Historical Impact of Malaria on Military Conflicts

INTRODUCTION: Malaria is a parasitic infection induced by a Plasmodium, which lives part of its life in Anopheles mosquitoes and part in humans and creates one of the most important health concerns on a global scale in so far as over one-third of the world’s population is threatened by malaria. It prevails in the tropical areas of South America, Central America, Africa, and Asia and endangers millions of the inhabitants of endemic areas. The annual malaria occurrence rates are estimated at about 350 to 500 million worldwide. In 2009, the number of the infected victims was estimated at about 225 million and the number of deaths reached 781000 (Cohen JM et.al 2010). Military personal is confronted with a variety of vector-borne threats and diseases during their missions in war areas. Among all threats, malaria holds an important place as a major health problem in tropical or hyperendemic areas. Malaria control in war areas has been deemed one of the most challenging goals of different armies throughout history. According to the world health organization (WHO), the integrated vector management (IVM) is a promising method to improve the efficacy, cost-effectiveness, ecological acceptability, and sustainability of malaria control. The military is one of the mobile population risk groups that work in forest and border areas where transmission intensity of malaria is high (Wen S et.al 2016). Studies that were conducted with the military in different countries reported that diagnosis and treatment are often delayed because of barriers to accessing health services which can contribute to prolonging infectivity, increasing drug resistance, and promoting diseases transmission (Chretien JP et.al 2007). Many biological and environmental factors shape the transmission of malaria in a given location. An epidemic may occur when conditions such as climate effects along with human intervention allow the mosquito population to reach high figures. The incidence of malaria is mainly dependent on the environmental factors that control mosquito survival and breeding. The IVM combines chemical and non-chemical vector-control techniques with other disease-controlling parameters such as local vector biology and the dynamics that influence the disease transmission and morbidity. Development of drugs to prevent and treat malaria is a US military priority for several reasons. The infection can render military personnel unable to fight and can cause life-threatening disease. Insect repellent and bed nets do not guarantee protection. A protective vaccine does not exist. Troops may develop malaria after leaving malarious areas because of inadequate prophylaxis or poor prophylaxis compliance. Mosquitoes capable of transmitting malaria exist in the United States, and returning troops can transmit it to others. Malaria had a major impact in the Spanish-American War, the Pacific and India-Burma-China theaters in World War II, and the Vietnam War. Malaria also afflicted troops in the Korean War and Operation Restore Hope in Somalia (Bwire R et.al 1999). In Liberia in 2003, of 290 troops who stepped ashore during peacekeeping operations, 80 (28%) developed malaria, and 69 (44%) of the 157 who spent at least 1 night ashore were afflicted. Five malaria-infected marines developed severe disease requiring intensive care unit support.

In the last century, malaria historically caused greater loss of manpower than combat-related injuries during deployments to tropical regions (W.D. Porter 2006). In 1972 the number of malaria cases among U.S. military personnel sharply decreased from over 4000 per year (T.H. Holtz et.al 2001) to less than 50 annually, but malaria has remained a militarily relevant infectious disease negatively impacting operational readiness among deployed forces. Deployed forces to malaria-endemic regions have experienced outbreaks, and noncompliance with personal protective measures had been a recurrent risk factor associated with these outbreaks. During the deployment of 30,000 U.S. military troops to Somalia from 1992 to 1993, P. falciparum malaria was diagnosed in 48 personnel whose onset of illness occurred while still in-country; over 200 military service members developed symptoms after their return to the U.S(J.A. Newton et.al 1994). The risk factors for developing clinical malaria were failure to comply with the prescribed chemoprophylaxis (defined as missing any doses), failure to use bed nets all the time and not keeping the uniform sleeves down. Most of the malaria cases occurred during the first five weeks of deployment, justifying the need for rapidly effective protection among troops who deploy to these regions (M.R. Wallace et.al 1996). The number of malaria cases among the troops quickly waned by deployment week 10 after supervised chemoprophylaxis with antimalarial medications and consistent reinforcement of other personal protective measures were initiated. The enormous impact of malaria threat on military operations was demonstrated once again in 2003 during an outbreak among 225 U.S. Marines who deployed to Liberia to provide security services for the U.S. Embassy. The Marine unit spent only 10 days in Liberia, and eighty Marines developed acute febrile illness within one day of leaving the country. Forty-four members were confirmed to have malaria and eventually recovered, but 5 members developed severe, complicated malaria, requiring critical care and prolonged hospitalization. All malaria cases fully recovered. Negative outcomes were largely associated with poor adherence to chemoprophylaxis and personal protective measures (T.J. Whitman et.al 2010).

