Dr Jeannine van Lochem, SASTM
In the early evening of a day in mid-April, (“Day 1”), a 60 old male, British national, presents to a small clinic on a mine, approximately 70 kilometres west of the Malian border, in Senegal, West Africa.
Patient complains that he “...feels like he is burning up,...” and has lower abdominal and back pain over kidney region. He is nauseas, not vomiting, but has no appetite.
BP: 123/86 mmHg; Pulse: 98 beats/minute; Respiratory rate: 22 beats/minute;
Temp: 39.3 C; SpO2: 98%
On examination: Lower abdominal and renal angle pain and tenderness, nil else remarkable.
Question 1: What else do you want to know?
Answer to Q1
The patient had a laparotomy for unknown reason 15 years ago and a cholecystectomy 5 years ago.
No chronic medication and no malaria prophylaxis.
Vaccine cover - all childhood vaccines covered plus Yellow Fever, Meningococcal disease, Typhoid, Hepatitis A and B.
Lives in Scotland. Been working on this mine for the last two years on a 6 weeks on 2 weeks off roster.
Side room laboratory examination reveals:
Dark, concentrated urine
Blood Glucose: Not done.
Malaria Rapid Test for P falciparum [HRP2]: Negative
No other laboratory investigations possible on site (blood can be sent on a twice weekly, two-hour charter flight to a private laboratory in Dakar).
Question 2: What is your differential diagnosis based on the available clinical and laboratory information?
Answer to Q2
The patient reveals that he has been seeing a urologist for “bladder problems” on and off for some time - this had not been mentioned before.
A diagnosis is made: “A Urogenital Infection”
At midday the patient is seen in the communal dining room - he says he is feeling a lot better - and he is apyrexial.
The patient returns to the clinic mid-afternoon for a follow up visit: He is “… feeling terrible again….”
Vital signs: B/P 112/90; Pulse 91 beats per minute; Temperature 39.2 C ; Oxygen saturation 96%.
Question 3: Which test MUST you repeat now?
Answer to Q3
Malaria rapid antigen test
A repeat Malaria test: Negative
Rest of parameters negative or within normal limits.
@ 16h52 - Temperature: 38.8C. Patient booked off, but sent back to room to overnight.
Patient back in clinic for follow up.
Vitale signs: B/P 100/57; P 63 beats per minute; T 36.3C; Oxygen saturation 98%.
Urine test: SG 1025; PH 6; Rest of results negative / non-remarkable.
Recommenced infusion, push oral fluids. At midday the temperature is normal at 36.4C; Mid-afternoon the vital signs are essentially normal with a normal blood pressure of 122/78 but the patient complains about a lot of pain over his kidney area again - more, more painful on the left side. The patient has been apyrexial all day and it is decided to continue his antibiotics and maintaining a good urine flow.
Question 4: In an ideal setting - what would you have requested at this point in time?
Answer to Q4
The patients’ temperature has settled and vital signs normalized but the on-going loin pain is reason for concern in a patient with a urological history.
The patient presents himself to the clinic for review stating that he feels 100% better, except for a headache.
Vital signs: B/P 123/73; Pulse: 70 beats per minute; T 36.6 C; Oxygen saturation 98%.
Urine test: Macroscopically clear. SG 1010; PH 6; Blood +; Glucose Trace. Bilirubin +; Leucocytes+.
Medication: Paracetamol for the headache.
In the mid-afternoon a mild temperature of 37.9C is noted.
There is a roster charter flight to Dakar the next day.
Question 5: Would you -
Answer to Q5
It was decided to refer the patient to Dakar to see an Urologist in the light of the recurrence of mild fever and the recurrence of / on-going blood in his urine. Sending the biological specimens only does not make sense - if the results require sophisticated treatment the patient would have to wait for the next charter four days later or require a dedicated air ambulance at considerable expense to all.
The patient refuses to see a Urologist in Dakar - insists on going home to his ‘own doctor’.
The patient is considered well enough to fly home on his own on a commercial flight.
The patient arrives back in the UK without further ado but feels unwell enough to consult his doctor.
Question 6: If you were the ‘own doctor’ in the UK, what would you consider as the top five likely diagnoses in this patient?
Answer to Q6
Question 7: Assuming a non-remarkable examination and knowing the patients history as described earlier, which laboratory investigations would you request?
