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Gulf War and Health: Volume 5. Infectious Diseases 6 DISEASES AND AGENTS OF SPECIAL CONCERN TO VETERANS OF THE GULF WAR, OPERATION IRAQI FREEDOM, AND OPERATION ENDURING FREEDOM Several diseases and agents have been reported in the published literature or in the popular press to have infectious components and to have caused illnesses in veterans of the Gulf War, Operation Iraqi Freedom (OIF), and Operation Enduring Freedom (OEF). This chapter provides information on each of those diseases and agents—Al Eskan disease, idiopathic acute eosinophilic pneumonia, wound and nosocomial infections (for example, infections caused by Acinetobacter baumannii), mycoplasmas, and biologic-warfare agents. AL ESKAN DISEASE In the early 1980s, King Khalid of Saudi Arabia attempted to settle Bedouins in a group of villages, including one in Riyadh called Al Eskan (Korenyi-Both et al. 1992). However, the villages were never used until the US military came to the region for Operation Desert Shield (ODSh) and Operation Desert Storm (ODSt). The 316th Station Hospital personnel lived in Al Eskan village from January 12 until March 12, 1991. Korenyi-Both and colleagues observed among the troops a vague systemic illness (causing primarily respiratory symptoms) that they termed Al-Eskan disease or Desert Storm pneumonitis (Korenyi-Both et al. 1997; Korenyi-Both et al. 1992; Korenyi-Both et al. 2000). Their investigations ascribe the illness to an immune response to sand-particle exposure (Korenyi-Both et al. 1997; Korenyi-Both et al. 2000). However, the hypotheses and conclusions of those researchers have not been uniformly accepted and have generated considerable debate (Clooman et al. 2000; Kilpatrick 2000). During ODSh and ODSt, about 697,000 US troops were deployed. It is not possible to determine the exact number of troops affected by Al Eskan disease. However, data on respiratory illnesses in troops are available; those data are summarized in detail in Chapter 4. Respiratory symptoms were more common in those with a history of lung disease, smoking, and longer deployment and they were more common in those with less outdoor exposure and most prominent in personnel who slept in air-conditioned facilities. Among the 282 316th Station Hospital personnel who lived in the Al Eskan village, the prevalence of respiratory illness was 43% (Korenyi-Both et al. 1992). During the period September-March of 1992, the marines reported respiratory illness in 2.3% of troops, and the Air Force reported 2.6%. A brigade of a separate mechanized infantry (1,800 soldiers) conducted training in the same region of Saudi Arabia over five summer seasons and reported respiratory
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Gulf War and Health: Volume 5. Infectious Diseases illness in 0.2% of the soldiers. Al Eskan disease or a similar illness has not been reported in troops deployed to OIF or OEF. Description of Acute Illness Al Eskan disease was first reported in 1992 (Korenyi-Both et al. 1992). The disease is characterized by sudden or insidious onset of chills, fever, sore throat, hoarseness, nausea and vomiting, and generalized malaise and then respiratory tract complaints, including increasingly severe dry cough or expectoration of tan sputum. Some patients experience symptoms of gastroenteritis. Physical findings are minimal, and x-ray pictures on occasion reveal “atypical pneumonitis”. The disease appears to be self-limited, and less than 1% of patients with the complaints had a relapse. Systematic description and precise case definition of Al Eskan disease are unavailable. Long-Term Adverse Health Outcomes No data link Al Eskan disease to any specific chronic illness. In their initial report, Korenyi-Both et al. (1992) indicated that most patients had recovered within 6 weeks and that the relapse rate was less than 1%. They argued later that exposure to sand particles can serve as a source of pneumoconiosis and can stimulate a severe and perhaps chronic allergic immune response (Korenyi-Both et al. 1997; Korenyi-Both et al. 2000). They refer to such a chronic immune response as the “second phase of Al Eskan disease”, which they imply might explain some of the health problems noted in Gulf War veterans (Korenyi-Both et al. 1997). Pathogenesis Military personnel deployed to the Persian Gulf are inevitably exposed to sand. Working at the Armed Forces Institute of Pathology, Irey (1994) reported birefringent sand particles in the lungs of some of 86 casualties from the Kuwait theater of operations. However, the author found no long-term lung inflammation. Korenyi-Both et al. demonstrated that although many sand grains were agglomerated, 18% of the sample included dispersed particles in the range of 0.1-0.25 µm; such particles would be expected to bypass lung defenses (Korenyi-Both et al. 1992). The sand material was extremely rich in calcium and silicon. Sand from Iraq had a calcium-to-silicon ratio of 4.2:1, and sand from Kuwait had a ratio of 3.75:1 (Korenyi-Both et al. 1997). Both the size of the sand grains and their composition differ considerably from those of sand samples harvested from other sites (for example, sand taken from Hawaii). Cultures of the sand showed some filamentous fungi, yeast, and staphylococcal species. No mycobacteria or chlamydia specimens were recovered. Contamination of sand with weapons of chemical warfare has been proposed but not studied (Korenyi-Both et al. 2000). Korenyi-Both et al. have argued that Al Eskan disease is most likely a form of acute silicosis aggravated by the pulmonary immune response and perhaps other genetic and environmental factors (Korenyi-Both et al. 1997; Korenyi-Both et al. 1992; Korenyi-Both et al. 2000). However, there are no clinical data to support that hypothesis and no reports of chronic lung disease consistent with silicosis in veterans.
