Idle...... Corneal TI'lIIIlIIII
apter 104 txt:ernal Eye Manifestations of Chemical d Biological Warfare ig A. Skolnick
spectrum of blologicaJ and chemical agents that can During World War II. Japan conducted experiments in used in warfare is frightenjng, Healthcare providers which prisoners were Infected with various bacteriaL be alert to patterns o f Illness and the constellation of pathogens, which led to at least 10000 deaths.] Many findings associated with an outbreak of biological Chinese cities were anacked by contaminating water chemJcaJ warfare. The intentional release of an unusual supplies and food items with pure cultures o( B. anthracis, in/,m'Dm agent can be difficult to recognize since many Vibrio dlolera~, Shigella spp. Salmonella spp. and Yersin;Q the commonly used organisms are rarely seen in their pestis. International concern heightened during the late form. When used as weapons, there is potential for 1960$, which led to the Signing of the1972 Biological and immense number of casualties due to ease of dispersal, Toxin Weapons Convention. The treaty prohibited the i onset of efied, and lack of preparation for contaln development, possession, and stockpiling of pathogens or and defense. Timely recognItion of symptoms and toxins in "quantities that have no Justification for prophy treatment are key to victim survival. lactic, protective or other peaceful purposes.I!4 Transferring technology or expertise between countries was also prohibited. 10 19 79. the ineffectiveness of the convention Background was demonstrated by an accidental airborne release of deliberate use of microorganisms and toxins as weapons anthrn spores by a Sov1et military microbiology facility dates back to the middle ages. During the 14th-cenrury in $verdlovsk (now Ekaterinburg, Russia), which led to siege of KaHa (now Feodossla, Ukraine), the attacking Tatars numerous deaths.s Non-state-sponsored biological terrorism catapulted plague-infested cadavers into the city in order began to surface In the 19805, which culminated with the to initiate an epidemic. I South American aborlginals are 1995 sarin gas attack of the TOkyo. Japan, subway system well known for using curare and amphjbian-derived toxins by the Aum Shinrikyo cult. as arrow pol~ons , and British forces used smallpo1t against Dative North Americans during the French and Indian War of the mid-18th century. The advent of modem micro Mechanism of Attack biology and Koc h's postulates during the 19th century A biological weapon Is more than a microorganism or afforded the opportunity to isolate and produce stockpiles toxin. It Is a system composed of fow major components of specific pathogens. There is evidence that Germany - payload (the biolOgical agent), munition (a container develo ped an aggressive biological warfare program during that keeps the payload intact and virulent during delivery), World War I, including operations to infect livestock and delivery system (missile, artillery shell, aircraft, etc.), and co ntaminate animal feed of the Allied forces using Baal/us dispersal mechanism {an explosive force or spray device to anthracis and BUlkholderia (pseudomonas) mallei, the etiologic dispense the agent to the target populatlon).6 Certain agents agents of anthrax and glanders. are attractive because of low visibility, small volume, high The first vvidespread use of chemical weapons oc'curred potency, and easy delivery. Aerosolization would be the during World War I, when mo re than 1 million casualties predomlnant method of dissemination because advanced ~ulted from the use of sulfur, mustard, and chlorine gases. delivery systems are not required, and small quantities These horrors led to the first international diplomatic make transportation and concealment quite easy. In 1970, efforts to limit weapons of mass destruction. The 1925 the World Health Organization predicted the effect of an Geneva Protocol for the Prohibition of the Use in War of aerosol release of SO kg of biological weapon over a city of Asphyxiating, Poisonous, or Other Gases. and of Bacterio 500 000 people (rable t 04. t ).7.8 Highly contagious organisms logical Methods of Warfa re was enacted to pro hibit the use with delayed onset of symptoms make ideal weapons for a of biological weapons.! Unfortunately. there were no covert attack. In an overt attack. chemical agents are likely provisions fOT inspection, and many counlTies that ratified to be deployed, caUSing rapid