Answer to Q7
The laboratory results reveal:
Question 8: How will you treat the patient?
Answer to Q8
Treat the acute infection with oral artemether / lumefantrine.
Check for Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Treat with Primaquine 15mg / day for 14 days to eradicate liver hypnozoites
Back on site you receive a report that the patient received Riamet® (Co-artem) and then Primaquine from the treating doctor in the UK and pending a repeat full blood count, malaria smear and ultra-sound abdomen, will be returning to site in a week.
Question 9: Are you satisfied that the patient received the correct treatment and that he is fit to return to site?
Answer to Q9
Riamet® is the trade name for Coartem® produced by Novartis in Europe. Both contain artemether / lumefantrine. It is therefore considered adequate treatment for the acute phase of both uncomplicated P falciparum and P ovale malaria. Primaquine must be used to eradicate any hypnozoites in the liver to avert a relapse weeks to months later.
Primaquine cannot be used in persons who are fully G6PD deficient and all persons in whom the administration of Primaquine is considered must be tested for enzyme deficiency first. However, African patients tend to have less severe mutations than those of Asian origin, and alternate regimens of Primaquine should be discussed with a Travel Health or Infectious Diseases specialist for advice.
It is best practice to do a repeat blood screen and malaria smear to ensure that all parasites have gone and make sure the platelet count has returned to normal and that the haemoglobin has remained within normal limits. There is no specific benefit in performing an ultrasound of the liver.
It is best to make double sure that all clinical and laboratory parameters have normalized before allowing a previously ill patient back on to a remote site with limited medical facilities.
Question 10: Why is confirmation of the actual diagnosis in this case of particular importance to you as the medical provider on this remote mine site in Senegal?
Answer to Q10
It is common knowledge that 95% of the malaria in Sub-Saharan Africa is caused by Plasmodium falciparum, the most lethal form of malaria and responsible for the majority of deaths due to malaria in the world.
Non-falciparum malaria is known to occur in the region but not routinely looked for by either clinicians or laboratory technicians as it very scarce and seldom the cause of complications and death in otherwise well patients.
Rapid antigen tests that are single species specific will not detect non-falciparum malaria if intended solely for the detection of P falciparum. Rapid antigen tests that can detect multiple species are generally much less reliable and their interpretation prone to mistakes.
It is therefore of epidemiological and public health importance to confirm the diagnosis as this may be the index case highlighting the fact that there is non-falciparum malaria on site and that it might be prudent to change the malaria management protocol on site, assuming that this particular patient did not contract P ovale elsewhere in the world where P ovale is well known to occur.
Plasmodium ovale malaria is not commonly diagnosed in South Africa
As Plasmodium falciparum malaria is the most common, as well as the potentially most lethal form of malaria in Sub-Saharan Africa, we tend to focus on the clinical diagnosis, laboratory investigation and management of acute uncomplicated and complicated falciparum malaria in travel health teaching and discussions in South Africa.
This case puts the focus on the other, somewhat ‘neglected’ malaria species on the continent.
In our travel health practice we consult approximately 3 500 travellers a year and, on remote sites in Sub-Saharan Africa, take care of roughly 600 expatriates and 5 700 national client employees on any given day of the year.
We annually diagnose about 280 malaria cases on the remote sites (implying that less than 1% of the total number of persons under our care in malaria endemic areas are diagnosed with malaria) and perhaps 10 in returned travellers and medevac cases in our Johannesburg based clinic.
We have been doing this for more than fifteen years.
This is the first case of non-falciparum malaria emanating from one of our sites in which it can be considered that we ‘missed’ the diagnosis. In total we are aware of about three cases of non-falciparum a year amongst our entire client base, including that of an international health insurance company for whom we provide medical cover. Most of these cases originated from Mozambique and the actual diagnosis of non-falciparum malaria could not be confirmed in more than one of them, illustrating the fact that the diagnosis of non-falciparum malaria is often not an easy one in a non-endemic area.
We are aware of one other case - the patient worked on a remote site in Liberia and was diagnosed with P ovale in Australia. We could however not say with certainty that he contracted the malaria on site in West Africa as he had travelled and worked in South East Asia, where P ovale is much more common, extensively.
