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Gulf War and Health: Volume 5. Infectious Diseases 3 INFECTIOUS DISEASES ENDEMIC TO SOUTHWEST AND SOUTH-CENTRAL ASIA THAT HAVE LONG-TERM ADVERSE HEALTH OUTCOMES In Chapter 2, the committee developed an extensive list of infectious diseases that are endemic to southwest and south-central Asia (Table 2.1) and then narrowed the list to diseases or syndromes with known long-term adverse health outcomes (Box 2.2). Although most diseases in that subset have not been reported in military personnel deployed to southwest and south-central Asia, they have historically been diagnosed in local populations and thus pose a theoretical risk to US troops deployed to the region. Also, given the nature and duration of Operation Iraqi Freedom and Operation Enduring Freedom, some of the diseases in Box 2.2 could be diagnosed after a person’s deployment or period of military service. The committee decided that the most effective way to give additional information on the diseases listed in Box 2.2 would be to present them in tables containing A description of the acute syndrome in adults, A description of the potential long-term adverse health outcomes in adults with clinical disease, The frequency with which the long-term adverse health outcomes occur in adults with clinical disease, The delay, if any, between acute infection and onset of long-term adverse health outcomes. Tables 3.1-3.4 categorize the infections of interest by type of pathogen (viral, bacterial, helminthic, or protozoan), and Table 3.5 describes sexually transmitted diseases. The infectious diseases with long-term adverse health outcomes that have been diagnosed in military personnel and that the committee reviewed in depth (see Chapter 5) are also included here.

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Gulf War and Health: Volume 5. Infectious Diseases TABLE 3.1 Bacterial Diseases That Are Endemic to Southwest and South-Central Asia and Have Potential Long-Term Adverse Health Outcomes     Potential Long-Term Outcomes in Adults with Clinical Disease Disease or Syndrome Acute Syndrome(s) in Adults Disease(s), Syndrome(s), or Clinical Features Frequency of Occurrence of Outcomesa Delay Between Acute Infection and Onset of Outcomesb More Prevalent in Southwest and South- Central Asia Than in the United States Anthrax (Bacillus anthracis) Abdominal anthrax: initially fever, acute gastroenteritis, vomiting, bloody diarrhea; hemorrhagic lesions of intestinal lumen followed by massive infected ascites, septicemia, death Sepsis or infection-related organ damage Frequent No   Inhalational anthrax: fever, chills, malaise, cough, nausea or vomiting, dyspnea, sweats, chest discomfort or pleuritic pain, muscle aches, headache followed by respiratory distress due to hemorrhagic mediastinitis and mediastinal lymphadenitis with pleural effusions; often terminates in respiratory damage, shock, death Sepsis or infection-related organ damage Frequent No   Oropharyngeal anthrax: fever, lesion in oral cavity, pharyngeal pain, cervical edema, local lymphadenitis Sepsis or infection-related organ damage Frequent No   Cutaneous anthrax: eschar with surrounding edema, regional lymphadenopathy, fever, malaise, headache; bacteremia in 5% of untreated persons Sepsis or infection-related organ damage Rare No Brucellosisc (Brucella spp) (see Chapter 5 for detailed discussion) Fever, headache, myalgia, hepatosplenomegaly, arthritis, meningoencephalitis Arthritis Common (if untreated) Yes (weeks to years)   Fatigue Common Yes (weeks to years)   Hepatic abnormalities Rare Yes (weeks to years)   Mental inattention Rare Yes (weeks to years)   Neurologic disease Rare Yes (weeks to years)

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Gulf War and Health: Volume 5. Infectious Diseases     Potential Long-Term Outcomes in Adults with Clinical Disease Disease or Syndrome Acute Syndrome(s) in Adults Disease(s), Syndrome(s), or Clinical Features Frequency of Occurrence of Outcomesa Delay Between Acute Infection and Onset of Outcomesb     Osteomyelitis; cardiovascular, splenic, renal, hepatic, respiratory, nervous system, other abscesses Rare Yes (weeks to years)     Sepsis or infection-related organ damage Very rare No     Chronic meningitis and meningoencephalitis Very rare Yes (weeks to years)     Eye involvement (including uveitis) Very rare Yes (weeks to years) Enteric fever (typhoid fever, Salmonella enterica serovar Typhi; paratyphoid fever, S. enterica serovars Paratyphi A, B, C) Fever, bacteremia, headache, lymphadenopathy, enlarged liver or spleen, encephalopathy, intestinal rupture and hemorrhage Endovascular infection Rare No Postinfection enteropathyd Rare No Sepsis or infection-related organ damage Rare No Chronic intestinal carriage Rare Yes (months to years) Infection of gall bladder or gall stones Rare Yes (months to years) Focal infections or abscesses Very rare Yes (weeks to months) Helicobacter pylori infection Usually asymptomatic; occasionally gastritis Atrophic gastritis Common Yes (years to decades)     Duodenal ulcer disease Rare Yes (months to years)     Gastric ulcer disease Rare Yes (months to years)     Gastric cancer Very rare Yes (years to decades) Plague (Yersinia pestis) Bubonic plague: sudden onset of high fever, enlarged and tender lymph nodes; patchy bleeding under skin, may progress to pneumonia or septicemic forms Sepsis or infection-related organ damage Frequent No Pneumonic plague: headache, fever, malaise, muscle pain, pneumonia with cough and bloody sputum; often terminates in respiratory collapse, hemodynamic collapse, death Sepsis or infection-related organ damage Frequent No