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Gulf War and Health: Volume 5. Infectious Diseases Treatment Korenyi-Both et al. (1992) indicate that cephalosporin antibiotics and expectorants were useful and that no response to the quinolone antibiotic ciprofloxacin was observed. Supporting data were not presented. Summary There is no evidence that the syndrome or disease observed in troops in Al Eskan village was caused by a communicable microbial pathogen. Indeed, Koryeni-Both et al. have argued that the disease is caused by exposure to the unique sand dust of the central and eastern Arabian Peninsula and in particular to the silica in the sand. They note that given the sand-mediated damage to helicopters in the fields and silicosis in Somali camels, sand-mediated disease in humans would be expected. More than 13 years have passed since the initial description of Al Eskan disease appeared in the literature, but little progress has been made in linking chronic respiratory diseases in military personnel to exposure to Persian Gulf sand. IDIOPATHIC ACUTE EOSINOPHILIC PNEUMONIA Idiopathic acute eosinophilic pneumonia (IAEP) is a syndrome characterized by a febrile illness, diffuse pulmonary infiltrates, and pulmonary eosinophila (Allen et al. 1989; Badesch et al. 1989; Philit et al. 2002). Patients with IAEP have no history of asthma, allergy, or chronic lung disease and no discernable infection. Relapse is uncommon after recovery. Severe pneumonia was reported in 19 military personnel deployed in OIF, 10 of whom had IAEP (Shorr et al. 2004). Prospective surveillance from March 2003 to March 2004 led to detection of eight additional cases of IAEP (Shorr et al. 2004). Twelve patients required mechanical ventilation, and two died. Given that 183,000 personnel were deployed in Iraq during the study period, the incidence rate of IAEP was calculated as 9.1/100,000 person-years. Of the 18 patients, 15 were in the Army, two in the Navy, and one in the Marines; 16 were men. The peak incidence of IAEP was in the summer months. Description of Acute Illness Patients with IAEP present with fever, diffuse pulmonary infiltrates, cough, shortness of breath, and, not infrequently, respiratory failure. The case definition of IAEP requires recovery of pulmonary eosinophils in high concentration in bronchial lavage (Allen et al. 1989; Badesch et al. 1989; Philit et al. 2002). In six lavage specimens recovered from military recruits, eosinophils made up 24-75% of the cells recovered (Shorr et al. 2004). Peripheral blood eosinophilia may or may not be present and may increase during the course of illness (Shorr et al. 2004). Lung biopsies reveal acute and organizing alveolar damage with eosinophils filling alveolar and interstitial air spaces (Tazelaar et al. 1997). Long-Term Adverse Health Outcomes Most IAEP patients who survive the acute illness make a complete recovery. Twelve of 16 military IAEP survivors were evaluated 1-4 months after diagnosis; none required corticosteroid therapy (Shorr et al. 2004). Three patients reported mild residual dyspnea and one
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Gulf War and Health: Volume 5. Infectious Diseases had wheezing. Pulmonary-function tests showed that forced vital capacity was 97% of predicted, and forced expiratory volume 94% of predicted. However, mean carbon monoxide diffusing capacity was 82% of predicted. Pathogenesis In many cases, IAEP has been associated with cigarette smoking and exposure to dust (Badesch et al. 1989; Pope-Harman et al. 1996; Rom et al. 2002). Shorr et al. (2004) found that the most common exposures in the IAEP-diagnosed military patients were cigarette-smoking (100%), exposure to dust or sand (94%), convoy operations (70%), and exposure to the local population (71%). However, cases were different from controls only in their tobacco exposure. All the patients were smokers and 14% were new smokers, whereas only 67% of controls were smokers and only two of seventy-two controls were new to smoking (OR 1.22, p < 0.001). Other investigators have related cigarette-smoking to IAEP (Badesch et al. 1989; Shintani et al. 2000; Watanabe et al. 2002). Treatment Corticosteroids are the mainstay of therapy for IAEP and most patients respond quickly to it (Allen et al. 1989; Badesch et al. 1989; Philit et al. 2002). Some patients with IAEP require mechanical ventilation. Summary Eighteen soldiers deployed to OIF developed IAEP. By definition, no causative pathogens were detected or implied by the immune response of soldiers with IAEP (Allen et al. 1989; Shorr et al. 2004). Toxocara canis and other helminthic pathogens known to produce eosinophilic pneumonia were specifically excluded (Roig et al. 1992; Shorr et al. 2004). Survey results failed to identify a common source of environmental, drug, or toxin exposure (Shorr et al. 2004). Rapid detection of this condition is essential for a positive outcome. IAEP would not be expected to have long-term adverse health outcomes. WOUND AND NOSOCOMIAL INFECTIONS (INCLUDING INFECTIONS WITH ACINETOBACTER SPP.) Soldiers can experience a wide variety of exposures to pathogens from explosives or combat (wound infections) or in health-care settings (nosocomial infections). Trends in casualty rates in modern US military warfare indicate rising wounded-to-killed ratios in the most recent wars (Department of Defense, 2005). Military personnel who might have been killed in an earlier era may now live to be hospitalized because of the use of body armor, better helmets, and more rapid emergency care. These soldiers with serious wounds can carry organisms of environmental origin (for example, from soil or water) into the hospital setting. Organisms of environmental origin that are prevalent in wound infections can colonize fomites and be transmitted to others via hospital personnel. Nosocomial infections in military hospitals may have different microbial profiles from those in civilian hospitals in that they represent soil or water organisms prevalent in wounds suffered in explosions or combat. Nosocomial organisms that are familiar in civilian settings can
