Chapter S5: Infections in War Veterans

In the past half-century, there have been dozens of major armed conflicts involving millions of combatants from numerous countries throughout the world. Several of these wars have been multinational in scope and have involved the deployment of large numbers of ground forces from their home countries to distinct areas of conflict in developing portions of the world, such as southwestern and central Asia (e.g., Iraq, Afghanistan) and Africa. In the United States alone, there are estimated to be more than 18 million living veterans, many of whom served in combat theaters.

Troops who are deployed as combatants or in other military capacities on foreign soil are at heightened risk of acquiring infectious diseases on the bases of intimate human and environmental exposures and immunologic naiveté to local endemic or enzootic pathogens. This risk is magnified by the crowded social conditions engendered by mass troop deployments, infrastructure destruction, and population displacement; it is further amplified by vulnerabilities in public health, such as lapses in hygiene and sanitation that invariably accompany armed conflicts. The clinical spectrum of communicable illness acquired in this setting includes acute infections in the combat theater, acute infections with delayed clinical manifestations, and chronic or relapsing infections. The latter two scenarios have the potential to cause illness in veterans returning from foreign wars.

The impact of acute infectious diseases of war, once a major cause of noncombat mortality, has significantly lessened in modern conflicts, largely because of the use of preventive vaccines, improved hygiene and sanitation, and the early institution of antimicrobial therapy as clinically indicated. Nonetheless, such acute diseases remain an important cause of morbidity in deployed military personnel (Table S5-1). Several, such as influenza, meningococcal meningitis, hepatitis A, and adenoviral respiratory disease, can largely be prevented by routine vaccination of troops. Others, such as bacterial gastroenteritis and viral respiratory tract infections, continue to represent common causes of minor morbidity among deployed forces. The incidence of several other acute infections, such as malaria and dengue, can be favorably impacted—although not completely abrogated—by the use of classic public health interventions: chemoprophylaxis, personal protective measures, and vector control. Infections that have short incubation periods and are acquired just days before departure from a combat theater may theoretically become clinically manifest only upon the return of troops to their countries of origin. One such example was a cluster of African tick typhus cases that occurred during short-term U.S. troop deployments to Somalia and Botswana in the early 1990s. However, because most acute infections with brief clinical incubation periods are self-limited or responsive to treatment, they are not typically seen in returning war veterans and, with the exception of malaria, will not be addressed further in this chapter.

Certain infectious diseases acquired in a theater of military operations may become apparent in combatants only after they have returned to their home countries. Although of unclear incidence, these complications of military service—manifesting clinically with either acute or chronic signs and symptoms—may cause significant morbidity in affected veterans and in some settings may endanger the public health through secondary transmission or contamination of the blood supply. Of a sample of nearly 53,000 U.S. veterans of the Persian Gulf War (1990–1991), 7% were diagnosed with an infectious disease in the aftermath of the war; no excess risk of mortality was observed over a 6-year follow-up in comparison with nondeployed veterans.

This chapter focuses on infectious diseases that either have occurred or have been a source of concern in returning war veterans over the past quarter-century. During this period, several pathogens have been associated with disease in this population; some have been associated with only rare case reports in war veterans; and some, given their epidemiology, may pose a risk in future conflicts. It is practical to classify infections with delayed signs and symptoms related to prolonged incubation periods or significant clinical latency in terms of their potential to manifest clinically as acute illnesses or chronic/relapsing diseases. Table S5-2 provides details regarding the epidemiology, clinical characteristics, diagnosis, therapy, and prevention of infectious diseases of concern in war veterans. Figure S5-1 illustrates a differential diagnostic approach—based on prominent signs or symptoms—to suspected infections in this population.

Malaria

(See Chap. 219) Malaria, resulting from infection with Plasmodium species of protozoa, has historically caused significant battlefield morbidity and lost duty time among armed forces in combat environments. These phenomena have been affirmed by recent global military experiences in Africa and central Asia. Approximately 30–145 cases of malaria were reported annually among U.S. service members in the decade from 2006 to 2015. Because of its worldwide prevalence, its complex pathophysiology, the lack of an effective vaccine, and suboptimal adherence rates to chemoprophylaxis due in large part to poor tolerability of antimalarial agents, malaria remains an important cause of infection both during military operations and in returning war veterans.

