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Malaria among United States troops in Somalia
Malaria Among United States Troops in Somalia Mark R. Wallace, MD, San Diego, California, Trueman W. Sharp, MD, MPH, Bethesda, Maryland, Bonnie Smoak, MD, PhD, MPH, Washington, DC, Craig Iriye, MD, Oakland, California, Patrick Rozmajzl, MS, Naples, Italy, Scott A. Thornton, MS, Bethesda, Maryland, Roger Batchelor, PhD, Cairo, Egypt, Alan J. Magill, MD, Washington, DC, Hans O. Lobel, MD, Atlanta, Georgia, Charles F. Longer, MD, Washington, DC, James P. Burans, PhD, Bethesda, Maryland PURPOSE:United States military personnel deployed to Somalia were at risk for malaria, including chloroquine-resistant Plasmodium falciparum malaria. This report details laboratory, clinical, preventive, and therapeutic aspects of malaria in this cohort. PATIENTSAND METHODS:The study took place in US military field hospitals in Somalia, with US troops deployed to Somalia between December 1992 and May 1993. Centralized clinical care and country-wide disease surveillance facilitated standardized laboratory diagnosis, clinical records, epidemiologic studies, and assessment of chemoprophylactic efficacy. RESULTS:Forty-eight cases of malaria occurred among US troops while in Somalia; 41 of these cases were P falciparum. Risk factors associated with malaria included: noncompliance with recommended chemoprophylaxis (odds ratio [OR] 2.4); failure to use bed nets (OR 2.6); and failure to keep sleeves rolled down (OR 2.2). Some patients developed malaria in spite of mefloquine (n = 8) or doxycycline (n = 5) levels compatible with chemoprophylactic compliance. Five mefloquine failures had both serum levels _>650 ng/mL and metabolite:mefloquine ratios over 2, indicating chemoprophylactic failure. All cases were successfully treated, including 1 patient who developed cerebral malaria. CONCLUSIONS:P falciparum malaria attack rates were substantial in the first several weeks of From the Departments of Internal Medicine (Infectious Disease Division) and Clinical Investigation (MRW), Naval Medical Center, San Diego, California; Naval Medical Research Institute (TWS, SAT, JPB), Bethesda, Maryland; Walter Reed Army Institute of Research (BS, AJM, CFL), Washington, DC; Naval Medical Center (Cl), Oakland, California; Navy Environmental and Preventive Medicine Unit #7 (PR), Naples, Italy; Naval Medical Research Unit #3 (RB), Cairo, Egypt; and United States Center for Disease Control (HOL), Atlanta, Georgia. This report was sponsored by the Chief, Bureau of Medicine and Surgery, Navy Department, Washington, DC, Clinical Investigation Program #84-16-1968493, as required by HSETCINST.6000.41A. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government. Requests for reprints should be addressed to CDR M. R. Wallace, MC, USN, c/o Clinical Investigation Department, Naval Medical Center, San Diego, California 92134-5000. Manuscript submitted September 16, 1994 and accepted in revised form June 6, 1995.
Operation Restore Hope. While most cases occurred because of noncompliance with personal protective measures or chemoprophylaxis, both mefloquine and doxycycline chemoprophylactic failures occurred. Military or civilian travelers to East Africa must be scrupulous in their attention to both chemoprophylaxis and personal protection measures. alaria has had a profound impact on military campaigns throughout history, including US forces operating in malarious areas in both World War H and the Vietnam conflict.~ Modem military operations in malarious regions must contend with drug resistance, suboptimal chemoprophylaxis compliance, and difficulties inherent in using personal protection measures such as bed nets, insect repellents, and long-sleeved uniforms. During the planning of Operation Restore Hope, malaria was recognized as a substantial threat to the more than 30,000 US troops who eventually deployed to support the humanitarian relief effort in Somalia. ~4 Both Plasmodium falciparum and Phhsmodium vivax malaria were known to be endemic in Somalia (with the possible exception of the capital city of Mogadishu), and chloroquine resistance had been reported. 2 The effectiveness of other malarial chemoprophylactic agents (doxycycline and mefloquine) was unknown. The presence of many other febrile illnesses in the area, which could mimic the clinical presentation of malaria, posed diagnostic problems for field medical personnel. In response to the malaria threat, comprehensive operational policies emphasizing malaria chemoprophylaxis and personal protective measures were instituted. In addition, an infectious disease control team consisting of infectious disease physicians, microbiologists, and epidemiologists was sent to Somalia to identify, investigate, and manage infectious diseases as they occurred. This report describes epidemiologic, clinical, and laboratory aspects of all confirmed cases of malaria that occurred among US troops stationed In Somalia between December 9, 1992, at the start of the operation, up to May 4, 1993, when operations were transferred to the United Nations.
M
PATIENTS AND METHODS United States mih'tary personnel in Somalia with fever (_>38.5°C) and no obvious focal source of infecJanuary 1996 The American Journal of Medicine ® Volume 100
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tion were evaluated for malaria at one of two field hospitals in Mogadishu or occasionally on offshore US Navy ships. Health care proxaders were briefed extensively on the importance of early diagnosis of malaria; rapid transportation was available to the field hospitals by ground or air (within 12 hours). All but 2 confirmed malaria cases occurring in the country were diagnosed and cared for at the US Marines 1st Medical Battalion Field Hospital in Mogadishu (December 15, 1992 through January 18, 1993) or at the US Army 86th Evacuation Hospital at the Mogadishu Airport (January 18 through May 4, 1993). The other cases were diagnosed and treated on ships. All the malaria cases at the field hospitals were cared for by one of three infectious-disease physicians (MRW, CFL, AJM) who prospectively compiled data on each patient's presentation, use of chemoprophylaxis, clinical course, and response to therapy. L a b o r a t o r y Evaluations Febrile patients (n = 389) had thick and thin malaria smears performed as part of their evaluation; initially negative patients without an apparent sottrce of fever had repeat smears done 2 to 3 times per day until a diagnosis was established or their fevers and symptoms spontaneously resolved. Rapid diagnosis of malaria was also attempted in 280 consecutive patients using a fluorescent quantitative buffy-coat (QBC) technique (Becton Dickinson; Baltimore, Maryland) with a × 100 research quality fluorescence nticroscope. 5,6 Malaria patients admitted to one of the field hospitals had serum obtained for determination of antimalarial drug levels. White blood cell (WBC) count, hematocrit, and platelet count were determined by standard techniques. Following initiation of therapy, malaria parasitemia was quantitated twice daily until no parasites were detected in two consecutive specimens. Serum doxycycline levels were measured by a standard bioassay (Microbiology Reference Laboratory; Cypress, California). Serum mefloqume levels were performed at the US Centers for Disease Control and Prevention by high-performance liquid chromatography. 7 Epidemiology All 389 febrile patients cared for at the field hospitals were interviewed by an ep.jdemiologist (TWS, BS) using a standardized questionnaire to ascertain exposure history and compliance with personal preventive measures and chemoprophylaxis. Because 38% of cases of malaria diagnosed in Somalia came from one location near the Jubba River (Baardera), a unit of Marines stationed there (n = 530) was administered a confidential, self-completed questionnaire prior to leaving Somalia to ascertain information on exposures and compliance with malaria prevention recommendations. This unit arrived in late 50
December and remained in Baardera for approximately 5 weeks; they then moved to the Mogadishu area for 3 weeks prior to leaving for the United States. While in Baardera, troops were billeted approximately 1 mile from the river; some of the unit had to man guardposts overnight along the river. The field conditions and threat of armed confrontation at these riverine posts made compliance with personal protective measures difficult. This unit took daily doxycycline prophylaxis until January 15, 1993, when more than 95% switched to weekly mefloquine. All US personnel were given either doxycyclme (100 mg orally per day) or mefloquine (250 mg orally per week) beginning 1 to 2 weeks prior to arrival in Somalia as chemoprophylaxis. Mefloquine loading doses were not used. During the first 4 to 6 weeks of the operation, a roughly equal number of US troops took each chemoprophylactic agent. Subsequently, most of the doxycycline users were switched to mefloquine, and the newly arriving troops (except aircrews and some engineers) were given mefioqtfine prophylaxis. The changeover to mefloquine was done to ensure operational uniformity in chemoprophylaxis and to improve compliance. Patients switching from doxycycline did not receive a loading dose of mefloquine; about one half overlapped their doxycycline by a week, while the others discontinued doxycycline 1 day and began mefloqulne the next. Troops were provided with topical insect repellent (33% DEET in a controlled-release polymer base), bed nets, permethrin spray for uniforms and bed nets, and longsleeved uniforms; they were instaaacted and reminded from time to time in the proper use of these items. The total number of troops in Somalia taking doxycycline and mefloquine chemoprophylaxis in the first 8 weeks of Operation Restore Hope were estimated from surveillance records and retrospective interviews with senior medical personnel. Statistical Analysis Mantel-Haenszel chi-square analysis was performed using EPIINFO computer software (Centers for Disease Control, Atlanta, Georgia), and unconditional multivariate logistic regression analysis was performed using SPSS/PC Plus computer software (SPSS, Chicago, Illinois).
