Deidentified data from the US National Malaria Surveillance System (NMSS) from 1985 to 2011 were used in this analysis and have been described elsewhere [8]. In brief, malaria cases diagnosed by blood film, polymerase chain reaction, or rapid diagnostic tests are mandated to be reported to local and state health departments by healthcare providers or laboratory staff. Case investigations are conducted by local and state health departments, and reports are transmitted to CDC through the NMSS or through direct CDC consults. Malaria cases were categorized by infecting species: P. falciparum, P. vivax, P. malariae, and P. ovale. Cases infected with more than one species, typically referred to as mixed infections, were rare and not included in this analysis. In addition, cases where the species was not reported were not included in the main analyses. The zoonotic malaria from Southeast Asian macaques caused by Plasmodium knowlesi [15] has been reported only once in a returning traveler in the United States [16] and is not considered in the current analysis. Although species confirmatory services are available at the state and federal levels, most cases are not confirmed and species confirmation is usually only sought in nonplausible scenarios, eg, P. vivax acquired in Haiti.

Cases of severe malaria were defined as those with one or more of the following manifestations: death, neurologic symptoms, renal failure, severe anemia, acute respiratory distress syndrome (ARDS), jaundice, or ≥5% parasitemia. To attempt to include severe cases in which clinical criteria were not reported, persons who received a regimen recommended for the treatment of severe malaria (ie, parenteral artesunate or quinidine, and/or an exchange blood transfusion) despite having no specific severe manifestations reported also were counted as a severe case in this analysis. Neurologic symptoms or cerebral complications were defined as impaired consciousness, coma, or repeated generalized convulsions. For surveillance purposes, severe illness is categorized by CDC and not by the treating physician. In 2008, CDC revised the case report form to collect information on parasitemia density, treatment with artesunate, quinine or quinidine, and modified the anemia classification [17]. The anemia complication before 2008 was for those with hemoglobin (Hb) < 11 g/dL and hematocrit < 33%. Beginning in 2008, severe anemia was defined as Hb < 7 g/dL to be in line with the World Health Organization definition for severe cases. Beginning in 2010, CDC established a partnership with the Armed Forces Health Surveillance Center to identify additional cases occurring among military personnel that might not have been identified previously by local or state health departments or private healthcare providers [18]. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using SAS version 9.3 (Cary, NC). P values < .05 were considered statistically significant.

With the varying number of cases with unknown species, a sensitivity analysis was performed to assess the impact of possible misclassification of these cases on the prevalence of severe malaria. The percentage of cases that were classified as being severe was recalculated for P. falciparum and for P. vivax under the assumption that all of the unknown cases were severe P. falciparum or P. vivax, respectively, to determine the range of possible ORs. In addition, to assess the differential impact of hyperparasitemia (>5%), which more commonly occurs with P. falciparum, the analyses were repeated excluding cases of severe malaria due to hyperparasitemia alone without another accompanying severe clinical syndrome.

P. vivax has been increasingly reported as an important cause of severe disease syndromes. When we analyzed all 29 489 single-species cases reported to the US CDC from 1985 to 2011, P. falciparum was ten times as likely to cause death and seven times as likely to be classified as severe compared with P. vivax. However, among the severely ill, the odds of death were not significantly different (8.6% and 6.1%; P = .1649) between the two species. Moreover, the odds of being classified as severely ill with a diagnosis of P. falciparum relative to P. vivax during 2008–2011, a period of improved data quality and reporting coverage, fell sharply to an OR of 3.8 (P < .0001). In 2008, the US CDC began applying substantially modified case detection, reporting, and illness classification algorithms (see METHODS). We consider those changes very probably responsible for the sharp increases in the proportion of reported cases classified as severe (see Figure 2). The greater sensitivity of the now current methods for detection and classification of severe illness, however, applied equally to all species of diagnosis. Therefore, these changes to surveillance methods were unlikely to have confounded the measured risks of severe illness with a diagnosis of one species relative to another in any given year between 2008 and 2011. Comparisons of trends across years, especially before and after 2008, should be interpreted with caution. We do not conclude, for example, the rising odds of severe illness in P. vivax relative to P. falciparum as evidence of increasingly threatening parasite behavior.

The downward trend in OR for risk of severe illness with P. falciparum versus P. vivax (see Figure 4) seems to be driven by other factors. These factors could include changes to the reporting form as well as increased provider awareness of the severe complications possible with P. vivax illness. Although rising resistance to chloroquine by P. vivax may also be a factor [19], this phenomenon has not been seen thus far as a common problem in the management of post-travel vivax malaria in the United States. Furthermore, pernicious virulence in P. vivax had been evident in neurosyphilis patients treated with repeated severe paroxysms of vivax malaria during the 1920s and 1930s [1]. The character and frequency of severe morbidity and mortality in those patients was essentially similar to that in hospitalized patients in endemic zones today—typically manifest as severe anemia, pulmonary distress, altered consciousness, renal and hepatic dysfunction, and circulatory collapse. Similar clinical syndromes were observed in patients diagnosed with P. vivax and treated in US hospitals during 1985–2011.