The risk of malaria is exacerbated by several factors inherent to war: inadequate shelter promoting increased troop exposure to vectors; abeyance of organized governmental programs for vector control in combat zones; and ecologic changes potentially leading to an increased vector presence in the contested environment. Because of the complex life cycle of the parasite and the predilection of two species—P. vivax and P. ovale—to remain latent in their liver stages of development for prolonged periods, malaria in foreign-stationed troops may become clinically apparent only after their return home. In the aftermath of the Vietnam War, more than 13,000 cases of malaria—the vast majority due to P. vivax—were imported into the United States. Of the 7683 Soviet troops diagnosed with P. vivax malaria acquired during the U.S.S.R.’s war in Afghanistan in the 1980s, 76% developed clinical manifestations >1 month after their return to the U.S.S.R., with some cases developing as long as 3 years later.

Imported malaria with prolonged clinical latency periods remains a problem among veterans returning from wars in endemic areas. In a cluster of 112 cases of imported disease in U.S. Marines returning to the United States from deployment to Somalia in 1993, falciparum malaria was diagnosed as late as 12 weeks after return; some cases due to P. vivax were diagnosed after an additional 2 months. In an outbreak of imported P. vivax malaria among U.S. Army Rangers deployed to Afghanistan in 2002, the median time to diagnosis was nearly 8 months after return.

Although malaria is largely preventable through the combined use of vector control, personal protective measures (e.g., bed nets, insect repellent, long sleeves, permethrin-treated clothing), and chemoprophylaxis, nonadherence to these measures and/or to chemotherapy (including terminal primaquine prophylaxis to eradicate the liver stages of P. vivax and P. ovale) appears to be responsible for the majority of cases in recent U.S. military experiences. However, there is also evidence to support chemoprophylaxis failures in a small subgroup of cases of P. falciparum and P. vivax malaria acquired during U.S. deployments to Somalia. Thus, imported malaria in returning war veterans remains possible despite appropriate adherence to chemoprophylaxis.

Viral Hepatitis

(See Chap. 332) The incidence of viral hepatitis, once a major scourge of military campaigns and their aftermath, has declined considerably over the past half-century of military engagements. Although more than 115,000 cases of viral hepatitis, most due to hepatitis A virus, were reported among Soviet troops serving in Afghanistan in the 1980s, only rare reports of hepatitis A and B were noted during the massive, short-term deployment of U.S. troops to the Persian Gulf in the early 1990s. Hepatitis A and E, endemic in many parts of the developing world, present clinically as acute infections transmitted by the fecal–oral route and can be largely controlled with interventions practiced widely among military forces from industrialized countries: appropriate food and water hygiene and predeployment vaccination against hepatitis A. Contamination of serum-stabilized yellow fever vaccine with hepatitis B virus caused a large outbreak of hepatitis B among U.S. forces during World War II; such events are currently unlikely, given the use of modern virus-inactivation techniques in vaccine manufacturing. Despite their potential—as a consequence of prolonged clinical incubation and latency periods—to cause disease in returning veterans, hepatitis B and hepatitis C have been acquired relatively rarely in theater because of risk factor mitigation: routine drug testing of modern armies and screening of the blood supply to exclude viral contamination.

Rabies

(See Chap. 203) Deployed soldiers are often in close contact with feral dogs and other potentially rabid animals in both urban and remote combat environments. In the period 2001–2010, 643 animal bites were documented during medical encounters among U.S. forces in the combat theaters of southwestern and central Asia; the majority of these potential exposures were dog bites. Of bitten personnel, 18% received rabies postexposure prophylaxis. In 2011, a U.S. soldier developed rapidly progressive signs and symptoms of rabies 8 months after a dog bite in Afghanistan and died within 17 days of illness onset. This case, which represents the first rabies death in nearly 40 years in a member of the U.S. military who acquired the infection overseas, reinforces both the lethality of the disease and the need to practice vigilant exposure precautions among deployed military personnel and to administer postexposure prophylaxis to troops who are bitten by animals in high-risk areas.

