The 14 confirmed and 30 presumptive, cases of malaria among the 44 Marines presented represent the largest single outbreak of P. falciparum
malaria in the U.S. Military since Operation Restore Hope in Somalia during 1993–1994.5
If the additional 36 presumptive cases that did not require evacuation from the ship are included, this outbreak in 80 patients was the largest cluster of malaria cases in the U.S. Military since the Vietnam Conflict.25
We now summarize key clinical findings and review host and parasite factors identified in our outbreak investigation that contributed to this event.
The mean onset of symptoms in this cohort was only 15.4 days after initial exposure in Liberia. This time was significantly shorter than a mean of 28 days recorded among British soldiers deployed to Sierra Leone in 2000.26
In addition, our cohort contracted malaria after only 10 days ashore, which is a considerably shorter duration of exposure compared that in British and French soldiers in whom malaria developed after months in either Sierra Leone or Côte d'Ivoire.26,27
We observed a malaria attack rate of 196 cases/1,000 persons/10 days when considering this cohort of 44 Marines and 356/1,000 persons if the entire group of 80 febrile Marines is included. This rate was significantly higher than a previously reported attack rate of 5.1 cases/1,000 persons per month in British travelers returning from Nigeria, Ghana, and the Gambia, and 53 cases/1,000 persons/month (during the rainy season) in French soldiers deployed to Sierra Leone.27,28
In comparison, U.S. servicemen in Somalia had an attack rate that peaked at 30 cases/1,000 persons/per week, and U.S. servicemen in Afghanistan had an attack rate of 52 cases/1,000 persons.3,5
We suspect that the markedly higher attack rate in our cohort and the decrease in time to contract disease and time to onset of symptoms were a reflection of high local transmission intensity and the minimal use of malaria preventative measures.
Five Marines met the World Health Organization criteria for the definition of complicated malaria with parasitemia levels ranging from 2% to 17% combined with pulmonary and/or cerebral complications ().29
All five required monitoring in an intensive care unit, mechanical ventilation (range = 4–9 days), and vasopressor support. The remaining 39 Marines with uncomplicated malaria were treated with atovaquone/proguanil per guidelines of the Centers for Disease Control and Prevention.30
All 44 showed complete recoveries.
Fever and headache were the most common initial symptoms in this cohort. Loose stools, a less frequently recognized but common symptom of P. falciparium
infection, were observed in 62% of the Marines.25
Of interest, severe diarrhea was a prominent initial symptom among several of the first Marines in which illness developed. This symptom misled shipboard physicians to initially diagnose them with travelers' diarrhea and treat then empirically with ciprofloxacin while their conditions continued to worsen. In retrospect, the failure to recognize diarrhea as a symptom of malaria led to a delay in diagnosis and prompt initiation of correct treatment.
The use of malaria rapid testing (NOW ICT test) proved to be essential in expeditiously evaluating the first 32 Marines who arrived at NNMC.15
Because rapid test kits offer speed and accuracy when compared with traditional microscopy, these tests are critical in making a timely diagnosis of malaria in resource-limited environments or in the setting of an outbreak of a febrile illness in travelers returning from the tropics. As a case in point, in the chaotic setting of preparing and reading blood smears for the first 32 Marines arriving at NNMC, one patient was originally reported as having a negative thin blood smear although the results of the NOW ICT test were positive. After further review of the thin blood smear, P. falciparum
malaria was confirmed.15
This outbreak of malaria was the result of inadequate use of personal protective measures and poor adherence with chemoprophylaxis. The use of topical insect repellents, permethrin-treated clothing, and bed nets are effective measures in decreasing malaria transmission and have been incorporated into military deployment doctrine.31–33
However, because of the urgency of the deployment, bed nets were not brought ashore. Despite receiving a preventive medicine brief, less than half of the Marines consistently used insect repellent. Permethrin was not frequently used because shipboard stocks had been depleted by treatment of desert uniforms used in Iraq and Djibouti, whereas jungle uniforms were required for Liberia. Reviewing factors associated with poor adherence to personal protective measures highlights the challenges of rapidly deploying large numbers of troops in a short period.
