An Outbreak of Malaria in US Army Rangers Returning From Afghanistan FREE

War and conflict have had a long historical partnership with malarial outbreaks.^1- 7 Disruptions in health care infrastructure, displacement and cross-border movement of civilian populations, invasion and maneuver of numerous military personnel, and exposure of individuals with nominal or no immunity all bring about an increased risk for the disease. Throughout history, disease and nonbattle injuries have caused more casualties than combat action among military personnel, with malaria having a significant impact on many military operations.^6- 8

Since 1995, military clinicians have reported an average of 42 cases of malaria per year in US soldiers,⁹ with the majority of these cases acquired while serving in the Republic of Korea. Although this incidence rate and the epidemiological pattern have been relatively stable over the past decade, outbreaks associated with an increase in the number of military troops deployed to malarial areas have occurred and may continue to account for an increase in malaria cases imported into the United States.¹⁰

Malaria is endemic to more than 100 countries and territories worldwide and is predominantly found in the tropic and subtropic regions. More than 90% of malaria cases occur on the African continent, with the remainder concentrated in parts of the Pacific, Latin America, and Asia.^11- 12

Most US soldiers currently deployed in war zones are in Afghanistan or Iraq where malaria transmission is seasonal and varies geographically. While Plasmodium vivax historically accounts for 80% to 90% of indigenous cases in Afghanistan and 95% of cases in Iraq, with Plasmodium falciparum causing the majority of the remaining cases,^13- 14 these numbers are likely to be inaccurate due to unreliable reporting in recent years from these war-torn areas.

The US Army directs soldiers operating in these areas to consume antimalaria chemoprophylaxis and use personal protective measures, to include minimizing exposed skin through proper wear of the uniform and use of bed nets, impregnating uniforms and bed nets with permethrin, and frequently applying topical insect repellent (33% diethyltoluamide [DEET]) to exposed skin.⁸ Although bed nets are an integral component of this directive, front-line soldiers, like those described in this study, may be afforded only limited protection through this measure because nighttime patrols and vigilance during dusk and dawn (when mosquitoes are prevalent) often preclude their intended use.

We analyzed patient information stored in an electronic database that was created and maintained by Ranger Regiment medical personnel. As the primary care clinicians, the authors collected data during the evaluation, treatment, and follow-up periods to track trends and provide comprehensive and concurrent updates to the commanders of Rangers who had contracted malaria. Additionally, in July 2003, a retrospective anonymous survey designed by the US Army Center for Health Promotion and Preventive Medicine was conducted among the 725 soldiers in the task force following the deployment to ascertain self-reported compliance with malaria countermeasures. Because the survey was anonymous and administered before the detection of all 38 malaria cases it was not possible to accurately examine noncompliance with preventive measures and other potential risk factors in the context of the disease outcome.

Both the clinical case review and survey portions of this study were initially conducted as a public health investigation to protect US military personnel from disease. The authors obtained approval to conduct a retrospective review of the data from the institutional review board at the University of Texas Medical Branch, Galveston; and the Uniformed Services University of the Health Sciences, Bethesda, Md. Patient identifiers and protected health information remained confidential throughout the conduct of the study, and participation in the survey was not mandatory.

The exposed population consisted of 725 personnel assigned or attached to the 75th Ranger Regiment, Fort Benning, Ga, which had deployed and conducted operations in eastern Afghanistan from June through September 2002. In addition to standard personal protective measures, antimalaria chemoprophylaxis prescribed to soldiers for this deployment consisted of weekly 250-mg mefloquine tablets ingested from 2 weeks predeployment through 4 weeks postdeployment, and daily 15-mg primaquine tablets ingested during the first 2 weeks of the 4-week postdeployment period. The entire task force was tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency before the initiation of primaquine, with no affected individuals noted.

The attending medical officers made the initial diagnosis of malaria based on clinical signs and symptoms and confirmed each case through demonstration of malaria parasite stages in red blood cells, according to the case definition from the US Centers for Disease Control and Prevention (CDC).¹⁵ Laboratory personnel at either the 339th Combat Support Hospital in Afghanistan or Martin Army Community Hospital at Fort Benning prepared blood smears and microscopically visualized parasitemia.