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Gulf War and Health: Volume 5. Infectious Diseases also be seen in soldiers, given the conditions prevalent in intensive-care units (ICUs) and hospital wards when universal precautions are not adhered to. Concerns Regarding Acinetobacter baumannii One condition that is more prevalent in OEF and OIF troops than in civilian settings is infection with Acinetobacter calcoaceticus-baumannii complex, a well-recognized cause of wound infection in general and among military troops in particular (CDC 2004; Davis et al. 2005). The complex is also a cause of nosocomially-acquired infection when wounded, infected soldiers are intermingled with other patients in the ICU, emergency room, or hospital ward. Acinetobacter spp. infection has been discovered in wounds from OEF and OIF and in European and American hospitals because of nosocomial transmission (CDC 2004; Davis et al. 2005; Joly-Guillou 2005). It is likely that wound infections become a nidus for nosocomial transmission to others, particularly in an ICU setting, because of suboptimal handwashing by hospital personnel (Joly-Guillou 2005). A. baumannii is the species isolated most often. Acinetobacter spp. infection was described decades ago as a cause of postsurgical urinary tract infections, but in the early 21st century is seen more often as an extremity wound infection, a respiratory tract infection, or bacteremia (CDC 2004; Davis et al. 2005; Joly-Guillou 2005). The human body louse has been reported to be a likely vector (La Scola and Raoult 2004). Multiple-drug-resistant A. baumannii has been reported in troops deployed in OIF and OEF (CDC 2004; Davis et al. 2005; Zapor and Moran 2005), in Israelis hospitalized in Tel-Aviv (Abbo et al. 2005), in patients in a Brazilian tertiary referral hospital (Reis et al. 2003), and in South Korean hospital patients (Lee et al. 2003). Environmental sources are ubiquitous, including soil and river water worldwide, including in the United States (Ash et al. 2002). Examples of extremity infections include osteomyelitis, postburn lesions, open fractures, and deep wounds. The origin of Acinetobacter spp. infection can therefore be the original soil contamination due to the injury, a hospital, or, very rarely, a community source unrelated to a known wound. A patient’s history and epidemiologic circumstances can indicate which source is most likely to be responsible. Although most Acinetobacter spp. infections are not life-threatening, multiple-drug-resistant strains are now prevalent among US military troops returning from OEF and OIF (CDC 2004; Davis et al. 2005). Extended use of combination antibiotics to which the organisms are sensitive was successful in curing all patients in a case series of 23 infected US soldiers reported in 2005 (Davis et al. 2005). Among the 38 isolates obtained from these 23 men, susceptibility varied from 3% to 29% for amoxicillin-clavulanate, cefepime, cefotetan, ceftazidime, ceftriaxone, ciprofloxacin, gentamicin, tobramycin, and trimethoprim and sulfamethoxazole. About half the 38 isolates were sensitive to amikacin and to ampicillin and sulbactam. Imipenem was effective against 89% of the multiple-drug-resistant strains. Colistin was effective against 100%, but only three isolates were tested (Davis et al. 2005). To minimize the risk of nosocomial A. baumannii spread, Iraqi-based US military facilities now isolate new wound patients until results of colonization swabs are known (Davis et al. 2005). Earlier generation antibiotics that are not in widespread current use (including colistin and polymyxin B) have been administered to multiple-drug-resistant A. baumannii patients. However, A. baumannii resistant to polymyxin B was reported in Brazil in 2003 (Reis et al. 2003). The Brooke Army Medical Center experience in San Antonio suggested a median of 6 days and a maximum of 12 days between an OIF- or OEF-acquired war injury and the presentation of Acinetobacter spp. in a defined wound or bone infection (bone, draining
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Gulf War and Health: Volume 5. Infectious Diseases purulence, or wound) (Davis et al. 2005). Of blood, urine, wound, or sputum specimens obtained from March 2003 to May 2004, 145 of 24,114 (0.6%) were positive for Acinetobacter spp. Among those sampled were 237 active-duty patients with injuries, 151 of whom had been deployed to OEF or OIF. Blood, wound, sputum, urine, and skin cultures were obtained on 84 of those deployed soldiers, and 48 of them (32%) were Acinetobacter spp.-positive. Thirty of the 237 patients were judged to have either wound injuries or related osteomyelitis; the wound or bone infections represented 63% of the culture positives, 36% of all OEF- or OIF-deployed men who were cultured and hospitalized, and 20% of all those with injuries who had been deployed to OEF or OIF. Those results demonstrate that Acinetobacter spp. is a common cause of wound infection or related osteomyelitis in men hospitalized for their war-related injuries from OEF and OIF. That no soldier had more than 12 days between injury and infection is informative, although a larger series would be needed to assess more accurately what a maximal incubation period might be. Another contemporaneous case series of 102 patients with A. baumannii bacteremia was published; the cases presented in 2002-2004 at the Landstuhl Regional Medical Center (which accounted for about 78% of the patients), Walter Reed Army Medical Center (WRAMC), Brooke Army Medical Center (BAMC), National Naval Medical Center, and the US Navy hospital ship Comfort (Joly-Guillou 2005). The typical patient was a male soldier who experienced a traumatic injury in Iraq. In this multihospital series and the BAMC series, A. baumannii bacteremia was common in OEF and OIF returnees who were hospitalized for injuries, but it was rare before the start of OEF and OIF (CDC 2004; Davis et al. 2005; Zapor and Moran 2005). No late manifestations (months after injury) were reported in either case series (CDC 2004; Davis et al. 2005). Death from A. baumannii is unusual. The only four deaths at WRAMC from 2003 to 2004 attributable to A. baumannii were in immunosuppressed patients whose ages were 35 years (renal transplantation and nosocomial pneumonia), 72 years (prolonged hospitalization with congestive heart failure), 78 years (diabetes and prior malignancy), and 84 years (in nursing home, mental status changes, and nosocomial pneumonia) (Zapor and Moran 2005). Fifty-three multiple-drug-resistant A. baumannii cases were seen at WRAMC in the 2003-2004 period, 34 in civilians and 19 in active-duty personnel. Zapor and Moran assert that successful reduction of risk to noncombatants and combatants alike who share hospital wards with infected combatants will require more rigorous universal precautions with thorough education of staff, patients, and family members. Emerging infectious diseases, by definition, may arise from unanticipated sources. A previously unrecognized Acinetobacter-like organism from dog and cat bites was reported in 2002 (Kaiser et al. 2002). It is possible that organisms will emerge from southwest and south-central Asia that are not recognized as threats to soldiers or civilians. Hospital-based microbiologic and epidemiologic surveillance should be conducted on newly recognized organisms, as was done with the reports of drug-resistant A. baumannii in US military hospitals (CDC 2004; Davis et al. 2005). Other Wound Infections Nearly any war-theater injury, whether combat-derived or otherwise, may result in infection. The risk of infection is inherent in military service, training, readiness activities, transport, or combat (Zapor and Moran 2005). Men and women deployed to OEF and OIF face the risk of being injured by explosive devices of many types, including improvised explosives,