Leishmaniasis

(See Chap. 221) Various forms of leishmaniasis may be acquired during military deployment and may present with myriad chronic clinical manifestations in war veterans. Because the protozoal Leishmania species are endemic throughout much of southwestern and central Asia, the diseases they cause have occurred in veterans returning from several recent conflicts there. The widespread distribution of various species of Leishmania elsewhere throughout the developing world suggests that leishmaniasis may complicate future conflicts as well.

Leishmaniasis may present clinically as cutaneous, mucocutaneous, or visceral disease; all forms are transmitted to humans by the bite of infected phlebotomine sandflies via zoonotic (small mammal) reservoirs. In rare circumstances, infection may be transmitted through blood transfusion. Transmission to humans is enhanced by factors that bring them into close proximity with animal reservoirs, such as life in dense, mobile populations; disruption of ecologic niches; and infrastructural breakdown. All of these factors are common sequelae of war.

At least 1300 cases of cutaneous leishmaniasis caused by L. major or L. tropica have been diagnosed in American soldiers deployed to Iraq and Afghanistan over the past decade; however, the actual burden of infection may be higher due to underreporting, as lesions spontaneously resolve in many cases. The infection manifests clinically as one or more chronic, painless skin ulcers or nodules that may persist for 6–12 months. Rarely, lesions of cutaneous leishmaniasis may disseminate locally or diffusely.

Visceral disease (kala-azar) is typically caused by L. donovani and may be life-threatening. There have been at least five confirmed reports of U.S. veterans returning from recent deployments with classic visceral leishmaniasis associated with chronic fever, weight loss, pancytopenia, hypergammaglobulinemia, and organomegaly. As systemic leishmanial infection is known to manifest clinically years after exposure and may recrudesce if host immunity wanes due to unrelated causes, it remains possible that additional cases may yet surface.

Chronic Diarrhea

Although acute bacterial gastroenteritis remains a major noncombat cause of morbidity and duty days lost during troop deployments, chronic illness is unusual. However, selected bacterial and parasitic enteric pathogens may cause chronic infections or illnesses in returning veterans. Such infections have been uncommonly noted in recent deployments, but, because of their worldwide prevalence, they pose potential threats in future wars.

Giardiasis (Chap. 224), amebiasis (Chap. 218), and cryptosporidiosis (Chap. 224), which usually cause self-limited protozoal gastroenteritis in immunocompetent hosts, may result in persistent symptoms in immunocompromised populations or when complicated by secondary illness. Giardia infection has been associated with chronic diarrhea due to postinfectious irritable bowel syndrome and with chronic signs and symptoms of systemic illness in association with postinfection fatigue or protein-losing enteropathy. Cryptosporidiosis may cause chronic diarrhea or malabsorptive syndromes in immunocompromised individuals. Amebic infection of the colon may be associated with several serious complications in addition to diarrhea, including perforation, fistulae, and obstruction; extraintestinal spread of amebiasis may result in hepatic or pleural/pulmonary invasion leading to abscess formation.

Systemic Illness Due to Enteric Pathogens

Certain helminthic infections are endemic in many parts of the developing world and may pose continuing risks to infected military veterans after their return from war. Larvae of the intestinal nematode Strongyloides stercoralis (Chap. 227) either may be passed in the feces and develop into the infective stage in the external environment or may persist in the human small intestine and initiate new infective cycles in a process known as autoinfection. Autoinfection with Strongyloides may result in chronic clinical manifestations such as pruritus, rash, abdominal pain, weight loss, diarrhea, and eosinophilia. In immunocompromised hosts, chronic strongyloidiasis may cause a life-threatening hyperinfection syndrome, likely triggered by high parasite burdens and resulting in a multiorgan, systemic illness consistent with severe inflammatory response syndrome. In some cases, Strongyloides hyperinfection syndrome may be complicated by gram-negative sepsis or meningitis related to bacterial seeding from parasitic involvement of the lungs or gastrointestinal tract. Although not described in association with recent wars, chronic strongyloidiasis was an uncommon phenomenon affecting a small number of World War II and Vietnam War veterans; one study estimated that there were up to 400 affected, living individuals in Great Britain in 2008. The pathogen may pose a risk to troops deployed in the future to tropical and subtropical regions of the world where the parasite is endemic.