RESULTS Epidemiology A total of 389 febrile patients were evaluated at the field hospitals between December 15, 1992 and May 4, 1993. There were 48 documented cases of malaria among US personnel during this period. Other causes of fever included: dengue (74 confirmed cases); febrile diarrhea-(79 cases); unspecified spontaneonsly resolving fever (110 cases); and miscellaneous infec-
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Rate of Malaria Cases Per Week Operation Restore H o p e 7 7
w .
6-
o .
RATES Overall: 1.8/10,000/wk Wks 1-8: 3.0/10,000/wk Wks 9-22: 0.68/10,000/wk
5.3
.
5-
°
o °
4.
3-
2.7 2
2-
4
n
2
1.2
1.3
10
11
1• 0
Figure. Rate of malaria cases per 10,000 troops per week.
-
0 -
~
1
4
5
6
7
8
9
12
Cases per 10,000 Troops per W e e k
tions, such as celhilitis and respiratory and urinary and bed nets, and an additional 29% used it only intract infections (78 cases). The attack rate for malaria frequently. Only 41 (8%) reported complete compliclimbed rapidly during the first few weeks of the op- ance with all chemoprophylaxis and personal proteceration, reaching a peak of 7 cases per 10,000 troops tive measures; 2 of these Marines developed malaria. per week in week 5 and declining rapidly thereafter Ninety-fourpercent (n = 499) of the Marine unit from (Figure). Forty-one of these cases were Pfalciparum Baardera completed and returned a questionnaire. infection, 5 were P v/vax, and 1 was Plasmodium Thirteen (2.6%) of those surveyed developed P fa/c/ma/ar/ae; in 1 case, species was undetermined (later parum malaria while in Som~]ia_ In addition, 40 (8%) shown by PCR to be P v/vax; PCR performed by Dr. of those surveyed developed P v/vax malaria and 1 Kevin Kain, The Toronto Hospital, Toronto, Canada). (0.2%) mixed Pfalziparum-vivax subsequent m their One Marine had malaria twice (P falciparum then return to the United States.8 Risk factors for the deP v/vax). In these 48 cases, the patients had been in velopment of malaria in this group were analyzed conSomalia for a mean of 37 days (range 12 to 106) be- sidering all malaria cases using an unconditional muifore becoming ill. Twenty cases occurred after expo- tiple logistic regression analysis (Table I). Failure to sure in the southern riverine areas of Somalia, 12 ad- fully comply with chemoprophylaxis (defined as missditional cases occurred among troops who had not left ing any doses), failure to use bed nets all the time, not Mogadishu, and the rest were from various locations keeping sleeves roiled down consistently, and having throughout Somalia. All malaria patients were male; 71% (n = 34) were white. Many of the patients did not TN3LEI Risk Factors for t~e Development of Malaria perceive mosquitos to be a major Among 499 Troops in Baardera, Somalia nuisance; history taken at the time Adjusted 95% Confidence of admission revealed that 15% of Potential Odds Ratio* Interval Risk Factor the malaria patients could not recall Age 0.8 0.1-1.7 any mosquito bites, and 31% reRace (white versus nonwhite) 0.9 0.6-1.3 ported only "occasional" bites. Two Missing any chemoprophylaxis 2.4 1.7-3.0 thirds reported missing at least one Not using bed nets regularly 2.6 1.8-3.4 Junior enlisted rank 2.4 1.7-3.1 dose of their chemoprophylaxis. Failure to keep sleeves down 2.2 1.4-3.1 Forty-three percent had never used Not using permethrin spray 1.1 0.4-1.8 bed nets or used them only occaNot using topical insect repellent 1.0 0.3-1.7 sionally; 70% did not use their topiGuard duty along river >7 nights 2.2 1.6-2.9 cal insect repellent; 25% never used "Calculated using unconditional multiple logistic regression. permethrin spray on their uniforms January 1996 The American Journal of Medicine° Volume 100
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MALARIA AMONG US SOMALIA TROOPS/WALLACE ET AL TABLE II Symptoms of US Troops Diagnosed With Malaria in Somalia Symptoms Number Reporting (%) Fever 48 (100) Malaise 47 (98) Headache 46 (96) Chills 43 (90) Myalgias 40 (83) Cough 15 (31) Pharyngitis 14 (29) Diarrhea" 4 (8) "Three or more loose or watery stools per day.
been stationed overnight near the river were all independent risk factors for acquiring malaria. Clinical P r e s e n t a t i o n
A flulike illness was the presenting complaint in all but 2 patients. All patients reported subjective fever prior to admission and most noted chills, headache, malaise, and myalgias. Pharyngitis and cough were each noted by approximately one third of the cohort ( T a b l e II). The mean number of days between symptom onset and admission for evaluation of fever was 2.9. Physical examination was generally without notable findings except for fever, rigors, diaphoresis, and tachycardia. Four patients had a palpable spleen; none had a rash or hepatomegaly. All but 2 patients had a documented fever >38.3°C during their first 24 hours in hospital; the median temperature on admission was 39.3°C.