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Gulf War and Health: Volume 5. Infectious Diseases mortars, and grenades. Torso injuries are less common than in prior conflicts because of widespread use of body armor, but it does not protect the extremities or head. Infections of skin and orthopedic wounds of the extremities are the most common reported causes of inpatient consultations for OEF and OIF returnees at WRAMC (Zapor and Moran 2005). A BAMC wound-bacteriology survey was conducted in 2004 at a Combat Support Hospital in Baghdad, Iraq (Zapor and Moran 2005). It covered 49 soldiers who had 61 wounds, primarily blast injuries of the extremities. Eighteen of the soldiers (with 20 wounds) underwent wound lavage, had antibiotics administered at the time of the injury, or both. Of the 40 bacteria obtained from 30 wounds, most were obtained from soldiers before they received antibiotics. Gram-positive commensal skin bacteria, such as Staphylococcus spp. and Micrococcus spp. were found in 93% of isolates. Less common were gram-negative bacterial genera, such as Pseudomonas, Chryseobacterium, and Escherichia. Two isolates demonstrated broad antibiotic resistance; both were methicillin-resistant Staphylococcus aureus. To reconcile the differences in the bacteriologic profiles noted in this unpublished survey with those at stateside military hospitals (the latter see more Acinetobacter spp. and extended-spectrum -lactamase-producing lactose-fermenters), Zapor and Moran recommended larger field hospital surveys from multiple locations, using best-practice sampling and microbiologic methods (Davis et al. 2005; Zapor and Moran 2005). Wound infections occur shortly after the wounds themselves, with exceptions, such as infections associated with chronic osteomyelitis that are rare with modern medical care. Therefore, making an epidemiologic link to service in the war theater is rarely difficult. Current military medical practices include surgical debridement of wounds, probing of deep tissues, and cultures of wounds, bone, deep tissues, skin, and other fluids to find and treat infection. Such aggressive management prevents chronic osteomyelitis in the vast majority of wounded soldiers. If a stateside civilian, military, or Department of Veterans Affairs (VA) medical facility encounters chronic osteomyelitis, it is the one clear example of an infection that may result from underdetection and undertreatment or from hospital acquisition. That condition can theoretically manifest far from the war and later, although it will be rare, as judged from the near absence of modern case reports. Each case must be evaluated as to the epidemiologic, clinical, and microbiologic characteristics of the infectious disease to judge whether it is linked to the war or is community-acquired. Other Nosocomial Infections Many potential nosocomial organisms may go unrecognized if an outbreak is not apparent and not investigated. Observant clinical providers may reveal outbreaks that might otherwise be missed. For example, a nebulizer from a local manufacturer in Saudi Arabia caused an outbreak of Burkholderia cepacia in US National Guard troops deployed in the Middle East (Balkhy et al. 2005). US manufacturing adhering to Food and Drug Administration requirements would have been expected to virtually eliminate contaminated respiratory products for US troops, but the overseas pharmaceutical plant that made the inhalant medication was not under such scrutiny. Another example is a keratoconjunctivitis outbreak caused by adenovirus type 8 in troops in a hospital setting, but that may have been mistaken for a community-acquired organism if seen out of the context of the outbreak (Colon 1991). Given the relatively short time between exposure and symptoms, most nosocomial conditions would be associated temporally with active military duty in southwest and south-central Asia and would not present any confusion for
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Gulf War and Health: Volume 5. Infectious Diseases stateside medical staff if the troops have not been disbursed; if they have been, the nosocomial origin of the condition might be masked by the “isolated” cases seen by many practitioners. Other causes of nosocomial infections in OEF- and OIF-deployed troops and civilian military employees include those familiar in civilian settings, such as infections caused by methicillin-resistant Staphylococcus aureus (LaMar et al. 2003) and anaerobes (Brook and Frazier 1993). The origin of those infections (southwest and south-central Asia) is evident from the temporal association with deployment, as was the case in the 1991 Gulf War with Irish troops (Humphreys et al. 1988) and in the present conflicts among US troops (CDC 2004; Davis et al. 2005; Zapor and Moran 2005). Returning soldiers may serve as a nidus of organisms that can infect others in the same hospital or rehabilitation unit. A number of prevention research projects have evaluated colonization rates, including those among family members of returning soldiers (Fishbain et al. 2003; Kenner et al. 2003). Unrecognized sources of contamination of the hands of hospital workers are also being investigated, for example, computer keyboards in an ICU (Bures et al. 2000). Nosocomial risks that have been recognized in US military facilities also may be of importance in the field setting, depending on the specific circumstances of the field hospital or clinic (Blatt et al. 1993; Conger et al. 2004; Cumberland and Jones 1987; John 1977; Lamarque et al. 1992). Given the rarity of chronic infections related to wounds, the committee believes that unrecognized wound or nosocomial infections will pose a diagnostic dilemma for returning veterans only in the most unusual circumstances, such as a late-presenting osteomyelitis. A penetrating injury of an extremity (from stepping on a pressure-detonated mine) resulted in chronic osteomyelitis and later squamous-cell carcinoma in a Vietnam veteran in 1987 (Coy 1994). Cultures taken 20 years after the injury (and