1 Infectious Diseases

followed by direct sequencing of the resulting amplicon. This technique is particularly relevant for small ocular samples, including aqueous and vitreous taps.

TREATMENT

While colonization should not be treated, infection should. Acinetobacter spp. has a chromosomic beta-lactamase not inhibited by clavulanate, active against first generation cephalosporine but not against ticarcillin. Nevertheless, due to the importance of resistant strains, susceptibility testing is required for each clinically significant strain. Throughout the years multiresistant strains have emerged in hospitals. Some strains of A. baumannii are considered as the most resistant of all Gramnegative bacteria. Mechanisms of resistance are numerous:

●secretion of β-lactamases encoded either by the chromosome or by plasmids,

●acquisition of plasmids encoding resistance to aminosides,

●mutation of the DNA gyrase causing resistance to quinolones,

●transposon encoding resistance to chloramphenicol, etc.

Antibiotics

Aminoglycosides (with amikacin the most active one > tobramycin > gentamicin), carbapenems (meropenem, imipenem — but associated with the rapid and worrying development of resistance), and fluoroquinolones remain the mainstay of therapy.

Among b-lactams, although the carbapenems are still the most active antimicrobials against Acinetobacter species, carbapenems resistant strains have been reported in nosocomial outbreaks. Acinetobacter remains highly sensitive to other β-lactams: piperacillin/tazobactam, ticarcillin/clavulanate, ceftazidime, cefepime. Reappraisal of older compounds (e.g. polymyxin B, ampicillin/sulbactam) is necessary.

Regarding fluoroquinolones, novel third and fourthgeneration fluoroquinolones demonstrate superior activity (×4 to ×16) when compared to ciprofloxacin: clinafloxacin > gatifloxacin > levofloxacin > trovafloxacin > gemifloxacin = moxifloxacin. They should be the first line drugs in the treatment of acinetobacter endophthalmitis (before ciprofloxacin) because of their good biodisponibility and intra ocular penetration.

Other antibiotics: trimethoprim-sulfamethoxazole are effective against most strains whereas chloramphenicol, tetracycline, macrolides have little and/or no activity against

Acinetobacter.

Acinetobacter baumannii remains susceptible to antiseptics or disinfectants.

REFERENCES

Gopal L, Ramaswamy AA, Madhavan HN, et al: Endophthalmitis caused by Acinetobacter calcoaceticus. A profile. Indian J Ophthalmol 51:335– 340, 2003.

Heinemann B, Wisplinghoff H, Edmond M, et al: Comparative activities of ciprofloxacin, clinafloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, and trovafloxacin against epidemiologically defined Acinetobacter baumannii strains. Antimicrob Agents Chemother 44:2211– 2213, 2000.

Jain R, Danziger LH: Multidrug-resistant Acinetobacter infections: an emerging challenge to clinicians. Ann Pharmacother 38:1449–1459, 2004.

Kämpfer P, Tjernberg I, Ursing J: Numerical classification and identification of Acinetobacter genomic species. J Appl Bacteriol 75:259–268, 1993.

Kau HC, Tsai CC, Kao SC, et al: Corneal ulcer of the side port after phacoemulsification induced by Acinetobacter baumannii. J Cataract Refract Surg 28:895–897, 2002.

Kirwan JF, Potamitis T, el-Kasaby H, et al: Microbial keratitis in intensive care. BMJ 314:433–434, 1997.

Rudolph T, Welinder-Olsson C, Lind-Brandberg L, et al: 16S rDNA PCR analysis of infectious keratitis: a case series. Acta Ophthalmol Scand 82:463–467, 2004.

Van Gelder RN: Applications of the polymerase chain reaction to diagnosis of ophthalmic disease. Surv Ophthalmol 46:248–258, 2001.

Van Looveren M, Goossens H: Antimicrobial resistance of Acinetobacter spp. in Europe. Clin Microbiol Infect 10:684–704, 2004.

2 ACQUIRED AND CONGENITAL

SYPHILIS 095.8

Ismail A. Shalaby, MD, PhD

Baltimore, Maryland

Syphilis is a chronic systemic infection caused by the spirochete Treponema pallidum, for which humans are the only natural host. It has been known as a cause of ophthalmic disease for more than 100 years. Infections occurring through passage of the organism from an infected mother across the placenta to her fetus define congenital syphilis. Acquired syphilis is usually transmitted sexually. Although congenital and acquired syphilis are caused by the same organism and are treated in a qualitatively similar fashion, their clinical course and physical findings are sufficiently different to warrant separate discussions.

