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Pitfalls in Diagnosis and Management of Malaria
Jeanne Rini Poespoprodjo a,b*
a Mimika District Hospital and Timika Research Facility, Timika, Indonesia
 b Pediatric Research Office, Department of Child Health, Universitas Gadjah Mada, Yogyakarta, Indonesia
*Email: didot2266@yahoo.com
Malaria continues to be a major public health problem in Indonesia with P. falciparum and P. vivax infections are similarly prevalent (1-3). In Timika (Papua-Indonesia), a high malaria transmission area, the risk of malaria starts at birth and malaria accounted for 33% of infant and children under-fives hospital presentation (Hospital research database, unpublished). 

In the case of malaria diagnosis and management, clinicians are often faced with challenging clinical decision-making associated with the complex nature of the disease presentation. Firstly, malaria in Indonesia varies in its transmission intensity and is known for a wide range of clinical manifestations from asymptomatic to severe disease and death (4-6). Secondly, the diagnosis of malaria relies on parasitological confirmation by microscopy and it is considered as the gold standard of malaria diagnosis if read by an experienced personnel (7).

There are three most common pitfalls of diagnosis and management of malaria found in daily clinical practice. The following sections briefly discuss the pitfalls and its recommendations.

Fail to screen for malaria
Signs and symptoms of malaria are not specific and could mimic other infectious disease or could present as comorbidity to other non-infectious diseases, a condition that could delay the decision to screen for malaria. Fail to screen for malaria in patients with history of living in or visiting to moderate to high malaria transmission area would delay treatment and could be fatal (8, 9). 

In high malaria endemic area, any patients presenting to health facilities with fever and/or severe manifestations should be screened for malaria and promptly treated with an effective antimalarial drugs. In Timika (Papua-Indonesia), where malaria screening were performed to all hospital presentations, 33% of children had malaria and of those presenting with severe clinical manifestations, 81% presenting with fever, 57% with signs of respiratory insufficiency, 47% had spleen enlargement and 24% had liver enlargement (Hospital research database, unpublished). This warrants malaria screening should be done in all symptomatic patients living in moderate to high malaria endemic area.

Interpretation of microscopy results for treatment evaluation
Another pitfall is interpreting malaria blood smear result during therapy. Malaria blood smear result should be interpreted with caution by carefully assess whether the patient has received and taken the required dosage and compliant to treatment and assess the clinical condition of the patient. If in doubt, repeat microscopy reading by more experienced personnel. Rapid diagnostic tests (RDT) could not be used to evaluate treatment response as it could remain positive despite parasite clearance (10).

Dihydroartemisinin-piperaquine (DHP), a form of artemisinin-based combination therapy (ACT), is a highly efficacious oral antimalarial agents, with 100% parasite clearance at day 3 following treatment (11, 12). Intravenous artesunate is also superior to parenteral quinine with the risk of deaths from severe malaria is significantly lower compared to those of quinine (13, 14). In view of this, persistent parasitaemia beyond day 3 found during treatment follow up is unlikely and should be carefully reviewed.

Fail to identify presence of severe disease and co-morbidity
Differentiating clinical presentation of malaria (uncomplicated or severe disease) is crucial as it determines treatment options. Fail to screen for presence of severe clinical and laboratory manifestations in patients with malaria parasitaemia could be fatal (8, 9). 

Severe malaria should be managed as medical emergency and treated with intravenous artesunate to rapidly clear the parasites and improved perfusion to vital organs (8, 15). Oral route is less effective for the treatment of severe malaria. Oral dihydroartemisinin component of DHP has a much lower plasma drug concentration and slower time to achieve maximum therapeutic drug concentration compared to those of intravenous artesunate (Cmax 1140-29,644 ng/mL versus 900-2043 ng/mL and Tmax 2 minutes versus 54-120 minutes, respectively) (16, 17). 

Severe clinical and laboratory manifestation of malaria are sometimes overlapped with other infectious diseases (eg pneumonia, diarrhea and sepsis) (15, 18). In malaria endemic area where P. falciparum is the predominant infections, comorbidity with invasive bacterial infections (IBI) occurred in about 5-12% of children with severe malaria and one third of mortality from severe malaria is associated with bacteremia (15, 19-21). In settings where microbiology assessment is not available the decision to give antibiotics could be challenging. Considering that untreated bacteremia could be fatal, the WHO recommends that all children with severe malaria should also receive broad spectrum antibiotics (15). In practice, assessment of possible co-infections has to be made on case-by-case basis.