after 18 years of draining of a sinus tract) grew Bacteroides fragilis, Proteus vulgaris, P. aeruginosa, and Enterococcus faecalis; the patient had been treated with cleocin, erythromycin, and tobramycin (no culture sensitivity results were presented) (Coy 1994). No details were given as to why those complications were manifest and so unsuccessfully managed. Regional Experiences in Non-Americans A number of reports of A. baumannii and other wound infections have come from countries neighboring Iraq or Afghanistan. The reports may provide lessons that inform the care of US troops, especially in the evolution of antibiotic resistance in environmentally acquired A. baumannii. In 2002, A. baumannii infection occurred in 21 patients in a trauma ICU in Qatar; the outbreak was attributed to poor infection-control management and environmental contamination (El Shafie et al. 2004). The organism was sensitive only to amikacin among 17 antibiotics tested, including the carbapenems (El Shafie et al. 2004). In a series of 36 patients infected with 38 strains of A. baumannii in January 2000-August 2001 in a Turkish teaching hospital, only the carbapenems and colistin were fully efficacious against all strains in the laboratory (Ayan et al. 2003). A devastating earthquake in the Marmara region of Turkey in 1999 resulted in the hospitalization of 630 trauma victims at one hospital, of whom 240 were hospitalized for more than 48 hours. Of the 240, 41 patients (17%) had 43 nosocomial infection episodes that resulted in analysis of 143 culture specimens. In the 48 specimens with positive results (34% of specimens), A. baumannii was most common (31%), followed by S. aureus (19%), P. aeruginosa (15%), E. coli (13%), Klebsiella pneumoniae (13%), other Pseudomonas spp. (6%),
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Gulf War and Health: Volume 5. Infectious Diseases and Stenotrophomonas (now called Xanthomonas) maltophilia (4%) (Oncul et al. 2002). Mortality was high, and antibiotic resistance was common, including methicillin resistance in all nine S. aureus strains and resistance to all tested antibiotics, such as carbapenems, in two A. baumannii strains and one P. aeruginosa strain (Oncul et al. 2002). In a 1999 outbreak, 12 of 170 (7%) ICU patients in a Turkish hospital acquired A. baumannii infection; of 25 strains isolated, all were carbapenem-resistant, and the ICU had to be closed and disinfected because of environmental contamination and continuing transmission (Aygun et al. 2002). Wound infections in a Saudi Arabian hospital were assessed in the hot summer months of an unspecified year, possibly 1994 or 1995; of 2331 wounds, 193 (8%) were infected with 283 bacterial strains, and the most prevalent organisms were S. aureus (35% of strains), E. coli (31%), P. aeruginosa (25%), and Klebsiella spp. (10%) (Abussaud 1996). Neonatal ICUs have also experienced multiple-drug-resistant Acinetobacter spp. infections in the Middle East; one series of seven Saudi neonates (of whom three died) demonstrated sensitivity only to imipenem and resistance to 12 other antibiotics tested (probably in 2002 or 2003) (Manzar 2004). One hundred and fifty-seven patients (96% men) at a military hospital in Turkey in 1994-1999 were admitted because of maxillofacial fractures (Ortakoglu et al. 2004). The precipitating events were from traffic accidents (44%), combat (27%), falls (17%), work accidents (10%), and sports (3%). Infectious complications occurred in local wounds and with osteomyelitis due to delayed primary treatment or delayed evacuation. Organisms of concern were not detailed, nor were the treatment experiences of the infected patients. In two ICUs in Saudi Arabia and Kuwait where gram-negative bacterial isolates were studied in 1994-1995, A. baumannii isolates made up 42 of 207 isolates from 172 patients; they were much more common in Kuwaiti isolates (33%) than in Saudi isolates (8%) (Rotimi et al. 1998). Detailed susceptibility testing suggested that all 42 A. baumannii isolates were sensitive to imipenem (both sites) and that all 33 isolates in Kuwait were sensitive to ciprofloxacin and 89% (eight of nine isolates) in Saudi Arabia (Rotimi et al. 1998). War in Lebanon in 1984 was associated with A. baumannii infection in 36 patients with isolates obtained from sputum, wounds, blood, urine, ulcer swab, or vaginal swab (Matar et al. 1992); the organisms were largely sensitive to minocycline, imipenem, and ciprofloxacin at that time. Osteomyelitis was common in 210 patients with maxillofacial injuries seen at the Mostafa-Khomeini Hospital in Tehran, Iran, during the 1981-1986 Iran-Iraq war (Akhlaghi and Aframian-Farnad 1997). Missile or blast hits accounted for 94% of cases, and motor-vehicle accidents 6%. Twenty-four persons (11%) had infectious complications: eight with mandibular and one with maxillary osteomyelitis, one with cervical abscess, six with foreign-body infections (four in silicone implants), and eight with other infections. The authors attributed the high incidence of osteomyelitis to the inability to evacuate and promptly treat patients with wounds, something that will occur only rarely in US military troops (such as in capture after injury with later release). No organisms or treatment approaches were presented in the Iranian series, although the surgical antibiotics used were limited to cephalotin, gentamycin, ampicillin, and penicillin. Afghan guerrilla combatants and civilians seen in a Pakistani hospital in 1985-1987 also had very high wound- and bone-infection rates, which were attributed to the long time between injury and medical attention (Bhatnagar et al. 1992). In 1274 patient records reviewed, about 50% of the patients had musculoskeletal injuries. Comminuted fractures and foreign bodies were
