Diagnosing malaria can be missed when there is a significant time lag from exposure and negative initial tests. As clinicians we must always consider the diagnosis in the appropriate clinical setting as a
missed diagnosis can potentially result in serious consequences.
A 27 year old female student from Nigeria presented with a two day history of headaches, mild photophobia, sweats and fever. She arrived from Nigeria eight months previously and had not been back since. On admission she was unwell with a temperature of 38.5?C, pulse 110/min but otherwise haemodynamically stable. Examination revealed a soft ejection systolic murmur and signs of meningism, but her neurological assessment was otherwise entirely normal. Her initial investigations showed a haemoglobin level of 11.8g/dl, white cell count 3.9×109/l, lymphocytes 0.5×109/l, platelets 118×109/l, C-reactive protein 121mg/l; urea and electrolytes and liver function tests were normal.
She was commenced on ceftriaxone 2g daily with a presumptive diagnosis of meningitis. She had a normal CT head, which was followed by a normal lumbar puncture. Two sets of blood cultures and a mid-stream urine sample had no growth after 48 hours. The initial admission pyrexic thick and thin blood film and malarial antigen test (Optimal, DiaMed) were negative.
She improved initially with antibiotics and intravenous fluids. 24 hours into her admission, having been reviewed by a number of senior doctors, her working diagnosis was changed to one of a viral illness and plans were made for her discharge. Malaria was felt to be unlikely given that not only was she eight months post exposure for malaria, her blood film and antigen test were negative.
However, on the day of discharge she was found to spike a temperature of 38?C and remained thrombocytopenic (108×109/l). It was decided that in view of her origin (Nigeria) and the fact that she remained thrombocytopenic, malaria still needed to be considered. Even though a thick and thin blood film and malarial antigen test (Optimal, DiaMed) were negative, we felt three negative blood films were needed before excluding malaria and labelling her as a patient with a viral illness.
Interestingly a repeat blood film showed malarial parasitaemia of 5% Plasmodium falciparum [Figure 1]. Her haemoglobin dropped to 9g/dl and platelets dropped to 93×109/l over the next two days, which then recovered. She was treated with intravenous quinine (10mg/kg) for 48hrs and converted to oral quinine for seven days followed by three tablets of oral pyrimethamine with sulfadoxine (Fansidar). She was discharged home with a negative parasitaemia.
The Office of National Statistics reports increasing international travel in our population with 25 million visitors to the UK and 61 million trips abroad in 2003. According to the Health Protection Agency (HPA) there were 1722 cases of malaria in the UK in 2003, 78% were Plasmodium falciparum, all of which were diagnosed within five months of arrival in the UK. Their statistics also show that 59% of malarial cases in UK are from those of African ethnicity, and patients who were infected in Nigeria contribute one third of all Plasmodium falciparum cases in UK and 2 out of 16 deaths in 2003.
Immunity to malaria is acquired slowly, is incomplete and on leaving the infectious environment falls over about 1-2 years. Those who have been out of exposure for greater than 1 year or been born in UK are classed as non-immune. These individuals if exposed usually develop malaria within one month of leaving the endemic area. In contrast those who are from endemic areas and arrive in the UK as an immigrant, visitor or student (our patient) are classed as semi-immune. In these individuals and those who have taken malaria prophylaxis, incubation can be significantly prolonged, and may have milder symptoms. In those countries with high transmission rates, severe disease is usually a disease of the young (1 month to 5 years) or non-immune adults (vast majority of travellers to endemic areas). Children in areas of high transmission often show tolerability of the parasites due to constant parasitaemia without signs of disease, and paradoxically those living in low transmission areas have high clinical disease burden 1.
Reviewing the HPA statistics, of the 1722 cases reported in 2003, 52% were visiting family and friends in their country of origin and probably non-immune as they had been born or lived in the UK for some time, 22% were from endemic areas (immigrants, visitors, students), and 26% were almost certainly non-immune (business travel, holiday, expatriates). Diagnosis of malaria in the 22% group, who arrive from an endemic area and are semi-immune, is often difficult because they can present late with clinical malaria, as demonstrated with our patient being in the UK for eight months prior to presentation.