onset of symptoms and an the treal:y still began research programs to develop biological overwhelming demand for eme.rgency medical services. weapons. Both biological and chemical weapons can incapacitate .12 • -'-" TQIe 104.1 Estimated ~llies fOf ill hypothetical biological Box 104.1 warfare attack on a city of 500 000· Do__1d Biological d lseaM!s No • .... Anthrax (80ci/lIJS anthracis) rudI (km) ...... kK..,ac:lbted Botulism (C/cstridilJm botlJiinlJm toxin) - I~r Rift Valley 1 <00 )5 000 Pla9ue (Yeninio pt1fis) Smallpol< (Variola maior and minor) Tkk·bomr 1 9500 35000 enceph<'lli(i5 Tularemia (Fronciseiio wiarensil) Vir~l hemorrhagic fever} Typhus 5 19000 85000 F iloviruse ~ - Eboia, M Aren avirU 5e~ - Lassa, Junin, Machupo, Guanarito, S~ bia Brucellosis 10 SOD 100000 Adllpted from reference~ 10 and 73, Table 1, Center! for 0Ise.rse Cootrol.nl Pfevention: Siological Dise.JosesJAgents WL A"'3i Lable at Q lever .20 150 125000 hltp:flwww.bI..cdc.goyIAgenllage«Jist..up, Ian updated 10104/02. Boric L (nQ~ Oy T; Peter.; q et aI: Hemorrhagic fever viNi I I bioIoglul Tularemitl .20 30 000 125000 weapons: medical and pUblk ~eal1h m " n~g emen t, JAMA 287(18):2391-2405, 2002. Anthrall .20 950000 125000 ' ThIS mod~ OJWrrn'S 111m $0 J:g 01 agmt is depJoy ~ from PI' oirt:raft a/oog " ) km line upwind from Ihf: city. from ~ftrt!1U 8, po~ J I), rob/r 2, AkCovtm rw Christophe, Cw, social disruption; and require special action for 1 lJlJtfl EM: CIIlOtltOUJ "",nif~o' iom 01 biolo9lCai worlore and ftkntd Ihr«JI health preparedness. I Most of these agl'"nt.s have signiti ogt'nil. "'ell Oemlalol IJS.-JII·122. 19.99. Copyfighl e (/999) .Americon ~1f1CUl AsS«.ialoOl!. All nght$ revrwd. ca nl ophthalmic manifestations that may aid in diagnosis o r complicate management. an entire dry and impede the mobilization of military Biological Diseases personnel. Anthrax Warning Signs B(lcillus onthracis is the ideal biologic weapon because In mder to recognize a bioterror anack, one must be familiar stability in spore fo rm. its ease to grow in culture, .•• •,. . ' with. the various clinical presentations of these agents. The of natural immunity In many industrialized nations, American College of PhYSicians and the American Society the severity of infection. of Internal Medicine have suggested that the follOwing epidemiological clues be considered .? Microbiology/epidemiology 1. Unusual temporal or geographic clustering of illness. Badl/u.s anthracis is an encapsulated, aerobic, Gra rr.·p''''iI' ~ 2. Unusual age distribution of common disease (Le., an spore-forming, rod-shaped bacterium. Spores form illness that appears to be chickenpox in adults but is environmental nutrients are depleted, such as really smaUpox). dry soil, the narural reservoir. Spores can survive 3. Large epidemic, wi th greater case loads than expected, in contaminated ~lIs or workplaces and can resist 12 13 especia ll y in a discrete population. rures of over IOO°C for prolonged periods. · I 4. More severe disease than expected. can OCCUT fro m animaJ products, such as wool fibers 5. Unusualwute of ex posure. bo ne meal, leading to o utbreaks in slaughterhouses, 6. A disease that is outside its normal transmission industries, and tanneries. 14 Herbivores such as canle, season, or is impossible to transmit natura!ly in the and sheep ingest spores and selVe as the natural absence of its normal vector. mitten of infection. Humans become infected 7. Multiple simultaneous epidemics of different diseases. direct contact ,'lith contaminated carcasses or iTom 8. A disea se outbreak with health consequences to infected meat. Animal h usbandmen, butchen, and humans and animals. adam are most susceptible. 12 9. Unusual strains or variants of organisms o r antimicrobial resistance patterns. Clinic.al manifestations The Centers for Disease Control and Prevemion Three principal forms of anthrax occur in (CDC) of the United States has listed the high-priority cutaneous, inhalationaI, and gastroi ntestinal. The biological dIseases (Box 104.1)10 that pose significant risk of naturally occurring disease is cutaneous, co.mpOSil to national security based on the {onowing: can be easil y mo re than 95% of casesY Inhalalional anthrax is disseminated and/o r tlansmitle Irt;~:::~: .mthrax ential diagnosis of cutaneous anth.ra-x also Includes spider kr disease begins as a small, painless, pruritic, red bite, ecthyma gangrenosum, u1ceroglandular tularemia, that progresses 10 a papule