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Gulf War and Health: Volume 5. Infectious Diseases each seen in 6% of patients. Wound infections were seen in 14% of the men, and chronic osteomyelitis in 11%, most often in the femur or tibia. No microbiologic data or infection-treatment outcomes were reported. Those experiences from non-Americans in Afghanistan, Iraq, and neighboring nations suggest that the experience of US military with A. baumannii and combat-related wound infections in southwest and south-central Asia is not unique. Summary Both wound infections and nosocomial infections are hazards for US personnel deployed to OEF and OIF. Given modern medical and surgical treatment and the ability to evacuate injured military personnel rapidly, most infections will be seen within days or weeks of wounds. Longer-term adverse health outcomes are possible but unlikely. MYCOPLASMAS Mycoplasmas are ubiquitous microorganisms found as commensal colonizers and as pathogens in plants, insects, and animals. They are the smallest known free-living organisms (150-250 nm) (Baum 2005; Murray et al. 2005). They are pleomorphic and filamentous and have a deformable membrane, which allows them to pass through filters that retain bacteria. They are fastidious and difficult to culture on cell-free media; at the same time, because of their common presence as nonpathogenic colonizers, they are common contaminants of cell cultures. The propensity for contamination of cell cultures can lead to false conclusions about the association of mycoplasmas with a variety of clinical syndromes (Baum 2005). Furthermore, the major antigenic determinants of mycoplasmas are glycolipids and proteins in the cell membrane, which are serologically cross-reactive with bacteria and human tissues (Murray et al. 2005). Mycoplasmas lack a cell wall, so they are resistant to antibiotics that inhibit cell-wall synthesis, such as penicillins, cephalosporins, and glycopeptides, for example, vancomycin. However, they have been shown to be sensitive to a variety of antibiotics that act at sites other than the cell wall, such as doxycycline, clindamycin, and quinolones (Hayes et al. 1993). Taxonomically, mycoplasmas are assigned to their own class, Mollicutes. Mycoplasmas that can infect humans are members of the family Mycoplasmataceae. Sixteen species of mycoplasma have been found to colonize humans, and five of them have been associated with disease. Mycoplasma pneumoniae is a common cause of tracheobronchitis and pneumonia and can cause outbreaks in crowded settings such as would be found in military deployments (McDonough et al. 1996). M. pneumoniae has also been associated with numerous extrapulmonary manifestations, including a variety of rashes, cardiac abnormalities, aseptic meningitis and meningoencephalitis, and arthralgias. M. hominis has been associated with a variety of genitourinary infections (primarily pelvic inflammatory disease). M. fermentans (incognitus strain) and M. penetrans have been associated with a severe multisystem disease in both healthy people and people with AIDS (Lo et al. 1989). Culture of M. fermentans on cell-free media (which decrease the risk of contamination) has been extremely difficult, and this has led to controversy over whether the organisms are true pathogens or merely contaminants. M. fermentans has been found in the blood of 11% of HIV-seropositive patients but not in seronegative patients (Hawkins et al. 1992). Although Montagnier, codiscoverer of HIV, at one time postulated that M. fermentans and other mycoplasmas were cofactors for progression to
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Gulf War and Health: Volume 5. Infectious Diseases AIDS, no increase in prevalence of M. fermentans was seen with later-stage AIDS (Cotton 1990; Hawkins et al. 1992). The authors speculated that mycoplasmas may survive as colonizers of mucosal surfaces for many years and that acquisition may be related to high-risk sexual behaviors associated with acquisition of HIV infection. Mycoplasmas and “Gulf War Illness” There have been no reports of cases of M. hominis infection in troops deployed to southwest and south-central Asia. There are no published reports of cases of M. pneumoniae infection; however, search results from a Department of Defense Gulf War hospitalization database identified 5 cases of this infection (see Chapter 4). Nicolson and Rosenberg-Nicolson have suggested that many of the symptoms of “Gulf War Illness” (GWI) could be explained by “aggressive pathogenic mycoplasma infections, such as Mycoplasma fermentans or Mycoplasma penetrans, and they should be treatable with multiple courses of antibiotics, such as doxycycline (100-200 mg/day) or macrolides” (Nicolson and Rosenberg-Nicolson 1995). Nicolson et al. (2003) hypothesized that the source of the infections may have been contamination of the multiple vaccines received by troops before and during deployment. They noted a study by Steele (2000) that found chronic symptoms consistent with GWI in 34.2% of Gulf War veterans who reported receiving vaccines during the war, 11.5% of Gulf War-era veterans (people in the military in 1990-1991 who did not serve in the Gulf War) who reported receiving vaccines, and 3.7% of Gulf War-era veterans who did not receive vaccines. Steele suggested that vaccines used during the war may have contributed to GWI. Nicolson et al. (2003) noted anecdotally that 55 of 73 Gulf War veterans with whom they spoke “indicated that they had good responses to doxycycline and eventually returned to normal duty.” Nicolson et al. referred to an article by Lo et al. (1991), who discovered M. fermentans (incognitus strain), as evidence of the ability of the organism to cause chronic infections. Nicolson et al. further suggested that the presence of similar symptoms in family members supported the possibility of a transmissible agent. Nicolson and Nicolson (1996) reported a sampling of veterans with GWI and 21 healthy controls with a gene-tracking technique. The technique was designed by the authors to detect hybridization signals of M. fermentans DNA in nuclear fractions from the blood cells of subjects. Of 30 subjects, 14 had evidence of infection of leukocytes with this test method (65% were infected with M. fermentans only); 11 of the 14 responded to multiple cycles of antibiotics to which mycoplasmas are sensitive. Four of the successfully treated veterans were retested; results were negative for M. fermentans gene sequences. Further studies by Nicolson et al. (2002) using polymerase chain reaction (PCR) to detect mycoplasma found a 9-fold increase in mycoplasma infections and an 18-fold increase in M. fermentans compared with healthy control subjects. Other investigators have found similar rates of positivity in patients with chronic fatigue syndrome who had no exposure to multiple vaccinations or deployment to the Gulf War (Teixeira et al. 2006). Using their gene-tracking technique, Nicolson and Nicolson (1996) claim to have detected “highly unusual DNA sequences” that “included a portion of a retrovirus genome (the HIV-1 env gene), but not all of the genes that make up the virus.” They speculated further that “the presence of the viral envelope gene in the mycoplasma could be due to genetic manipulation, or much less likely natural causes,” and they went on to say that “the mycoplasmas that we have found in Gulf War veterans are not naturally occurring organisms, or to be more specific, they could have been genetically manipulated to be more invasive and pathogenic (potent biological weapons).”