Acquired syphilis

occurred in the 1970s. Between 1981 and 1990, the incidence of primary and secondary syphilis increased from 13.7 to 20.3 per 100,000 persons. This increase, which primarily involved urban minorities, was attributed to various factors, including illegal drug use, trading sex for drugs, concurrent human immunodeficiency virus (HIV) infection, and decreased access to healthcare. Although by 2001 the national rate had fallen to 2.2 cases per 100,000, there was yet another rate increase in 2002 reaching 2.4 cases per 100,000. This increase occurred only in men, and in particularly among men who have sex with men (MSM). It is reported that a substantial number of MSM with syphilis report meeting anonymous partners in venues such as bathhouses and Internet chat rooms.

Syphilitic uveitis, the most common ocular manifestation of syphilis, occurs in about 5% of patients with syphilis and accounts for about 1% to 2% of all cases of uveitis.

COURSE/PROGNOSIS

Primary syphilis

T. pallidum penetrates intact mucous membranes at the site of sexual contact and causes an ulcerated papular lesion known as a chancre in 10 to 90 days (mean, 21 days), depending on the size of the inoculation. Multiple chancres are common, particularly in HIV-infected patients. Regional nontender lymphadenopathy appears within 1 week of onset of the chancre but is absent in chancres involving the anus, lower vulva and cervix, which drain to deep lymph nodes. Most chancres heal without scarring in 4 to 6 weeks, but lymphadenopathy may persist for months.

●inflammatory lesions of the cardiovascular system (aortitis, aortic regurgitation, and saccular aneurysms) in about 10% of patients, and

●gummas (gummata), which are rubbery, granulomatous, nodular lesions that can involve the skin, skeletal system, mouth, respiratory tract, liver, stomach and CNS. Gummas of the skin are often painless and indolent and may heal spontaneously with scarring. Gummas of the skeletal system frequently involve the long bones of the legs and often present with focal pain and tenderness.

Neurosyphilis

Five patterns of syphilitic infection of the CNS are as follows:

1.Asymptomatic neurosyphilis: abnormal CSF findings only; frequently progresses to clinical neurosyphilis.

2.Acute meningitis: cranial nerves 7 and 8 most commonly involved.

3.Meningovasculitis: classic picture of meningovascular syphilis is a relatively young adult who presents with a stroke syndrome that was preceded by subacute symptoms of meningitis and encephalitis.

4.Parenchymatous neurosyphilis: tabes dorsalis and generalized paresis. Tabes dorsalis symptoms include ataxia, paresthesia, wide-based gait and foot drop, deep pain, impotence, bladder disturbance, Charcot’s joints, and optic nerve atrophy. General paresis presents with widespread symptoms according to the mnemonic paresis (personality, affect, reflexes [hyperactive], eye [Argyll Robertson pupils], sensorium [illusions and delusions], intellect [dementia, orientation, and so on] and speech).

5.Gummatous neurosyphilis.

Secondary syphilis

This stage of infection is characterized by localized or diffuse mucocutaneous lesions and generalized nontender lymphadenopathy. A primary chancre may persist in 15% to 25% of patients. The frequently pruritic skin rash consists of macular, papular, papulosquamous, and occasionally pustular lesions or a combination of all patterns. Condylomata lata (broad, moist, pink or gray-white vegetations resulting from enlargement and erosion of papular lesions in moist intertriginous areas) are seen in 10% of patients and are highly infectious. Superficial painless mucosal erosions called mucous patches occur in as many as 15% of patients and involve the lips, oral mucosa, tongue, palate, vulva, vagina, and glans penis. Flu-like symptoms such as malaise, weight loss, anorexia, sore throat, headache, and fever occur in 50% of patients. Patchy, nonscarring alopecia may be present. Uveitis and the many other ocular manifestations usually occur in this stage (see later).

Latent syphilis

Latent syphilis is marked by immunity, the absence of clinical signs of infection, and an increased incidence of false-negative nontreponemal tests. One third of patients with untreated latent disease develop tertiary syphilis, usually 2 to 20 years after primary infection but much sooner in HIV-infected patients.