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Gulf War and Health: Volume 5. Infectious Diseases     Potential Long-Term Outcomes in Adults with Clinical Disease Disease or Syndrome Acute Syndrome(s) in Adults Disease(s), Syndrome(s), or Clinical Features Frequency of Occurrence of Outcomesa Delay Between Acute Infection and Onset of Outcomesb   Septicemic plague: skin infection leads to bacteremia and severe endotoxemia, often followed by shock, disseminated intravascular coagulation, acute respiratory distress syndrome; fatal if untreated Sepsis or infection-related organ damage Frequent No Q feverc (Coxiella burnetti) (see Chapter 5 for detailed discussion) Fever, headache, myalgia, pneumonitis, hepatosplenomegaly, meningoencephalitis Neurologic residua of meningoencephalitis Very rare No Endovascular infections, osteomyelitis Very rare Yes (weeks to months) Chronic hepatitis Very rare Yes (weeks to months) Post-Q fever fatigue syndrome Unknown Unknown Tuberculosisc (Mycobacterium tuberculosis) (see Chapter 5 for detailed discussion) Initial infection asymptomatic (positive tuberculosis skin test or gamma interferon release assay); progression to active tuberculosis in 1-5% Tuberculosis of lungs, pleura, lymph nodes; meningitis; musculoskeletal, genitourinary, other system effects Common Yes (months to decades) Long-term adverse health outcomes of active tuberculosis Common Yes (months to decades) Enteric infections         Campylobacter infectionc (Campylobacter jejuni) (see Chapter 5 for detailed discussion) Diarrhea, fever, abdominal pain Postinfection enteropathyd Very rare No Guillain-Barré syndrome Very rare Yes (weeks) Reactive arthritis Very rare Yes (weeks) Uveitis Very rare Yes (weeks) Ankylosis spondylitis Very rare Yes (months) Cholera (Vibrio cholerae) Watery diarrhea, may be severe Shock-related organ damage Rare No Escherichia coli gastroenteritis         Enterohemorrhagic E. coli Bloody diarrhea, low or absent fever, hemolytic uremic syndrome, 5-10 days after onset of gastroenteritis Renal damage Common No

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Gulf War and Health: Volume 5. Infectious Diseases     Potential Long-Term Outcomes in Adults with Clinical Disease Disease or Syndrome Acute Syndrome(s) in Adults Disease(s), Syndrome(s), or Clinical Features Frequency of Occurrence of Outcomesa Delay Between Acute Infection and Onset of Outcomesb Other pathogenic strains of E. coli Watery diarrhea, may be severe Postinfection enteropathyd Very rare No Shock-related organ damage Very rare No Melioidosis (Burkholderia pseudomallei) Fever, chills, pneumonia, cellulitis, osteomyelitis, abscesses, bacteremia Sepsis or infection-related organ damage Rare No Abscesses, osteomyelitis Rare Yes (weeks to years) Relapses of pulmonary disease Rare Yes (weeks to years) Plesiomonas shigelloides infection Intestinal manifestations—watery diarrhea or colitis-like dysentery; fever Chronic diarrhea Rare No Sepsis or infection-related organ damage Very rare No Salmonellosis (nontyphoid)c (Salmonella spp.) (see Chapter 5 for detailed discussion) Diarrhea, abdominal pain, nausea, fever Endovascular infection Very rare No Postinfection enteropathyd Very rare No Prosthesis infection Very rare No Sepsis or infection-related organ damage Very rare No Reactive arthritis Very rare Yes (weeks) Reiter’s syndrome (inflammatory arthritis, conjunctivitis, urethritis) Very rare Yes (weeks) Abscesses, local infection Very rare No Chronic intestinal colonization Very rare No Gall bladder infection Very rare No Shigellosisc (Shigella spp.) (see Chapter 5 for detailed discussion) Diarrhea (may be bloody), fever, abdominal pain Postinfection enteropathyd Very rare No Sepsis or infection- related organ damage Very rare No S. dysenteriae: hemolytic uremic syndrome (HUS) Renal failure (HUS-related) Very rare Yes (days)   Reactive arthritis Very rare Yes (weeks)   Uveitis Very rare Yes (weeks)   Ankylosis spondylitis Very rare Yes (months) Yersinia enterocolitica infection Diarrhea, abdominal pain, fever, mesenteric lymphadenopathy, intestinal obstruction, Reactive arthritis Common Yes (weeks)