Approximately 40,000 French military members are deployed to various malaria-endemic African countries annually, and from 2002 through 2006, over 1700 cases of P. falciparum malaria were reported among French soldiers who were expected to take malaria chemoprophylaxis (R. Migliani et.al 2014). In 2009, an outbreak of malaria cases was reported among 14 out of 110 French military members who were returning from Cote d’Ivoire after a four-month operational assignment; the outbreak was associated with poor compliance with chemoprophylaxis despite the provision of education on the preventive measures on a regular basis (A.P. Bellanger et.al 2011). A fatal case of P. falciparum malaria in a young U.S. Navy active duty member who was deployed in Liberia in 2009 served as a sobering reminder of the severe consequences of non-adherence to personal protective measures and the crucial role of careful planning, preparation and compliance with force health protection. The enforcement of malaria protective measures by military commands has likely resulted in a reduction of fatal malaria cases in the U.S. military in the recent years. However, outbreaks of malaria infection among U.S. troops and other military forces will likely occur in the near future as long as they continue to deploy to malarious regions. Mefloquine is a once-a-week oral medication used to treat malaria, a mosquito-borne disease caused by parasites. It was originally developed by the United States Army at the Walter Reed Army Institute in the 1970s and commercially introduced in 1989. Early prelicensure studies on mefloquine were conducted predominantly among male prisoners, military personnel, and subjects in third-world countries.

Vertigo and nausea were commonly reported in these early trials, but the drug was considered to be largely free of severe psychiatric and neurological effects. When reports of severe psychiatric side effects, including amnesia, confusion, and psychosis, first emerged, these symptoms were frequently dismissed as coincidental or attributed to pre-existing or latent mental illness. In 2001, studies were conducted and the results demonstrated that the incidence of specific psychiatric symptoms including nightmares, anxiety, and psychosis were at least 100 times more common than previously reported. More recent reports of suicide and suicidal ideation, and studies linking the drug to acts of violence, have raised additional safety concerns. Nevertheless, mefloquine remained in widespread use by the United States military until around 2009 when Pentagon officials, responding to concerns over the above-mentioned psychiatric and neurological effects, issued a policy listing it as a last-choice preventive in areas where malaria strains are resistant to other available medications. In 2013, the Food and Drug Administration (FDA) placed its strongest warning (i.e. black box warning) on mefloquine, indicating the drug can cause ongoing or permanent neurological and psychiatric conditions, including the following:

Dizziness

Loss of balance

Tinnitus

Anxiety

Depression

Paranoia

Hallucinations

Importantly, FDA noted that these conditions may persist even after discontinuing the use of mefloquine.

Methodology: A systematic review was done to investigate the effects of mandatory malaria treatment on military personnel. The searching process for retrieving relevant publications was conducted in PubMed, PMC, Medline, Embase, Google Scholar. The following keywords (MeSH terms) were used: malaria control; malaria prevention; malaria treatment effect in military personal and war areas. No restrictions on paper status or publication date were exerted; hence, different language papers were obtained, but only English language papers were included. Additionally, the reference lists of the relevant papers were reviewed for other appropriate scientific sources. As vectors, the mosquito species Anopheles were considered as the main subject. In order to evaluate the future status of the IVM strategies in military medicine as an environmental approach, relevant studies in the field of biological control, chemical control, and environmental management related to malaria were retrieved. 263 studies were identified by electronic database of which147 are potentially eligible and 116 are excluded upon review of title duplicates. Out of 147 ,38 full articles were selected for final review. In this study, the inclusion criteria were defined and specified in terms of the IVM methods, including environmental management, biological control plans, and chemical control techniques and its effect on military personals.