which vesiculates, plague, scrub typhus, rickettsial spotted fever, rat bite fever, and ulcerates. It thell forms a classic 1- 5 em brown staphylococcal or streptococcal ceUuJitis, and herpes simplex :c~, )-t')"k eschar surrounded by slgn ilic3m non pitting viTUS.24•U The term anUuax is derived from the Gleek Gastrointestinal anthrax ;",,,",,,, meaning "coal" It appears at the site of inoeu Gastroi.ntestinal anthrax liIo:el y results from the in gestion (spo r ~ o r badlli) within 3 to 10 days, The edema spread, and lIansluctnt epidermal bullae vesides often of latge numbers of vegetative bacilli from poorly cooked Infected meat.2.S The oral-pharyngeal form of disease results the lesion _ the so-called "pearly wreath. "'ll After in an oral or esophageal ulcer which leads to the develOp 4 weeks the eschar sloughs away, leaving an exposed of granulation tissue. Although fatalities due to ment of regional lymphadenopathy, edema, and sepsis. Disease In the terminal Ileum or cecum present.s ¥tith disease 3re rare, 10% to 20% of untreated patients malignant edema, septicemia, shock, renal failure, nausea, vomiting, and malaise, and progresses rapidly to bloody d iarrhea, acute abdomen, and sepsis.u death.' InhalaUonal anthrax manifestations InhaJation anthrax, or wool-sorters disease, generall y findings in rutaneOU$ anthrax rtlate to eyelid presents as a two-stage illness. A prodromal stage begins ,,;;:;~~,~~;Il. IS-I ' The roain complication is cicatricial tt due to late eyelid scarring (Fig. 104.1) .11' Lid mal With nonspecific symptoms of fever, cough, malaise, head ache, and dyspnea . l ~ Some patients have transient improve causes exposure keratopathy which can lead to ment after 2 to 4 days, but the fulminant stage often ensues !,""lial breakdown and secondary infectious keratitis. rapidly with respiratory distress, diaphoresiS, shoc.k, and scarring is more likely to occur in patients who death. Inhaled spores germ!nate In hilar nodes and cause late wHhout treatment during the acute stage. It mecUastinal lymphadenopathy and hemorrhage. lhis Is that upper eyeJid involvement Is more like1y to detected radiographically by a widened mediastinum in ectropion. Severely affected patients have under and pleural effusions, which may be hemorrhagic. 27 Meta· re lease of connactuces and fuU-thickness postauricuLar static infection results in hemorrhagic menJngitti in up with satisfactory resolution of ectropion.ll Tem to sO% of cases, leading 10 meningismus, delirium, and mery i.n.fIammation has been reported as a compli obtundatton.!9 of oVNlying cutaneous anthrax.2(l Co wpox, an uncommon infectio n transmitted by the DiagnOSiS cat, can mimic an anthrax lesion .21- U The dlffer Anth rax bacilli can be vi~ualized by Wright or Gram stain of peripheral blood or isolated by blood culture_ DlagnosNc testing (or cutaneous disease includes Gram stain and culture of vesicular fluid, and tissue biopsy. ImmunolOgiC tests indude specihc enzyme-linked immunosocbent assays (ELISAs) to measure antibody titers, immunomagnetic electrochemilumlnescence (EeL) assays for antigen detec tion, and polymerase chain reaction (peR) for nucleic add detecrion.14 Spores have a diameter of 2 to 6 mm, which is Ideal for entrapment in the lower respiratory tract. The time for infection is variable because spores must germinate into badlli aher phagocytOSIS by tissue macrophages. The dose of anthrax in an exposure is inversely correlate Treatment Treatment or inhalational and gasnointesrinal anthrax should begin with intravenous ciproOoxacin 400 mg every 12 hours (Table 104 .2).19. Doxycycline lOOmg every 12 hours can be used, but has poorer central nervous system peuetration. One Dr (\\'0 of the following additional anti . 104.1 Cut,meow anthrax. A. Swelling and cf)'t.hema in !.he early biotics should be added until susceptibility testing is . I, Crntral ulceration with black, nccJolk tiuu~ in the latter . (From reference 19, page 1007, Figure I, NOeller TP: 8iological performed: rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, cU ndamycin, and clarithro ~ 7.~~~~~~;~"~=~:ri;$'m : recognition and management, Cleve (lin J 1297 1:1 6,2001 . mycin. Cutaneous disease can be treated with either oral THie 104.2 CDC recommendations for anlimicrolXitl tht!rapy 19.Iinn anthrax PO~ l expow re mg by mouth twice a day by mouth every OR OR Doxycycline 100 mg by mouth twice a day Doxycycline: ,.8 yrs and .