Kotwal RS, Wenzel RB, Sterling RA, Porter WD, Jordan NN, Petruccelli BP. An Outbreak of Malaria in US Army Rangers Returning From Afghanistan. JAMA. 2005;293(2):212-216. doi:10.1001/jama.293.2.212
Author Affiliations: Army-Navy Aerospace Medicine
Residency, Naval Operational Medicine Institute, Pensacola, Fla (Dr Kotwal);
Department of Preventive Medicine, University of Texas Medical Branch, Galveston
(Dr Kotwal); Department of Military and Emergency Medicine, Uniformed Services
University of the Health Sciences, Bethesda, Md (Drs Kotwal and Wenzel); Regimental
Surgeon (Dr Wenzel) and Battalion Physician Assistant (Mr Sterling), 75th
Ranger Regiment, Fort Benning, Ga; Division Preventive Medicine Officer, 1st
Cavalry Division, Fort Hood, Tex (Dr Porter); and Epidemiology and Disease
Surveillance, US Army Center for Health Promotion and Preventive Medicine,
Aberdeen Proving Ground, Md (Ms Jordan and Dr Petruccelli). Dr Kotwal was
formerly Battalion Surgeon, 75th Ranger Regiment, Fort Benning, Ga.
Context With numerous US military personnel currently deployed throughout the
world, military and civilian health care professionals may encounter imported
malaria from this population.
Objective To identify malaria in US Army personnel deployed to a combat zone.
Design, Setting, and Patients Case series in the US Army health care system. A total of 38 cases of
malaria were identified in a 725-man Ranger Task Force that deployed to eastern
Afghanistan between June and September 2002.
Main Outcome Measures Identification of malaria cases and soldiers’ self-report of compliance
with antimalarial measures.
Results A total of 38 patients were infected with Plasmodium
vivax, yielding an attack rate of 52.4 cases per 1000 soldiers. Diagnosis
was confirmed a median of 233 days (range, 1-339 days) after return from the
malaria endemic region, with additional laboratory findings noting anemia
and thrombocytopenia. One case was complicated with acute respiratory distress
syndrome during the patient’s primary attack and a spontaneous pneumothorax
during relapse. This case accounted for 1 of 2 relapse cases in the study
population. From an anonymous postdeployment survey of 72% (521/725) of the
task force, the self-reported compliance rate was 52% for weekly chemoprophylaxis,
41% for terminal (postdeployment) chemoprophylaxis, 31% for both weekly and
terminal chemoprophylaxis, 82% for treating uniforms with permethrin, and
29% for application of insect repellent.
Conclusions Delayed clinical presentation can occur with P vivax. Symptoms are often vague, but malaria should be included in the differential
diagnosis for soldiers returning from an endemic region. Suboptimal compliance
with preventive measures can result in a malaria outbreak.
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
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
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
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
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
Corresponding Author: Russ S. Kotwal, MD,
MPH, Army-Navy Aerospace Medicine Residency, Naval Operational Medicine Institute,
Pensacola, FL 32508 (email@example.com).
Author Contributions: Drs Kotwal, Wenzel, and
Petruccelli had full access to all of the data in the study and take responsibility
for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Kotwal, Wenzel, Petruccelli.
Acquisition of data: Kotwal, Wenzel, Sterling,
Analysis and interpretation of data: Kotwal,
Wenzel, Porter, Jordan, Petruccelli.
Drafting of the manuscript: Kotwal, Wenzel.
Critical revision of the manuscript for important
intellectual content: Kotwal, Wenzel, Sterling, Porter, Jordan, Petruccelli.
Statistical analysis: Kotwal, Sterling, Porter,
Administrative, technical, or material support:
Kotwal, Wenzel, Jordan, Petruccelli.
Study supervision: Kotwal, Petruccelli.
Funding/Support: No outside funding or support
was received for this study.
Role of the Sponsor: The study design and conduct,
data collection and management, data analysis and interpretation, and manuscript
preparation and review were conducted solely by the authors. Approval to release
the manuscript was obtained through Headquarters, 75th Ranger Regiment and
the US Army Special Operations Command.
Disclaimer: The views, opinions, and/or findings
contained in this report are those of the authors and should not be construed
as official US Department of the Army or Department of Defense position, policy,
or decision, unless so designated by other official documentation.