Visceral Leishmaniasis (Kala-Azar) and Malaria Coinfection in an Immigrant in the State of Terengganu, Malaysia: a Case Report

Journal of Microbiology, Immunology and Infection (2011) 44,72e76

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CASE REPORT Visceral leishmaniasis (kala-azar) and malaria coinfection in an immigrant in the state of Terengganu, Malaysia: A case report

Ahmad Kashﬁ Ab Rahman a,*, Fatimah Haslina Abdullah b a Infectious Disease Clinic, Department of Medicine, Hospital Sultanah Nur Zahirah, Jalan Sultan Mahmud, 20400 Kuala Terengganu, Malaysia b Microbiology Unit, Department of Pathology, Hospital Sultanah Nur Zahirah, Jalan Sultan Mahmud, 20400 Kuala Terengganu, Malaysia

Received 28 April 2009; received in revised form 30 July 2009; accepted 30 November 2009

KEYWORDS Malaria is endemic in Malaysia. Leishmaniasis is a protozoan infection rarely reported in Amphotericin B; Malaysia. Here, a 24-year-old Nepalese man who presented with prolonged fever and he- Coinfection; patosplenomegaly is reported. Blood film examination confirmed a Plasmodium vivax ma- Leishmaniasis; laria infection. Despite being adequately treated for malaria, his fever persisted. Bone Malaria; marrow examination showed presence of Leishman-Donovan complex. He was success- Treatment fully treated with prolonged course of amphotericin B. The case highlights the impor- tance of awareness among the treating physicians of this disease occurring in a foreign national from an endemic region when he presents with fever and hepatosplenomegaly. Coinfection with malaria can occur although it is rare. It can cause significant delay of the diagnosis of leishmaniasis. Copyright ª 2011, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. All rights reserved.

Introduction leishmaniasis is not. Malaysia is considered free of endemic Leishmania species although few species of Malaysian sandﬂies have been described, possibly because the sand- Malaysia is a tropical country and located in the region of 1,3 Southeast Asia. Malaria is endemic in this region, whereas ﬂies are not largely anthropophilic. However, with the advancement of world travel today, including migration of * Corresponding author. Infectious Disease Clinic, Department of refugees or workers from endemic regions, visceral leish- Medicine, Hospital Sultanah Nur Zahirah, Kuala Terengganu, 20400 maniasis (VL) has emerged as an increasingly important and Terengganu, Malaysia. imported infection in many countries. Cases of cutaneous E-mail address: [email protected] (A.K. Ab Rahman). leishmaniasis have doubled and tripled in the Netherlands

1684-1182/$36 Copyright ª 2011, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.jmii.2011.01.014 Visceral leishmaniasis and malaria coinfection 73 and the United Kingdom, respectively, in the past decade, After 7 days of adequate antimalarial therapy, he still whereas cutaneous leishmaniasis and VL cases in Australia has persistent spikes of temperature and did not look well. have increased in significant numbers over the past few His appetite remained poor. Posttreatment blood films for years.2 Therefore, this condition needs to be suspected in malaria parasite were negative for plasmodium parasite. someone who presents with prolonged fever and has history He was referred to Hospital Sultanah Nur Zahirah (HSNZ) of recent travel or among the immigrants originated from during the second week of treatment. HSNZ is located in endemic area. Kuala Terengganu, the capital city of Terengganu. HSNZ Here, we report a case of a foreign worker who had been serves as a referral and secondary hospital for the state of referred to us from a district hospital for the management Terengganu. of prolonged fever after successful treatment of malaria At presentation to HSNZ, he looked lethargic but not ill. infection. His vital signs were in the normal range. His body temperature was 38.3C. He appeared pale but not jaundiced. His Case report skin looked normal. The spleen was visibly enlarged, crossing the umbilical line, and firm but nontender. He was The patient was a 24-year-old apparently healthy gentleman also noted to have enlarged liver, approximately 6 cm from Nepal, arrived in Malaysia in August 2007 after being below the right subcostal margin (Fig. 2). successfully secured an employment as a construction Ultrasonic study of the abdomen and pelvis was normal. worker in one of the states in Malaysia. His problem started 2 A 2D echocardiography was carried out to look for evidence weeks after his arrival, with insidious onset, on and off of bacterial endocarditis, which was later found to be moderate grade of fever. Subsequently, he developed vague normal. He had another cycle of septic workup mentioned abdominal pain, which was mild and intermittent in nature. above, and the results were all negative. He stayed in an overcrowded temporary hostel with other Because of worsening pancytopenia (Table 1), he new immigrant workers from various countries of origin. He underwent a diagnostic bone marrow aspiration procedure, ate the same food with others. He denied any history of and the result of marrow aspirate is shown in Fig. 3A and B. vomiting or diarrhea. With the above findings, daily intravenous infusion of At the second week of illness, his condition got worse, amphotericin B deoxycholate was started. He became with more persistent fever. The left-sided abdominal pain afebrile on Day 5 of the treatment and remained well until persisted and became more intense and unbearable. At the day he was discharged home. He received a total this point, he decided to seek for medical treatment. He cumulative dose of 1.26 g or 21 mg/kg of amphotericin B. admitted himself at one of the district hospital in the state His renal function was monitored at biweekly interval. of Terengganu, one of the 14 states in Malaysia. Septic Serum creatinine and serum potassium were normal workup, including blood culture, blood film for malaria throughout the course of treatment with amphotericin B. parasite, urine culture, typhus serology, and typhoid Serial follow-up of full blood counts during the course of serology was carried out. treatment showed spontaneous recovery of all the three The blood film result was positive for Plasmodium vivax cell lines (Table 2). Six months after discharge, he was seen with a parasite density of 8,000/mL(Fig. 1). Oral chloro- again at the clinic. He was otherwise well and asymptom- quine (600 mg) was given initially as a loading dose, fol- atic. No repeat bone marrow examination was carried out. lowed by another 300 mg 6 hours later and subsequently 300 mg daily for 2 more days. Oral primaquine (15 mg daily) Discussion was then added on (after reviewing his glucose-6-phos- phate dehydrogenase profile). Oral primaquine was given Differential diagnoses in patient with massive hepatos- for a total of 14 days. plenomegaly, fever, and pancytopenia are not many.

