Plasmodium ovale: a case of not-so-benign tertian malaria

Severe malaria is most commonly associated with Plasmodium falciparum. Plasmodium vivax is increasingly recognized as being capable of causing severe disease. In contrast, Plasmodium ovale is considered as a cause of benign disease and evidence supporting the occurrence of severe or complicated ovale infection is rare. This report describes a case of severe P. ovale infection in a patient presenting with jaundice, respiratory distress, severe thrombocytopenia, petechiae, and hypotension. He had no apparent underlying risk factors for severe disease.


Background
Malaria is the most important parasitic disease of man [1]. According to the World Health Organization (WHO) an estimated 3.3 billion people are at risk of malaria [2]. Annually there are over 200 hundred million clinical cases of malaria with an estimated 660,000 deaths, 90% of which occur in sub-Saharan Africa, where children under five years are most severely affected [2].
Although the clinical presentations of Plasmodium ovale and P. vivax infections largely overlap, severe disease due to P. ovale is extremely rare [1,3,9]. This case report describes an uncommonly severe case of ovale malaria in a patient with no apparent underlying risk factors for severe disease. The existing literature documenting severe or complicated presentations of P. ovale infection is reviewed.

Case presentation
A 42-year-old male, with no significant previous medical history, was referred by a general practitioner to the Steve Biko Academic Hospital, Pretoria, South Africa. The patient presented with fever, nausea and vomiting, general body pains and shortness of breath. He complained of feeling weak and tired for the last three weeks. In the preceding six months he had worked in two malaria-endemic regions: Kalia in the north-west region of Guinea, and most recently Mozambique, from where he had returned a month previously. He had not taken malaria chemoprophylaxis during his stay in these areas.
Upon physical examination the patient was awake and alert, with no signs of meningism. He was visibly jaundiced. Abdominal examination revealed a tender right upper quadrant, there were bilateral fine crepitations on auscultation of the lungs, and petechiae were visible on his upper and lower limbs. The patient was hypotensive (blood pressure 78/58 mmHg), tachycardic (pulse rate 110 per minute) and tachypnoeic (respiratory rate 28 per minute). The temperature was 39.5°C. The chest x-ray was unremarkable.
The diagnosis of malaria was made by microscopic examination of Giemsa-stained blood smears, showing characteristic P. ovale parasites ( Figure 1). The parasitaemia was 1.4%. Rapid diagnostic tests for P. falciparum antigen (histidine-rich protein 2) were repeatedly negative. Mixed Plasmodium species infection was excluded and the diagnosis of P. ovale malaria was confirmed by multiplex PCR [10,11].
The patient was admitted to high care and treated with a course of intravenous quinine (600 mg eight hourly) and doxycycline (100 mg twelve hourly). Ceftriaxone was added to cover for possible bacterial sepsis. The septic screen investigations, which comprised two sets of blood cultures and a urine culture, were negative. The timing of the blood cultures in relation to antibiotic administration is unclear.
The patient demonstrated a good clinical response to treatment, and he was stepped down to a general ward. Subsequent laboratory evaluations showed an improvement in full blood count, renal and liver functions as well as inflammatory markers, which returned to normal before discharge. Primaquine, 30 mg orally for 14 days was administered to eradicate hypnozoites and prevent possible relapses.

Discussion
Endemic transmission of P. ovale is traditionally described as limited to sub-Saharan Africa and the islands of the western Pacific [9]. Infections with P. ovale have also been documented from India, the Middle East and parts of Southeast Asia [6,9]. Two non-recombining sympatric forms of P. ovale occur globally [12]. Plasmodium ovale curtisi (classic type) and Plasmodium ovale wallikeri (variant type) have been proposed as two distinct species [12,13].
Much of what is currently known regarding the epidemiology of P. ovale is based upon surveys utilising light microscopy as diagnostic tool [6]. From these surveys, the prevalence of P. ovale is generally considered to be low and ranges between 3-5% and greater than 10% in areas of West and Central Africa [6]. The utility of light microscopy is limited by difficulties in distinguishing between P. ovale and P. vivax in smears, as well as the low parasitaemias characteristic of P. ovale infection. In addition, immunochromatography-based rapid diagnostic tests display poor sensitivity for the detection of P. ovale infection [14,15]. This may lead to underestimating the true burden of disease as is evident when more sensitive diagnostic modalities, such as  PCR-based methods targeting small subunit rRNA, are employed [6]. Plasmodium ovale is known to cause mild disease with a low parasitaemia [6,9]. Literature describing severe or complicated cases of P. ovale infection is limited. These rare reports include six cases complicated by acute respiratory distress syndrome (ARDS)(one of which further complicated by renal failure and metabolic acidosis), two cases of splenic rupture, and a single case of splenic infarction [16][17][18][19][20][21][22][23][24][25]. Clinical and therapeutic data for these cases are shown in Table 1.
The current WHO treatment guidelines for severe malaria recommend intravenous (IV) artesunate for the treatment of severe malaria due to all Plasmodium species [26]. Intravenous artesunate is currently not registered in South Africa for clinical use and is only available for named patients on application under Section 21 of the Medicines and Related Substances Act, usually at selected sentinel hospitals through the current artesunate access programme. The patient discussed in this case report was treated with IV quinine, which according to the current South African treatment guidelines, is still the treatment of choice for severe malaria in adult patients if IV artesunate is not readily available [27].
The pathophysiology of P. falciparum as the leading cause of severe malaria has been examined extensively. Various parasite, host, geographic and social factors contribute to severe disease manifestations; however, sequestration of mature parasitized red blood cells is considered to be the key pathogenic event [28,29].
Plasmodium vivax, long considered to cause benign infection, is increasingly recognised as a cause of severe malaria [30,31]. Similar to P. falciparum infection, multiple factors contribute to severe disease [30]. Evidence is emerging that P. vivax infected red blood cells can also cytoadhere and sequestrate in the microvasculature, but to a lesser extent than P. falciparum [32]. It remains to be elucidated to what degree sequestration contributes to severe disease manifestations in vivax infections [30,32].
The pathophysiological correlates and risk factors for severe P. ovale infection are not yet fully established. Reports of severe ovale infection remain rare; however, when the diagnostic difficulties both in the detection of a low parasitaemia and distinguishing P. ovale from P. vivax, based on traditional light microscopy is taken into account, severe cases of ovale malaria may actually be underreported.

Consent
Verbal consent was obtained from the patient; however, due to his unavailability, written consent could not be obtained. Thus, ethical approval was obtained from the University of Pretoria Ethics Committee. The letter of approval from the Committee is available for review.