Our case was notable in that our patient had an initial negative microscopy and malaria antigen test. The latter is a new method for detecting malaria. It is a rapid dipstick immunoassay that detects circulating antigens of either histidine rich protein-2 of falciparum (HRP-2f) or plasmodium lactate dehydrogenase (pLDH). These are near-patient testing kits that have recently been developed to ease and speed up diagnosis, particularly in places that do not have access to microscopes or trained laboratory staff. The malarial antigen test Optimal (DiaMed) used in this case detects presence of pLDH. This assay can detect parasitaemia levels of 100-200 parasites per ?L of blood, equivalent to 0.002% 2 and has been found to have a sensitivity of 95.3% and a specificity of 100% for Plasmodium falciparum 3. However, a meta-analysis of ten popular brands showed that HRP-2 was more accurate than the pLDH tests 4. Though quick to use and easy to read they are not as accurate nor as good at detecting species as microscopy using thick and thin films, hence why microscopy remains the method of choice.
We believe most general physicians would have felt that on initial presentation our patient was unlikely to have malaria. She presented with non-specific symptoms and signs of meningism; over eight months had elapsed since her return from Nigeria and lastly initial investigations were negative for malaria. Many might have put her presentation down to a viral illness, though she had the characteristic lymphopenia and thrombocytopenia for malaria (sensitivity for thrombocytopenia in those with malaria is 60%, and specificity is 95%) 5. It is noteworthy however that a study in Nigeria found that headache, fever, chills and rigors were the commonest malaria symptoms in adults6. Further, a fact that we all forget is that the HPA advises us to consider malaria in a patient who has been potentially exposed up to 12 months. Finally if the clinical suspicion for malaria is high, three sets of malarial blood films must be taken before suggesting a negative result – easily forgotten by clinicians.
In conclusion we would like to reinforce to all clinicians the advice by the Health Protection Agency that it is important to consider malaria due to Plasmodium falciparum as a differential in those who have had malaria exposure in the last 12 months and to always take three blood films if there is any clinical suspicion to make a diagnosis of malaria.
Figure 1: Patients blood film showing malarial parasites
1. Reyburn H, Mbatia R, Drakeley C, Bruce J, Carneiro I, Olomi R, Cox J, Nkya WMMM, Lemnge M, Greenwood BM, Riley EM
Association of Transmission Intensity and Age With Clinical Manifestations and Case Fatality of Severe Plasmodium falciparum Malaria
Journal of American Medical Association 2005; 293:1461-1470
2. Palmer CJ, Lindo JF, Klaskala WI, Quesada JA, Kaminsky R, Baum MK, Ager AL
Evaluation of the OptiMAL Test for Rapid Diagnosis of Plasmodium vivax and Plasmodium falciparum Malaria
Journal of Clinical Microbiology 1998; Jan: 203-206
3. Kolaczinski J, Mohammed N, Ali I, Ali M, Khan N, Ezard N, Rowland M
Comparison of the OptiMAL rapid antigen test with field microscopy for the detection of Plasmodium vivax and P. falciparum: considerations for the application of the rapid test in Afghanistan
Annals of Tropical Medicine and Parasitology 2004; 98(1): 15-20
4. Marx A, Pewsner D, Egger M, Nuesch R, Bucher HC, Genton B, Hatz C, Juni P
Meta-analysis: accuracy of rapid tests for malaria in travelers returning from endemic areas
Annals of Internal Medicine 2005; 142(10): 836-46
5. D’Acremont V, Landry P, Mueller I, Pecoud A, Genton B
Clinical and laboratory predictors of imported malaria in an outpatient setting: an aid to medical decision making in returning travelers with fever
American Journal of Tropical Medicine and Hygiene 2002, 66: 481-486
6. Harrison NE, Odunukwe NN, Ijoma CK, Mafe AG
Current clinical presentation of malaria in Enugu, Nigeria
Nigerian Postgraduate Medicine J. 2004; 11(4): 240-5