Antimalarial prophylaxis failure: Malaria in a returning traveler despite mefloquine prophylaxis

Abstract

This case report presents a perplexing case of Plasmodium malariae breakthrough infection despite prophylaxis with appropriate antimalarial prophylactic regimen of mefloquine in a compliant patient. A 78-year-old missionary who travels each year to the African subcontinent for multiple weeks to months, over 25 years, adheres to stringent antimalarial prophylaxis with Mefloquine as prescribed, starting prior to the trip and continuing after the return to the U.S.A. She gave no prior history of malaria during her 25 years of travel to Africa and back. Since she had no prior history of malaria and due to her excellent compliance with antimalarial regiment, despite her presentation which were suggestive of malaria, neither the patient nor her providers recognized the onset of malaria in this case. Infectious diseases physicians approached this case with an open mind, investigated appropriately, requested appropriate tests, found the presence of malarial parasite, identified as P. malariae species thereafter. She was started on antimalarial treatment in a timely fashion and showed an excellent response. This intriguing recovery of malarial parasite and response to treatment despite the patient being on antimalarial prophylaxis raised the possibility of mefloquine failure as an antimalarial prophylactic agent against P. malariae species.

INTRODUCTION

Malaria, the most common vector-borne parasite infection worldwide, results from infection by the Plasmodium species. Plasmodium malariae is unique in its ability to cause attacks even decades after exposure; the mechanism of persistence is unknown.[1] Mefloquine is effective against the blood stages of all human malaria species, including the recently recognized fifth species, Plasmodium knowlesi.[2] This case represents a failure of mefloquine antimalarial prophylaxis resulting in malaria infection with Plasmodium malaria in a compliant patient.[3]

CASE REPORT

Here, we report the case of a 78-year-old female with a history relevant for multiple trips to the African Continent on missionary work over the last 25 years using mefloquine as prophylaxis against malaria as directed. She gave no previous history of symptomatic malaria despite her multiple trips to Sub-Saharan Africa. She presented approximately 1 month after returning to the U.S.A from her trip to Africa with a 10-day history of fever and chills. On presentation, she had a high fever of 103.7°F. Laboratory data were relevant for leukopenia, anemia, mildly elevated liver function tests, and an ultrasound with nonobstructing gallstones without murphy sign. She was admitted with a working diagnosis of possible cholecystitis and was expected to undergo surgery. Malaria was suspected due to her relevant travel history and appropriate labs were requested. Peripheral blood smear for parasites showed intraerythrocytic inclusion body suggestive of malaria, identified as malaria with specific Malaria Protein Antigen [Figure 1]. Species was confirmed as P. malariae by Plasmodium species polymerase chain reaction (PCR) methodology. She was started on Artemether-Lumefantrine with excellent response with reduction of parasitemia after initiation of treatment with improvement in her symptoms and laboratory values in complete blood count, liver function tests and parasitemia[4] [Table 1-3].

Figure 1.

Peripheral blood smear showing intraerythrocytic malarial parasite

Table 1.

Complete blood count

Lab parameter	Date							Units	Reference range
	September 28, 2022	September 30, 2022	October 1, 2022	October 2, 2022	October 3, 2022	October 4, 2022	December 1, 2022
WBC	3.40	2.80	2.60	4.80	4.80	4.20	4.4	×103/m	4.80–10.80
RBC	3.55	3.12	3.20	3.36	3.38	3.16	3.98	×106/m	4.20–5.40
Hgb	11.10	9.70	9.90	10.10	10.20	9.50	12.2	g/dL	12.0–16.0
Hct	32.70	29.60	29.20	31.20	30.60	28.6	38.0	%	37.0–47.0
Platelet	112	85	64	31	53	84	253	×103/m	130–400

WBC: White blood cell count, RBC: Red blood cell count, Hgb: Hemoglobin, Hct: Hematocrit

Table 3.

Parasitemia

Lab parameter	Date							Units	Reference range
	September 29, 2022	September 30, 2022	October 1, 2022	October 2, 2022	October 3, 2022	October 4, 2022	December 1, 2022
Malaria smear	Parasites seen	Parasite seen	Parasite seen	Parasite seen	Parasite seen	Parasite seen	None seen		None seen
Parasitemia (%)	1.6	1.6	0.7	0.2	0.1	0.2	N/A	%	≤0.0
Malaria antigen		Positive							Negative

Malaria Antigen Interpretation: Positive for malaria protein antigen. Malaria antigen was found to be negative upon subsequent testing. N/A: Not available

Table 2.

Liver function tests

Lab parameter	Date			Units	Reference range
	September 28, 2022	September 29, 2022	September 30, 2022
ALT	44			Unit/L	7–40
AST	42			Unit/L	15–40
Alkaline phosphatase	78			Unit/L	45–117
Bilirubin
Bilirubin total	1.92	1.89	1.34	mg/dL	0.30–1.20
Bilirubin direct	N/A	0.63	0.29	mg/dL	0.00–0.45

ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, N/A: Not available

DISCUSSION

Antimalarial prophylaxis with appropriate regimen is recommended for people traveling to endemic areas with malaria. The prophylaxis is determined based on chloroquine sensitive versus chloroquine resistant areas. Since the African subcontinent has significant Plasmodium falciparum, chemoprophylaxis with mefloquine is recommended to cover different species of malaria which can cause both mild illness like Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi or Plasmodium falciparum which causes the most severe disease.[2]

Review of literature suggests that mefloquine prophylaxis prevents malaria in 91% of people taking it as directed and reporting excellent compliance. This indicates that a significant number of people contract malaria despite prophylaxis indicating failure of mefloquine as an antimalarial prophylactic medication.[3] Most antimalarial agents act on the parasite’s blood stage and hence may not be able to prevent late onset illnesses, such as the species responsible for relapsing malaria.[4] This case reveals the need for keeping a high index of suspicion to diagnose malaria in returning travelers and to treat them with appropriate agents in a timely fashion to prevent significant mortality and morbidity.[5] Antimalarial prophylactic agents work well to minimize the risk of contracting malaria, but their effectiveness depends on the compliance by the individual. The choice and regiment of prophylactic agents should take into account the ease of compliance and regional resistance patterns.[6]

Sometimes, the parasites are not detected on a thick blood film as they might be in a prepatent period. A prepatent period is defined as the time until the first day the parasites are detected in a thick blood film.[7] A prepatent period can be as short as 16 days or as long as 59 days, as seen in a few reports with a mean range from 27 to 37 days.[7] Malaria may not be diagnosed despite classical presentation in some patients as they might be in the prepatent period. If the index of suspicion is high enough, thick blood smear should be periodically repeated in an effort to establish the diagnosis. The blood smears and PCR testing may not provide definitive diagnosis if the disease is caused by species of malaria which have a low circulating biomass.[8] In addition, they should be treated empirically for malaria with appropriate antimalarial medications as the consequences of not treating it result in poor outcomes.[9]

CONCLUSION

High index of suspicion is needed along with the importance of good travel history in diagnosing clinical malaria despite appropriate antimalarial prophylaxis in a compliant traveler. Accurate diagnosis and timely intervention is life saving and avoids needless clinical interventions. P. malariae causes mild infection in most cases but can present with severe illness and cause significant morbidity in elderly patients with concomitant comorbidities.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.