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The authors report the first indigenous case of Plasmodium ovale infection from Bangladesh. The diagnosis was confirmed by PCR and sequence analysis. The patient had neither been outside of the country nor ever received blood transfusions. The authors concluded that there was evidence for a local transmission of P ovale malaria in Bangladesh. P ovale malaria should therefore always be considered a potential differential diagnosis in the indigenous population as well as travellers and migrants returning from South Asia, possibly up to years after their return.
Until very recently, infections with Plasmodium ovale could largely be excluded from the spectrum of differential diagnosis in febrile patients returning from Asia. It was not until the late 1990s that the first cases of PCR-confirmed ovale malaria were reported. Since then a number of studies have reported varying (but invariably low) percentages of ovale malaria from a number of countries in Asia.1 Out of a total number of 34 359 malaria cases imported into the UK between 1987 and 2006, P ovale infections from Asia accounted for only 30 (0.09%) cases suggesting that a considerable proportion of cases may have been missed.2 We present the first case of P ovale malaria reported from Bangladesh, who, based on the assumption that P ovale does not exist in Bangladesh, was wrongly diagnosed as a case of Plasmodium malariae and later developed a relapse from dormant liver stage parasites. This case illustrates the importance of including P ovale malaria as a differential diagnosis in febrile patients living in or returning from countries like Bangladesh.
On 27 August 2008, a 12-year-old Bangladeshi female was referred to the Malaria Research Initiative Bandarban outpatient department in Bandarban in the Chittagong Hill Tracts in South-Eastern Bangladesh with intermittent episodes of fever within the last 7 days prior to presentation. She reported to have chills, headache, myalgia, arthralgia, dizziness, fatigue and abdominal pain. On presentation she had no fever and all her vital signs were within the normal range for this age group. Liver and spleen were not enlarged and the physical examination showed no significant findings. The patient had no signs and symptoms of severe malaria. In this highly malaria-endemic region of Bangladesh, malaria was considered the primary suspected diagnosis. She reported never to have travelled out of the country and had never received blood transfusions. A venous blood sample was taken and thick and thin blood smears were prepared. The patient's blood sample tested negative in a rapid diagnostic test (RDT; FalciVax; Zephyr Biomedicals, Goa, India) for the two commonly diagnosed types of malaria in Bangladesh, namely falciparum and vivax malaria. The Giemsa-stained thick blood film was microscopically examined and presented a picture typical for malaria with trophozoites, gametocytes and schizonts. The thick film showed a parasitaemia of 2600 parasites/µl of blood. At first glance, the parasite morphology in the thick film seemed consistent with quartan (P malariae) malaria. Based on the negative result of the RDT for falciparum and vivax malaria, the parasite morphology, as well as the fact that ovale malaria had never been reported from the country, the patient was diagnosed with uncomplicated quartan malaria. The patient therefore received oral treatment with 600 mg chloroquine base on examination followed by 300 mg daily for the next 2 days consistent with the national treatment guideline for P malariae infections. The patient was advised to return for follow-up whenever fever or signs and symptoms consistent with malaria should reappear. Two drops of blood were collected on filter paper for confirmation of the diagnosis by PCR.
On 15 October 2008, 49 days after the initial presentation, the patient returned to the clinic with intermittent fever for 4 days and signs and symptoms consistent with malaria. At that time, her axillary temperature was 38.9 °C, her blood pressure 100/60 mm Hg, her pulse 88 beats/min and her respiration 24 breaths/min. Spleen and liver were not enlarged and the physical examination was considered normal. The patient presented with moderate chills, myalgia, athralgia, dizziness, abdominal, pain, runny nose and mild fatigue and nausea. The RDT was once again negative for falciparum and vivax malaria. Microscopic examination of the thick film showed malaria parasites morphologically comparable to the ones seen at initial presentation. The patient was once again classified as P malariae with 6680 parasites/µl and received treatment according to the national treatment guidelines. The patient quickly recovered and during a follow-up visit on day 7 she had cleared all parasites. The patient was seen for another safety follow-up 12 months later. The physical examination and all lab parameters were normal. She reported no history of fever or episodes of malaria and had taken no antimalarial drugs since her last visit. She also tested negative for malaria by RDT and microscopy.
As treatment failures are uncommon and relapses never occur in P malariae malaria, the blood samples collected for molecular diagnosis were analysed at the laboratories of the Medical University of Vienna, Austria. The DNA was extracted from the filter papers and analysed by nested PCR targeting the small subunit ribosomal RNA gene, which allows for a highly sensitive and specific diagnosis of all human malaria parasites.3 Molecular analysis showed that both samples from initial presentation and follow-up were positive for P ovale monoinfection. The diagnosis was confirmed by sequence analysis.
This first case of P ovale infection in Bangladesh was detected at a relatively well-equipped research facility in the rural southeast of the country demonstrating some common pitfalls associated with the diagnosis of febrile illnesses and malaria in the tropics. Despite the fact that physicians, microscopists and laboratory technicians at this facility are highly trained, diseases that have never previously been reported from a region are typically excluded from the spectrum of possible differential diagnoses. In this case, reasons for not including P ovale malaria as a primary diagnosis are threefold. (1) P ovale malaria had never previously been reported from this highly malaria-endemic region of Bangladesh. (2) The limited laboratory resources available at field level make a distinction of malaria parasites difficult. This particularly applies to the rare species, such as P ovale and Plasmodium knowlesi (which so far has also not been reported from Bangladesh).4 (3) RDTs commonly used in malaria-endemic countries of Asia are either limited to diagnosing falciparum and vivax malaria or (in case of RDTs using pan-malaria antigens for diagnosis) are not sensitive and specific enough for the detection of non-falciparum infections.5
Despite the fact that RDTs are convenient, fast, relatively inexpensive and easy to perform, the UK malaria treatment guidelines recommend the use of RDTs only in addition to, but not as a replacement for, microscopy, and all patients with suspected malaria to have blood films prepared and examined.5 Typically RDTs today achieve a sensitivity of over 95% for falciparum malaria. Unfortunately, this statement does not necessarily apply to non-falciparum malaria. The sensitivity of malaria RDTs tends to drastically decline with decreasing numbers of parasites and as non-falciparum infections inherently present with lower parasitaemia, RDTs alone are not a good option for diagnosing malaria.6
Particularly in resource-limited healthcare systems, as typically encountered in malaria-endemic countries, adequate diagnosis can be a major challenge. Without the necessary logistics, presumptive diagnosis remains the most common means of malaria diagnosis typically resulting in massive overdiagnosis of malaria in febrile patients.7 However, this case also demonstrates that under certain circumstances even highly trained research microscopists can fail.
Competing interests None.
Patient consent Obtained.