Figure 1. Blood ﬁlm smear of the patient showing the Figure 2. Photograph of the patient’s abdomen with massive presence of Plasmodium vivax trophozoite. hepatosplenomegaly. 74 A.K. Ab Rahman, F.H. Abdullah

Table 1 Series of full blood count results showing worsening leucopenia, anemia, and thrombocytopenia during malaria treatment in Hospital Sultanah Nur Zahirah Nov 18, 2007 Nov 25, 2007 Dec 03, 2007 Dec 09, 2007 (Day 1) (Day 8) (Day 15) (Posttreatment completion) TWC (109/L) 1.6 1.5 0.9 1.0 Hb (g/dL) 7.7 7.9 6.6 6.8 Platelet (cells/mm3) 141,000 134,000 69,000 63,000 Hb Z hemoglobin; TWC Z total white blood cell count.

Chronic myeloid leukemia, myelofibrosis, non-Hodgkin knowledge in managing this illness may lead to unnecessary lymphoma, and Gaucher disease are some of the recognized delay in the treatment initiation. To our knowledge, this is noninfectious causes of these conditions. Infectious causes the second case of VL reported in Malaysia. The first case of of massive splenomegaly in tropical countries and malarial VL in Malaysia was reported in a young immigrant suspected endemic area are chronic malaria and tropical spleno- to have hematological malignancy in 1995.4 megaly. Little information exists on the true incidence of The Leishmania donovani complex includes Leishmania leishmaniasis in Malaysia, especially among the immigrants chagasi and Leishmania infantum and causes VL, a dissem- coming from the endemic region, because it is not a notifi- inated and potentially fatal form of leishmaniasis. It is able disease in this country. Physicians generally are not transmitted by indigenous sandflies, which is the only aware of this disease, and the lack of experience and vector responsible for the transmission of the parasite. Leishmaniasis is considered to be endemic in many countries, including India, Nepal, and Bangladesh. India alone may contribute as many as 40% to 50% of the world’s cases.5 The confirmatory diagnosis of leishmaniasis relies on either the microscopical demonstration of Leishmania amastigotes in the relevant tissue aspirates or the biopsies, such as bone marrow, spleen, lymph nodes or liver, slit skin smears or biopsies, or in the peripheral blood buffy coat. Splenic aspiration appears to be more sensitive than bone marrow aspirate with Leishman-Donovan bodies found in 90% and 76% to 85%, respectively.6,7 However, the safety of splenic aspiration procedure is operator dependant. It is not widely used as a diagnostic procedure in this country. Bone marrow aspiration is widely practiced here for the diagnosis of other disease conditions. It is considered as a more acceptable mode of diagnosis, less hazardous with no major complications, although it has a sensitivity of about 50% to 60%.7 Apart for diagnostic purposes, bone marrow biopsy findings can also be helpful for assessing the prognosis of VL patients, in terms of recovery of affected marrow cells. The outcome of treatment seems to be excellent in cases of hypercellular marrow. The presence of extensive fibrosis and necrosis of the marrow associated with very poor outcome, whereas granuloma if present is usually resulted in moderate response.8 In the above-mentioned case, the marrow architecture was hypercellular, without the presence of significant necrosis or granuloma. We expected that he will have a good chance of total recovery with regard to the marrow profiles. The direct agglutination test (DAT) is a highly specific and sensitive test. It is cheap and simple to perform, making it ideal for both field and laboratory use. DAT in various studies has been found to be 91% to 100% sensitive and 72% to 100% specific.7 For long time, DAT remained first-line diagnostic tool in resource poor countries. However, polymerase chain Figure 3. (A) Marrow aspirate of the patient showing reaction has been proven to be the most specific and numerous extracellular amastigotes (thick arrow). (B) Intra- sensitive technique (100% and 80e93.3%, respectively), macrophage amastigotes of Leishmania (Leishman-Donovan albeit limited to tertiary care hospitals and research bodies) (thin arrow). laboratories.7 Visceral leishmaniasis and malaria coinfection 75

Table 2 Series of full blood count results showing recovery of leucopenia, anemia, and thrombocytopenia during treatment with amphotericin B Dec 17, 2007 Dec 24, 2007 Dec 31, 2007 Jan 16, 2008 (Day 8) (Day 15) (Day 21) (Posttreatment completion) TWC (109/L) 3.8 2.5 4.1 4.6 Hb (g/dL) 6.4 8.4 9.6 9.5 Platelet (cells/mm3) 105,000 153,000 125,000 253,000 Hb Z hemoglobin; TWC Z total white blood cell count.

