommon in P. falciparum malaria . Weight loss and anemia, on the other hand, are hallmark of both VL and malaria and an increased severity of the anemic status, as observed in co-infected patients, may therefore be the result of an added effect displayed by both diseases on the polyparasitized host. In apparent contradiction is the finding, whereby co-infected patients suffered from less severe hepato-splenomegaly. Suggesting a less advanced state of the diseases in the co-infected patients, the result may be explained by their earlier hospitalization compared to mono-infected VL patients. Patients with concomitant VL and malaria, in fact, presented at hospital nearly 10 days earlier, on average, than those with only VL, possibly due to their more severe symptomatology. Importantly, this may have also had positive implications for their prognosis, which was found to be similar to the controls’ one.
In antithesis to the positive resolution of VL-malaria co-infections during the 2005-2010 survey, is the significantly higher fatality rate (P-value 0.001) associated with co-infected patients enrolled by MSF at Um-el-Kher and Kassab Hospital in 1998. During this trial, co-infected patients were nearly four and half times more likely to die compared with the VL mono-infected patients, whose mortality (2.8%) on the other hand, compares well to what found in the most recent survey (3.1%). Different anti-malarial regimen were used within the two study groups: SP and quinine in 1998 for uncomplicated and severe malaria, respectively; artemisinin derivatives (alone or in combination) and more rarely quinine between 2005 and 2010. Sudan’s choice to introduce artemisinin-based combination therapies (ACTs) for treatment of uncomplicated and severe malaria was implemented nation-wide in 2004 , following increasing evidence of resistance against chloroquine, SP and quinine, for which failure rates up to 76.9, 16.1 and 16.7%, respectively, were recorded in eastern Sudan prior to ACT era [35–38]. The 11.2% mortality rate of VL-malaria co-infections observed in 1998 at Um-el-Kher Hospital may therefore have partially resulted from treatment failures attributable to either SP or quinine, besides the more severe malaria course in patients receiving quinine. In fact, no major differences for age, median Hb level, nutritional status, spleen size and duration of on-going disease distinguished the co-infected patients’ group at Um-el-Kher and Kassab Hospitals from the one surveyed in 2005-2010 and from its relative controls. The only exception is to be found in the significantly higher number of VL patients who developed severe anemia when co-infected with malaria, similarly to what was observed during the 2005-2010 survey, though to a less extent. Hence, concomitant malaria may not only cause aggravation of VL patients’ clinical condition, but it may also result in a poorer prognosis, if failed to be treated. Among co-infected patients surveyed in 2005-2010, an increased mortality risk, not ascribable to differences in Leishmania intensities, was observed when quinine (P-value 0.07) and artemether (P-value 0.04) were administered as antimalarials, suggesting either increased malaria severity or inadequate drug treatment.
The population surveyed within this study consists of VL patients residing in over 300 different villages, mainly located in Gedarif and Sennar States. Within these districts, Tabarakallah Hospital and Al`Azaza kala-azar Clinic are two rural hospitals receiving patients from some of the worst-affected villages. It should be noted, however, that the cohort of VL patients surveyed here might be sub-representative of the local VL community, as the number of VL-related hospitalizations carried out by the two MSF’s treatment centers in Gedarif Sate (>4000 per year between 1997 and 1999 ) exceeds by far the one recorded by the three study hospitals (1324 in total between 2005 and 2010). Other limitations apply to this study, the most important ones being the lack of non-VL malaria infected patients and the quality of diagnosis. Unlike VL, uncomplicated malaria infections are commonly treated on an outpatient basis in hospitals, clinics or simple practices, resulting in few data being systematically recorded by the different facilities. Moreover, malaria patients are rarely found in VL-dedicated hospitals, such as those surveyed in this study. This resulted into the lack of valid malaria controls, essential to investigate whether VL might predispose or rather protect towards a malarial attack and whether it might influence its course and clinical presentation. In absence of quality control, quality of diagnosis remains questionable. Variable outcomes, as documented in medical records, may have suffered from poor standardization, due to the different techniques implemented by clinicians in the different treatment centers and the possible involvement of different health workers in filling these files.