Chronic schistosomiasis (Chap. 229) results from intravascular infection by trematode parasites whose larval forms penetrate the skin of humans through contact with freshwater inhabited by the snail intermediate host. The pathogens are widely distributed throughout large portions of the developing world. A chronic inflammatory response in the portal circulation to the eggs of Schistosoma mansoni and Schistosoma japonicum leads to fibrosing disease in the liver and eventually to cirrhosis. Similar pathophysiologic events occur in the vascular plexus of the human genitourinary tract in response to chronic S. haematobium infection, leading to fibrosing changes in the human bladder and ureters—a precursor to bladder cancer. Rarely, individuals with chronic schistosomiasis develop a syndrome of persistent or relapsing bacteremia with Salmonella typhi, which is the etiologic agent of typhoid fever and is not otherwise a typical infectious cause of chronic disease in veterans.

Other Chronic Infections/Syndromes

Awareness of the potential threat of troop exposure to agents of biological warfare (Chap. S2) has been heightened over the past several decades by revelations regarding Iraq’s state-sponsored chemical weapons program in the 1990s, the known broad availability of such technology, and ongoing escalations of global and geopolitical conflicts as well as of international acts of terrorism. Most of the high-risk pathogens posing a threat of bioterrorism cause acute clinical manifestations; however, selected agents, such as those causing Q fever and brucellosis, may result in chronic diseases, whether exposure is natural or intentional. Isolated cases of naturally acquired Q fever and brucellosis have been reported in recent U.S. veterans of the wars in Iraq and Afghanistan. To date, there has been no confirmed evidence of infections related to exposure to biological weapons in returning war veterans.

HIV-1 infection (Chap. 197), ubiquitous throughout the world, continues to pose a potential bloodborne and sexually transmitted risk to soldiers engaged in armed conflict in high-prevalence areas. Several reports describe war veterans returning to their countries of origin harboring HIV-1; in some of these cases, novel viral genotypes acquired during deployments have been imported into the population with returning veterans. Although tuberculosis (Chap. 173) is also endemic throughout much of the developing world and is prevalent in several areas of recent multinational conflicts, the risk of acquiring this infection appears to be low—0.6% in one retrospective study. The incidence of latent tuberculosis infection in returning war veterans has been shown to be no different from that in nondeployed service members.

Several chronic infections that pose a risk to war veterans tend to recur or become clinically active in immunocompromised individuals and may be particularly aggressive in this population. Latent infections such as leishmaniasis, tuberculosis, histoplasmosis, brucellosis, Q fever, and strongyloidiasis in otherwise healthy veterans returning from war may be clinically expressed only much later in the setting of chronic glucocorticoid use, monoclonal antibody therapy, organ transplantation, cytotoxic chemotherapy, advanced HIV-1 disease, hematologic malignancy, or other immunosuppressive conditions. Thus, physicians should remain vigilant regarding the potential development of symptomatic disease due to such latent microbes in immunologically compromised veterans who may have initially acquired an infection years previously while serving in the military.

A number of syndromes of possible infectious etiology, some of which may present with chronic clinical manifestations, have been noted in veterans returning from recent wars. After the Gulf War in 1990–1991, numerous veterans from several countries experienced constellations of various common, nonspecific symptoms, including fatigue, musculoskeletal pain, sleep disturbances, and difficulty concentrating. Despite exhaustive investigations of several hypotheses regarding potential etiologies of this chronic multisystemic illness, including those involving infectious agents, no unifying or single cause has yet been identified. In a randomized, placebo-controlled trial, a prolonged course of doxycycline failed to alleviate “Gulf War syndrome” symptoms at 1 year. In 2003, a small outbreak of acute idiopathic eosinophilic pneumonia was reported among U.S. troops serving in southwestern Asia. Although a thorough investigation failed to elucidate an infectious etiology, it is noteworthy that symptoms developed up to 11 months after arrival in the theater of combat; this time frame suggests that such cases may become clinically manifest after return to the home front.

