Late-presenting Plasmodium falciparum Malaria in a Non-Endemic Setting During COVID-19 Travel Restrictions

ABSTRACT We report a case of febrile Plasmodium falciparum malaria in a 36-year-old male patient occurring 14 years after immigration from and more than 12 months since a return visit to the endemic area. The critical need for awareness regarding late presentations of P. falciparum is discussed.


INTRODUCTION
Despite decades of intense, coordinated efforts aimed at malaria elimination and eradication, the World Health Organization estimates 229 million cases of malaria occurred in 2019, resulting in 409,000 deaths. Coronavirus disease 2019 (COVID-19)-driven disruptions of malaria control efforts may have resulted in an increase in 19,000-100,000 malaria deaths in sub-Saharan Africa during 2020. 1 The majority of malaria cases diagnosed in the USA are acquired in Africa (91%) and due to Plasmodium falciparum (77%). 2 Migrants from endemic countries, permanently settled in non-endemic countries, who are "visiting friends and relatives" (VFRs) during return visits to their country of origin are one of the highest-risk groups for presenting with imported malaria. 2,3 Although P. falciparum infection in nonimmune travelers typically results in clinical malaria within 1-2 months of departing an endemic region, 4 semi-immune migrants are at risk of delayed presentations. [5][6][7] We report a case of P. falciparum malaria occurring more than 1 year after the last possible exposure in the setting of COVID-19-related travel restrictions. The case emphasizes the challenge P. falciparum represents and the need for clinician vigilance when assessing VFRs presenting outside typical incubation periods, particularly in light of lingering questions regarding the maintenance of naturally acquired immunity.

CASE REPORT
In January 2021, a 36-year-old active duty male service member was admitted to Dwight D. Eisenhower Army Medical Center (Fort Gordon, GA, USA) for a 7-day history of fevers, headache, malaise and exertional dyspnea. Prior outpatient evaluations primarily focused on ensuring rapid detection of COVID-19 due to the nonspecific nature of his symptoms and lack of physical examination findings suggestive of other focal infection. He tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on three separate occasions (nasopharyngeal swab polymerase chain reaction on days 1 and 7 and nasopharyngeal SARS-CoV-2 antigen test on day 5). He was admitted (day 7) when his febrile episodes did not resolve and laboratory evaluations revealed leukopenia (white blood cell count 3.6 × 10 9 cells/L), normochromic, normocytic anemia (Hb 112 g/L), and thrombocytopenia (35 × 10 9 platelets/L). The patient reported immigrating to the USA from Cameroon in 2006. He had visited Cameroon every 1-2 years since, with the most recent visit being of 4-week duration 13 months before presentation. He denied using malaria chemoprophylaxis during these visits and further denied any history of fevers or malaria treatment after his immigration. He denied travel to any other malaria-endemic region or a history of transfusion. Review of his medical records revealed the presence of sickle cell trait. At admission, he was febrile to 39.0 • C, consistent with the twice-daily fevers he reported occurring before admission. Physical examination was notable for tachycardia to 126 beats per minute, but otherwise unremarkable. Serum electrolytes, creatinine, and liver enzyme levels were all within normal limits. The erythrocyte sedimentation rate (33 mm/h), Ddimer (2.87 mg/L), and fibrinogen (5.35 g/L) were elevated. Serum haptoglobin undetectable at <80 mg/L, lactate dehydrogenase 459 U/L, total bilirubin 0.25 g/L, and urinalysis with elevated urobilinogen (40 mg/L) suggested intravascular hemolysis, and direct antiglobulin testing was negative arguing against an autoimmune etiology. Surprisingly, a rapid malaria antigen test (BinaxNow Malaria; Alere Scarborough, Inc., Scarborough, ME, USA) was positive for P. falciparum (Fig. 1B). Microscopic examination of initial thick and thin blood smears from a specimen collected during an afebrile period did not reveal the presence of malaria. A subsequent specimen collected when the patient was febrile revealed parasitemia 0.7% with intracellular ring stage Plasmodium trophozoites without a formal species identification, but most consistent with P. falciparum (Fig. 1A). The patient was treated with atovaquone/proguanil 1,000/400 mg once daily for 3 days. Within 24 hours he enjoyed resolution of fever, headache, and malaise and reported improvement in fatigue and dyspnea. After confirming the absence of glucose-6phosphate dehydrogenase (G6PD) deficiency, presumptive antirelapse therapy was provided given the residual question of a mixed infection with Plasmodium ovale or Plasmodium vivax 8 and the patient was discharged. Quantitative reverse transcription polymerase chain reaction 9,10 was performed on a stored blood sample collected approximately 24 h after initiation of atovaquone/proguanil therapy. Positive results were obtained for pan-Plasmodium spp. and P. falciparum-specific primers, with C t values supporting an estimated 15,219 ± 396 parasites/µL of blood, corresponding to a parasitemia of 0.46%. P. ovale, P. vivax, and Plasmodium malariae were not detected. Review of all thick and thin smears did not demonstrate evidence to support coinfection with P. ovale, P. malariae, or P. vivax. At follow-up the patient was fully recovered and repeat thick and thin blood smears have remained negative.