Pentavalent antimony (Sb) like sodium stibogluconate Chronic VL is known to cause CD4 lymphopenia and and meglumine antimoniate remains the first-line treat- a low CD4:CD8 ratio, whereas blood CD4:CD8 ratio ment in all regions of the developing world because of remains unaltered during malarial paroxysms. The study decades of clinical experience. It has proven efficacy with by Rohatgi et al.16 in leishmaniasis patients found that the greater than 90% of long-term cure rate with acceptable pretreatment CD4 cell count was depressed in the cost. peripheral blood of acute and chronic VL cases but higher The development of resistance to first-line therapy in the bone marrow. An influx of CD4 cells to the bone necessitated the use of even more expensive and more marrow and spleen might account for the fall in the toxic second-line drugs like amphotericin B.9 Data from the CD4:CD8 cell ratio in the blood observed.16 Studies using immunocompetent European VL patients demonstrated experimental models of malaria in immune-deficient mice that 100% cure rate was achieved if treated with a total and chickens have shown that resistance to blood-stage dose of greater than 21 mg/kg of amphotericin B.10 More infection is mediated by protective antibodies and T cell- commonly now, at least in India, infusions of 1 mg/kg given dependent cell-mediated mechanisms of immunity.17 either daily for 20 days or on alternate days (15 infusions Therefore, it seems that leishmaniasis-mediated CD4 over 30 days) for a total dose of 15 mg/kg are used, lymphopenia may have nullified the protective effect resulting in uniformly high efficacy with long-term cure rate against malaria.14 of greater than or equal to 96%.11,12 A more recent study by Leishmaniasis is not endemic in this region. However, it Sundar et al.12 in 2007 found that amphotericin B can be is becoming important to recognize this disease, espe- effectively and safely given at a lower dose, that is, cially among the migrants from endemic regions or those 0.75 mg/kg daily for 15 days (total dose, 11.25 mg/kg) with who had recently traveled to those countries. Because of comparable cure rates (96%) and shorter duration of the issue of safety and familiarity with the procedure, hospital stay. bone marrow examination remained the preferred method Results from another study in India demonstrated that of parasite identification. The treatment of VL is prolong lipid formulation amphotericin, that is, AmBisome and and expensive. In many countries, including Malaysia, Abelcet produced an overall cure rates similar to conven- conventional amphotericin B still has a role in the treat- tional amphotericin B (amphotericin B >96%, AmBisome ment of VL. With close and regular monitoring of renal >96%, and Abelcet >92%), with fewer infusion-related function and ensuring good hydration status of the reactions and little toxicity.13 However, the cost of these patient, its toxicity effect can be minimized. Coinfection drugs is expensive, thus limiting its potential use in the with malaria is rare, but it may have significant impact on treatment of leishmaniasis in many countries. the delay of diagnosis. A high clinical suspicion is neces- For the case under discussion, conventional amphoter- sary among the primary care practitioners about the icin B was chosen because it is more readily available and threat of imported infectious disease, especially among comparatively much cheaper than the lipid formulation the patients who presented with prolonged febrile illness amphotericin. Pentavalent antimony is not available here. and hepatosplenomegaly. Lipid formulation amphotericin is expensive and not readily available in most government hospitals in Malaysia. He completed a total cumulative dose of 21 mg/kg of intra- Acknowledgment venous infusion of amphotericin B. Close monitoring of the renal function and serum electrolyte as well as ensuring The authors thank Dr Alawiyah Awang (hematologist) and good hydration status were carried out during the treat- Dr Salmi Abdullah (pathologist) for their contribution in ment period, hence minimizing the risk of amphotericin- the preparation of this case report. related toxicity. VL with chronic malaria in undernourished children was References known as malarial cachexia in Imperial India, although presently, concomitant infection is rarely reported. Only 1. Khadri MS, Depaquit J, Bargues MD, Ferte´ H, Mas-coma S, few human cases of concomitant malaria and leishmaniasis 14,15 Lee HL, et al. First description of the male of Phlebotomus have been reported. In previously reported case of betisi Lewis and Wharton, 1963 (Diptera: Psychodidae). Para- malaria coinfection, marked pancytopenia with severe sitol Int 2008;57:295e9. 14 neutropenia was noted, as what had happened to our 2. Stark D, Hal SV, Lee R, Marriott D, Harkness J. Leishmaniasis, patient. However, the abnormalities were self-limited and an emerging imported infection: report of 20 cases from improved dramatically with the initiation of therapy. Australia. J Travel Med 2008;15:351e4. 76 A.K. Ab Rahman, F.H. Abdullah

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