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Gulf War and Health: Volume 5. Infectious Diseases Independent attempts to confirm the results of Nicolson and colleagues have been unsuccessful. Gray et al. (1999) studied serum from symptomatic and asymptomatic Gulf War veterans who had given prewar and postwar blood samples. They used immunoblot banding for M. fermentans at the University of Alabama Diagnostic Mycoplasma Laboratory, and none of the banding profiles was associated with reported symptoms in veterans. The study revealed that 10.9% of Gulf War veterans and 9.3% of nondeployed veterans who served in the military during the same period as the Gulf War veterans had prewar antibodies to M. fermentans. Of those without pre-existing antibodies, 19.2% of Gulf War veterans and 13.7% of nondeployed veterans developed serologic evidence of new M. fermentans infections. A matched case-control study was conducted to determine the prevalence of M. fermentans antibodies in military personnel before and after Gulf War deployment and seroconversion rates in veterans with and without complaints of GWI (Lo et al. 2000). The study found a predeployment prevalence of M. fermentans-specific antibodies of 4.8% in veterans with GWI and 5.2% in controls; no difference in rates of seroconversion (1.1% in GWI cases and 1.2% in controls) during deployment was found. Lo et al. noted that their serologic test has been shown to be highly sensitive and specific and that most patients, including immunocompromised patients with AIDS, produce detectable species-specific antibodies to M. fermentans. That specificity suggests that the results are not an artifact of intracellular infections that do not yield antibody responses. Lo et al. also noted that “it is difficult to assess the validity and specificity of the NGT [nuclear gene tracking] testing [of Nicolson and colleagues, as discussed above], as there is no precedent for identifying any viral, mycoplasmal, or bacterial infection in clinical specimens using this uncommon technique.” A report prepared for the US Senate Committee on Veterans Affairs Special Investigation Unit on Persian Gulf War Illness stated in part that “M. fermentans has been at times suspected of causing various diseases in humans and, therefore, the center of some controversy” but that “this organism is considered to be a member of the normal human flora” (Dybvig, 1998). Dybvig noted that the NGT method used by Nicolson and colleagues was “an inappropriate diagnostic method for detection of M. fermentans” and that neither the specificity nor the sensitivity of the test had been established. He noted further that “M. fermentans DNA resides within the mycoplasmal cell and would not be present in the material assayed by this procedure, namely, host nucleoprotein.” Dybvig also wrote that genetic engineering of M. fermentans was not technically feasible at the time of his report and certainly did not occur before the Gulf War. Because of the conflicting data related to M. fermentans infections and their possible association with GWI and the suggestion of possible benefits of treatment with doxycycline, the VA conducted a randomized placebo-controlled trial to determine whether doxycycline given at 200 mg/day for 12 months could improve functional status of persons with GWI (Donta et al. 2004). In the trial, 491 deployed Gulf War veterans with GWI and detectable mycoplasma DNA in the blood were randomized to receive either doxycycline or a placebo for 12 months. Of the participants, 324 (66%) had an M. fermentans infection, 197 (40.1%) had an M. genitalium infection, and 53 (10.8%) had an M. pneumoniae infection, either singly or in combination as detected with PCR testing. Although a higher fraction of doxycycline participants than controls showed improvement at 3 months (21.5% vs 9.9%), there was no statistically significant difference at 9, 12, and 18 months. Overall, there was no statistically significant difference between the doxycycline-treated and placebo groups on the primary outcome measures. There was a trend toward fewer unscheduled clinic visits and hospitalizations among doxycycline-treated veterans than placebo subjects, but this was not related to the presence of mycoplasma
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Gulf War and Health: Volume 5. Infectious Diseases infections. Rates of mycoplasma positivity decreased significantly during the 18-month study but did not differ between treatment and placebo groups. Specifically, 55% of the doxycycline-treated participants and 58.2% of the placebo subjects had negative results on tests for any mycoplasma species at 6 months of treatment, and 90% and 86.6%, respectively, had negative results at 18 months. Participants in the doxycycline group had a higher incidence of nausea and photosensitivity. The accompanying editorial by Wesseley (2004) noted that “we are fortunate that it was large enough and conducted diligently enough to give an unequivocal answer for both its primary and secondary end points. Doxycycline treatment has no effect on the health of symptomatic Gulf War veterans.” Summary Several studies by Nicolson and colleagues report a link between M. fermentans and health problems in Gulf War veterans (Nicolson et al. 2002; Nicolson et al. 2003; Nicolson and Rosenberg-Nicolson 1995; Nicolson and Nicolson 1996). However, other investigators were not able to duplicate their work and there are concerns about the NGT technique used by Nicolson et al. (Dybvig, 1998; Gray et al. 1999; Lo et al. 2000). In addition, a well-conducted randomized placebo-controlled trial in which doxycycline was administered to veterans with GWI and mycoplasma infection did not improve the health status of the treated veterans (Donta et al. 2004). After reviewing the evidence on mycoplasmas, the committee believes that mycoplasma infection is not related to the symptoms reported by Gulf War veterans. Mycoplasmas are known to cause other types of acute and long-term adverse health outcomes, as noted in Table 3.1. BIOLOGIC-WARFARE AGENTS Biologic warfare (BW) is defined as the use of microorganisms or toxic products derived from microorganisms to inflict mass casualties in military and civilian populations (Horn 2003). Living microorganisms can multiply in a living target host and cause adverse health effects but require an incubation period of 24 hours to 6 weeks between infection and the appearance of symptoms (Rosenbloom et al. 2002). Toxins cannot reproduce themselves but are more lethal and act relatively quickly. At the time of the Gulf War, Iraq had an active BW program. Iraq’s BW program probably began sometime in the middle 1970s with studies on Clostridium botulinum, bacillus spores, and influenza virus (Leitenberg 2001; Roffey et al. 2002). In the middle 1980s, the program began “in earnest”, and as many as 30 agents might have been investigated for potential use as biologic weapons (Roffey et al. 2002; Zilinskas 1997). Iraq conducted intensive study of five bacterial strains (four strains of Bacillus anthracis and one of Clostridium perfringens), one fungal strain (wheat cover smut), five viruses (Congo-Crimean hemorrhagic virus, yellow fever virus, enterovirus 17, human rotavirus, and camelpox virus), and four toxins (aflatoxin, botulinum toxin, ricin, and tricothecenes) (Zilinskas 1997). Bacillus anthracis, aflatoxin, botulinum toxin, and possibly ricin were weaponized (Roffey et al. 2002; Zilinskas 1997). Iraq is reported to have manufactured almost 10,000 L of botulinum toxin during the 1980s and 1990s (Han and Zunt 2003). Iraq developed bombs, missile warheads, aerosol generators, and helicopter and jet spray systems for dispersal of BW agents (Leitenberg 2001). Iraqi sources reported that aflatoxin, botulinum toxin, and Bacillus anthracis were loaded in missiles and air-delivery bombs in