Historical references istretching from the Philippines to the Gold Coast in West Africa, of what was likely Plasmodium ovale can be found in the literature from 1900 onwards. It had been reported from Indonesia and has been introduced to Vietnam, Thailand and India. Two sub-species have recently been documented: P. ovale curtisi and P. ovale wallikeri.ii
P ovaleiii is seldom seen except in Sub-Saharan Africa and some western Pacific islands (New Guinea and the Philippines). In SSA it makes up part of the less than five percent of non-falciparum malaria diagnosed annually, amongst a sprinkling of P malariae and some P vivax. P ovale has been documented in Senegal and The Gambia before. Prevalence rates in children in the Republic of Congo, Liberia, Cameroon and Gabon are in the region of 1,9% to 9% but this must be seen on the background of a prevalence of malaria of 24,5 to 30% amongst the same children. In a study in Dielmoiv , Senegal only three cases of P ovale was detected out of a total number of 162 malaria patients. All the others had P falciparum malaria and this in turn was responsible for 61% of febrile episodes recorded in the study. Other countries from which P ovale infestations had been documented include: Southern Sudan, Uganda, Zimbabwe, Ethiopia, Zambia, Tanzania and Kenya.
Sporozoites injected by the mosquito rapidly invade the liver where it matures in about 9 days. This corresponds with a prepatent / ‘incubation’ period of 12 to 20 days with a median in one study of 14 days. Hundreds of merozoites are released to invade young red cells. Some of the parasites remain behind in the liver in limbo to form hypnozoites. They may only develop into merozoites months to years later.
The merozoites in the red cells will erupt and invade a next batch of red cells after about 49 hours. After another 49 hours some of the merozoites become gametocytes.
Mosquitoes then take up these microgametocytes during a blood meal, so completing the developmental cycle in the mosquito. Sprozoites appear in the salivary glands weeks after the mosquito had become infested.
Fever spikes occur roughly every 49 hours.
P ovale malaria smears usually record low parasite counts in comparison to P falciparum and P vivax infections due to the parasites restriction to reticulocytes. This makes diagnosis by conventional smear as well as per rapid antigen test relatively difficult. Persons who have previously had P ovale may have reduced parasite levels and lower fever peaks.
Relapsing infection occurs in P ovale due to the presence of hypnozoites in the liver. These may be asymptomatic - posing a potential public health threat with the ‘silent’ introduction of the parasite in to a P ovale naïve community, such as a mine or construction camp.
A first relapse may occur 17 days after completion of treatment of the primary attack but has been recorded up to 255 days later.
Delayed primary attacks may occur up to four years after infestation of the liver due to the effect of malaria prophylaxis or treatment taking at the time of what would have been the usual primary attack.
The parasite makes use of a wide range of Anophelene mosquitoes as vectors, with A gambiae and funestus being the most likely.
The diagnosis of P ovale is normally done by microscopic examination of a Giemsa stained peripheral blood smear. It is difficult to differentiate P ovale from P vivax!
P ovale produces fewer merozoites in the red cell and does not distort / enlarge the erythrocyte as much as P vivax. It does however produce a higher percentage of ‘oval’ / elliptical red cells and more Schüffner’s stippling - for those of you that cant wait to rush out to a microscope!
Human malaria parasite species can be differentiated by making use of PCR - this should be reserved for difficult cases and use in research and is NOT intended as first in line for day to day diagnosis of malaria in the clinical setting.
The case under discussion provides an opportunity to revisit a number of well-known dictums in the diagnosis and treatment of malaria in Africa and adds a few new one’s to consider:
Plasmodium ovale is seldom diagnosed in returned travellers in South Africa but some cases may be missed either because they are subclinical or because they are reported as P falciparum by less experienced laboratories in non-endemic areas. Treatment with the standard first line regime of artemether / lumefantrine will be effective in warding off the primary attack. Any person who has a relapse soon or weeks after an initial episode of malaria should be considered as perhaps harbouring P ovale or P vivax and a specific attempt made to confirm such as diagnosis to afford the patient a radical cure with Primaquine and avert the possible introduction of P ovale into a previously un-infested community when he returns to the malaria endemic area.
Thank you to everyone who took the time to work through this case study - the author would welcome any constructive remarks and comments.
I would like to thank Prof John Frean, NICD and University of the Witwatersrand for his input on the content of this case.
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