Statistical analysis of noncompliance data was performed using SPSS version 11.0 (SPSS Inc, Chicago, Ill). Odds ratios (ORs) and 95% confidence intervals (CIs) were generated. Two-sided Pearson χ² or Fisher exact estimates were used as needed; results were considered significant at the P<.05 level.

Thirty-eight active-duty men from the 725-man Ranger Task Force contracted malaria while operating at 2 particular forward-operating bases located in eastern Afghanistan, resulting in an observed attack rate of 52.4 cases per 1000 soldiers. Nearly all patients presented with fever, with many also reporting additional symptoms including chills, headache, nausea, or myalgias. Diagnosis was confirmed a median of 233 days (range, 1-339 days) after returning from the area of operations. The mean age at time of diagnosis was 21 years (range, 19-39 years). All cases were infected with P vivax. Two cases relapsed and were treated again at 459 and 508 days, respectively, after the end of the deployment (or 179 and 266 days, respectively, following initial diagnosis and treatment). A 17-day treatment regimen was prescribed to all patients and consisted of chloroquine, 600 mg on day 1 and 300 mg on days 2 and 3, and primaquine, 15 mg on days 4 through 17.

A complete blood cell count was available for 31 of the 38 patients (82%). Most patients had evidence of mild to moderate anemia (28/31 cases, with a hematocrit less than 42.0%) and thrombocytopenia (26/31 cases, with a platelet count less than 150 × 10³/μL). The median and range of each blood count parameter was as follows: white blood cells, 5.4 × 10³/μL (range, 2.3-15.4 × 10³/μL); red blood cells, 4.6 × 10⁶/μL (range, 3.7-6.2 × 10⁶/μL); hemoglobin, 13.5 g/dL (range, 10.2-15.6 g/dL); hematocrit, 38.6% (range, 30.5%-43.6%); normal mean corpuscular volume, 84 μm³ (range, 67.0-92.7 μm³); and platelets, 109 × 10³/μL (range, 40-308 × 10³/μL).

One case was complicated with acute respiratory distress syndrome (ARDS) during the primary attack, manifesting with bilateral diffuse pulmonary infiltrates and hypoxemia as evidenced by a PaO₂/FIO₂ ratio of less than 150 mm Hg. Initially treated with bilevel positive airway pressure, this patient’s condition progressively worsened, necessitating endotracheal intubation, high-frequency mechanical ventilation, and bilateral tube thoracostomies. Following discharge and recovery, this patient incurred a malarial relapse 6 months later that resulted in hospitalization complicated by a spontaneous pneumothorax and treated with a tube thoracostomy. Microscopic testing showed no evidence of coinfection with P falciparum on serial blood smears performed during both hospitalizations. This case accounted for 1 of the 2 relapse cases that occurred in the study population. The second patient experienced relapse 9 months after his initial episode but did not incur complications.

From the task force, 521 of 725 soldiers (72%) responded to the postdeployment compliance survey. Nonresponse was due to an additional deployment of part of the task force during the time of the survey, absence of some individuals due to other commitments, and also due to several individuals who elected not to respond. All respondents were male, 371 (71%) were younger than 25 years, and 318 (61%) were junior-ranking enlisted soldiers.

Among respondents, 443 (85%) indicated they had deployed to Afghanistan. Within this subgroup 222 of 430 respondents (52%) indicated that they had fully complied with weekly chemoprophylaxis while in Afghanistan; 176 of 425 (41%) reported full compliance with terminal prophylaxis; and 132 of 425 (31%) reported full compliance with both chemoprophylaxis regimens. Twenty soldiers were known to have contracted malaria at the time the survey was conducted. The corresponding compliance among those who responded to the survey was 6 of 17 (35%) recalling full compliance with weekly prophylaxis, 6 of 16 (38%) recalling full compliance with terminal prophylaxis, and 3 of 16 (19%) claiming full compliance with both.