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Gulf War and Health: Volume 5. Infectious Diseases     Potential Long-Term Outcomes in Adults with Clinical Disease Disease or Syndrome Acute Syndrome(s) in Adults Disease(s), Syndrome(s), or Clinical Features Frequency of Occurrence of Outcomesa Delay Between Acute Infection and Onset of Outcomesb   hemorrhage perforation, sepsis           Abscesses, local infections Very rare No   Sepsis or infection-related organ damage Very rare No   Reiter’s syndrome Very rare Yes (weeks)   Ankylosing spondylitis Very rare Yes (weeks to months) Rickettsioses         Boutonneuse fever (Rickettsia conorii and related species) Dermal eschar followed by fever; headache; myalgias; rash on trunk, extremities, and face; disseminated vascular infection and vascular leakage; focal hepatocellular necrosis; granuloma-like lesions Shock or infection-related organ damage Rare No Ehrlichiosis (Ehrlichia chaffeensis) and anaplasmosis (Anaplasma phagocytophilum) Abrupt onset of fever, severe headache, myalgia, vomiting, nausea, rash, lymphadenopathy, confusion, decreased blood counts, liver abnormalities Shock or infection-related organ damage Very rare No Louse-borne typhus (R. prowazekii) Abrupt onset of headache, fever, chills, myalgia; rash begins at axillary folds of trunk and spreads to extremities; sometimes also nonproductive cough, deafness, tinnitus; high fever causes altered mental state Shock or infection-related organ damage Rare No Recurrence of acute symptoms, sometimes without rash (Brill-Zinnser disease) Very rare Yes (years to decades) Murine typhus (R. typhi) Abrupt onset of fever, severe headache, chills, myalgia, nausea, rash, enlarged liver and spleen, cough, confusion, mental-status changes Shock or infection-related organ damage Rare No Spirochetal illnesses         Leptospirosis (Leptospira interrogans and Wide range of symptoms from subclinical to severe; abrupt onset of flu-like illness, Sepsis or infection-related organ damage Rare No

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Gulf War and Health: Volume 5. Infectious Diseases     Potential Long-Term Outcomes in Adults with Clinical Disease Disease or Syndrome Acute Syndrome(s) in Adults Disease(s), Syndrome(s), or Clinical Features Frequency of Occurrence of Outcomesa Delay Between Acute Infection and Onset of Outcomesb others) lymphadenopathy, jaundice, hepatosplenomegaly, conjunctival suffusion, aseptic meningitis, uveitis, pneumonitis, bleeding, diathesis, sepsis       Rat-bite fever (Spirillum minus) Painful, swollen, ulcerated bite site; swollen lymph nodes, fever, headache, rash, relapses if untreated Relapses (if acute syndrome untreated) Rare No Sepsis or infection-related organ damage Rare No Endocarditis Very rare No Relapsing fever (Borrelia recurrentis louse-borne; other species, tick-borne) Range of severity; fever, headache, myalgia, jaundice, enlarged liver and spleen, rash, central nervous system infection, iritis, iridocyclitis, hemorrhage, mycocarditis, relapses Sepsis or infection-related organ damage Rare No Yaws (nonvenereal treponemal infection, Treponema pertenue) Rash, osteitis Rash (if untreated) Very rare No Of special concern to US troops or veterans Mycoplasmal infection (primary atypical pneumonia) Fever, malaise, cough, headache, rash, cryoglobulinemia, myocarditis, arthritis, meningitis, myelitis, encephalitis, hemolytic anemia, glomerulonephritis, Stevens-Johnson syndrome, arthritis Sepsis or infection-related organ damage Very rare No Bacterial diseases against which all military personnel were immunized and vaccines are highly or fully protective Diphtheria (Corynebacterium diphtheriae) Pharyngeal or wound infection with necrotic membrane formation, respiratory damage, myocarditis Sepsis or infection-related organ damage Frequent No Haemophilus influenzae type B infection Meningitis, epiglottitis, arthritis, osteomyelitis Sepsis or infection-related organ damage Rare No

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Gulf War and Health: Volume 5. Infectious Diseases     Potential Long-Term Outcomes in Adults with Clinical Disease Disease or Syndrome Acute Syndrome(s) in Adults Disease(s), Syndrome(s), or Clinical Features Frequency of Occurrence of Outcomesa Delay Between Acute Infection and Onset of Outcomesb Tetanus (Clostridium tetani) Wound infection leading to muscle spasm, respiratory damage, autonomic instability Sepsis or infection- related organ damage, lockjaw Frequent No Bacterial diseases against which all military personnel were immunized and vaccines are partly protective Meningococcal disease (Neisseria meningitidis) Meningitis, sepsis Sepsis or infection-related organ damage Frequent No Pertussis (whooping cough, Bordetella pertussis) Respiratory tract infection, secondary infections, encephalopathy Trauma from severe cough Rare No Bacterial diseases not more prevalent in Southwest and South-Central Asia than in the United States Actinomycosis (Actinomyces) Abscesses, soft-tissue infection Orofacial, pulmonary, genitourinary disease; osteomyelitis Common Yes (months) Bartonellosis (Bartonella) Cat-scratch disease, systemic infection, encephalopathy, retinopathy Sepsis or infection-related organ damage Rare No Capnocytophaga infection Bite-site infection (dogs), bacteremia, sepsis Sepsis or infection-related organ damage Rare No Chlamydia pneumoniae infection Respiratory tract infections Sepsis or infection-related organ damage, focal infection Rare No Botulism (Clostridium botulinum) Neurotoxicity, cranial nerve palsies, respiratory damage Sepsis or infection-related organ damage Rare No Gas gangrene (Clostridium perfringens) Gas gangrene, wound infection Sepsis or infection-related organ damage Rare No Tularemia (Francisella tularensis) Pneumonia, typhoidal illness, sepsis Sepsis or infection-related organ damage Rare No