nosis which was confirmed by thick and thin smears. Two cases (4%) were negative by QBC, but positive by thick smears prepared from the same sample; a single patient was diagnosed by QBC alone. The calculated sensitivity of QBC as compared with thick smears was 95%. All parasitemias were <1% at admission. In 80% of cases, a diagnosis of malaria was made on the first sample obtained. Two patients (both with extremely low parasitemia) were not diagnosed until the third day of hospitalization. Only 2 patients were empirically treated for malaria in the field; the diagnosis was confirmed in both of these cases upon admission to the field hospital. No other cases were treated for malaria prior to a confirmed diagnosis. The admission WBC count ranged from 2,100 to 8,400/mm 3 (mean 4,880 + 1,710). The platelet count ranged from 54,000 to 285,000/mm 3 (mean 124,000 + 60,000). These values were similar to those of patients with dengue fever (mean WBC count 5,200/mm 3 and platelet count 150,000/mm3). The WBC count in shigellosis patients was consistently higher (range 5,800 to 23,700, mean ll,200/mm3); a WBC count >8,500 mm 3 helped differentiate shigeUosis from dengue or malaria (P <0.01). Treatment
Malaria was treated preferentially with quinine (650 mg orally TID for 3 days) and pyrimethamine/sulfadoxine (3 tablets as a single oral dose). Other regimens were used in selected patients with a history of sulfa allergy or other mitigating factors ( T a b l e III). The treatment was uneventful in 47 of 48 cases. Fever lasted 1 to 5 days (median 2) after initiation of therLaboratory Studies apy; chills, myalgias, and headache resolved after a All but 1 patient were proven to have malaria by median of 2 days. Serial QBC and thick malaria visualization of parasites in thick and thin malaria smears were negative by 48 hours in 60°/5of cases; no smears. In 95% of cases, QBC established the diag- patient had detectable parasites beyond day 4. Virtually all patients reported nausea, dizziness, tinnitus, and anorexia durTABLE III ing their 3-day course of quinine, but Therapy" for Malaria Cases serious toxicities therapy were not Regimen Patients Treated Rationale noted; quinine therapy was not disQuinine plus 39 Regimen of choice continued prematurely in any papyrimethamine/sulfadoxine tient. A total of 47 of the 48 patients Quinine plus doxycycline 3 Sulfa allergy returned directly to their operational Mefloquine 2 Readily available units; the median hospital stay was 8 Quinine plus clindamycin IV 2 Prophylactic doxycycline days (range 4 to 11). failures with sulfa allergy Quinidine IV plus clindamycin IV 1 Cerebral malaria Delirium d e v e l o p e d in 1 patient, Chloroquine 1 Plasmodium vivax infection progressing to o b t u n d a t i o n ap"All 5 known Plasmodium wvax infected patients received primaquine after their initial therapy. p r o x i m a t e l y 12 hours following adFour of 5 were treated with regimens usually reserved for Plasmoduim falciparum malaria bemission and institution of t h e r a p y cause of concerns about subdetectable mixed infections. Dosages were as follows: quinine 650 mg orally ~o for 3 days; pyrimethamine/sulfadoxine 3 tablets as a single oral dose; doxycyeline with oral quinine and doxycycline, 100 mg orally e,D for 7 days; mefloquine 1,250 mg as a single oral dose; clindamycin 900 mg despite a relatively low-grade paraIV every 8 hours for 3 days; quinidine as a 10-rng/kg IV load followed by 0.02 mg/kg per minute. IV = intravenous. sitemia ( u n d e r 1%). He was then treated with IV quinidine and clin52
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TABLE IV
Subject No.
Serum Mefloquine and Metabolite Levels in 13 Malaria Patients Prescribed Three Weekly Doses or Greater of Mefloquine Ratio" Mefloquine (ng/mL) Metabolite (ng/mL) Metabolite: Mefloquine
1" 1,067 4,014 2" 889 3,028 3" 851 5,366 4' 830 2,627 5' 738 1,537 6" 529 3,209 7" 329 1,291 8" 272 613 9 787 1,045 10 559 856 11 571 801 12 537 107 13 0 0 All patientsreportedfull complianceexceptsubject 13. "Primarymetabolite:mefloquineratios >-2 are consistentwith compliance. rAil mefloquinedoseswere 250 mg orallyweekly.
damycin, returning to a normal mental status after 24 hours of IV therapy. He was euglycemic throughout this episode and suffered no long-term sequelae. Chemoprophylaxis
Twenty patients developed malaria while taking doxycycline prophylaxis, 13 during mefloquine prophylaxis and 14 during or within 2 weeks after a doxycycline to mefloquine switchover. One had recently switched from mefloquine to doxycycline prior to developing malaria. The estimated attack rates dttfing the first 8 weeks of the operation for troops taking doxycycline were 4.3 cases per 10,000 exposure weeks; mefloquine rates were 0.9 cases per 10,000 exposure weeks (relative risk [RR] 4.7, 95% confidence interval [CI] 1.7 to 14.2). Attack rates for those who switched from doxycycline to mefloquine were 7.7 cases per 10,000 exposure weeks during the first 2 weeks after the switchover (compared with mefloquine, RR 7.7, CI 2.8 to 21.2). Compliance with the prescribed chemoprophylactic regimen was verified using serum mefloquine levels and serum doxycycline levels. Because most patients received mefloquine in a witnessed, compulsory setting, 12 of the 13 (92%) patients who had been taking mefloquine at least 3 weeks had measurable levels (Table IV). In 8 of these patients, the ratio of metabolite to the parent drug was >2, strongly suggesting compliance with the weekly prophylaxis, s The serum mefloquine levels of these 8 patients ranged from 272 to 1,067 ng/mL, with a mean of 688 ng/mL (2 of these patients were reported previously in a brief communication:J). Of the 20 patients purportedly taking doxycycline (not supervised), only 10 (50%) had measurable levels. Five of
3.8 3.4 6.3 3.2 2.1 6.1 3.9 2.3 1.3 1.5 1.4 0.2 0
Weeks of Regiment 8 4 8 12 6 7 6 3 5 7 5 14 Noncompliant
TABLE V Doxycycline Levels in 20 Malaria Patients Subject No. Doxycycline Level (ng/mL) 1-10 11-15 16 17 18 19 20
0 0.1 1.0 1.5 1.9 4.8 7.5
these had a level of 0.1 ng/mL, probably consistent with intermittent compliance, while the other 5 had levels of 1.0 to 7.5 ng/mL (Table V). Eight of 13 patients who had been switched from doxycycline to mefloquine within 2 weeks of their admission for malaria had measurable mefloquine levels, ranging from 52 to 881 ng/mL (mean 525), but none had a metabolite:mefloquine ratio >2. Toxic reactions to chemoprophylactic drugs requiring hospitalization were rare; only 4 of 20,000 US servicemen in Somalia from December through February were hospitalized for complications of their chemoprophylaxis. All 4 men were receiving doxycycline, and all had odynophagia with dehydration requiring hospitalization for 2 to 7 days. Minor complaints attributed to malaria chemoprophylaxis by deployed US troops were conunon. The unit of Marines stationed at Baardera is unique in that they took each chemoprophylactic agent for approximately 1 month; analysis of their questionnaires revealed that sunburn, indigestion, and dizziness occurred with equal frequency with both of the chemoprophylactic agents, whereas nightmares and insomnia were significantly more common while taking mefloquine (Table VI).
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TABLE VI Reported Side Effects of Antimalarial Chemoprophylaxis From Survey of Crossover Experience" of 499 Troops in Operation Restore Hope, Somalia, 1992 to 1993 Mefloquine Doxycycline Side Effect n (%) n (%) P Valuer Sunburn 20 (4) 24 (5) NS Gastrointestinal complaint 72 (14) 85 (17) NS Insomnia or nightmares 91 (18) 45 (9) <0.01 Dizziness 65 (13) 48 (10) NS "This cohorttook doxycycline(100 mg per day) and then changedtheir chemoprophylaxisregimen.to mefioquine(250 mg per week). tp valueswere calculatedby two-sampletestingof binomialproportions.