Chronic Wound Infections and Osteomyelitis

War wounds, an important cause of morbidity in all armed conflicts, are at high risk of infection due to contamination with environmental bacteria and the presence of retained foreign bodies at the time of initial injury. In recent conflicts, improved survival rates due to enhanced and expedited care of combat casualties have had the unintended consequence of increasing the potential for infectious complications, a situation exacerbated by repeated and at times prolonged exposure to health care environments and their associated pathogens. Many wounds sustained in recent wars have resulted from penetrating soft-tissue trauma and open fractures of the extremities—injuries attributable to improvised explosive devices used as antipersonnel weapons and to body armor that leaves the limbs unprotected. Cultures of samples taken at the time of injury at a combat support hospital in Iraq revealed that most contaminated wounds harbored gram-positive commensal skin bacteria; other investigators, however, have noted an early predominance of gram-negative bacteria, including multidrug-resistant (MDR) pathogens.

Approximately 3% of nearly 17,000 combat injuries sustained between 2003 and 2009 in U.S. military operations in Iraq and Afghanistan involved soft tissue infections. Although it is not clear how many of these infections became chronic or progressed to involve deeper tissue structures, a significant number were managed in tertiary-care facilities, many on the home front. The bacteriology of infected combat wounds comprises predominantly gram-negative bacilli and MDR organisms. Broad-spectrum antimicrobial prophylaxis administered at the time of injury appears to be a risk factor for subsequent infection; nosocomial acquisition of health care–associated MDR pathogens likely contributes as well. Chronic wound infection is associated with excessive morbidity, including increased risk for delayed secondary limb amputation.

During the past decade of wars in Iraq and Afghanistan, MDR strains of Acinetobacter baumannii (Chap. 157) have emerged as important pathogens in both wound and bloodstream infections among returning veterans treated at U.S. health care facilities. The majority of isolates display in vitro susceptibility to amikacin and variable susceptibility to carbapenems but are largely resistant to other commonly used antimicrobial agents. Antimicrobial treatment should be guided by in vitro susceptibility data; patients who are critically ill, are immunocompromised, or have significant medical comorbidities may benefit from combination therapy. Colistin (polymyxin E) has been shown to be clinically effective against Acinetobacter infections caused by isolates resistant to both aminoglycosides and carbapenems. Mortality rates have been low among immunocompetent hosts receiving appropriate antimicrobial treatment and undergoing debridement; however, Acinetobacter infections in immunocompromised individuals are associated with higher mortality risk. Strict adherence to hand-washing and other infection control procedures is important to limit the nosocomial spread of MDR organisms.

Invasive fungal infections have recently emerged as a significant cause of morbidity in a subset of military personnel with combat wounds acquired during service in southwestern and central Asia. Specific risk factors appear to include excessive blast injuries from improvised explosive devices while “dismounted” (i.e., on foot); above-the-knee traumatic amputations; large-volume blood transfusion requirements; and macroenvironmental conditions favoring mold contamination. Molds from the order Mucorales, Aspergillus species, and Fusarium species make up the vast majority of isolates in invasive fungal infections; multiple fungal species are noted in a significant minority of cases. Aggressive and often repeated surgical debridement of infected tissue is the primary form of therapy; broad-spectrum empirical antifungal therapy is indicated initially, pending the results of mycologic studies. Invasive fungal infections have been shown to delay initial wound closure and increase the frequency of proximal amputation revisions.

Chronic osteomyelitis related to either extension of a contiguous soft-tissue infection or an infected prosthesis also represents a burgeoning problem for wounded veterans of recent wars. Limited microbiologic data have shown a predominance of gram-negative etiologic agents—most often Acinetobacter and Pseudomonas aeruginosa—in the initial episodes of osteomyelitis but a shift to staphylococcal isolates in the majority of recurrent cases—a change that may be related to nosocomial acquisition. Relapses have been noted to occur 1 month to 1 year after treatment of the initial infection.

Veterans with traumatic brain injury, who have accounted for 22% of American casualties in recent wars in Iraq and Afghanistan, are at risk for infectious complications due to several factors: the presence of foreign bodies or prosthetic material related to their traumatic wounds; the acquisition of a wide range of nosocomial infections during repeated interactions with the health care system; and injury-induced cognitive changes that may increase impulsivity and risk-taking behaviors. In line with the last-mentioned factor, this subgroup of veterans may be at heightened risk for substance abuse and other practices that expose them to various bloodborne and sexually transmitted infections. Moreover, they may be at risk for post-neurosurgical complications, such as pyogenic meningitis due to MDR Acinetobacter species.

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