DISCUSSION
Plasmodium falciparum remains one of the leading causes of potentially life-threatening illness in febrile returning travelers and a main cause of death. 4 Clinician's recognition of P. falciparum infection in non-endemic areas is of critical importance as delays in diagnosis and treatment contribute to an increased risk of developing severe disease. 11 An accurate travel history is usually the key to making the diagnosis of malaria 12 but clinicians must recognize that migrant patients in particular may present far outside the routinely quoted incubation periods for P. falciparum and the other malarias. 5 The discordance between the often delayed clinical presentation in migrants from endemic regions and the incubation patterns that must be relied upon to guide the recognition of malaria in malaria-naïve individuals is of considerable significance in light of immigrant VFRs more recently representing the majority of individuals diagnosed with malaria in non-endemic countries. 2 Moreover, for members of the U.S. Military forces, immigrant VFRs (particularly those born in countries in western Africa) were found to represent a significant portion of malaria diagnoses and to be among the highest-risk groups for presenting with malaria. 13 The duration of our patient's P. falciparum infection before his presentation cannot be definitively determined. With no history of transfusion, occupational exposure, or evidence of autochthonous transmission, the patient acquired the infection with high certainty during time spent in endemic Cameroon. His last travel to the region was shortly before the institution of COVID-19 travel restrictions, confidently establishing a minimum of 13-month duration for his infection before symptom onset. Alternatively, our patient may have acquired an asymptomatic infection during an earlier (but not his most recent) VFR visit to Cameroon. This possibility highlights ongoing uncertainty regarding the durability of naturally acquired immunity in individuals who have departed endemic regions. It is well established that the ability of individuals to control their parasitemia at low levels without symptoms results from the slow acquisition of immunity following repeated or protracted exposure over years, and naturally acquired immunity dissipates without continued exposure. 2,12 Although the rate of such decline and subsequent clinical impact is not defined, 2 presumably our patient's ability to acquire a clinically asymptomatic infection was diminished at each subsequent visit if he had not been infected previously. In theory, the patient could have been carrying a P. falciparum infection since his immigration 14 years before presentation consistent with his denial of any prior episodes of symptomatic malaria or receipt of antimalarials for treatment or chemoprophylaxis during the post-immigration period. Dauby et al. 5 reported a median of 3 years between the last stay in an endemic region and the onset of clinical malaria among migrants presenting in non-endemic settings. Their literature review identified a maximum duration of 10 years in two separate cases. Similarly, Ashley et al. 14 systematically identified reported cases of P. falciparum infection with delayed presentations, and falciparum malaria transmitted via transfusion or transplant more than 6 months after the donor left an endemic region. The median duration of infection was 3 years and slightly less than 2 years, respectively, with the longest duration calculated as 13-17 years in one instance and possibly 15 years in another, lending credence to the possibility that our patient may have presented after infection 14 years prior.
Host genetic factors influence the severity of malaria infections. The strongest protective effect against severe malaria conferred by a hemoglobin variant results from heterozygous carriage of HbS (sickle cell trait), followed by homozygous α-thalassemia. 15 Our patient's HbAS status augmented his ability to maintain an asymptomatic infection, and relatively low parasitemia after symptoms developed, but thalassemia was ruled out via the hemoglobin electrophoresis results that established his HbAS status. Notably, he possesses O blood group which is also associated with diminished malaria severity. 15 Other polymorphisms known to be protective against some manifestations of severe P. falciparum infection were either not present (G6PD deficiency) or deemed unlikely (e.g., Dantu blood group, only found regularly in East African populations) or unknown (e.g., complement receptor 1 polymorphism).
Although P. falciparum is responsible for 95% of malaria infections in Cameroon, 8 the patient's delayed presentation was, more conventionally, suggestive of P. ovale or P. vivax relapse. This case illustrates the difficulty of ruling out mixed infections. Rare P. ovale or P. vivax parasites may be missed during microscopic examination of blood smears containing predominantly P. falciparum, and the decreased sensitivity of rapid malaria antigen tests for P. vivax and P. ovale results in a significant risk of infections that fall below the limit of detection. In this case where the patient's G6PD status was already established it was felt prudent to provide antirelapse therapy with primaquine which the patient tolerated without issue.
This case of a patient presenting symptomatically with P. falciparum malaria in a non-endemic setting, in the midst of an ongoing COVID-19 pandemic, more than 1 year after the last possible exposure and potentially up to 14 years after the initial infection, highlights challenges malaria poses for the healthcare system. No combination of clinical signs or symptoms is reliably diagnostic for malaria, so clinicians must remain alert to the possible diagnosis and aware that delayed presentations can occur, particularly in individuals with significant prior exposure. Furthermore, mixed infections are common, but can be difficult to rule out, necessitating a comprehensive approach to diagnosis, treatment, and follow-up.