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Gulf War and Health: Volume 5. Infectious Diseases     Potential Long-Term Outcomes in Adults with Clinical Disease Disease or Syndrome Acute Syndrome(s) in Adults Disease(s), Syndrome(s), or Clinical Features Frequency of Occurrence of Outcomesa Delay Between Acute Infection and Onset of Outcomesb Haemophilus influenzae infection Exacerbation of chronic obstructive pulmonary disease Pneumonia Common No Acute maxillary sinusitis Chronic sinusitis Common No Empyema, brain abscess, cavernous sinus thrombosis Very rare No Community-acquired pneumonia Infection-related organ damage Very rare No Middle-ear infection Meningitis, brain abscess, sinus thrombosis, mastoiditis, acute petrositis, facial paralysis Very rare No Purulent conjunctivitis Keratitis Very rare No Legionnaire’s disease (Legionella) Respiratory tract infections Sepsis or infection-related organ damage Rare No Listeriosis (Listeria monocytogenes) Diarrhea, meningoencephalitis, endocarditis Sepsis or infection-related organ damage Very rare No Lyme disease (Borrelia burghdorferi) Fever, flu-like illness, arthritis, rash, myocarditis, meningoencephalitis Chronic arthritis Common (if untreated) Yes (weeks to months) Moraxella catarrhalis infection Respiratory tract infection Sepsis or infection-related organ damage Common No Nocardiosis (Nocardia) Soft-tissue infection, pneumonia, brain infection Chronic and progressive tissue damage (Madura foot) Rare Yes (months) Noncholera Vibrio infection Wound infections, diarrhea, bacteremia, sepsis Sepsis or infection-related organ damage Rare No Nontuberculosis mycobacteria infection Chronic soft-tissue infections Chronic focal infections Common No Pasteurella infection Bite-site soft-tissue infection (from cats, dogs), bacteremia, sepsis Sepsis or infection-related organ damage Rare No

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Gulf War and Health: Volume 5. Infectious Diseases     Potential Long-Term Outcomes in Adults with Clinical Disease Disease or Syndrome Acute Syndrome(s) in Adults Disease(s), Syndrome(s), or Clinical Features Frequency of Occurrence of Outcomesa Delay Between Acute Infection and Onset of Outcomesb Staphylococcus infection Focal infections, pneumonia, bacteremia Sepsis or infection-related organ damage Rare No Streptococcus infection Pharyngitis, bacteremia, pneumonia, focal infections Sepsis or infection-related organ damage Rare No Glomerulonephritis Very rare No Rheumatic fever Very rare No Streptococcus pneumoniae infection Respiratory tract infection, meningitis, bacteremia, sepsis Sepsis or infection-related organ damage Rare No Antibiotic-resistant or common nosocomial bacterial infections Acinetobacter infectionc (multiple-drug-resistant) Skin and soft-tissue infections, abscesses, pneumonia, bacteremia, urinary tract infections Sepsis or infection-related organ damage Rare No Enterococcus infection (vancomycin resistant) Skin and soft-tissue infections, abscesses, bacteremia, urinary tract infections Sepsis or infection-related organ damage, endocarditis Rare No Klebsiella infection (multiple-drug-resistant) Skin and soft-tissue infections, abscesses, pneumonia, bacteremia, urinary tract infections Sepsis or infection-related organ damage Rare No Pseudomonas aeruginosa infection Skin and soft-tissue infections, abscesses, pneumonia, bacteremia, urinary tract infections Sepsis or infection-related organ damage Rare No Staphylococcus aureus infection (methicillin-resistant) Skin and soft-tissue infections, abscesses, pneumonia, bacteremia Sepsis or infection-related organ damage, endocarditis Rare No Osteomyelitis Rare Yes (months) Stenotrophomonas maltophilia infection Respiratory tract infection, bacteremia Sepsis or infection-related organ damage Very rare No

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Gulf War and Health: Volume 5. Infectious Diseases NOTE: The term infection refers to a primary infection that leads to disease. aProbability calculated as percentage of acute cases. Frequent, >50% of cases; common, >5-50% of cases; rare, 1-5% of cases; very rare, <1% of cases. bDelay defined as adverse health outcome not evident at time of acute illness. cReported in military personnel in Gulf War, Operation Enduring Freedom, or Operation Iraqi Freedom as of December 2005. dPostinfection enteropathy: syndrome of chronic or intermittent diarrhea and/ or constipation that follows elimination of previous infectious enteropathy; poorly defined etiology and pathogenic mechanism; often self- limited over months to years. SOURCE: GIDEON 2006; Heymann 2004; Mandell et al. 2005; Nester et al. 2004; Wilson 1991.

