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Cryptic Plasmodium ovale concurrent with mixed Plasmodium falciparum and Plasmodium malariae infection in two children from Central African Republic

By Pierre Bush, PhD Moderator | 18 Aug, 2017

Dear Colleagues,
Here is a case that most of us would struggle to diagnose properly in the absence of molecular testing help.
Highest regards.

Since several malaria parasite species are usually present in a particular area, co-infections with more than one species of Plasmodium are more likely to occur in humans infected in these areas. In many mixed infections, parasite densities of the cryptic species may be low and often not recognized in clinical practice.
Case presentation
Two children (3 and 6 years old) adopted recently from Central African Republic were admitted to hospital because of intermittent fever. Thin blood smears stained with Giemsa showed Plasmodium falciparum and Plasmodium malariae co-infection for both children at admission. They were both treated with atovaquone-proguanil combination for 3 days. At day 7, both thin blood smears examination remained negative but at day 28, thin blood smear was positive for P. malariae trophozoites and for Plasmodium ovale for the girl and her brother, respectively. Samples collected at day 1 and day 28 were submitted to real-time PCR showing the presence of the three parasite species (P. falciparum, P malariae and P. ovale) in admission blood samples from the two children and only P. ovale at day 28.


Twenty-eight days follow-up after treatment led to detection of a third parasite species in the blood of these two patients suggesting covert co-infection and a delayed appearance of one cryptic species following treatment. Concurrently infecting malaria species could be mutually suppressive, with P. falciparum tending to dominate other species. These observations provide more evidence that recommendations for treatment of imported malaria should take into account the risk of concurrent or cryptic infection with Plasmodium species. Clinicians and biologists should be aware of the underestimated frequency of mixed infections with cryptic species and of the importance of patient follow-up at day 28. Future guidelines should shed more light on the treatment of mixed infection and on the interest of using artemisinin-based combinations for falciparum and non-falciparum species.

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Iveth González Replied at 8:40 AM, 18 Aug 2017

Thank you Pierre for sharing this paper.
It is important to keep in mind that while control of malaria due to P. falciparum improves, other Plasmodium species would start to be more visible and little is known about their real global distribution and impact. Improved diagnostic tests able to detect all forms of malaria are needed in order to provide adequate treatment, and more specifically, the prescription of primaquine to avoid P. vivax and P. ovale relapses.

[FIND - Because diagnosis matters]<http://www.finddx.org/>

Iveth J. González
Head of Malaria Programme
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FIND, Campus Biotech, Chemin des Mines 9
1202 Geneva, Switzerland

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Sungano Mharakurwa Moderator Replied at 5:26 AM, 19 Aug 2017

Thank you Pierre and Iveth. It is also interesting to note that the P. ovale infection as indentified by real-time PCR survived treatment with quite a potent combination antimalarial. That seems to suggest possible relapse from liver stage hypnozoites that need primaquine treatment for clearance, though some recent studies also implicate a potential concurrence of relapse and recrudescence (see https://link.springer.com/article/10.1007%2Fs00436-016-5043-0).

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Pierre Bush, PhD Moderator Replied at 9:33 PM, 19 Aug 2017

Hello Sungano & Iveth,
You raise important points. Should primaquine be made available, especially for those patients who are not G6PD deficient? The challenge would again be the availability of screening kits for G6PD.
Highest Regards.

Ahishakiye Alain Replied at 4:06 AM, 20 Aug 2017

Thank you Pierre Bush. This is very interesting and in some countries we need to get this Real time PCR.

Sungano Mharakurwa Moderator Replied at 5:21 PM, 20 Aug 2017

Indeed, G6PD deficiency screening kits would be important in the scale up for elimination to deal with emerging non-falcipaum species.

Morrison Sinvula Replied at 9:17 PM, 20 Aug 2017

Thank you Pierre for sharing this. I think the paper highlights the pitfalls of clinical practice and why clinicians.
1. The diagnosis of co-infection with 2 plasmodium species in both children in the initial thi smears should have triggered suspicion of the possibility other co-infections especially on the background imported malaria. Real time PCR diagnostics would therefore have been applied much earlier

2. Attention to history: What other malaria species are in this region? This should sharpen the diagnostic acumen and determine management

Chitalu Chanda Replied at 2:04 AM, 21 Aug 2017

Interesting cases that have been presented. Often we don't look out for other species of malaria and the clinical follow up of the patients is lacking. Is there another way of detecting the other species apart from PCR ?

Sungano Mharakurwa Moderator Replied at 5:00 AM, 21 Aug 2017

Thank you for that question Chitalu. Indeed there are non-PCR ways of detecting other species. Microscopy can be used to differentiate species by thin film once infection is detected by the thick film (films stained by Giemsa or other suitable Romanovsky stain). Skilled microscopists are needed and in areas where Plasmodium knowlesi occurs, distinction from P. falciparum is especially challenging. Another approach is to use multi-species malaria rapid diagnostic tests (Combo RDTs) that can differentiate infecting species. For both microscopy and RDTs, low-grade infections (less than 100 parasites/ul) may be miss detection (microscopy can detect much lower levels with more stringent examination criteria, e.g. examining 100 fields of view before declaring a slide negative). PCR is what can detect the low-grade infections. Nonetheless, for infections that have high enough counts to cause illness, both Combo RDTs and microscopy are quite reliable diagnostic tools that can differentiate malaria parasite species.

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NIRMAL GHIMIRE Replied at 6:48 AM, 23 Aug 2017

Thanks pierre..
how feasible is the use of G6PD kits in low Income countries?
It will b a great asset if it is easily available

Pierre Bush, PhD Moderator Replied at 12:03 PM, 25 Aug 2017

Hi Nirmal,
There are affordable qualitative screening kits for G6PD (results: Normal, Deficient, and intermediate). Quantitative methods are quite expensive.

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tsamo vigny Replied at 9:48 PM, 1 Sep 2017

Thank you very much for this case, its really interesting.
with my little intelligence as a medical student, from the case, i can also justify the hidden P.Ovale and the negative thin blood can be explain by the hepatic stage from his life cycle, and therefore his abscence from the periphal circulation, though the ambiguity of the biological testing.
as for the treatment, your suggestion is actually good and is on line with the WHO recommendations for the management of malaria 2015 ie with Artemisinin Combined Therapy. in my Country, our National guideline from the WHO recommendation says.
the malaria sould first of all be classified as either simple or severe (severity criterias or evidence of any organ failure).
simple malaria: Artemisinine Combined Therapy the most commonly used ones here are artesunate amodiaquine (ASAQ) or Arthemeter+Lumefantrine (AL) for 3 days and has been proven very effective.
severe malaria with as first line Artesunate injectable, second line Quininine drip, and third line Arthemether injectable for abt 6 days or 3 days and then a relay with ACT for 3 remaining days.
if interested i can found you a soft copy of the guidiline...

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