Results: From 38 publications finalized for the inclusion in the review process, some articles were about historical perspective on malariology and malaria in war time, some discussed the IVM, and some proposed new biological and chemical control methods for malaria prevention and treatment in endemic areas, some discussed the effect of the implementation of the treatment in military personel,side effects of the malaria treatment in military personnel. The outcomes from the reviewed studies were investigated and categorized by the authors in five sub-categories, namely transmission, symptoms and diagnosis, biological control, chemical control, and environmental management.

The IVM was acknowledged and promoted by the WHO after its interesting results in African and Asian endemic countries. The IVM strategies can protect military personal in endemic areas by manipulating the concept of prevention through the reduction and interruption of the transmission cycle of malaria. Different types of malaria vector-control methods have been proposed by experts such as using insecticide-treated nets, long-lasting treated nets, and indoor residual spraying (Walker K et.al 2007). The above methods are classified under the chemical control plans and should be combined with other environmental techniques for effective adult and larval control of malaria mosquitoes. According to the recommendations of the WHO, the use of proper combinations of chemical and nonchemical methods can guarantee the successful implementation of the IVM. The IVM strategies are practical and effective inasmuch as they offer a set of options of vector-control methods that can be applied in different combinations for multiple geological and ecological conditions. The AMUs should seek to target vectors in every stage of their life cycle such as larval and pupal stage in their breeding habitats like swamps and marshlands. Based on the reviewed publications, the IVM is an environmentally friendly, sustainable, and cost-effective method for malaria prevention and control in endemic areas, including tropical and subtropical areas, marshy lands, and humid dense forests, which motivated us to assess the IVM concepts in relation to war areas from a military perspective. Fortunately, many promising and successful results in the utilization of the IVM in hyperendemic areas have been observed and documented. One of the most appealing applications of the IVM is its capability to confer preventive advantages by habitat modifications, especially in war areas, which may lead to cost-effective malaria treatment.

Discussion: Malaria was among the most important causes of the sickness of troops at some stages in the Second World War in endemic areas, including tropical and Mediterranean zones. The occurrence of the disease in its transmission season period endangered numerous military campaigns and operations. For example, the malaria incidence in 1943 was as high as 746/1000 in the Indo-Burma Front. Even in the Middle East, the admission rate for malaria rose to a peak of 677 in 1940 and fell to 380/1000 in 1945. The infection rates in West Africa were reported as follows: 762/1000 in 1942; 442/1000 in 1943; 278/1000 in 1944; and 92/1000 in 1945. In Europe, the disease was epidemic at a steady annual rate of 13.8/1000 between July and September 1944, particularly in the northern and western parts of the continent, but this rate fell to 9/1000 in October and December 1944. In the meantime, in the Central Mediterranean Zone and the northern part of Africa, malaria had a much higher occurrence rate and hunted down the troops. These reported data should, however, be interpreted with caution because the ethnic compositions of the troops were different (Ferguson HM et.al 2010). Integrated Vector Management is a decision-making process for the management of vector populations, so as to reduce or interrupt transmission of vector-borne diseases. Its characteristic features include: Selection of methods based on knowledge of local vector biology, disease transmission and morbidity; Utilization of a range of interventions, often in combination and synergistically; Collaboration within the health sector and with other public and private sectors that impact on vector breeding; Engagement with local communities and other stakeholders; A public health regulatory and legislative framework; rational use of insecticides; Good management practices. An IVM approach takes into account the available health infrastructure and resources and integrates all available and effective measures, whether chemical, biological, or environmental. IVM also encourages an integrated approach to disease control.