DISCUSSION The 48 in-country cases of malaria that occurred among US troops in Somalia during the first 6 months of Operation Restore Hope and the more than 200 c a s e s of malaria in personnel after return to the United States represent the largest US military experience with malaria since Vietnam. ~ Although Pfalciparum malaria accounted for 90°/5 of cases in Somalia, the vast majority of the cases that occurred after return to the United States had P v/vax.10 This "in-country" predominance of P falciparum followed by P v/vax c a s e s after return to the United States parallels that of the Vietnam malaria experience.H Troops deployed throughout Somalia were at risk for developing malaria, including those never leaving the previously malaria-free capital of Mogadishu. The majority of c a s e s occurred in the first 5 weeks of the deployment. Subsequent public health interventions, particularly supervised weekly mefloquine dosing, reinforcement of personal protective measures, and a withdrawal of US troops from the most malarious areas around the Jubba river, likely contributed to negligible attack rates by week 10 of the operation. The clinical presentation of malaria in the deployed troops was remarkably similar and nonspecific. Experienced physicians could not reliably identify presenting signs and symptoms of dengue, prediarrheal shigellosis, and malaria, a situation that was documented in other settJngsY Although the parasitenfias encountered in our patients were relatively low (< 1%) and occasionally undetectable at presentation, many patients had impressive systemic toxicity typical of nonimmune hosts with malaria, la The use of chemoprophylactic medications may have made the diagnosis of malaria more difficult; all patients presented with low-grade parasitemias (< 1%), w h i c h sometimes required thorough examination of b l o o d films every 8 to 12 hours for 2 to 3 days before parasites were detected. Routine hematologic testing (WBC, hematocrit, and platelet count) was not helpful in distinguishing malaria from dengue, but leukocytosis (WBC count >8,500/mm 3) did help distinguish 54
malaria and dengue from prediarrheal shigeUosis and other sporadic, less common bacterial infections (pyelonephritis, pneumonia, and so forth). Persona] protection (topical repellent, permethrinsprayed bed nets and uniforms, keeping sleeves rolled down) is undoubtedly a critical factor in minimizing malaria cases. Among the Marines in the Baardera area, who were operating in a malarious riverine area, failure to consistently use bed nets was a major risk factor for developing malaria. The use of bed nets has been shown to be an important part of malaria prevention.14 The lack of effectiveness of DEET insect repellent was probably due to widespread noncompliance owing to the sticky, dust-attracting quality of the preparation. The mefloquine and doxycycline levels of those patients who failed their chemoprophylmxis demonstrate that neither agent affords complete protection from malaria in East Africa. Earlier studies in Somalia during 1986 and 1989 showed that although chloroquine resistance was increasing in some localities, all isolates studied retained in vitro susceptibility to mefloquine. 15 Eight of our mefloquine chemoprophylactic "failures" had demonstrable serum levels consistent with compliance. The mefloquine level estimated to provide 95% effective protection against P falciparum in Africa has previously been estimated to be 641 ng/mL16; a recent survey of mefloquine prophylaxis failures in Africa defined chemoprophylactic failure as a patient developing Pfalciparum malaria in spite of a mefloquine level _>400 ng/mL and a metabolite:mefloquine ratio >_2.8 Using these two criteria, either 5 or 6 of our patients (Table IV) represent true chemoprophylactic failures. Doxycycline failures generally resulted from n o n c o m pliance or intermittent compliance, but 5 patients vigorously denied missing any doses and had confirmatory serum levels (Table V). Although recent Australian military experience confirms that doxycycline is an efficacious agent in areas of chloroquine-resistant Pfalciparum malaria, 17 breakthrough low-grade parasitemias with both P v/vax and Pfalciparum malaria have been reported in refugees on the Thai-Burmese border receiving doxycycline prophylaxis. 18 The least effective chemoprophylaxis occurred in those w h o switched from doxycycline to mefloquine. The lower mefloquine serum levels in this group (mean 525 ng/mL) and the high attack rates suggest that whenever a switchover to mefloquine is planned in a malarious area, a rapid-loading dose of mefloquine must be given to ensure adequate levels before the other agent is discontinued. Rapid-loading dosages (one 250-mg tablet daily for 3 consecutive days) have been s h o w n to result in steady-state blood c o n c e n t r a t i o n s in 3 d a y s # as compared with 7 to 9 weeks when weekly dosing is used. 2° Military personnel and other travelers to highly malarious areas who will be taldng meflo-
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quine chemoprophylaxis should either take several weekly pretravel doses or, if time does not permit, employ a rapid-loading regimen. Given that approximately equal numbers of troops were taking each chemoprophylactic agent early in the operation (primarily for logistic reasons most Marine, Navy, and Air Force personnel were receiving doxycycline while most Army units took mefloquine), an oppommity was afforded to compare these agents in terms of toxicity and effectiveness. Our analysis showed that malaria occurred approximately one fifth as often in subjects receiving mefloquine. This finding has been corroborated by a cross-sectional survey of troops stationed at a single location/1 It seems likely that the greater effectiveness of mefloquine as a prophylactic agent in Somalia resulted more from better compliance (due to its weekly dosing interval) than intrinsically superior antimalarial activity, as failures occurred at drug levels usually felt to be protective with both agents. Our survey of 499 Marines who used both agents showed that overall toxicity was minor and tolerable with both agents, but a statistically significant increase in sleep disturbances was noted during their mefloquine prophylaxis. Sleep disturbances have been reported with mefloquine therapy, ~ but the frequency and severity of these complaints remain controversial. ~ No failures were encountered with any of the treatment regimens used. Although 2 patients were treated successfully with mefloquine alone, we would recommend therapy with two drugs (quinine or quinidine plus pyrimethamine/sulfadoxine or doxycycline) that were not part of the failed chemoprophylaxis for patients with P falciparum acquired in East Africa. As pyrimethamine/sulfadoxine resistance continues to spread throughout Africa, ~4 the use of a two-drug therapeutic regimen including quinine (or quinidine) should minimize the risk of inadequate therapy. American troops operating in Somalia had a low overall rate of malaria, a major achievement given the difficult circumstances encountered. The US military experience with malaria in Somalia should, however, also serve as a cautionary note for future mih'tary and humanitarian operations in other areas where malaria transmission would be much more intense than in the Horn of Africa. Prior studies had shown that malaria was mesoendemic in the riverine areas and hypoendemic in the coastal and inland plateau areas of Somalia, with transmission being seasonal in all areas. 15,',5The occurrence of 48 cases of malaria among US troops in a previously low-risk environment, despite extensive efforts at chemoprophylaxis and personal protection, reminds us of the tenacity of this parasite. A similarly sized deployment to West Africa, Southeast Asia, or highly malarious areas of South America could expect malaria attack rates many times greater than those encountered in Somalia. Continued
efforts to develop and use improved personal protective gear, chemoprophylaxis and, most significantly, a malaria vaccine are of paramount importance.
ACKNOWLEDGMENT The a~ors thank R.K. Hanson, MD, R.F. DeFraites, MD, and J.L. Sanchez, MD for their field surveillance data and editorial review; Mike Kozar for his technical assistance in the field; Marcylin Shelton and Cecilia Cesena for their help in preparing this manuscript; and S.L. Hoffman, MD for his critical manuscript review and assistance during the Somalia deployment.