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Gulf War and Health: Volume 5. Infectious Diseases     Potential Long-Term Outcomes in Adults with Clinical Disease Disease or Syndrome Acute Syndrome(s) in Adults Disease(s), Syndrome(s), or Clinical Features Frequency of Occurrence of Outcomesa Delay Between Acute Infection and Onset of Outcomesb         zoster     Varicella pneumonitis Very Rare No delay after herpes zoster     Hepatitis Very Rare No delay after herpes zoster     In complicated cases: Infection-related organ damage Rare No Viral enteritis (Enterovirus spp.) Fever and pharyngitis, rash, aseptic meningitis, epidemic conjunctivitis, herpangina, hand-foot-and-mouth disease, myocarditis, pericarditis, pleurodynia, acute flaccid paralysis, conjunctivitis Heart failure due to myocarditis Very rare No Chronic meningoencephalitis Very rare No West Nile feverc (Flavivirus spp.) (see Chapter 5 for detailed discussion) Usually: asymptomatic If symptomatic: West Nile neurologic disease Very rare No Sometimes: fever, headache, body aches, nausea, vomiting, swollen lymph glands, rash Acute flaccid paralysis Very rare No Cognitive, physical, or functional impairment Very rare No Uncommon: high fever, headache, neck stiffness, stupor, disorientation, coma, tremors, convulsions, muscle weakness, vision loss, numbness and paralysis       NOTE: The term infection refers to a primary infection that leads to disease. aProbability calculated as percentage of acute cases. Frequent, >50% of cases; common, >5- 50% of cases; rare, 1-5% of cases; very rare, <1% of cases. b Delay defined as adverse health outcome not evident at time of acute illness. c Reported in military personnel in Gulf War, Operation Enduring Freedom, or Operation Iraqi Freedom as of December 2005. SOURCE: GIDEON 2006; Heymann 2004; Mandell et al. 2005; Nester et al. 2004; Wilson 1991.

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Gulf War and Health: Volume 5. Infectious Diseases TABLE 3.3 Protozoan Diseases That Are Endemic to Southwest and South-Central Asia and Have Potential Long-Term Adverse Health Outcomes     Potential Long-Term Outcomes in Adults with Clinical Disease Disease or Syndrome Acute Syndrome(s) in Adults Disease(s), Syndrome(s), or Clinical Feature Frequency of Occurrence of Outcomesa Delay Between Acute Infection and Onset of Outcomesb Amebiasis (Entamoeba histolytica) Diarrhea, fever, abdominal pain, intestinal perforation and hemorrhage, fulminant colitis, hepatomegaly, liver abscesses, fistulae, rarely amebic empyema or amebic pericarditis Postinfection enteropathyc Rare No Liver abscesses Rare Yes (weeks to years) Empyema, pericarditis Very rare Yes (weeks to years) Intra-abdominal and cutaneous fistulae Very rare Yes (weeks to years) Cryptosporidiosis (Cryptosporidium spp.) Diarrhea (may last 1-4 weeks), nausea, fever, myalgia Chronic diarrhea (in people immunocompromised at time of infection, diarrhea may be persistent despite treatment) Rare No Postinfection enteropathyc Rare No Cryptosporidial cholangitis and acalculous cholecystitis (only in people immunocompromised at time of initial infection) Very rare Yes (weeks to months) Cyclosporiasis (Cyclospora cayetanensis) Diarrhea, nausea Postinfection enteropathyc Rare No Giardiasis (Giardia lamblia) Diarrhea, abdominal cramps, bloating, flatulence, malaise, nausea, anorexia Chronic diarrhea, malabsorption, weight loss Common (if untreated) No Postinfection enteropathyc Rare No Isosporiasis (Isospora belli) Diarrhea, nausea, eosinophilia Persistent diarrhea (if untreated) Rare No Postinfection enteropathyc Rare No Leishmaniasisd (Leishmania spp.) (see Chapter 5 for detailed discussion) Cutaneous leishmaniasis (CL): any of variety of skin lesions ranging from small, dry, crusted areas to large, deep, disfiguring ulcers CL: Lesions may persist 3-24 months Common No Scarring Common No Contractures over joints Very rare Yes (weeks to months)