>45 kg: 100 mg by mouth every 12 hn >8 yl"i and $45 kg: 2.2 mglkg by mouth every 12 hrs ~8 yl"i: 2.2 mg/kg by mouth every 12 hrs CutaneoUl ~ nthru mg mg/kg by mouth every t2 hrs" OR Doxycycline 100 mg by mOUlh twice a day DoKycycline: ,.8 yJ'$ and >45 kg: 100 mg by mouth every 12 hrs XI yr~ and ~5 kg: 2.2 mg/kg by mOuth fNf':ry 12 hI'S s.8 yrs: 2.2 mg/kg by mouth every 12 hrs Inhalational anthrax mg every 12 hrs 10-15 mg/kg lntravenomfy every 12 hIS' DOxycycline 100 mg intravenously every 12 hl"i Ooxy ·Ciplollo.oClC/n dmt It! (fIIJdrrn 001 10 excffii I gldcry. 'rom~ 19. ~ 1008, 1~ 1, Hod~ TP: BioIogl(OJotKIchemi(O/l~iJtn: 't(;0gn4ion lNldrnonogtmtnl. Cleve Ctin I Med 611(11J, IQOI-IOI6, 1001 . ciprofloxacin or dOlC}'cycline alone. Treatment should be chemoprophylaxis with either dl"ofloxa.on m dC"I""Ictin< continued for 60 days because of the possibility o( delayed orally until al least three doses of vaccine have germination of spores.2S Direct contact with wound or administered,u The safety of the vaccine was studied ill wound drainage should be avoided when caring for a military personnel, and 1% of inoculations were associated patient with cutaneous anthrax. with one or more systemiC events (i.e., headache, Despite aggressive supportive therapy and antibiotics. blurred vision, nausea). Interestingly, two cases of ""••"",. fatality is very high. In the 2Oth-century series of 18 patients Optic neuritis have been reported after anthrax in the Uni ted States, the mortality rate of occupationally vacctnation.YI One patient resolved without n.,m"n~ acquired inhalational anthrax was 89%, but the malority the other had bilateral involvement that reqUired of these cases occurred before the development of critical immunosuppression to maintain vision. Retinal and care units and antibiotics.2S After Ihe September 2001 nerve autoanlibodies were presenl in this patient. 0"""" terrorist attacks on the United Stales, anthrax spores were of unilateral optic neuropathy, bilateral anter10r sent to various locations via the postal service, resultlng In bIlateral posterior scleritis, bilateral sensorineural 11 cases of inhalatlonal anthrax with five deaths.25 loss, and fo cal segmental giomerulosclerosis has also reported, likely due to an Immune-mediated {eaction Prevention the vaccine.l l Since there aTe no data to support person·la-person trans mission of anthrax, patient contacts do not need immu Botulism nization or prophylactic treatment unless they were exposed 10 the aerosol or surface contamination al the liJne o f Borulism is a serious paralytic illness caused by a attack. toxln produced by the bacterium Clostridium be,,,,;,,,,,,, A vaccine derived fTOm an attenuated strain of anthrax It poses a major bioweapons threat because of its is available, and studies in rhesus monkej's indicate that it potency and lethality, its ease of production, '''"''IPD'tatloo, 29 298 is protective (or inhalational anthrax. Should an anack and misuse, and the need for prolonged intensive occur, those exposed must be vaccinated and receive among affected persons.ll External Eye Manifestations of Chemical. and BJoiogical. Warfare ~;:~:~~:I'bo~ru;/inum is a rod-shaped, spore-formio& obli Box 104.2 anaerobe commo nly fouod jn soil . There are seven of toxin designated A through G, which are defined Signs and lY"'ptoms of food-bome and wound botulllm their absence of cross-neutralization (Le., anti-A antl Signs does not neutralize toxin types S-G).32 Types A, B, Ventilatory (rl!spiratory) problems Extraocular muscle paresis or paralysis (including eyelids) E account for greater than 9m of human botulisrn,ll Muscle paresis or paralysis A toxJ o is the most potent poison known to humans, Dry mucous membranes in mouth, throat times more toxic than sarin nerve gasY Once Dilated, fixed pupils the toxin is catr\ed via the blood to peripheral Ataxia synapses. It irreversibly binds to the presynapUc Somnolence junction, where it is internalized and blocks Hypotl!nsion (including postural) Nystagmus release, causing paralysis. Interestingly, a vlal ~crNsed to ab§ent deep tendon reflexes Botox® (Allergan. Irvine, CA. USA) contains Fever (more common for wound botulism) about 0.3%01 the estimated human lethal inhaJationaJ 5ensoty deficits (very rare) and 0.005% of the estimated lethal ora~ dose,l] Symptoms Visual disturbances (blurred vision, diplopla, photophobia) Dy~phagia fcnns of narurally OCCUrring botulism exist: food Dry mouth wound, and intestinal. The o ldest