REFERENCES 1. Beadle C, Hoffman SL. History of malaria in the United States naval forces at war: World War I through the Vietnam conflict. Clin Infect Dis. 1993; 16:320-329. 2. Oldfield EC, Rodier GR, Gray GC. The endemic infectious diseases of Somalia. Clin Infect Dis. 1993; 16(suppl 3):$132-S 157. 3. Heppner DG, Magill AJ, Gasser RA, Oster CC. The threat of infectious diseases in Somalia. NEJM. 1993;382:1061-1068. 4. Laughlin LW, Legters U. Disease threats in Somalia. Am J Trop Med Hyg. 1993;48(2):6-10. 5. Rickman LS, Long GW, Oberst R, et al. Rapid diagnosis of malaria by acridine orange staining of centrifuged parasites. Lancet. 1989;1:68-71. 6. Anonymous. QBC malaria diagnosis. Lancet. 1992;339:1022-1023. Editorial. 7. Bergquist Y, Hellgren U, Churchill F. High performance liquid chromatographic assay for the simultaneous monitoring of mefloquine and its acid metabolite in biological samples using protein precipitation and ion-pair ex~action. J Chromatogr. 1988;432:253-263. 8. Lobel HO, Miani M, Eng T, Green M. Surveillanceof mefloquine prophylaxisfailures in Africa. In: Program and Abs~'acts of the 43rd Annual MeelJngof the American Society of Tropical Medicine and Hygiene.Cincinnati,Ohio: 1994. Abs~act no. 13. 9. Magill AJ, Smoak BL. Failure of mefloquine chemoprophylaxis for malaria in Somalia. NEJM. 1993;329:1206. 10. Newton JA, Schnepf GA, Wallace MR, et al. Malaria in U.S. marines returning from Somalia. JAMA. 1994;272:397-399. 11. Fisher FU, Lobel HO, Schultz MG. Malaria in soldiers returning from Vietnam. Am J Trop Med Hyg. 1970;19:27-39. 12. Hyams KC, Oldfield EC, Scott RM, et al. Evaluation of febrile patients in Port Sudan, Sudan: isolal]on of dengue virus. Am J Trop Meal Hyg. 1986;35: 860-865. 13. Freedman DO. Imported malaria--here to stay. Am J Med. 1992;93: 239-246. 14. Anonymous. Drawing the curtain on malaria. Lancet. 1991;337:1515-1516. Editorial 15. Warsame M, Wernsdorfer WH, Willcox M, et al. The changing pattern of P. falciparum suscepl]bility to chloroquine but not to mefloquine in a mesoendemic area of Somalia. Trans R Soc Trop Meal Hyg. 1991;85:200-203. 16. Lobel HO, Miani M, Eng T, et al. Long-term malaria prophylaxis with weekly mefloquine. Lancet. 1993;341:848-851. 17. Rieckmann KH, Yeo AET, Davis DR, et al. Recent military experience with malaria chemoprophylaxis. Med J Aunt. 1993; 158:446-449. 18. Pang L, Limsornwong N, Singharaj P. Prophylactic treab~ent of vivax and falciparum malaria wi~ Iowdose doxycycline. J Infect Dis. 1988; 158:1124-1127. 19. Boudreau EF, Schuster B, Sanchez JL, et al. Tolerability of prophylactic Lariam regimens. Trop Meal Parasitol. 1993;44:257-265. 20. Pennie RA, Koren G, Crevoisier C. Steady state pharmacokinetics of mefloquine in long-term travellers. Trans R Soc Trop MealHyg. 1993;87:459-462. 21. Sanchez JL, Defraites RF, Sharp TW, Hanson RK. Mefloquine or doxycycline prophylaxis in US troops in Somalia. Lancet. 1993;341:1021-1022. 22. Burke BM. Mefloquine. Lancet. 1993;341:1605-1606. 23. Ter Kuile FO, Dolan G, Nosten F, et al. Halofantrine versus mefloquine in treatment of multidrug-resistant falciparum malaria. Lancet. 1993;341: 1044-1049. 24. Wyler DJ. Malaria chemoprophylaxis for the traveler. NEJM. 1993;329: 31-37. 25. Wilson DB, Notley FB. Malaria in southern Somalia. East Afr Med J. 1943;20:255-262.
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Operation Restore Hope. While most cases occurred because of noncompliance with personal protective measures or chemoprophylaxis, both mefloquine and doxycycline chemoprophylactic failures occurred. Military or civilian travelers to East Africa must be scrupulous in their attention to both chemoprophylaxis and personal protection measures. alaria has had a profound impact on military campaigns throughout history, including US forces operating in malarious areas in both World War H and the Vietnam conflict.~ Modem military operations in malarious regions must contend with drug resistance, suboptimal chemoprophylaxis compliance, and difficulties inherent in using personal protection measures such as bed nets, insect repellents, and long-sleeved uniforms. During the planning of Operation Restore Hope, malaria was recognized as a substantial threat to the more than 30,000 US troops who eventually deployed to support the humanitarian relief effort in Somalia. ~4 Both Plasmodium falciparum and Phhsmodium vivax malaria were known to be endemic in Somalia (with the possible exception of the capital city of Mogadishu), and chloroquine resistance had been reported. 2 The effectiveness of other malarial chemoprophylactic agents (doxycycline and mefloquine) was unknown. The presence of many other febrile illnesses in the area, which could mimic the clinical presentation of malaria, posed diagnostic problems for field medical personnel. In response to the malaria threat, comprehensive operational policies emphasizing malaria chemoprophylaxis and personal protective measures were instituted. In addition, an infectious disease control team consisting of infectious disease physicians, microbiologists, and epidemiologists was sent to Somalia to identify, investigate, and manage infectious diseases as they occurred. This report describes epidemiologic, clinical, and laboratory aspects of all confirmed cases of malaria that occurred among US troops stationed In Somalia between December 9, 1992, at the start of the operation, up to May 4, 1993, when operations were transferred to the United Nations.