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Gulf War and Health: Volume 5. Infectious Diseases preparation for the Gulf War (Roffey et al. 2002). The comprehensive report of the special adviser to the director of central intelligence on Iraq’s weapons of mass destruction states that “at a meeting of the Iraqi leadership immediately prior to the Gulf War in 1991, Saddam Husayn personally authorized the use of BW weapons against Israel, Saudi Arabia, and US forces” (CIA 2004). No evidence was found that Iraq deployed any weapons containing BW agents (Roffey et al. 2002; Zilinskas 1997). After the Gulf War, Iraq was supposed to destroy all biologic agents developed for BW purposes. However, the United Nations Special Commission was not able to confirm that the destruction was complete (Zilinskas 1997). The Central Intelligence Agency reports that Iraq probably abandoned its BW program in 1995, although some BW-related seed stocks were discovered by US forces during OIF (CIA 2004). Of the four BW agents that Iraq reportedly weaponized—aflatoxin, botulinum toxin, Bacillus anthracis, and ricin—only anthrax is a living microorganism and capable of multiplying in infected people. Although it is infectious, Bacillus anthracis has little potential for person-to-person transmission (Cieslak and Eitzen 2000). Aflatoxin, botulinum toxin, and ricin are toxins derived from microorganisms and cannot replicate. SUMMARY Al Eskan disease, mycoplasma infection, and exposure to BW agents have long been of concern to veterans of the Gulf War and have been proposed as possible causes of the veterans’ health problems. IAEP and A. baumannii infections have been diagnosed in a number of military personnel serving in OIF and OEF. Having reviewed the data, the committee does not believe that Al Eskan disease and IAEP are caused by infectious organisms. Al Eskan disease might be caused by exposure to silica in the sand; the long-term adverse health outcomes of this disease are unknown. The committee does not expect that people who survive IAEP will experience long-term health outcomes related to that illness. Long-term adverse health outcomes from A. baumannii infections are unlikely to occur, given modern medical and surgical treatments. The evidence does not support mycoplasma infections as a cause of the symptoms reported by Gulf War veterans. No evidence has been found that Iraq deployed anthrax-containing weapons. REFERENCES Abbo A, Navon-Venezia S, Hammer-Muntz O, Krichali T, Siegman-Igra Y, Carmeli Y. 2005. Multidrug-resistant Acinetobacter baumannii. Emerging Infectious Diseases 11(1):22-29. Abussaud MJ. 1996. Incidence of wound infection in three different departments and the antibiotic sensitivity pattern of the isolates in a Saudi Arabian hospital. Acta Microbiologica et Immunologica Hungarica 43(4):301-305. Akhlaghi F, Aframian-Farnad F. 1997. Management of maxillofacial injuries in the Iran-Iraq War. Journal of Oral and Maxillofacial Surgery 55(9):927-930. Allen JN, Pacht ER, Gadek JE, Davis WB. 1989. Acute eosinophilic pneumonia as a reversible cause of noninfectious respiratory failure. New England Journal of Medicine 321(9):569-574.
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Gulf War and Health: Volume 5. Infectious Diseases Lee K, Lee WG, Uh Y, Ha GY, Cho J, Chong Y. 2003. VIM- and IMP-type metallo-beta-lactamase-producing Pseudomonas spp. and Acinetobacter spp. in Korean hospitals. Emerging Infectious Diseases 9(7):868-871. Leitenberg M. 2001. Biological weapons in the twentieth century: A review and analysis. Critical Reviews in Microbiology 27(4):267-320. Lo SC, Dawson MS, Newton PB 3rd, Sonoda MA, Shih JW, Engler WF, Wang RY, Wear DJ. 1989. Association of the virus-like infectious agent originally reported in patients with AIDS with acute fatal disease in previously healthy non-AIDS patients. American Journal of Tropical Medicine and Hygiene 41(3):364-376. Lo SC, Buchholz CL, Wear DJ, Hohm RC, Marty AM. 1991. Histopathology and doxycycline treatment in a previously healthy non-AIDS patient systemically infected by Mycoplasma fermentans (incognitus strain). Modern Pathology 4(6):750-754. Lo SC, Levin L, Ribas J, Chung R, Wang RY, Wear D, Shih JW. 2000. Lack of serological evidence for Mycoplasma fermentans infection in army Gulf War veterans: A large scale case-control study. Epidemiology and Infection 125(3):609-616. Manzar S. 2004. Outbreak of multidrug resistant Acinetobacter in the neonatal intensive care unit. Saudi Medical Journal 25(7):961-963. Matar GM, Gay E, Cooksey RC, Elliott JA, Heneine WM, Uwaydah MM, Matossian RM, Tenover FC. 1992. Identification of an epidemic strain of Acinetobacter baumannii using electrophoretic typing methods. European Journal of Epidemiology 8(1):9-14. McDonough C, Benjamin C, Gray GC. 1996. Select Bibliography of Mycoplasma Pneumoniae Citations with Military Relevance. Bethesda, MD: Naval Medical Research and Development Command. Murray PR, Rosenthal KS, Pfaller MA. 2005. Mycoplasma and Ureaplasma. Medical Microbiology. 5th Edition. New York: Mosby Publishing. Nicolson GL, Nicolson NL. 1996. Diagnosis and treatment of mycoplasmal infections in Persian Gulf War illness-CFIDS patients. International Journal of Occupational Medicine, Immunology and Toxicology 5:69-75. Nicolson GL, Rosenberg-Nicolson NL. 1995. Doxycycline treatment and Desert Storm. Journal of the American Medical Association 273(8):618-619. Nicolson GL, Nasralla MY, Haier J, Pomfret J. 2002. High frequency of systemic mycoplasmal infections in Gulf War veterans and civilians with Amyotrophic Lateral Sclerosis (ALS). Journal of Clinical Neuroscience 9(5):525-529. Nicolson GL, Nasralla MY, Nicolson NL, Haier J. 2003. High prevalence of mycoplasma infections in symptomatic (Chronic Fatigue Syndrome) family members of mycoplasma-positive Gulf War illness patients. Journal of the Chronic Fatigue Syndrome 11(2):21-36. Oncul O, Keskin O, Acar HV, Kucukardali Y, Evrenkaya R, Atasoyu EM, Top C, Nalbant S, Ozkan S, Emekdas G, Cavuslu S, Us MH, Pahsa A, Gokben M. 2002. Hospital-acquired infections following the 1999 Marmara earthquake. Journal of Hospital Infection 51(1): 47-51.
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