and most com· Ge:neralired weakness (tnUally bilateral) form observed on a worldwide basis is food·bome, Nau~a or vomiting Dizziness or vertigo occurs after ingestion of food that contains pre· Abdominal pain, cramps, discomfort 33 neurotoxin. Typical cases result from ingestion Oiantlea improperly prepared hOme-canned food. The m ost Urinary retention or incontinence ro~,::::~; form of botulism reponed in the United States is Sore throat in intestinal botulism.14 Unlike the food·borne rype, Constipation infant form is a combination of iniection and intoxi· Par.lISthesias resulting from ingestion of C. botulinum spores, Adapted from ~ference )3, p&ge 28, Table$ 1 and 2, Caya IG: Clostridium germinate within the gastrointestinal tract and I.>oMirom and the ophthal~: a ~ of boWIiirn, including bIoIogIuI warfom! ramifiutions of botulinum toxirI, SuN Oph,hoIrno( "6:2~) transmitted until the onset of the rash, Z'.~ so diagnosis against PoxviridaeP 1n 1796, Edwardjenner demonstrated . the prodromal stage with subsequent quarantine that an Lniection caused by cowpox protected against small be essential to limit additional exposure. pox. which led to the worldwide practice of vacdnatioo.S3 Curremly, smallpox vaccine is prepared from li ve vaccinia lp~~~~:I:~~~ manifestations virus using cell culture techniques,l4 In led to blindness in 2% to 5% of students in blind The interval between an aerosol release of variola and 4 of developing countries in Africa . 8-30 Typically, a diagnosis of the first cases is as much as 2 weeks,H Fortu conjunctivitis appears around the fifth day of illness nately, the virus is Inactivated after 2 days, eliminating subconjunctival hemo rrhage in some cases. Actual further exposure. Individuals in whom infection is suspected whIch resemble phlyctenules may form on the should be vaccinated within 4 days of ex.posure and placed or tarsal conjunctiva and even involve the limbu s.~l under surveillance. Vaccination programs ended in 1972 lesions are very inflamed and painful and can lead in the United States, and it Is presumed that few people I and ulceration of the cornea. Less frequently, who wefe vaccinated have lasting protective levels of imerSlitial 01 disciform keratitis evolves (Fig. 104.2). Lid immunity. and punctal stenosis may result when pustules the cUla and punda. respectively. Ankyloblepharon Complications of vaccination also been reported due to severe eyelid adhesions Vaccination is not without risk. Life-threatening encephal the upper and lower canthiY Secondary infectious itis occurs at a rate of 1 case per 300 OOO.H ProgreSSive can ocCur late and lead to significant morbid ity; vaccinia or vaccinia gangrenosum results from neao!>ls ~'me , antibiotic prophylaxis is warranted. Dense comeaJ of the skin at the vacdnation site, with advanced cases can leave patients phthiSical and blind. involving underlying bone and viscera."'" Patients wtth a history of eczema are at risk of developing extensive vaccinial lesions (eczema vacdnaturn) over affected sites ,be"atorv diagnosis of smallpox can be confirmed with (Fig. 104,3). In some vaccine recipients. blood-bome diss.emi· microscopy of vesicular o r pustular nuld, or nation of virus leads to a self-limiting generalized vactinial rash. TransmISSion of vaccinia froro the si te of vaccination ~~§~:,G uamieri bodies can be visualized under light Virus culture of skin lesions, oropharynx, to close contacts, or autoinoculatjon to sites such as face, and urine is definitive. peR techniques can mouth. eyelid, aod genitalia, can take place. Vaccinia ~ between strains and offer a more rapid immune globulin is used to treat these complications with variable success. r""'n,e.,, and vaccination Vaccinia ophthalmic manifestations is no specific systemic or ocular treatment for small Inadvertent autoinoculation of vaccinia from the deltoid , although cidofovir has In vitro and In vivo activity site accounts for the ophthalmic co mpUcations of vacci nation. The majority of patients have vaccinia of the eyelid!> or conjunctiva, but a smaller percenlage have comeal involvement. ss Typically, patients present 4 to 7 days after vaccination with advanced blepharoconjunctivitis and Ag. 104.2 '.'ilfiol.... (sm allpox). This patient demonstmtes a centrlll Fig. 104.3 Eczema vaCtinllll)nl. Vaccinial s.kin leJioru extending (!Ver the not scar from a sm~lIpox or variola infection, area currently afflicted with eczema. (Courtl!.