Integrated vector management (IVM) includes five key elements: 1) evidence-based decision-making, 2) integrated approaches 3), collaboration within the health sector and with other sectors, 4) advocacy, social mobilization, and legislation, and 5) capacity-building. In 2004, the WHO adopted IVM globally for the control of all vector-borne diseases. Important recent progress has been made in developing and promoting IVM for national malaria control programmes in Africa at a time when successful malaria control programmes are scaling-up with insecticide-treated nets (ITN) and/or indoor residual spraying (IRS) coverage. While interventions using only ITNs and/or IRS successfully reduce transmission intensity and the burden of malaria in many situations, it is not clear if these interventions alone will achieve those critical low levels that result in malaria elimination. Despite the successful employment of comprehensive integrated malaria control programmes, further strengthening of vector control components through IVM is relevant, especially during the "end-game" where control is successful and further efforts are required to go from low transmission situations to sustained local and country-wide malaria elimination. To meet this need and to ensure sustainability of control efforts, malaria control programmes should strengthen their capacity to use data for decision-making with respect to evaluation of current vector control programmes, employment of additional vector control tools in conjunction with ITN/IRS tactics, case-detection and treatment strategies, and determine how much and what types of vector control and interdisciplinary input are required to achieve malaria elimination. Similarly, on a global scale, there is a need for continued research to identify and evaluate new tools for vector control that can be integrated with existing biomedical strategies within national malaria control programmes. The IVM is a dynamic method which discusses specific strategies to achieve disease control in the most cost-effective manner while minimizing negative impacts on ecosystems, reducing the adverse health effects of insecticides and their toxic residues, and decreasing the insect resistance to some extensively applied drugs and pesticides (Bang YH et.al.1975) Compared with a conventional method of vector control (e.g. chemical spraying), the IVM highlights the value of understanding the local patterns and the ecology of the local vector for disease distribution and decides the correct vector-control methods from the range of available options (Fillinger U et.al 2006). The IVM also proposes a well-thought-out structure for the protection of the individual that employs environmental management tools like physical barriers along with chemicals such as insecticide-treated nets. And last but not least, it should be borne in mind that the most important purpose of treatment is to provide access to appropriate medication for the initial infection stages to avoid the development of the life-threatening stages, which require hospital admission. Nevertheless, providing perfect treatment such as chemotherapy is still problematic, particularly in war areas. IVM stresses the importance of first understanding the local vector ecology and local patterns of disease transmission, and then choosing the appropriate vector control tools from the range of options available. These include environmental management strategies that can reduce or eliminate vector breeding grounds altogether, through improved design or operation of water resources development projects; and the use of biological controls (e.g. bacterial larvicides and Larvivorous fish) that target and kill vector larvae without generating the ecological impacts of chemical use. IVM stresses the importance of first understanding the local vector ecology and local patterns of disease transmission, and then choosing the appropriate vector control tools from the range of options available. These include environmental management strategies that can reduce or eliminate vector breeding grounds altogether, through improved design or operation of water resources development projects; and the use of biological controls (e.g. bacterial larvicides and larvivores fish) that target and kill vector larvae without generating the ecological impacts of chemical use. The WHO published a special issue in 2004 to declare the Global Strategic Framework for Integrated Vector Management, which clarifies the purposes, requirements, and principles of the IVM methods. The IVM is supported and optimized by the WHO as a rational decision-making procedure for the inclusive exploitation of resources for vector prevention and control. The exploitation of biological toxins for targeted mosquito vectors and the employment of natural enemies to reach efficient disease control are the principles of the biological control (Bradley DJ et.al 1994). Alternative examples in this method include Larvivorous fish, invertebrate predators, nematodes, Protozoa, fungi, and bacteria.