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Gulf War and Health: Volume 5. Infectious Diseases     Potential Long-Term Outcomes in Adults with Clinical Disease Disease or Syndrome Acute Syndrome(s) in Adults Disease(s), Syndrome(s), or Clinical Feature Frequency of Occurrence of Outcomesa Delay Between Acute Infection and Onset of Outcomesb   Visceral leishmaniasis (VL [kala-azar]): fever, chills, weight loss, hepatosplenomegaly, anemia, leukopenia, hypergammaglobulinemia VL: Reactivation (if immunosuppressed) Common Yes (months to years)   Delayed presentation of acute syndrome Rare Yes (months to years)   Viscerotropic leishmaniasis: fever, chills, weight loss, headache, splenomegaly, lymphadenopathy Post-kala-azar dermal leishmaniasis (disseminated nodular infiltration of skin with parasites after treatment of visceral leishmaniasis) Very rare Yes (weeks to years) Malariad (Plasmodium spp.) (see Chapter 5 for detailed discussion) P. falciparum: fever, chills, anemia, headache, myalgia, cerebral malaria (including seizures, coma, neurologic complications), hypoglycemia, acidosis, severe anemia, splenic disease, renal failure, respiratory failure P. falciparum: Anemia Common Yes (months) Shock or hypoperfusion-related organ damage Rare No Recrudescence Rare Yes (months) Ophthalmologic manifestations Very rare Yes (months to years) P. ovale and P. vivax: fever, chills, headache, myalgia, anemia, splenic disease, rarely respiratory failure Persistent neurologic deficits (consequence of cerebral malaria) Very rare Yes (months to years) P. malariae: Fever, chills, headache, myalgia, anemia, splenomegaly; if untreated, infection may be chronic P. ovale and P. vivax: Relapse of acute syndrome Common (if untreated) Yes (weeks to years) Splenic rupture Very rare Yes (weeks to months) P. malariae: Late presentation Rare Yes (years) Glomerulonephritis/nephrotic syndrome Very rare Yes (months to decades) Myelodysplastic syndrome Very rare Yes (months to decades) Microsporidiosis (Microsporidia spp.) Diarrhea (usually self-limited), kerato-conjunctivitis Postinfection enteropathyc Rare No If immunocompromised: persistent diarrhea, sinusitis, acalculous cholecystitis, pneumonitis, nephritis, systemic infection Self-limited diarrhea, unless immunocompromised at time of infection Very rare No

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Gulf War and Health: Volume 5. Infectious Diseases     Potential Long-Term Outcomes in Adults with Clinical Disease Disease or Syndrome Acute Syndrome(s) in Adults Disease(s), Syndrome(s), or Clinical Feature Frequency of Occurrence of Outcomesa Delay Between Acute Infection and Onset of Outcomesb Toxoplasmosis (Toxoplasma gondii) Range of symptoms: may be asymptomatic, fever, cervical lymphadenopathy, myositis, mononucleosis-like syndrome (pharyngitis, fever, hepatosplenomegaly, lymphadenopathy), encephalitis, myocarditis, chorioretinitis, rarely pneumonitis; congenital infection can occur if acute infection occurs during pregnancy Reactivation of disease (if immunocompromised) Common (if immuno-compromised) Yes (years)   Toxoplasmic brain abscesses (only in severely immunocompromised) Rare Yes (years)   Chorioretinitis Very rare (if infected as adult); Common (if infected in utero) Yes (years) a Probability calculated as percentage of acute cases. Frequent, >50% of cases; common, >5- 50% of cases; rare, 1-5% of cases; very rare, <1% of cases. b Delay defined as adverse health outcome not evident at time of acute illness. c Postinfection enteropathy: syndrome of chronic or intermittent diarrhea and/or constipation that follows elimination of previous infectious enteropathy; poorly defined etiology and pathogenic mechanism; often self-limited over months to years. d Reported in military personnel in the Gulf War, Operation Enduring Freedom, or Operation Iraqi Freedom as of December, 2005. SOURCE: GIDEON 2006; Heymann 2004; Mandell et al. 2005; Nester et al. 2004; Wilson 1991.

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Gulf War and Health: Volume 5. Infectious Diseases TABLE 3.4 Helminthic Diseases That Are Endemic to Southwest and South-Central Asia and Have Potential Long-Term Adverse Health Outcomes     Potential Long-Term Outcomes in Adults with Clinical Disease Disease or Syndrome Acute Syndrome(s) in Adults Disease(s), Syndrome(s), or Clinical Feature Frequency of Occurrence of Outcomesa Delay Between Acute Infection and Onset of Outcomesb Nematodes         Ascariasis (Ascaris spp.) Largely asymptomatic Transient respiratory symptoms associated with pulmonary infiltration and peripheral blood eosinophilia, intestinal obstruction or blockage Biliary duct obstruction, ascending cholangitis, acute pancreatitis, obstructive jaundice, peritonitis Very rare Yes (months to years) Enterobiasis (pinworm infection, Enterobius vermicularis) Largely asymptomatic Appendicitis Very rare Yes (months to years) Pelvic infection Very rare Yes (months to years) Symptomatic: perianal or perineal pruritus       Occasionally: abdominal pain       Filariasis (Wuchereria bancrofti) Lymphangitis, lymphadenitis, eosinophilia Episodes of fever and lymphangitis, may recur over several years Rare Yes (years) Lymphedema Rare Yes (years) Persistent adenopathy Rare Yes (years) Epididymitis Very rare Yes (years) Chyluria Very rare Yes (years) Orchitis Very rare Yes (years) Hookworm disease (Ancylostoma duodenale and Necata americanus) Largely asymptomatic Pruritus at dermal site of larval penetration Iron-deficiency anemia Common Yes (months to years) Onchocerciasis (river blindness, Onchocerca volvulus) Dermatitis, keratitis Skin hyperpigmentation, depigmentation, chronic dermatitis, dermal atrophy Common Yes (years to decades) Sclerosing keratitis Common (if untreated) Yes (years to decades)