$)' of Rkhard K. Forster, MD.) Ukely that newer antivirals (triOuridine) would be at least as effective as idoxuridine, as both inhibit viral DNA synthesis by thymidine kinase phosphorylation. Tularemia Microbiology and epidemiology The causative bacterial agent o f tularemia, Frandsella tularen..sis, is a highly infectious, aerobic, Gram-negative coccobacillus found in widely diverse animal hosts and habitats' throughout the world. Tularemia has epiderolc potential. but typically occurs in isolated cases in rural areas. The natural reservoirS fo r infection ate va rious small animals including ra bbits, squir rels, voles, mice, and wa tt ' rats that become infected through bites from ticks, rues, and mosquitoes, and through contact with contaminated soil, water, and vegetation.6J Humans become infected by various modes, including bites by arthropods, handllng infectious animal tissues or fluids, direct contact with or ingestion of contaminated water, food, or soil, and inha· lation of infective aerosols. fig. 104.4 Ocular vaccinia blepharoconjunctivilis wiUl typical umbilicated pus tules, (Cou rte~y 01 Richard K. Fo rster, MO.) Clinical manifestations The clinica l forms of tularemia depend on the virulence of the bacteria as well as the site o f inoculation. Disease pustules commonly affecting both lids (Fig. 104.4). The presentations include u keroglandular, glandular, oculG conjunctivitis is usua lly purulent and ulcerat ion can occur with adherent membrane formation and preauricular glandular, oropharyngeal, pneumonic, typhOidal, and septic forms. 8.63.6-I Alter an incubation of 2 to 10 days, there js lymphadenopathy.~! Severe cases present with periorbital rapid onset of fever, chills, rigors, headache, myalglas, edema mimicking orbital cellulitis.56 coryza, and sore throat. Frequently, there is a dry or slightly Vaccinial keratitis is the most feared ophthalntic compli productive cough mth substernal pain.63 Nausea, vomiting. cation. Corneal involvemen t develops in 20% to 37% of and diarrhea can occur and nearly half of patients demon· cases of ocular vaccinia.~ When virus inlects the corneal strate a pulse-temperature dissociatio n.M epithelium it produces a grayish, 6ne granular opacity Intentional aerosol release of F. ru/arensis would lead 10 with mild epitheJial edema .~ Diseased cells stain with rose the generali zed iUness wi th a significant number of patients bengal, and dendritic lesions are occasionall y present. developing pJeuropneumonitis, Hematogenous spread may Subepithelial infiltrates may form and lead to peripheral occur, with death resulting from sepsis, disseminated intra neovascularlza ti on and ulceration. Some patients develop vascular coagulation, adult respiratory distress syndrome, a disciform or necrotizing stromal keratitis with possible M 66 and multiple organ failure. . The largest recorded airborne perforation. ~)'s6 The diseased epithelium is less opaque and outbreak of tularemia occurred in a fanning community In swollen than that In herpes simplex and a conjunctival Sweden in 1966-1967. The strain was a less virulent form! follicular reaction is usually absent. The ulceration is more but sHU led to 140 serolOgically confirmed cases. Pulmonary rapid, extensive, and Irregular than 'In herpes.S6 Permanent sympto ms were present in 10%, conjunctivitis in 26%, sequelae indude corneal scarring, punctal stenosis, eyelid skin ulceration in 12%, pharyngitis in 31%, o ral ulcers in scarring, and loss of lashes. 9%, and 32% had various exanthemas, such as erythema frea/menl multHorrne and erythema o odosum.67 Person·to-person Topical steroid.s are effective for stromal opaCities, nea transmission is not known to occur.1» vascularization, and uveitis; however, treatment of the acute infection reqUires viral inactivation and steroids are Ophthalmic manifestations contraindicated. Topical and parenteral vaccinia immune Tularemia Is one of the causes of Parinaud's oculoglandular globulin is effective for ocular vaCCinia, ~1.sa especially with syndro me.68 Direct contaminatio n of the eye leads to COf). orbital inflammation.$6 Idoxuridine, an antiviral used for junctival ulceration, chemosiS, and herpes simplex, cao be used to trea t early vaccinial of the preauricular, submandibular, and cervical ke ratitis. ~U9 Idoxuridine was found effective in a rabbit The conjunctivitis is unilateral (90%) and model by Ka uhnan et al60, but Fulginiti et al61 fo und no typically With multiple yellow nodules involving sign1ficant difference when idoxuridine or vaccinla immune or bulbar surface. 