Only 28 of 438 respondents (6%), as well as 1 of 17 respondents (6%) known to have contracted malaria, claimed to have had adverse effects that prevented them from complying with antimalarial measures. When asked if it was “hard to keep up with pills because too many other things were happening,” 235 of 437 (54%) responded yes. In contrast, 15 of 17 (88%) who had been diagnosed with malaria responded yes to this question.

Self-reported presence of adverse effects and difficulty keeping up with pills were associated with noncompliance with mefloquine (OR, 2.9; 95% CI, 1.2-7.2 and OR, 2.5; 95% CI, 1.6-3.7, respectively) and primaquine (OR, 2.6; 95% CI, 1.1-8.1 and OR, 1.9; 95% CI, 1.2-2.8, respectively). Additionally, a perceived lack of a mosquito problem was associated with noncompliance with both mefloquine and primaquine (OR, 1.7; 95% CI, 1.1-2.6 and OR, 1.7; 95% CI, 1.1-2.8, respectively).

With regard to personal protection against mosquitoes, 361 of 439 soldiers (82%) stated compliance with treating uniforms with permethrin while deployed in Afghanistan, while only 126 of 439 soldiers (29%) reported compliance with the use of insect repellent. Corresponding numbers among those known to have contracted malaria were 16 of 17 (94%) reporting compliance with uniform treatment and 6 of 17 (35%) reporting regular DEET use. Fewer than half of all respondents (172/440 [39%]), but more than half of known malaria patients (10/17 [59%]), recalled being bitten by mosquitoes while deployed in Afghanistan. Soldiers with this reported exposure were significantly more likely to report using both permethrin (OR, 2.3; 95% CI, 1.3-4.2) and DEET (OR, 2.0; 95% CI, 1.3-3.1).

Since September 2001, the US Army 75th Ranger Regiment has conducted multiple deployments to both Afghanistan and Iraq. This outbreak of malaria in a Ranger Task Force appears to be related to an exposure that occurred while conducting operations in eastern Afghanistan during the summer of 2002. The transmission rate, incubation of illness, and incidence of relapse are consistent with historical norms for P vivax contracted during the typical season of this region.^13- 14

On day 169 after returning from Afghanistan, the majority of soldiers from the studied task force deployed again to conduct combat operations in Iraq. Attrition from illness, injury, training, and transfers accounted for turnover and replacement of a minor portion of the task force during and between deployments. Daily 100-mg doxycycline was the prescribed malaria prophylaxis for the Iraq deployment for all soldiers as per US Army Central Command guidance due to the additional benefit of doxycycline in a possible biological agent attack. After 52 days, the task force returned to the United States, discontinued the doxycycline, and did not initiate a terminal prophylactic regimen because the task force had operated solely in a nonmalarial region and season while in Iraq. However, 29 of 38 cases (76%) of malaria occurred in this regiment within 123 days of their return from Iraq. Serious consideration was thus given to the possibility that Iraq may have been the source of some, if not most, of the malaria cases. The consensus among the authors, and malaria consultants from both the Army and the CDC, was that all cases were highly likely to be delayed presentations from the Afghanistan deployment (conference call between the 75th Ranger Regiment, Martin Army Community Hospital, the US Army Special Operations Command, the US Army Southeast Regional Medical Command, the US Army Center for Health Promotion and Prevention, and the Centers for Disease Control and Prevention; May 16, 2003).

Factors that contributed to this conclusion were that (1) all documented cases had deployed to either one or both of the 2 particular forward-operating bases in eastern Afghanistan during the summer of 2002; (2) 5 of 38 cases (13.2%) had not deployed to Iraq; (3) there were no cases in individuals who had deployed solely to Iraq and not Afghanistan; (4) the Iraq deployment region and season were not favorable for malaria; and (5) no vectors were noted in the operational area during the Iraq deployment. Also, due to suboptimal compliance with primaquine terminal prophylaxis after the Afghanistan deployment, individuals most likely did not eliminate the hypnozoites. The doxycycline provided in Iraq then suppressed any possible blood-stage malaria until the soldiers returned to the United States. After the soldiers discontinued doxycycline, merozoites could emerge and cause clinical disease.^16- 17 Even without suppression of malaria during the deployment to Iraq (for example, in those who did not comply with doxycycline), the delay seen in presentation of clinical malaria is typical of P vivax disease from Central Asia.