M
PATIENTS AND METHODS United States mih'tary personnel in Somalia with fever (_>38.5°C) and no obvious focal source of infecJanuary 1996 The American Journal of Medicine ® Volume 100
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tion were evaluated for malaria at one of two field hospitals in Mogadishu or occasionally on offshore US Navy ships. Health care proxaders were briefed extensively on the importance of early diagnosis of malaria; rapid transportation was available to the field hospitals by ground or air (within 12 hours). All but 2 confirmed malaria cases occurring in the country were diagnosed and cared for at the US Marines 1st Medical Battalion Field Hospital in Mogadishu (December 15, 1992 through January 18, 1993) or at the US Army 86th Evacuation Hospital at the Mogadishu Airport (January 18 through May 4, 1993). The other cases were diagnosed and treated on ships. All the malaria cases at the field hospitals were cared for by one of three infectious-disease physicians (MRW, CFL, AJM) who prospectively compiled data on each patient's presentation, use of chemoprophylaxis, clinical course, and response to therapy. L a b o r a t o r y Evaluations Febrile patients (n = 389) had thick and thin malaria smears performed as part of their evaluation; initially negative patients without an apparent sottrce of fever had repeat smears done 2 to 3 times per day until a diagnosis was established or their fevers and symptoms spontaneously resolved. Rapid diagnosis of malaria was also attempted in 280 consecutive patients using a fluorescent quantitative buffy-coat (QBC) technique (Becton Dickinson; Baltimore, Maryland) with a × 100 research quality fluorescence nticroscope. 5,6 Malaria patients admitted to one of the field hospitals had serum obtained for determination of antimalarial drug levels. White blood cell (WBC) count, hematocrit, and platelet count were determined by standard techniques. Following initiation of therapy, malaria parasitemia was quantitated twice daily until no parasites were detected in two consecutive specimens. Serum doxycycline levels were measured by a standard bioassay (Microbiology Reference Laboratory; Cypress, California). Serum mefloqume levels were performed at the US Centers for Disease Control and Prevention by high-performance liquid chromatography. 7 Epidemiology All 389 febrile patients cared for at the field hospitals were interviewed by an ep.jdemiologist (TWS, BS) using a standardized questionnaire to ascertain exposure history and compliance with personal preventive measures and chemoprophylaxis. Because 38% of cases of malaria diagnosed in Somalia came from one location near the Jubba River (Baardera), a unit of Marines stationed there (n = 530) was administered a confidential, self-completed questionnaire prior to leaving Somalia to ascertain information on exposures and compliance with malaria prevention recommendations. This unit arrived in late 50
December and remained in Baardera for approximately 5 weeks; they then moved to the Mogadishu area for 3 weeks prior to leaving for the United States. While in Baardera, troops were billeted approximately 1 mile from the river; some of the unit had to man guardposts overnight along the river. The field conditions and threat of armed confrontation at these riverine posts made compliance with personal protective measures difficult. This unit took daily doxycycline prophylaxis until January 15, 1993, when more than 95% switched to weekly mefloquine. All US personnel were given either doxycyclme (100 mg orally per day) or mefloquine (250 mg orally per week) beginning 1 to 2 weeks prior to arrival in Somalia as chemoprophylaxis. Mefloquine loading doses were not used. During the first 4 to 6 weeks of the operation, a roughly equal number of US troops took each chemoprophylactic agent. Subsequently, most of the doxycycline users were switched to mefloquine, and the newly arriving troops (except aircrews and some engineers) were given mefioqtfine prophylaxis. The changeover to mefloquine was done to ensure operational uniformity in chemoprophylaxis and to improve compliance. Patients switching from doxycycline did not receive a loading dose of mefloquine; about one half overlapped their doxycycline by a week, while the others discontinued doxycycline 1 day and began mefloqulne the next. Troops were provided with topical insect repellent (33% DEET in a controlled-release polymer base), bed nets, permethrin spray for uniforms and bed nets, and longsleeved uniforms; they were instaaacted and reminded from time to time in the proper use of these items. The total number of troops in Somalia taking doxycycline and mefloquine chemoprophylaxis in the first 8 weeks of Operation Restore Hope were estimated from surveillance records and retrospective interviews with senior medical personnel. Statistical Analysis Mantel-Haenszel chi-square analysis was performed using EPIINFO computer software (Centers for Disease Control, Atlanta, Georgia), and unconditional multivariate logistic regression analysis was performed using SPSS/PC Plus computer software (SPSS, Chicago, Illinois).
RESULTS Epidemiology A total of 389 febrile patients were evaluated at the field hospitals between December 15, 1992 and May 4, 1993. There were 48 documented cases of malaria among US personnel during this period. Other causes of fever included: dengue (74 confirmed cases); febrile diarrhea-(79 cases); unspecified spontaneonsly resolving fever (110 cases); and miscellaneous infec-
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Rate of Malaria Cases Per Week Operation Restore H o p e 7 7
w .
6-
o .
RATES Overall: 1.8/10,000/wk Wks 1-8: 3.0/10,000/wk Wks 9-22: 0.68/10,000/wk
5.3
.
5-
°
o °
4.
3-
2.7 2
2-
4
n
2
1.2
1.3
10
11
1• 0
Figure. Rate of malaria cases per 10,000 troops per week.
-
0 -
~
1
4
5
6
7
8
9
12
Cases per 10,000 Troops per W e e k
tions, such as celhilitis and respiratory and urinary and bed nets, and an additional 29% used it only intract infections (78 cases). The attack rate for malaria frequently. Only 41 (8%) reported complete compliclimbed rapidly during the first few weeks of the op- ance with all chemoprophylaxis and personal proteceration, reaching a peak of 7 cases per 10,000 troops tive measures; 2 of these Marines developed malaria. per week in week 5 and declining rapidly thereafter Ninety-fourpercent (n = 499) of the Marine unit from (Figure). Forty-one of these cases were Pfalciparum Baardera completed and returned a questionnaire. infection, 5 were P v/vax, and 1 was Plasmodium Thirteen (2.6%) of those surveyed developed P fa/c/ma/ar/ae; in 1 case, species was undetermined (later parum malaria while in Som~]ia_ In addition, 40 (8%) shown by PCR to be P v/vax; PCR performed by Dr. of those surveyed developed P v/vax malaria and 1 Kevin Kain, The Toronto Hospital, Toronto, Canada). (0.2%) mixed Pfalziparum-vivax subsequent m their One Marine had malaria twice (P falciparum then return to the United States.8 Risk factors for the deP v/vax). In these 48 cases, the patients had been in velopment of malaria in this group were analyzed conSomalia for a mean of 37 days (range 12 to 106) be- sidering all malaria cases using an unconditional muifore becoming ill. Twenty cases occurred after expo- tiple logistic regression analysis (Table I). Failure to sure in the southern riverine areas of Somalia, 12 ad- fully comply with chemoprophylaxis (defined as missditional cases occurred among troops who had not left ing any doses), failure to use bed nets all the time, not Mogadishu, and the rest were from various locations keeping sleeves roiled down consistently, and having throughout Somalia. All malaria patients were male; 71% (n = 34) were white. Many of the patients did not TN3LEI Risk Factors for t~e Development of Malaria perceive mosquitos to be a major Among 499 Troops in Baardera, Somalia nuisance; history taken at the time Adjusted 95% Confidence of admission revealed that 15% of Potential Odds Ratio* Interval Risk Factor the malaria patients could not recall Age 0.8 0.1-1.7 any mosquito bites, and 31% reRace (white versus nonwhite) 0.9 0.6-1.3 ported only "occasional" bites. Two Missing any chemoprophylaxis 2.4 1.7-3.0 thirds reported missing at least one Not using bed nets regularly 2.6 1.8-3.4 Junior enlisted rank 2.4 1.7-3.1 dose of their chemoprophylaxis. Failure to keep sleeves down 2.2 1.4-3.1 Forty-three percent had never used Not using permethrin spray 1.1 0.4-1.8 bed nets or used them only occaNot using topical insect repellent 1.0 0.3-1.7 sionally; 70% did not use their topiGuard duty along river >7 nights 2.2 1.6-2.9 cal insect repellent; 25% never used "Calculated using unconditional multiple logistic regression. permethrin spray on their uniforms January 1996 The American Journal of Medicine° Volume 100
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MALARIA AMONG US SOMALIA TROOPS/WALLACE ET AL TABLE II Symptoms of US Troops Diagnosed With Malaria in Somalia Symptoms Number Reporting (%) Fever 48 (100) Malaise 47 (98) Headache 46 (96) Chills 43 (90) Myalgias 40 (83) Cough 15 (31) Pharyngitis 14 (29) Diarrhea" 4 (8) "Three or more loose or watery stools per day.
been stationed overnight near the river were all independent risk factors for acquiring malaria. Clinical P r e s e n t a t i o n
A flulike illness was the presenting complaint in all but 2 patients. All patients reported subjective fever prior to admission and most noted chills, headache, malaise, and myalgias. Pharyngitis and cough were each noted by approximately one third of the cohort ( T a b l e II). The mean number of days between symptom onset and admission for evaluation of fever was 2.9. Physical examination was generally without notable findings except for fever, rigors, diaphoresis, and tachycardia. Four patients had a palpable spleen; none had a rash or hepatomegaly. All but 2 patients had a documented fever >38.3°C during their first 24 hours in hospital; the median temperature on admission was 39.3°C.
