Imported Malaria in Countries where Malaria Is Not Endemic: a Comparison of Semi-immune and Nonimmune Travelers

Abstract

The continuous increase in long-distance travel and recent large migratory movements have changed the epidemiological characteristics of imported malaria in countries where malaria is not endemic (here termed non-malaria-endemic countries). While malaria was primarily imported to nonendemic countries by returning travelers, the proportion of immigrants from malaria-endemic regions and travelers visiting friends and relatives (VFRs) in malaria-endemic countries has continued to increase. VFRs and immigrants from malaria-endemic countries now make up the majority of malaria patients in many nonendemic countries. Importantly, this group is characterized by various degrees of semi-immunity to malaria, resulting from repeated exposure to infection and a gradual decline of protection as a result of prolonged residence in non-malaria-endemic regions. Most studies indicate an effect of naturally acquired immunity in VFRs, leading to differences in the parasitological features, clinical manifestation, and odds for severe malaria and clinical complications between immune VFRs and nonimmune returning travelers. There are no valid data indicating evidence for differing algorithms for chemoprophylaxis or antimalarial treatment in semi-immune versus nonimmune malaria patients. So far, no robust biomarkers exist that properly reflect anti-parasite or clinical immunity. Until they are found, researchers should rigorously stratify their study results using surrogate markers, such as duration of time spent outside a malaria-endemic country.

Keywords: Europe; VFR; clinical characteristics; diagnosis; imported; malaria; nonimmune; prophylaxis; semi-immune; treatment.

FIG 1

Number and movement of imported and exported cases of malaria between 2005 and 2015. (A) Average annual number of malaria cases (all species) exported from endemic to nonendemic countries (red) and imported to nonendemic from endemic countries (blue). (B) P. falciparum prevalence overlaid with flow lines showing country connectivity by average annual flows of >50 (>200 [red], 100 to 200 [orange], and 50 to 100 [yellow]) cases. (Reproduced from reference .)

FIG 2

Relationship between age and malaria severity. Protection from malaria is acquired gradually with repeated exposure, first against severe disease and then against clinical symptoms of disease, and at a lower rate against high levels of parasitemia. Premunition means protection from illness but not from infection. (Adapted from reference with permission from Elsevier.)

FIG 3

Hypothetical relationship between risk of disease and exposure. (A) A low but increasing incidence density equates to a high risk of disease. (B) Further increase in incidence induces NAI, resulting in decreasing risk of disease. (C) Sustained high incidence maintains the risk of disease at a low level. (D) High risk of disease in those with inadequate NAI, such as small children. (Adapted from reference .)

FIG 4

Prevalence of parasitemia across age groups in malaria-naive migrants to a malaria-endemic area. Prevalence is largely uniform after 8 months of exposure, while at 20 months of exposure an age-distinct pattern has developed. (Adapted from reference .)

FIG 5

Age-related susceptibility to death in relation to acute or chronic exposure. (A) Case fatality rates for malaria-naive American civilians (n = 1,111) traveling to malaria-endemic areas. (B) Mortality rates for populations living in holoendemic West Africa show an inverse trend. (Adapted from reference .)

FIG 6

Network of factors used to model immunity to malaria. Progression from infection to disease develops through stages (green arrows). Exposure to malaria by mosquito bites leads to low-level infections (only detectable by highly sensitive methods, like PCR) that can progress into high-level infections (only those were included in the figure), some of which can lead to clinical malaria (here defined as the presence of fever). Red lines indicate the inhibitory influence of immunity, and boxes demonstrate how immunity depends on age and exposure (annual entomological inoculation rate [aEIR]). (Adapted from reference .)