FIDSSA

Case Presentation:

A 26-year-old immunocompetent man from Nyanga with a history of mandrax and methamphetamine use presented to Groote Schuur Hospital. He had been unwell for 1 week with fever, myalgia, and vomiting. He reported no notable medical history except community assault 1 month previously, for which he did not seek medical attention. He took ‘Grand-Pa’ for headaches and used traditional herbal medications as required. He had no recent travel history and reported no exposure to animals.

He was deeply jaundiced, dehydrated, and unable to sit or stand. The temperature was 38.2°C, heart rate 116 beats/minute, and blood pressure 94/56 mmHg. The rest of his cardiorespiratory examination was normal. He had an isolated, non-tender 18 cm hepatomegaly. Apart from his jaundiced sclerae, his skin and mucous membrane examination was normal.

Initial investigations:

A presumptive diagnosis of severe leptospirosis (Weil’s disease) was made based on the clinical presentation of an acute onset febrile illness with hepato-renal dysfunction, thrombocytopenia, and leukocytosis. Intravenous ceftriaxone was initiated. Abdominal ultrasound confirmed hepatomegaly in the absence of focal lesions. This case was presented at the Antimicrobial Stewardship Round and the differential diagnosis was discussed.

Differential diagnosis
Malaria can present with non-specific febrile illness accompanied by acute kidney injury and jaundice. The acquisition of malaria in non-endemic areas is inherently unexpected but may occur from the bite of an imported mosquito.
Arboviruses such as dengue can present with fever, thrombocytopenia, and raised hepatic aminotransferases, however jaundice is uncommon.
Rickettsiosis can present similarly to the acute phase of leptospirosis. A distinguishing feature is rash and eschar at the site of the tick bite, which was absent.
Typhoid and paratyphoid fever can present with extra-intestinal complications involving the hepatobiliary and genitourinary systems, especially when presentation is delayed.
Viral hepatitides, adenovirus, and influenza can mimic the acute phase of leptospirosis.

Following this discussion, a malaria rapid diagnostic test (RDT) was requested and returned positive. Given this new result, the Infectious Diseases team was consulted. An additional history was obtained from the patient, who had a recent visitor from Mozambique, which is a malaria endemic area. This additional history favors a diagnosis of Odyssean malaria. However, surprisingly, the platelet count increased from 40 to 75 x10⁹/L over the 2 days prior to ID consult, without malaria treatment. In the setting of a non-immune person, this is highly unusual and seemingly went against the diagnosis of malaria. We considered the following clinical scenarios.

Odyssean malaria alone - in which there was no travel history to a malaria endemic area, but transmission possibly occurred via the visitor who had travelled to Mozambique recently.
Leptospirosis infection and false positive malaria RDT: False positive RDTs are uncommon but have been reported in autoimmune diseases associated with positive rheumatoid factor. False positive rates range from 2-13% in patients with positive rheumatoid factor, and especially in those with high levels.[1]
Malaria and leptospirosis co-infections with overlapping clinical features.

The patient had developed anuria and refractory hyperkalaemia, requiring dialysis in an Intensive Care Unit due to hypotension. We advised to initiate intravenous artesunate while waiting for malaria microscopy result. Subsequent microscopy showed scanty positive, Plasmodium falciparum trophozoites at 0.6% parasitaemia.

Management

Given these results, artesunate was continued and the patient subsequently completed a 3-day course of Coartem (artemether-lumefantrine). Dialysis was discontinued following resolution of renal failure. He completed 7 days of ceftriaxone as his leukocytosis suggested either translocation of Gram-negative bacteria from gut to bloodstream as a complication of severe malaria and/or leptospirosis co-infection. We notified this case to the Western Cape Department of Health Communicable Diseases Cluster.

The patient made a full recovery. Following his discharge from hospital, the result of Leptospira IgM antibodies returned positive. The combination of a positive assay for IgM antibodies to Leptospira and compatible symptoms provides supportive evidence for recent or current infection. Sensitivity and specificity of IgM ELISA using microscopic agglutination test as the gold standard are 86.0% and 84.5%, respectively.[2] Since the empiric antibiotic therapy that the patient received was a 7-day course of ceftriaxone, it is likely the severe leptospirosis was adequately treated.