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Gulf War and Health: Volume 5. Infectious Diseases     Potential Long-Term Outcomes in Adults with Clinical Disease Disease or Syndrome Acute Syndrome(s) in Adults Disease(s), Syndrome(s), or Clinical Feature Frequency of Occurrence of Outcomesa Delay Between Acute Infection and Onset of Outcomesb     Visual loss Common (if untreated) Yes (years to decades)     Iridocyclitis Rare Yes (years to decades) Strongyloidiasis (Strongyloides stercoralis) Diarrhea, intestinal irregularities, gluteal or perineal pruritus and rash, eosinophilia Hyperinfection syndrome, generalized strongyloidiasis Common (in immunosuppressed patients on steroids) Yes (months to decades) Cestodes         Cysticercosis (Taenia solium larvae [cysticerci]) Cerebral, ocular, or subcutaneous cysts usually without eosinophilia; involvement of central nervous system may present as seizures, increased intracranial pressure, altered mental status, eosinophilic meningitis, focal neurologic deficits, spinal-cord mass, or encephalitis Chronic seizure disorder Common Yes (years) Recurrence of acute symptoms Very rare Yes (months to years) Echinococcosis (Echinococcus multilocularis) Usually: asymptomatic Rarely: abdominal pain with or without apalpable mass in right upper quadrant, fever, pruritus, urticaria, eosinophilia, anaphylactic shock, cough, hemoptysis, chest pain Hepatic and metastatic cysts Common Yes (years to decades) Trematodes         Schistosomiasis (Schistosoma haematobium) Often asymptomatic Bladder inflammation, urinary obstruction, scarring, eosinophilia Recurrent urinary tract infection Common (if untreated) Yes (years) Cerebral mass, generalized encephalopathy, or focal epilepsy Very rare Yes (weeks to years) Transverse myelitis Very rare Yes (weeks to years) Bladder cancer (squamous Very rare Yes (decades)

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Gulf War and Health: Volume 5. Infectious Diseases     Potential Long-Term Outcomes in Adults with Clinical Disease Disease or Syndrome Acute Syndrome(s) in Adults Disease(s), Syndrome(s), or Clinical Feature Frequency of Occurrence of Outcomesa Delay Between Acute Infection and Onset of Outcomesb     cell)         Urinary obstruction (hydronephrosis) Very rare Yes (decades) Schistosomiasis (S. mansoni) Often asymptomatic Gastrointestinal symptoms, colonic polyps, hepatosplenomegaly, jaundice, cirrhosis, eosinophilia Fatigue, abdominal pain, intermittent diarrhea or dysentery, moderate anemia Common Yes (weeks to years) Gastrointestinal symptoms Common Yes (weeks to years) Hepatosplenomegaly and variceal hemorrhage Rare Yes (years) Cirrhosis Rare Yes (years to decades) Portal hypertension Rare Yes (years to decades) Transverse myelitis Very rare Yes (weeks to years) Right ventricular congestion or cor pulmonale Very rare Yes (years) Cerebral masses Very rare Yes (years to decades) a Probability calculated as percentage of acute cases. Frequent, >50% of cases; common, >5- 50% of cases; rare, 1-5% of cases; very rare, <1% of cases. b Delay defined as adverse health outcome not evident at time of acute illness. SOURCE: GIDEON 2006; Heymann 2004; Mandell et al. 2005; Nester et al. 2004; Wilson 1991.

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Gulf War and Health: Volume 5. Infectious Diseases TABLE 3.5 Sexually Transmitted Diseases That Are Endemic to Southwest and South-Central Asia and Have Potential Long-Term Adverse Health Outcomes     Potential Long-Term Outcomes in Adults with Clinical Disease Disease or Syndrome Acute Syndrome(s) in Adults Disease(s), Syndrome(s), or Clinical Features Frequency of Occurrence of Outcomesa Delay Between Acute Infection and Onset of Outcomesb More prevalent in Southwest and South-Central Asia Than in the United States Chancroid (Haemophilus ducreyi) Genital ulcers, inguinal lymphadenopathy Scarring Very rare Yes (weeks) Hepatitis A (hepatitis A virus [HAV]) Acute hepatitis (jaundice, nausea, anorexia, fever) if symptomatic Liver failure Very rare No Hepatitis B (hepatitis B virus [HBV]) Severe cases: acute hepatic necrosis Chronic infection Rare Yes (months to years) Cirrhosis Rare Yes (years) Most cases: no clinical signs Hepatocellular carcinoma Very rare Yes (years to decades) Clinically evident cases: insidious onset with anorexia, vague abdominal discomfort, nausea, vomiting Sometimes arthralgias and rash Jaundice: 30-50% of cases       Lymphogranuloma venereum (Chlamydia trachomatis serovars L1-L3) Genital ulcers, inguinal lymphadenopathy, proctitis Genital scarring and fistulae; perirectal abscess Unknown, but presumably rare Yes (month to years) Syphilis (Treponema pallidum) Genital ulcers (primary stage) Rash, fever, meningitis, stroke, nephrotic syndrome, hepatitis (secondary stage) Spontaneous abortion (any stage) Gummas, tabes dorsalis, dementia, meningovascular disease, generalized paresis, aortitis (tertiary stage) Common (if untreated) Yes (months to years) Potentially More Prevalent Among Troops in Southwest and South-Central Asia Than Among US Adult Population Chlamydia (Chlamydia trachomatis serovars D-K) Usually: asymptomatic Chronic pelvic pain, tubal infertility, ectopic pregnancy Common in untreated women Yes (months to years) Sometimes: cervicitis, pelvic inflammatory In infants born to infected    