nosis which was confirmed by thick and thin smears. Two cases (4%) were negative by QBC, but positive by thick smears prepared from the same sample; a single patient was diagnosed by QBC alone. The calculated sensitivity of QBC as compared with thick smears was 95%. All parasitemias were <1% at admission. In 80% of cases, a diagnosis of malaria was made on the first sample obtained. Two patients (both with extremely low parasitemia) were not diagnosed until the third day of hospitalization. Only 2 patients were empirically treated for malaria in the field; the diagnosis was confirmed in both of these cases upon admission to the field hospital. No other cases were treated for malaria prior to a confirmed diagnosis. The admission WBC count ranged from 2,100 to 8,400/mm 3 (mean 4,880 + 1,710). The platelet count ranged from 54,000 to 285,000/mm 3 (mean 124,000 + 60,000). These values were similar to those of patients with dengue fever (mean WBC count 5,200/mm 3 and platelet count 150,000/mm3). The WBC count in shigellosis patients was consistently higher (range 5,800 to 23,700, mean ll,200/mm3); a WBC count >8,500 mm 3 helped differentiate shigeUosis from dengue or malaria (P <0.01). Treatment
Malaria was treated preferentially with quinine (650 mg orally TID for 3 days) and pyrimethamine/sulfadoxine (3 tablets as a single oral dose). Other regimens were used in selected patients with a history of sulfa allergy or other mitigating factors ( T a b l e III). The treatment was uneventful in 47 of 48 cases. Fever lasted 1 to 5 days (median 2) after initiation of therLaboratory Studies apy; chills, myalgias, and headache resolved after a All but 1 patient were proven to have malaria by median of 2 days. Serial QBC and thick malaria visualization of parasites in thick and thin malaria smears were negative by 48 hours in 60°/5of cases; no smears. In 95% of cases, QBC established the diag- patient had detectable parasites beyond day 4. Virtually all patients reported nausea, dizziness, tinnitus, and anorexia durTABLE III ing their 3-day course of quinine, but Therapy" for Malaria Cases serious toxicities therapy were not Regimen Patients Treated Rationale noted; quinine therapy was not disQuinine plus 39 Regimen of choice continued prematurely in any papyrimethamine/sulfadoxine tient. A total of 47 of the 48 patients Quinine plus doxycycline 3 Sulfa allergy returned directly to their operational Mefloquine 2 Readily available units; the median hospital stay was 8 Quinine plus clindamycin IV 2 Prophylactic doxycycline days (range 4 to 11). failures with sulfa allergy Quinidine IV plus clindamycin IV 1 Cerebral malaria Delirium d e v e l o p e d in 1 patient, Chloroquine 1 Plasmodium vivax infection progressing to o b t u n d a t i o n ap"All 5 known Plasmodium wvax infected patients received primaquine after their initial therapy. p r o x i m a t e l y 12 hours following adFour of 5 were treated with regimens usually reserved for Plasmoduim falciparum malaria bemission and institution of t h e r a p y cause of concerns about subdetectable mixed infections. Dosages were as follows: quinine 650 mg orally ~o for 3 days; pyrimethamine/sulfadoxine 3 tablets as a single oral dose; doxycyeline with oral quinine and doxycycline, 100 mg orally e,D for 7 days; mefloquine 1,250 mg as a single oral dose; clindamycin 900 mg despite a relatively low-grade paraIV every 8 hours for 3 days; quinidine as a 10-rng/kg IV load followed by 0.02 mg/kg per minute. IV = intravenous. sitemia ( u n d e r 1%). He was then treated with IV quinidine and clin52
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TABLE IV
Subject No.
Serum Mefloquine and Metabolite Levels in 13 Malaria Patients Prescribed Three Weekly Doses or Greater of Mefloquine Ratio" Mefloquine (ng/mL) Metabolite (ng/mL) Metabolite: Mefloquine
1" 1,067 4,014 2" 889 3,028 3" 851 5,366 4' 830 2,627 5' 738 1,537 6" 529 3,209 7" 329 1,291 8" 272 613 9 787 1,045 10 559 856 11 571 801 12 537 107 13 0 0 All patientsreportedfull complianceexceptsubject 13. "Primarymetabolite:mefloquineratios >-2 are consistentwith compliance. rAil mefloquinedoseswere 250 mg orallyweekly.
damycin, returning to a normal mental status after 24 hours of IV therapy. He was euglycemic throughout this episode and suffered no long-term sequelae. Chemoprophylaxis
Twenty patients developed malaria while taking doxycycline prophylaxis, 13 during mefloquine prophylaxis and 14 during or within 2 weeks after a doxycycline to mefloquine switchover. One had recently switched from mefloquine to doxycycline prior to developing malaria. The estimated attack rates dttfing the first 8 weeks of the operation for troops taking doxycycline were 4.3 cases per 10,000 exposure weeks; mefloquine rates were 0.9 cases per 10,000 exposure weeks (relative risk [RR] 4.7, 95% confidence interval [CI] 1.7 to 14.2). Attack rates for those who switched from doxycycline to mefloquine were 7.7 cases per 10,000 exposure weeks during the first 2 weeks after the switchover (compared with mefloquine, RR 7.7, CI 2.8 to 21.2). Compliance with the prescribed chemoprophylactic regimen was verified using serum mefloquine levels and serum doxycycline levels. Because most patients received mefloquine in a witnessed, compulsory setting, 12 of the 13 (92%) patients who had been taking mefloquine at least 3 weeks had measurable levels (Table IV). In 8 of these patients, the ratio of metabolite to the parent drug was >2, strongly suggesting compliance with the weekly prophylaxis, s The serum mefloquine levels of these 8 patients ranged from 272 to 1,067 ng/mL, with a mean of 688 ng/mL (2 of these patients were reported previously in a brief communication:J). Of the 20 patients purportedly taking doxycycline (not supervised), only 10 (50%) had measurable levels. Five of
3.8 3.4 6.3 3.2 2.1 6.1 3.9 2.3 1.3 1.5 1.4 0.2 0
Weeks of Regiment 8 4 8 12 6 7 6 3 5 7 5 14 Noncompliant
TABLE V Doxycycline Levels in 20 Malaria Patients Subject No. Doxycycline Level (ng/mL) 1-10 11-15 16 17 18 19 20
0 0.1 1.0 1.5 1.9 4.8 7.5
these had a level of 0.1 ng/mL, probably consistent with intermittent compliance, while the other 5 had levels of 1.0 to 7.5 ng/mL (Table V). Eight of 13 patients who had been switched from doxycycline to mefloquine within 2 weeks of their admission for malaria had measurable mefloquine levels, ranging from 52 to 881 ng/mL (mean 525), but none had a metabolite:mefloquine ratio >2. Toxic reactions to chemoprophylactic drugs requiring hospitalization were rare; only 4 of 20,000 US servicemen in Somalia from December through February were hospitalized for complications of their chemoprophylaxis. All 4 men were receiving doxycycline, and all had odynophagia with dehydration requiring hospitalization for 2 to 7 days. Minor complaints attributed to malaria chemoprophylaxis by deployed US troops were conunon. The unit of Marines stationed at Baardera is unique in that they took each chemoprophylactic agent for approximately 1 month; analysis of their questionnaires revealed that sunburn, indigestion, and dizziness occurred with equal frequency with both of the chemoprophylactic agents, whereas nightmares and insomnia were significantly more common while taking mefloquine (Table VI).
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TABLE VI Reported Side Effects of Antimalarial Chemoprophylaxis From Survey of Crossover Experience" of 499 Troops in Operation Restore Hope, Somalia, 1992 to 1993 Mefloquine Doxycycline Side Effect n (%) n (%) P Valuer Sunburn 20 (4) 24 (5) NS Gastrointestinal complaint 72 (14) 85 (17) NS Insomnia or nightmares 91 (18) 45 (9) <0.01 Dizziness 65 (13) 48 (10) NS "This cohorttook doxycycline(100 mg per day) and then changedtheir chemoprophylaxisregimen.to mefioquine(250 mg per week). tp valueswere calculatedby two-sampletestingof binomialproportions.