According to White, antimalarial drug failures result from four main host and parasite factors; compliance (or adherence), pharmacokinetics, pharmacodynamics, and resistance.7
Good adherence to chemoprophylaxis prevents infection with malaria.18
Contrary to standard U.S. Navy/Marine Corps procedures, Marines were issued MQ without an established plan for DOT, which undoubtedly contributed to only a 55% self-reported adherence rate.34
Of note, the only explanation reported for missed doses was forgetfulness and not a concern about the highly publicized neuropsychiatric side effects related to MQ (this deployment occurred one year after reports of severe adverse events in soldiers that were initially linked to MQ).35
The adherence rate to chemoprophylaxis in our cohort was similar to that noted in U.S. servicemen infected with malaria after deployments to Somalia and Afghanistan.3–5
To explain such poor adherence, it is important to note that these Marines were issued MQ while deployed in Iraq and Djibouti in the months before deployment to Liberia and, regardless of adherence in those settings, malaria did not develop in any of them. Poor adherence in regions with low transmission intensity often has no negative consequences, which may have led the Marines to believe that malaria preventative measures in general are unnecessary. This outbreak accentuates the challenge military and civilian providers face when determining the true need for chemoprophylaxis because malaria transmission intensity varies significantly throughout the world. In addition, it emphasizes the importance of DOT in an operational setting.
Barriers to attaining serum MQ levels high enough to kill blood-stage parasites include poor absorption because of vomiting and increased clearance secondary to diarrhea (an interruption in enterohepatic cycling leads to increased clearance).7
Although several Marines had loose stools as an initial symptom, none had gastrointestinal symptoms before becoming ill, which suggests that altered absorption (or pharmacokinetics of MQ) and resultant decreased serum levels were factors in this outbreak.
Low serum levels may have resulted from deficiencies in the MQ tablets. However, at the time of admission, all blister packs examined were intact and none had exceeded the stamped expiration date. Although most Marines carried the tested MQ in their pockets for several weeks under a variety of climactic conditions (desert, ship board, and jungle environments), we found no evidence to suggest that a lack of drug potency or bioavailability contributed to low serum MQ levels. In addition, each of the five tablets tested met the FDA recommended dissolution criteria established for MQ hydrochloride.
Finally, despite the FDA-approved regimen of taking MQ at least one week before entering a malarious area, it can take up to 7–9 weeks to reach protective serum concentrations.36
However, an inadequate lead time was not an explanation for subtheraputic levels because these Marines had been issued MQ for their brief deployment in Djibouti at least a month before entering Liberia. Because MQ regimens also require taking the drug for four weeks after leaving the malarious area, if the Marines were adherent with their chemoprophylaxis, they should have had protective levels upon arriving in Liberia. Consequently, it appears that low serum MQ levels in these Marines were unlikely to be a reflection of a pharmacokinetic problem and most likely resulted from inadequate adherence with weekly dosing.
A drug-resistant strain of P. falciparum
could have altered the expected efficacy of MQ and been responsible for breakthroughs of prophylaxis. Occasional breakthroughs in non-immune travelers with therapeutic serum levels of MQ have been reported from sub-Saharan Africa, including west Africa.37–39
Although MQ is not widely used in west Africa, halofantrine, a structurally related drug, is widely available and used for treatment of persons with acute P. falciparum
Resistance to halofantrine may confer cross-resistance to MQ in vitro
and in vivo
Confirmation of emerging drug resistance relies on four pillars of proof: molecular markers, confirmatory drug levels, elevated IC50
, and known clinical outcome (not reinfection). In vitro
susceptibility measures the ability of a drug to inhibit the replication of asexual parasites and is often reported as an IC50
. The IC50
values for MQ in strains from west Africa are often higher than other strains worldwide (this had been reported before FDA approval and use of MQ), which suggests that MQ resistance could have contributed to this outbreak.37
Specimens sent for laboratory analysis of MQ levels and for drug susceptibility testing were blinded with regard to clinical symptoms and other laboratory data. Although one parasite in this cohort had an IC50 two-fold more resistant than a control clone from west Africa (Sierra Leone), all isolates were sensitive (IC50 < 45 ng/mL) to MQ, and molecular markers for amplification of the pfmdr1 gene showed no unusual results. On the basis of these findings, we conclude that a MQ-resistant strain of P. falciparum was not responsible for this outbreak.