Biological vector control is an innovative alternative in malaria control, when a lack of reliable vaccines and the emergence of drug resistance and unaffordable anti-malarial medications result in the failure in malaria control (Christophers SR 1939). In order to control malaria in war areas efficiently, the following steps are recommended: appropriate supervision of the IVM; identification of innovative and environment-friendly alternative technologies; exploration and development of logical compatible interventions in military bases; promotion of the existing strategies regarding their effectiveness and efficiency and their combinations with biological control of vectors; and endorsement of environmental management and surveillance. Chemicals and insecticides are integral parts of the IVM and play a key role in malaria control scenarios. They should, however, be launched swiftly to be effective at relatively low costs. Accurate timing in chemical application is compulsory at the early stages in the control process because it allows further control methods to be established and developed in an integrated vector-control strategy. Chemical application methods comprise targeted residual spraying, larviciding, and space spraying. In order to have an eco-friendly formulation of insecticides, the active or technical material should be combined with a variety of components that pose no toxic effects to environment as well as human. With respect to mud walls, because of the absorbent nature of their surfaces, the spraying process should be conducted in a way that the chemical agent particles remain on the surface and not be absorbed into the walls given the porosity of their surface. In case of the long-term settlement of troops, environmental management strategies should be employed to decrease the malaria infection burden through sustainable approaches. Environmental management strategies emphasize the avoidance of the formation of vector-breeding sites by altering natural habitats and improving soldiers’ habitation to lessen the abundance of the vectors. Examples of such strategies include marsh alteration, filling, grading, draining, vegetative plantings, and house screening. The systematic review shows that there are many problems in the administration of the treatment in military personals. Many of them consider that to be caused due to drinking water. Moreover, many neuropsychiatric disorders are observed in military personals. A large retrospective cohort study of U.S. military service members conducted by Angelia A. Eick-Cost et.al 2017, showed that the rates of neuropsychiatric outcomes (NPO) among mefloquine recipients were similar or less than the rates among two other antimalarial prescribed cohorts Doxycycline and Atovaquone/proguanil for the majority of outcomes investigated. This is the largest study that the authors are aware of evaluating potential NPOs after mefloquine exposure among U.S. military service members prescribed antimalarial medications. The IRR for anxiety disorder, tinnitus, and PTSD were all statistically significantly elevated among mefloquine users in certain cohorts; the elevated risk for anxiety disorder was only found in comparison to doxycycline among the deployed cohort, tinnitus was only found in comparison to A/P, and the risk of PTSD was only found among the nondeployed cohort in comparison to A/P. All three outcomes are known adverse events of mefloquine.29 In comparison to doxycycline recipients in the nondeployed cohort, mefloquine recipients were at a statistically significant lower risk for adjustment disorder, insomnia, anxiety disorder, depressive disorder, vertigo, and PTSD. The reason for this finding is not completely understood. Due to the nonexperimental nature of this study and the use of administrative data to assess exposure and outcomes, it is possible that residual and/or unmeasured confounding could be affecting the results. Although cases of other NPOs occurred in the mefloquine cohort, on a population level, no increased risk was identified as compared with the other cohorts. This null finding is similar to reports from other observational studies (Wells TS et.al 2006) Specifically among U.S. military deployers, Wells and others reported no association between mefloquine prescriptions and hospitalizations for a wide range of outcomes.5 Additional studies among deployed military populations reported mefloquine to be well tolerated, with the exception of individuals previously diagnosed with an NPO(Fujii T et.al 2007)Contrary to our findings, other studies have reported an association between NPOs and mefloquine(Schlagenhauf P et.al 2003) The study by Schlagenhauf and others was a randomized, double-blinded study among travelers and found mefloquine to have the highest proportion of moderate to severe NPOs compared with chloroquine/proguanil, doxycycline, and A/P. However, this study had small numbers and the outcomes were defined by a subjective questionnaire as opposed to medical diagnoses of the outcomes.