DISCUSSION The 48 in-country cases of malaria that occurred among US troops in Somalia during the first 6 months of Operation Restore Hope and the more than 200 c a s e s of malaria in personnel after return to the United States represent the largest US military experience with malaria since Vietnam. ~ Although Pfalciparum malaria accounted for 90°/5 of cases in Somalia, the vast majority of the cases that occurred after return to the United States had P v/vax.10 This "in-country" predominance of P falciparum followed by P v/vax c a s e s after return to the United States parallels that of the Vietnam malaria experience.H Troops deployed throughout Somalia were at risk for developing malaria, including those never leaving the previously malaria-free capital of Mogadishu. The majority of c a s e s occurred in the first 5 weeks of the deployment. Subsequent public health interventions, particularly supervised weekly mefloquine dosing, reinforcement of personal protective measures, and a withdrawal of US troops from the most malarious areas around the Jubba river, likely contributed to negligible attack rates by week 10 of the operation. The clinical presentation of malaria in the deployed troops was remarkably similar and nonspecific. Experienced physicians could not reliably identify presenting signs and symptoms of dengue, prediarrheal shigellosis, and malaria, a situation that was documented in other settJngsY Although the parasitenfias encountered in our patients were relatively low (< 1%) and occasionally undetectable at presentation, many patients had impressive systemic toxicity typical of nonimmune hosts with malaria, la The use of chemoprophylactic medications may have made the diagnosis of malaria more difficult; all patients presented with low-grade parasitemias (< 1%), w h i c h sometimes required thorough examination of b l o o d films every 8 to 12 hours for 2 to 3 days before parasites were detected. Routine hematologic testing (WBC, hematocrit, and platelet count) was not helpful in distinguishing malaria from dengue, but leukocytosis (WBC count >8,500/mm 3) did help distinguish 54
malaria and dengue from prediarrheal shigeUosis and other sporadic, less common bacterial infections (pyelonephritis, pneumonia, and so forth). Persona] protection (topical repellent, permethrinsprayed bed nets and uniforms, keeping sleeves rolled down) is undoubtedly a critical factor in minimizing malaria cases. Among the Marines in the Baardera area, who were operating in a malarious riverine area, failure to consistently use bed nets was a major risk factor for developing malaria. The use of bed nets has been shown to be an important part of malaria prevention.14 The lack of effectiveness of DEET insect repellent was probably due to widespread noncompliance owing to the sticky, dust-attracting quality of the preparation. The mefloquine and doxycycline levels of those patients who failed their chemoprophylmxis demonstrate that neither agent affords complete protection from malaria in East Africa. Earlier studies in Somalia during 1986 and 1989 showed that although chloroquine resistance was increasing in some localities, all isolates studied retained in vitro susceptibility to mefloquine. 15 Eight of our mefloquine chemoprophylactic "failures" had demonstrable serum levels consistent with compliance. The mefloquine level estimated to provide 95% effective protection against P falciparum in Africa has previously been estimated to be 641 ng/mL16; a recent survey of mefloquine prophylaxis failures in Africa defined chemoprophylactic failure as a patient developing Pfalciparum malaria in spite of a mefloquine level _>400 ng/mL and a metabolite:mefloquine ratio >_2.8 Using these two criteria, either 5 or 6 of our patients (Table IV) represent true chemoprophylactic failures. Doxycycline failures generally resulted from n o n c o m pliance or intermittent compliance, but 5 patients vigorously denied missing any doses and had confirmatory serum levels (Table V). Although recent Australian military experience confirms that doxycycline is an efficacious agent in areas of chloroquine-resistant Pfalciparum malaria, 17 breakthrough low-grade parasitemias with both P v/vax and Pfalciparum malaria have been reported in refugees on the Thai-Burmese border receiving doxycycline prophylaxis. 18 The least effective chemoprophylaxis occurred in those w h o switched from doxycycline to mefloquine. The lower mefloquine serum levels in this group (mean 525 ng/mL) and the high attack rates suggest that whenever a switchover to mefloquine is planned in a malarious area, a rapid-loading dose of mefloquine must be given to ensure adequate levels before the other agent is discontinued. Rapid-loading dosages (one 250-mg tablet daily for 3 consecutive days) have been s h o w n to result in steady-state blood c o n c e n t r a t i o n s in 3 d a y s # as compared with 7 to 9 weeks when weekly dosing is used. 2° Military personnel and other travelers to highly malarious areas who will be taldng meflo-
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quine chemoprophylaxis should either take several weekly pretravel doses or, if time does not permit, employ a rapid-loading regimen. Given that approximately equal numbers of troops were taking each chemoprophylactic agent early in the operation (primarily for logistic reasons most Marine, Navy, and Air Force personnel were receiving doxycycline while most Army units took mefloquine), an oppommity was afforded to compare these agents in terms of toxicity and effectiveness. Our analysis showed that malaria occurred approximately one fifth as often in subjects receiving mefloquine. This finding has been corroborated by a cross-sectional survey of troops stationed at a single location/1 It seems likely that the greater effectiveness of mefloquine as a prophylactic agent in Somalia resulted more from better compliance (due to its weekly dosing interval) than intrinsically superior antimalarial activity, as failures occurred at drug levels usually felt to be protective with both agents. Our survey of 499 Marines who used both agents showed that overall toxicity was minor and tolerable with both agents, but a statistically significant increase in sleep disturbances was noted during their mefloquine prophylaxis. Sleep disturbances have been reported with mefloquine therapy, ~ but the frequency and severity of these complaints remain controversial. ~ No failures were encountered with any of the treatment regimens used. Although 2 patients were treated successfully with mefloquine alone, we would recommend therapy with two drugs (quinine or quinidine plus pyrimethamine/sulfadoxine or doxycycline) that were not part of the failed chemoprophylaxis for patients with P falciparum acquired in East Africa. As pyrimethamine/sulfadoxine resistance continues to spread throughout Africa, ~4 the use of a two-drug therapeutic regimen including quinine (or quinidine) should minimize the risk of inadequate therapy. American troops operating in Somalia had a low overall rate of malaria, a major achievement given the difficult circumstances encountered. The US military experience with malaria in Somalia should, however, also serve as a cautionary note for future mih'tary and humanitarian operations in other areas where malaria transmission would be much more intense than in the Horn of Africa. Prior studies had shown that malaria was mesoendemic in the riverine areas and hypoendemic in the coastal and inland plateau areas of Somalia, with transmission being seasonal in all areas. 15,',5The occurrence of 48 cases of malaria among US troops in a previously low-risk environment, despite extensive efforts at chemoprophylaxis and personal protection, reminds us of the tenacity of this parasite. A similarly sized deployment to West Africa, Southeast Asia, or highly malarious areas of South America could expect malaria attack rates many times greater than those encountered in Somalia. Continued
efforts to develop and use improved personal protective gear, chemoprophylaxis and, most significantly, a malaria vaccine are of paramount importance.
ACKNOWLEDGMENT The a~ors thank R.K. Hanson, MD, R.F. DeFraites, MD, and J.L. Sanchez, MD for their field surveillance data and editorial review; Mike Kozar for his technical assistance in the field; Marcylin Shelton and Cecilia Cesena for their help in preparing this manuscript; and S.L. Hoffman, MD for his critical manuscript review and assistance during the Somalia deployment.
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