Several important limitations of our outbreak investigation must be considered. First, we report a case series of patients who were evacuated from ships off the coast of Africa to military hospitals. These ships had rudimentary laboratory capacity and limited medical expertise aboard. As a result, we were unable to obtain clinical, laboratory, or epidemiologic data from Marines who remained healthy. Ideally, a case–control study may have increased the power of our conclusions.
Second, only 14 (32%) of the 44 Marines (and 18% of the 80 Marines with febrile illness) were confirmed to have malaria by blood smear. We speculate that the broad-based initiation of empiric antimalarial therapy for febrile Marines while still shipboard (and 1–2 days before at Landstuhl or Bethesda where definitive testing was performed) is the most likely explanation for the low number of confirmed cases of malaria. We acknowledge that there would be a clearer sense of the true incidence of malaria in our cohort if peripheral blood smears were made for all febrile Marines before initiation of therapy and were available for review by expert microscopists.
When considering this second limitation, it is important to note that this outbreak was remarkable for the simultaneous presentation of 80 febrile patients, several of whom were critically ill, on a ship at sea. In light of this situation, once malaria was diagnosed in the initial patients who sought treatment, broad-based empiric antimalarial treatment was initiated to prevent further morbidity, and possible mortality, in this cohort of non-immune persons. Although we presume that all febrile patients had malaria, some Marines with negative blood smears could have been infected with another infectious disease endemic to Liberia such as leptospirosis, a rickettsial illness (that responded to doxycycline), or self-limiting gastroenteritis.
Third, adherence rates to malaria preventative measures were self-reported and based on a non-anonymous questionnaire, which raises questions concerning the true validity of marine responses. We suspect compliance with malaria preventative measures may have been even lower than reported because some Marines may have overestimated their adherence for fear of administrative sanctions.
As seen in the past, this most recent outbreak of malaria in military members resulted from poor adherence with personal protective measures and chemoprophylaxis. In the current political climate, we must assume that U.S. servicemen will be called on again to deploy to regions of the world in which malaria is endemic. Clearly, military members and their leadership must ensure that malaria prevention measures are viewed as equally importantly as other key elements of deployment, e.g., supplies and communications. Additionally, chemoprophylaxis should be given by DOT and, as advocated by Lieutenant General William Slim after witnessing the effects of malaria on British soldiers in World War II, leadership must be held accountable when servicemen do not adhere to DOT.41
Pre-travel discussions with all travelers should address differences in malaria transmission intensity in various regions of the world to guard against complacency with preventive measures and pill fatigue. Providers should use rapid diagnostic tests (e.g., NOW ICT test) and have a low threshold to initiate empiric treatment of malaria when evaluating a febrile patient returning from a tropical environment.
Ultimately, the development of new chemoprophylactic agents and an effective malaria vaccine will aid in the prevention of malaria in all travelers at risk, military and civilian alike. Until then, for the next precipitous deployment into a high transmission area, such as these Marines experienced in Liberia, the use of a drug that is dosed weekly, can take up to 7–9 weeks to achieve protective concentrations, and requires four weeks of post-exposure dosing is clearly suboptimal. Loading-dose regimens of MQ achieve protective drug levels in four days, but using MQ in this manner is not FDA approved.36
Although clearly supported by the peer-reviewed medical literature, Department of Defense policy does not permit the U.S. military to use medical products in a manner that is not FDA approved.42
Therefore, prescribing a loading dose of MQ cannot be used operationally by the U.S. military.42
The use of chemoprophylactic drugs such as atovaquone/proguanil or doxycycline, which provide protection after the first dose, would offer more rapidly attainable malaria chemoprophylaxis in deployment circumstances such as those encountered by the 26th Marine Expeditionary Unit.