In this study, the self-reported compliance rate with terminal chemoprophylaxis was 41%. Although this compliance rate is suboptimal, it is consistent with the 30% reported by Barrett et al¹ for soldiers returning from Vietnam and the 56% reported by Newton et al⁵ for US Marines in Somalia. Although assigned medical personnel provided a detailed medical threat brief and instituted appropriate malaria preventive measures before and during the deployment, leaders did not consistently observe the application of these countermeasures. Gambel et al¹⁸ reviewed the use of personal preventive measures, to include application of topical insect repellents and permethrin treatment of clothing and netting, among deployed personnel. Their study demonstrated that deployed soldiers do not understand the use of these measures and as a result fail to use them properly, if at all.

A prominent feature of P vivax infection is the persistence of exoerythrocytic bodies in the liver that can result in relapses occurring over many years. This case series included 2 relapse cases. Based on cited incubation periods, the potential to diagnose other initial cases from the task force has diminished as of this date. However, latent infections may still be present in this group if initially asymptomatic or if misdiagnosed as other diseases with similar symptoms. Relapse cases are possible at irregular intervals for up to 5 years and should be vigilantly anticipated.¹⁹

One observation in this case series that is not consistent with the typical course of vivax malaria is that one patient had significant pulmonary complications. This patient incurred a prolonged hospitalization secondary to ARDS and later experienced a malaria relapse complicated by a spontaneous pneumothorax. Although ARDS has been noted to occur with P vivax infection,^20- 23 complications including ARDS are anticipated to occur more frequently during P falciparum infection. Organ damage rarely occurs with P vivax infection because the parasite’s asexual stages circulate in the peripheral blood without sequestration and microvascular insult.²⁰

The terminal prophylactic dose of primaquine prescribed on the soldiers’ return from Afghanistan, 15 mg/d for 2 weeks, is the current efficacy-based US Food and Drug Administration approved regimen.²⁴ However, the effectiveness of this dose and the potential for parasitic resistance to the drug have been debated in the medical literature.^24- 25 Following the trends for effectiveness, the CDC currently recommends a higher dose of primaquine, 30 mg/d for 2 weeks, for individuals who travel to areas with known P vivax transmission.^24- 27 However, this dose may pose a higher risk for potentially serious hemolysis.²⁸ All US military services currently have policies in place for testing personnel for G6PD deficiency. As such, the appropriate prescribed dose for primaquine should be based on clinical judgment specific to each patient, taking into consideration the patient’s P vivax exposure and G6PD status, as well as demographics.

A number of factors limited the power and generalizability of this assessment. In particular, this is essentially a case series and, hence, one of the least powerful and generalizable types of studies. Because the population reported herein obtains health care as a cohort, case finding and ascertainment were quite complete, but neither the entire population at risk nor a random sample constituted the survey population. Also, due to the variable latency of vivax malaria, cases continued to be identified after administration of the survey instrument; because the survey was anonymous it was not possible to reclassify new incident cases of malaria. Partly compensating for this in risk factor comparisons are the probability that the resulting bias is toward the null and there was a substantially high ratio between noncases and cases. Still, a true case-control or case-cohort study was not achievable. Finally, any possible failure of chemoprophylaxis was not verified by clinical tests such as drug metabolite screening, so no definitive conclusions could be drawn in this regard.

A major cause of malaria prophylaxis failure is patient nonadherence to prescribed treatment. Providing continuous education about the need to comply with prophylaxis medications and having leaders directly observe therapy and enforce personal protective measures may help safeguard soldiers from vector-borne disease. Additionally, US military and civilian clinicians need to consider malaria in the differential diagnosis for military personnel who return from a malaria-endemic region and present with fever or an otherwise indistinct illness.