69 Rare ocular effects include globulin was used compared to rabbit contTols without treat ulceratlon, 68.M dacryocystiti S,1O acute glaucoma,lI 2 ment. Vidarabine (adenine arabinoside) has been proven genous retinitis, n and optic neuritis. 70 The differential more effective than idoxuridine in a rabbit model.62 It is nosis Includes bacterial conjunctivitis, adenoviral, ,,",bill,, External Eye Manifestations. of Chemical and Blologfcal Warfare disease, herpes simplex infection, and other one of four familie~: Filoviridae, Arenaviridae, Bunyaviridae, causes of PaMnaud's oculoglandular syndrome.~· 7o and Flaviviridae (Table 104.4).13 AJI are RNA viruses that in nature reside in animal hosts or arthropod vectors. Diagnosis Humans are Infected by the bile of an Infected arthropod, F. tularensis can be identified by examlnation of secretions via aerosol generated from Infected rodent excreta, or by or biopsy specimens using direct fluorescent antibody or direct contact with Infected animal carcasses. Some viruses immunohistochemi ca l sra!ns. 63 Cultures are definitive, but can lead to human-to-human transmission via direct con 63 be performed with cysteine-enriched medla. ,6-\ tact wtth blood, secretions, or tissues of lnfected patients Serological testing can be diagnostic; however, it can take or needlestick injurtes.73 Successful infection of rhesus longer than 10 days after the onset of illness for a signifi monkeys with Ebola virus has been shown w:ith aerosol 63 4 cant change In titers, proving less useful in an outbreak. preparatlom/ Via oral and conjunctival exposure. 7S There Several peR assays have been developed that would give fore, a biological attack would Illost likely utilize an aerosol faster results. H release of virus. Treatment Clinical manifestations Treatment is with streptomycin 1 g 1M bid for to days, The vascular system is primarily targeted by these viruses. with gentamitin (S mglkg 1M o r IV) as an alternative. Microvascular damage with changes in vascular perme 6J J 1 Ruoroqulnolones are probably as effective. · In a mass ability lead to a coagulopathy and Signs o f bleeding which ex posure situation or for postexposure prophylaxis, oral include conjunctival hemorrhage, mild hypotension, flush doxycycline 100 mg bid or cipro Ooxacin SOO mg bid can ing, and pelechiae. 71 Symptoms of fatigue, dizziness, and be: used for 14 days.6l Treatment for ocular disease should myalgjas are present during the first week of illness. Nausea include frequent topical gentamicin.~ , 70 and nonbloody diarrhea may accompany the high fevers after an incubation pertod that ranges from 2 to 21 days.n Viral hemorrhagic fever Disseminated intravascular coagulation with hematuria, hematemesis, and melena occurs as a late ominous sign. Microbiology and epidemiology In severe cases, shock and generalized mucous membrane Viral hemorrhagic fever is a clinical illness associated w:ith hemorrhage results with end-organ damage and death fever and bleeding diathesis caused by a virus belonging to within 1 to 2 weeks. Table 104A HelTlOfl"hagic f~er viruses ...... VI.... DI.... -.M .... -'" ... filoviridae Filovirus £bola' Ebola hemorrhagic fever Unknown -Africa Marburg Marburg hemorrhagic lever Unknown Afria Aremwiridae ArenlVirus La". Lass.a f~er Rodent West Africa New World A~na.,.'rldM' New World hemorrhagic fever ,.-. Americas- 8unyaviridae Nairovirus Crimean-Coogo Crimean-Congo nCk Atria, central Alia., Eastern hemorrhagic lever hemorrhagic fever Europe, Middle Ean Phlebovirus Rift Vall~ (ever Rift Valley lever Mosquito Africa. Saudi Arabia, Yemen Ha n\.o)virus Agenu of hemorrhagic HelT"lOfTflagic f~ with rellal RodMt Asia, Balkans. Europe, Eurasiai f~ with renal l)'ndrome syndrome Aaviviridae ~Javivirv s Dengue , Dengue leve."", Dengue Mosquito AsIa, Africa, Pacific. America~ hemon1ugic lever, and Dengue shock syndrome Yellow (ever Yellow fever MosquIto .Africa, tropical Americas Omd, hflmormaglc (ever Omsk hemorrhagic fever n (k Centr&1 Asia Kya.anur Forest disease Kyasanur Forest disease Tick India 'Bold indi({I1~~ tllmr>rrh"9k fever v,'ftlJe1/tlot post url""$ fisk a:I bioJogkol weapons. 1T~re art lovr wbrypt. of fbolo: loire, Sudon. Ivory Cool!, ond Rtf/on. . 