Final diagnosis

Malaria and leptospirosis co-infection

This case lends itself to discussion of two important topics: Odyssean malaria and malaria-leptospirosis co-infection.

1. Odyssean malaria

A case of Odyssean malaria is one in which there is no travel history. Outbreaks of Odyssean malaria were reported in Gauteng Province over a 6-year period. The case fatality rate was 9.5%, approximately 10 times higher than the national fatality rate for malaria.[3] This was primarily due to delayed diagnosis in patients presenting without a history of travel to a malaria endemic area. Odyssean malaria must be considered in a febrile patient with unexplained thrombocytopenia. A thorough history often provides crucial information. Pertinent questions to ask from an outbreak investigation aspect include: Does the patient live near a public transport node? Does the patient have any visitors from a malaria endemic area during the past 2-3 weeks?

Our patient’s percentage parasitaemia was very low (0.6%) despite clear signs compatible with severe malaria with jaundice and renal failure. This relates to sequestration of Plasmodium falciparum-infected erythrocytes on the endothelium of vital organs, which can cause a large discrepancy between the peripheral blood parasite count and the total body parasite burden. Therefore, the parasite count (reflecting circulating parasites only) in falciparum malaria can be misleading and variably underestimates the total malaria parasite biomass.

2. Malaria-leptospirosis co-infection

Malaria and leptospirosis share overlapping geographic distributions in tropical and subtropical countries.[4, 5] In a meta-analysis, the pooled prevalence of co-infection was 1% among 5838 patients presenting with a febrile illness.[6] An important limitation is that a positive microscopy is often an incidental finding in malaria endemic areas, because many people are semi-immune and have asymptomatic parasitaemia. All 15 studies included in this meta-analysis related to studies from malaria endemic areas.

The pooled prevalence of leptospirosis was 13% among patients with malaria.[6] Bangladesh had the highest prevalence (75%), which likely reflects a high proportion with semi-immunity to malaria. Leptospirosis is a zoonotic disease and rodents are main reservoirs. An explanation for the high seroprevalence of Leptospira is the presence of innumerable ponds and shallow waters in rural Bangladesh, which favors the transmission of Leptospira from rodents to humans, and excessive rainfall and flooding causing outbreaks.[7]

The overlapping clinical presentations of malaria and leptospirosis contribute to diagnostic uncertainty. However, chills and rigor with splenomegaly are significant distinguishing clinical features of malaria-leptospirosis co-infection, as compared to leptospirosis mono-infection.[8] In patients diagnosed with falciparum malaria, inadequate response to artemisinin combination therapy should raise the suspicion of co-infection.[9] Additionally, in patients with malaria and leukocytosis, one needs to consider concomitant Gram-negative bacterial infection, or rarely [as in this case] leptospirosis.

This case highlights the importance of considering malaria as a cause of unexplained fever and thrombocytopenia, even in the absence of a travel history. Making a clinical diagnosis of malaria and leptospirosis co-infection is challenging because neither has distinct clinical features, however the exclusion of falciparum malaria is crucial to avoid life-threatening complications. Odyssean malaria carries a high complication rate and mortality due to delayed or missed diagnosis, and the key to reducing mortality related to malaria is early recognition and treatment.

Frean J, Brooke B, Thomas J, Blumberg L. Odyssean malaria outbreaks in Gauteng Province, South Africa, 2007-2013: forum-clinical practice. South African Medical Journal. 2014 May 1;104(5):335-8.

White NJ. Severe malaria. Malaria journal. 2022 Oct 6;21(1):284.

Moxon CA, Gibbins MP, McGuinness D, Milner Jr DA, Marti M. New insights into malaria pathogenesis. Annual Review of Pathology: Mechanisms of Disease. 2020 Jan 24;15:315-43.

Karpagam KB, Ganesh B. Leptospirosis: a neglected tropical zoonotic infection of public health importance—an updated review. European Journal of Clinical Microbiology & Infectious Diseases. 2020 May;39:835-46.

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