Malaria diagnosis and management requires a thorough evaluation of the laboratory and clinical findings and treatment decisions should be made according to the degree of severity.
Keywords: malaria; diagnosis and treatment; pitfalls
1. WHO. World Malaria Report 2018. Available from https://apps.who.int/iris/bitstream/handle/10665/275867/9789241565653-eng.pdf 2018.
2. Elyazar IR, Gething PW, Patil AP, Rogayah H, Kusriastuti R, Wismarini DM, et al. Plasmodium falciparum malaria endemicity in Indonesia in 2010. PLoS One. 2011;6(6):e21315. Epub 2011/07/09.
3. Elyazar IR, Gething PW, Patil AP, Rogayah H, Sariwati E, Palupi NW, et al. Plasmodium vivax malaria endemicity in Indonesia in 2010. PLoS One. 2012;7(5):e37325. Epub 2012/05/23.
4. Burdam FH, Hakimi M, Thio F, Kenangalem E, Indrawanti R, Noviyanti R, et al. Asymptomatic Vivax and Falciparum Parasitaemia with Helminth Co-Infection: Major Risk Factors for Anaemia in Early Life. PLoS One. 2016;11(8):e0160917. Epub 2016/08/10.
5. Tjitra E, Anstey NM, Sugiarto P, Warikar N, Kenangalem E, Karyana M, et al. Multidrug-resistant Plasmodium vivax associated with severe and fatal malaria: a prospective study in Papua, Indonesia. PLoS Med. 2008;5(6):e128. Epub 2008/06/20.
6. Poespoprodjo JR, Fobia W, Kenangalem E, Lampah DA, Hasanuddin A, Warikar N, et al. Vivax malaria: a major cause of morbidity in early infancy. Clin Infect Dis. 2009;48(12):1704-12.
7. WHO. World Malaria Report. 2015.
8. WHO. Management of Severe Malaria. Available at http://apps.who.int/iris/bitstream/10665/79317/1/9789241548526_eng.pdf?ua=12012.
9. WHO. Guidelines for the treatment of malaria: Third Edition. Geneva2015.
10. Mayxay M, Pukrittayakamee S, Chotivanich K, Looareesuwan S, White NJ. Persistence of Plasmodium falciparum HRP-2 in successfully treated acute falciparum malaria. Trans R Soc Trop Med Hyg. 2001;95(2):179-82. Epub 2001/05/18.
11. Ratcliff A, Siswantoro H, Kenangalem E, Maristela R, Wuwung RM, Laihad F, et al. Two fixed-dose artemisinin combinations for drug-resistant falciparum and vivax malaria in Papua, Indonesia: an open-label randomised comparison. Lancet. 2007;369(9563):757-65.
12. Poespoprodjo JR, Kenangalem E, Wafom J, Chandrawati F, Puspitasari AM, Ley B, et al. Therapeutic Response to Dihydroartemisinin-Piperaquine for P. falciparum and P. vivax Nine Years after Its Introduction in Southern Papua, Indonesia. Am J Trop Med Hyg. 2018;98(3):677-82. Epub 2018/01/19.
13. Dondorp A, Nosten F, Stepniewska K, Day N, White N, Group. S. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet. 2005;366(9487):717-25.
14. Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet. 2010;376(9753):1647-57. Epub 2010/11/11.
15. Severe malaria. Trop Med Int Health. 2014;19 Suppl 1:7-131. Epub 2014/09/13.
16. Hien TT, Davis TM, Chuong LV, Ilett KF, Sinh DX, Phu NH, et al. Comparative pharmacokinetics of intramuscular artesunate and artemether in patients with severe falciparum malaria. Antimicrob Agents Chemother. 2004;48(11):4234-9. Epub 2004/10/27.
17. Batty KT, Thu LT, Davis TM, Ilett KF, Mai TX, Hung NC, et al. A pharmacokinetic and pharmacodynamic study of intravenous vs oral artesunate in uncomplicated falciparum malaria. Br J Clin Pharmacol. 1998;45(2):123-9. Epub 1998/03/10.
18. WHO. The Overlap in the Clinical Presentation and Treatment of Malaria and Pneumonia in Children: Report of a Meeting1992 10th April 2019. Available from: https://scholar.google.com/scholar?q=World+Health+Organisation.+The+Overlap+in+the+Clinical+Presentation+and+Treatment+of+Malaria+and+Pneumonia+in+Children:+Report+of+a+Meeting.+Geneva:+World+Health+Organisation,+1992.
19. Bronzan RN, Taylor TE, Mwenechanya J, Tembo M, Kayira K, Bwanaisa L, et al. Bacteremia in Malawian children with severe malaria: prevalence, etiology, HIV coinfection, and outcome. J Infect Dis. 2007;195(6):895-904. Epub 2007/02/15.
20. Nadjm B, Amos B, Mtove G, Ostermann J, Chonya S, Wangai H, et al. WHO guidelines for antimicrobial treatment in children admitted to hospital in an area of intense Plasmodium falciparum transmission: prospective study. BMJ. 2010;340:c1350. Epub 2010/04/01.
21. Church J, Maitland K. Invasive bacterial co-infection in African children with Plasmodium falciparum malaria: a systematic review. BMC Med. 2014;12:31. Epub 2014/02/20.
22. Miller LH, Baruch DI, Marsh K, Doumbo OK. The pathogenic basis of malaria. Nature. 2002;415(6872):673-9.

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