IRRs comparing mefloquine to doxycycline for both deployed and nondeployed cohorts revealed statistically significant reduced risks for a large number of outcomes. However, after adjustment, these outcomes were no longer statistically significant for the deployed cohort. Among the deployed cohorts, anxiety disorder had an elevated adjusted IRR of 1.12 (95% CI = 1.01–1.24) comparing mefloquine to doxycycline. Among the nondeployed cohorts, the adjusted IRRs for adjustment disorder, insomnia, anxiety disorder, depressive disorder, vertigo, and PTSD all remained statistically significantly protective for mefloquine compared with doxycycline. Among the nondeployed cohorts, the mefloquine cohort did not demonstrate a significantly elevated risk for any outcome. When comparing the mefloquine cohorts to the A/P cohorts for both deployers and nondeployers, tinnitus had a statistically significant elevated adjusted IRR This issue is especially relevant for the military since the proportion of mefloquine prescriptions to individuals with NPOs in the year prior has nearly doubled since 2010. However, it should be noted that not all of the NPOs investigated in this study are classified as contraindications to mefloquine. Before 2011, the percent of mefloquine recipients with a prior NPO diagnosis was similar to the percentage of mefloquine recipients with a contraindication reported among U.S. military deployers to Afghanistan in 2007 (4.8%), but lower than the percentage of contraindications reported among U.S and United Kingdom civilians (7.5–9%).35–37 In 2012 and 2013, prior NPO diagnoses among mefloquine recipients were higher than any of these previous reports. This rising proportion of mefloquine prescriptions for individuals with a history of NPOs suggests the potential need for improved scrutiny of each service member's medical history before prescribing mefloquine. It may be beneficial to implement patient alert cards for contraindication before being able to prescribe mefloquine. U.S. military aviators are currently restricted to the use of chloroquine or doxycycline for malaria prophylaxis. Ground forces are allowed the additional option of taking mefloquine. These medications are begun before deployment, must be taken for 4 weeks after leaving the malarious area, and primaquine must be added to the regimen the last 2 of those 4weeks. Compliance with this regimen is often poor, especially in populations who travel abroad frequently for short periods of time. Causal malaria prophylaxis offers potential benefits of decreased length of post deployment regimens and obviates the need for a second medication for terminal prophylaxis. Potential obstacles include adverse drug reactions, cost, and rapid development of resistance to new medications by Plasmodium species, which should be weighed against the risks to health and mission success in each deployment.

Conclusion: Malaria is a major global concern particularly for military personal who are working in war areas. Decisions about appropriate malaria chemoprophylaxis must consider the malaria risk of the geographic area and mission, the potential impact of side effects on the deployed individual ‘stability to safely perform his/her mission, the likelihood of compliance, and cost of the regimen. For most deployments involving large numbers of personnel and long stays abroad (>30days), current suppressive agents (chloroquine, doxycycline, and mefloquine) are appropriate prophylactic agents. However, for small units that deploy frequently to malarious areas for only days to weeks at a time, causal offer a less cumbersome alternative. Taefenoquine may eventually combine the advantage so chloroquine and mefloquine (weekly or perhaps even monthly dosing) with those of primaquine and Malarone (minimal post deployment doses) The use of mefloquine in the military has long been a controversial subject. Recent evidence presented to the current Defence Select Committee inquiry called mefloquine the ‘least safe of the available antimalarial regiments currently used and yet anecdotal evidence suggests that mefloquine has been routinely issued without an individual risk assessment, due to operational requirements, for several decades. The Ministry of Defence (MoD) has revealed that they possessed defined protocols for prescribing mefloquine since 1997, yet lacked internal measures to ensure that they were being applied in practice (Oral evidence, 12 January 2016). Given the high incidence of neuropsychiatric side effects, and the difficulty in ensuring appropriate prescribing and follow-up practices in the military setting this seems is odds with principles of good military medicine as well as being against the manufacturer’s own and GMC Good Practice guidelines

It can be concluded that several antimalarial drugs have been used as a prophylactic or for the treatment of malaria in military personal but it resulted in various side effects. The review shows that a strategy should be planned out to prevent malarial infection in military personal. The IVM methods in war areas and military bases located in high-risk regions looks promising, provided that sanitary units become familiar with the environmental concepts of the IVM. However, one of the remaining concerns is the climate change, which may render some areas of the world that are not currently endemic to malaria more climatically favoured to the transmission of the disease. In the malaria control process in war areas, prevention and treatment should be implemented simultaneously. Even the prevention of the disease transmission should be triggered in the larval source. Only in this situation can a significant reduction in malaria infection rates be expected. It is significant that international cooperation, followed by early diagnosis and prompt treatment, is fundamental to the successful application of the IVM to malaria prevention and control.

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