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Gulf War and Health: Volume 5. Infectious Diseases     Potential Long-Term Outcomes in Adults with Clinical Disease Disease or Syndrome Acute Syndrome(s) in Adults Disease(s), Syndrome(s), or Clinical Features Frequency of Occurrence of Outcomesa Delay Between Acute Infection and Onset of Outcomesb   disease, urethritis, conjunctivitis mothers:       In infants born to infected mothers: pneumonia, conjunctivitis Reactive airways disease Unknown Yes (years) Gonorrhea (Neisseria gonorrhoeae) Usually: asymptomatic Chronic pelvic pain, tubal infertility, ectopic pregnancy Common in untreated women Yes (months to years) Sometimes: cervicitis, pelvic inflammatory disease, urethritis, conjunctivitis       Uncommon: disseminated gonococcal infection (arthritis, tenosynovitis, rash, meningitis, endocarditis)       Of Concern to US troops, but No Evidence of Increased Frequency or Association with Service in Southwest or South-Central Asia Genital herpes (herpes simplex virus [HSV]) Usually: asymptomatic Recurrent genital herpes Common Yes (weeks to years) Sometimes: genital ulcers (HSV-2)       Uncommon: meningitis, radiculitis Recurrent meningitis (Mollaret’s) Very rare Yes (weeks to years) Human immunodeficiency virus Type 1 (HIV-1) Asymptomatic Primary infection syndrome (acute retroviral syndrome) Acquired immune deficiency syndrome (AIDS) AIDS-related opportunistic infection Frequent if untreated Yes (years to decades) HIV-related malignancies Common Yes (years to decades) Human papillomavirus infection Asymptomatic Cervical neoplasia Rare Yes (months to years) Genital warts Genital squamous cell cancers (penis, anus) Rare Yes (years) Tracheal infection in newborns of infected mothers Very rare Yes (months to years) Human T-cell lymphotropic virus infection (I) (HTLV-I) Asymptomatic Chronic persistent oligoarthritis Adult T-cell leukemia or lymphoma Rare Yes (years) HTLV-I-associated myelopathy Rare Yes (years)

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Gulf War and Health: Volume 5. Infectious Diseases     Potential Long-Term Outcomes in Adults with Clinical Disease Disease or Syndrome Acute Syndrome(s) in Adults Disease(s), Syndrome(s), or Clinical Features Frequency of Occurrence of Outcomesa Delay Between Acute Infection and Onset of Outcomesb Trichomoniasis (Trichomonas vaginalis) Asymptomatic Preterm delivery Rare No Vaginitis       Urethritis       NOTE: The term infection refers to a primary infection that leads to disease. aProbability calculated as percentage of acute cases. Frequent, >50% of cases; common, >5- 50% of cases; rare, 1-5% of cases; very rare, <1% of cases. bDelay defined as health outcomes not evident at time of acute illness. SOURCE: Baum 2005; Holmes et al. 1999.

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Gulf War and Health: Volume 5. Infectious Diseases REFERENCES Baum S. 2005. Introduction to Mycoplasma diseases. Mycoplasma Diseases. In: Mandell G, Bennett J, Dolin R, Editors. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, PA: Churchill Livingstone. Pp. 2269-2271. GIDEON. 2006. Global Infectious Disease and Epidemiology Network. [Online]. Available: http://www.gideononline.com [accessed April 12, 2006]. Heymann DL. 2004. Control of Communicable Diseases Manual. Washington, DC: American Public Health Association. Holmes KK, Sparling PF, Mardh P, Lemon SM, Stamm WE, Piot P, Wasserheit JN. 1999. Sexually Transmitted Diseases. 3rd ed. New York: McGraw-Hill. Mandell GL, Bennett JE, Dolin R. 2005. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, PA: Elsevier Churchill Livingstone. Nester EW, Anderson DG, Roberts JCE, Pearsall NN, Nester MT. 2004. Microbiology: A Human Perspective. 4th ed. New York: McGraw-Hill. Wilson ME. 1991. A World Guide to Infections: Diseases, Distribution, Diagnosis. New York: Oxford University Press.