'The New World Arem1Viridot Include M(J("/!vpo, the alUSt of &lIMon hemonhogic fever; Ivnin, Iht alll~e of A"i/tntint htmorr/lclgl.: f~; GlJllncmto, IfIt aJU~ of V~llielon hemorrhOiic fever; ond Sabia, thfl alUS~ 0( BFo~illon h~mofrllClglc ffIYflf .....n additional OffflaviflJ$ hell bei'n isolOled followlnQ Ih~ leJla! ,ru;~ 01 hemorroogic fevN In Califomfo, 1999-2000. 'A,kWona!1y, the IIgt nfl of HOnfovirvl pulmonary Jyndfllmt: how: btf!n /jo/<11OO In NOfItl Anlf'rl(o. 'rom refeflnct fJ. page 2392, rllblfl I, Bolio to Ingifllit r. PeltfS q fl 01: Hemorrhogic fever virvl OJ b~!oglrol ""OPO''': mMiclI ond public h«Jkh """""9"mfnt ).lIMA 287(18):2391-240$. 2002. Copyrighl C) (2002) Americoo Medical Aaooolion. AI1 righl~ rfltfVfd. 1 Some viral hemorrhagtc feve rs present with suggestive Treatment dlJ'licaJ features.]) Ebola and Marburg (FiloviTidae genus) are Treatment is supportive, but ribavirin may be beneficial especially virulent and can cause necrosis o f visceral o rga ns in A.renavjruses or Bunyaviruses.71 With the exception of (liver, spleen. kidneys). Adult respiratory distress syndrome yellow fever, there is no licensed vacone for an)' of the is a sequela of Onl" species 01 Hantavirus. Nephropathia viral hemorrhagie feve rs. epidemica is caused by Puwnala virus, and leads to an acute hemorrhagic tubular and Interstitial nephritis. Others Ophthalmic manifestations The CDC has listed additional biological agents that pose Fllovlridae Significant but less ri sk to public health than the agents Due to high mortality rates, Ebola and Marburg hemorrhagic already described. The known ophthalmic associations of Ih·ese a re listed in Box 104 .3.)0.8.>- 108 feve r are two of the most feared illnesses. Eye involvement presents wit h sympto ms of pain, photophobia, tearing. and blurred vision.'6 Conjunctival injection is seen in at least Chemical Agents one·haJj of patients during the acute phase, and may Chemical attacks can easily overwhelm medical '~:: especially in urban areas. Materials to manufactuIe I present with subconjunctival hemorrhage. Fifteen percent (3/20) of patients who survived the 1995 £bola outbreak weapons are inexpensive and easy to obtain. The nve in the Democratic RepubU c of the Congo developed acute classes of chemica! warfare agents are nerve ('""'h()I1~ anterjor uveitis with vitreous opacities in one patient ,76 esterase), vesicants (blister), pulmonary toxicants, (cyanogens), and incapacitating agents (Box 104.4).109 The onset of uveitis was 1 to 2 months after initial infec· tion. Treatment with topical cycloplegics and steroids was can be found as solids, Uquids, gases, vapors, and effective in all patients. A case of recurrent anterio r uveitis The state of an agent is chosen depending on its with elevated intraocular pressure occurred after a small outbreak of Malburg virus in Jo hannesburg. South Mrica, in 1975. Viru s was cultured fro m the amerio r chamber aspirate at presentation, SO days after initial infedion.71 Box 104.3 Nephropathia epldemkll. Biological agenU of ~econd highest priority and o"hth~."'. Some of the other less virulent causes of viral hemorrhagic manifestations fever also have ophthalmIc Sign s. Patients affected with Brucellosis (Bruulla spp .) _ uveitlsu,u with iridocyclitis nephropathia epidemica can present with eye pain, blurred chronic, granulomatous or nongranulomatous) and m"ltl'''''' cho roiditis (nodulllr Of geographic"), nummular keratitis,a vision, and photophobia. most prominent eye fi nding The (KUrTent eplscleritis!' optic n@uriti5 ,~ dacryoadenili5,'l is transient myopia due to forward movement of the endogenous endophtha lmjris9~ 78 anteri or diaphragm and thickening of the aystaUine lens. Epsilon toxin or Closlridium perfringem _ corneal ulcer,'I Usually the intraocular pressure is s lightly lowered;19 how· endogenous endophthalmitis'" so ever, acute glauco ma has been observed. Other Ilnd ings Solmonef/o spp. - Reiter'l $)'ndrome,n peripheral uktfatM include conjunctival injeCtion and hemorrhage, iritis, and keratitis,'6 steUtlite milculopathy and chorioretinitis,t1,,,,",,,.... retinal edema with hemorrhage. 81 Neuro·ophthalmlc endophthalmitis" findings include toniC pupils82 and Isolated abducens palsy.8.1 Escherichia coli 0157:H7 - keratitis, 99 endogen"oo~':'t:::::::: Sh¢la spp. _ Reiter's syndrome. keratitis,Q" 0 Rift Valley fever Glanders (Bur*.hokferia mtJllet) - none Rift Valley lever presents predominantly with retinal find· Melioidosis (Burfloldtfia pseudomalleJ) - anophth Box 104.5 N~ ~ent dgns SuKur u ioxide inhibit collagenolysis and quell chemical Z8. Br