Although the reported rates of deaths and severe illness with a diagnosis of P. vivax or P. falciparum were substantially lower in travelers in the United States than those typically reported from hospitals in malaria endemic areas [1], case fatality rates amongst those with severe illness were comparable. Those rates for P. falciparum and P. vivax were 9.3% and 1.3% for severe illness, and among those with severe illness, 8.6% and 6.1% case fatality, respectively. Although from a wide range of settings with differing data, quality rates of severe illness with these two diagnoses from hospitals in malaria endemic areas widely ranged between approximately 10% and 30% of admissions, and case fatality was typically between 5% and 15% [1]. The higher rates of severe illness observed in malaria endemic areas can likely be attributed to higher probabilities of comorbidities and the multitude of other factors associated with the poverty typical of most heavily malarious zones: endemic infections, geographic isolation and limited access to care, reluctance to seek expensive care, poor nutrition, etc. Although comorbidities can be present among international travelers, they typically represent a relatively healthy and wealthy subpopulation. These distinctions did not appear to impact the risk of death after the onset of severe complications.

Vivax malaria has long been thought to be a relatively benign condition, resulting in the occasional infarct or rupture of the spleen. Like many reports from endemic areas over the past decade [1, 2, 20–27], the findings in this analysis of malaria cases diagnosed and treated in the United States, especially in the period 2008–2011, challenge the dogma of vivax malaria being relatively harmless and not causing serious complications such as severe anemia, respiratory distress, shock, altered consciousness, and other syndromes typically linked to falciparum malaria. Although a diagnosis of P. falciparum carried a higher risk of severe illness relative to that of P. vivax (18.3% vs 5.5%; P < .0001) during 2008–2011, the risk of severe illness with vivax malaria should not be considered rare or limited to injury to the spleen. Although less likely to run a malignant course than P. falciparum, P. vivax also seems to be an inherently pernicious species capable of a fatal course in travelers and residents of endemic areas alike.

As with all routine surveillance systems, limitations around underreporting, data accuracy, and completeness exist in the NMSS [28]. However, these limitations are not species specific. It is possible that frontline clinicians define severity differently or could have a differential perception of severity by species, but severe illness and specific syndrome classification is completed by the CDC based on the provided information. Although most syndromes are not species specific, hyperparasitemia, defined as >5%, is more relevant and common for P. falciparum. However, the sensitivity analysis excluding hyperparasitemia alone as qualifying as severe illness showed that the initial results were robust. Although the inclusion of the use of parenteral artesunate or quinidine alone without other manifestations in the classification of severe illness could have overestimated the overall number of severe illness, this bias is not species specific and is not likely to impact the comparative results.

Authoritative guidances from the US CDC and others have recommended prophylactic antimalarials for prevention of malaria in travelers [29–31]. This strategy mostly aims at killing blood stages of the plasmodia as they emerge into the bloodstream, and these drugs (doxycycline, chloroquine, and mefloquine) have no effect on the latent liver stages of P. vivax responsible for repeated clinical attacks in the many months (up to about two years) following primary infection. Suppressive prophylaxis coupled with immediate post-travel presumptive anti-relapse therapy with primaquine is recommended for persons departing from vivax and ovale endemic areas after a period of extended exposure. In addition, the US CDC now recommends the use of primaquine for causal prophylaxis (a daily dose of 30 mg (approximately 0.5 mg/kg for the average adult) commencing with travel and ceasing seven days following travel to vivax-endemic areas) [29], which may currently be the only reliably effective chemoprophylaxis option for preventing both primary and secondary attacks by P. vivax [32–34].

In summary, although 1985–2011 malaria surveillance data affirms P. falciparum as the primary threat to travelers presenting in the United States both in terms of numbers of cases and relative risk of severe illness and fatal outcomes, P. vivax also constituted a significant clinical threat in all of these regards. Thus, appropriate caution is warranted in dealing with the prevention and treatment of vivax malaria. Although relatively very few cases of infection by P. malariae and P. ovale have been reported in the United States, the available data suggest these species could pose risk of severe and fatal illnesses. Providers recommending chemoprophylaxis or managing malaria in travelers should consider no species of Plasmodium inherently benign or clinically inconsequential. The clinical dichotomy of falciparum versus non-falciparum malaria, as a prognostic classification that practically separates threatening from nonthreatening malarias, ought to be abandoned as misleading and potentially dangerous to the patient.