Tertiary (late) syphilis

Tertiary syphilis is the end result of a slowly progressive inflammatory disease that begins early after the T. pallidum infection. Manifestations include:

●central nervous system (CNS) infection in about 8% of patients (see Neurosyphilis),

DIAGNOSIS

Ocular manifestations

Ophthalmic signs and symptoms can be present at any stage of syphilis and can involve any ocular structure. Eye disease is most frequently found in secondary syphilis and with CNS infection.

Primary syphilis

Chancres can present, albeit rarely, on the conjunctiva or eyelid.

Secondary syphilis

Iridocyclitis (usually granulomatous) is the most common finding. Other manifestations include papulosquamous eyelid rash, alopecia of the eyebrows and eyelashes, dacryocystitis, dacryoadenitis, conjunctivitis, episcleritis, scleritis, iris papules, lens dislocation, interstitial keratitis, intermediate uveitis, posterior uveitis, panuveitis, cystoid macular edema, retinitis (including retinal necrosis), pseudoretinitis pigmentosa, retinal periphlebitis, placoid posterior chorioretinitis, neuroretinitis, choroiditis and choroidal neovascular membrane. Optic nerve involvement includes optic neuritis, optic perineuritis, papilledema and papillitis. HIV-infected patients have more severe and more bilateral disease. In one study, more than half of the patients had ocular complaints as the initial manifestation of syphilis, usually with concurrent maculopapular rash.

Late syphilis

Manifestations include the presence of gummas on the optic nerve, retina, extraocular muscles, sclera and iris. Ptosis,

extraocular muscle weakness or palsy, pupillary abnormalities (Argyll Robertson pupils), optic nerve atrophy, retinal pigment hypertrophy and posterior pole/macular scars are other signs of late syphilis. Unexplained visual field defects may also be due to a late-stage syphilitic infection.

Neurosyphilis

Early CNS infections can present with iritis, iridocyclitis and other forms of uveitis. Late CNS disease causes pupillary abnormalities or optic atrophy. Ocular syphilis is more closely associated with cerebrospinal fluid (CSF) and neurologic abnormalities in HIV-positive than in HIV-negative patients. Acute syphilitic meningitis has occurred as early as 4 months after initial infection in HIV-infected patients.

Latent syphilis

This is defined as seroreactivity without other evidence of disease. Early latent syphilis is diagnosed in patients infected within the previous year by either a documented seroconversion, unequivacol symptoms of primary or secondary syphilis, or having had a sex partner documented to have primary, secondary or early latent syphilis.

Laboratory findings

Nontreponemal tests (Venereal Disease Research Laboratory [VDRL] and rapid plasma reagin [RPR]) are used to quantify antibodies against cardiolipin, and the titer may be used to assess the response to treatment. The titer is not proportional to the severity of disease; extremely high titers in HIV-infected patients may result from polyclonal B cell stimulation. Treponemal tests (fluorescent treponemal antibody absorption [FTA-ABS] and microhemagglutination-Treponema pallidum [MHA-TP]) are more specific but less quantifiable and the test remains positive after treatment. False-positive results can occur with either test; a weakly positive FTA-ABS often is a false positive. Because all positive nontreponemal tests require confirmation with a treponemal test and because 38% of patients with ocular syphilis had a negative VDRL in one study, it is recommended by many clinicians that both tests be ordered. All patients with syphilis should be tested for HIV infection.

Primary syphilis

Laboratory tests are negative for 1 to 2 weeks after infection, so diagnosis requires confirmation of treponemes in lesions by dark-field microscopy. Treponemal tests become positive earlier than nontreponemal tests.

Secondary syphilis

Both treponemal and nontreponemal tests are positive in nearly all cases.

Latent syphilis

Nontreponemal tests become negative in 99% of treated patients and 30% of untreated patients. Treponemal tests remain positive in 98% of treated and untreated patients. All patients who may have had syphilis for longer than 1 year should undergo lumbar puncture to look for evidence of neurosyphilis.

Neurosyphilis

Laboratory diagnosis and confirmation include a reactive serologic test plus a reactive VDRL in the CSF. However, neurosyphilis can be diagnosed if there is a positive serologic test with a negative VDRL, as long as there is elevated CSF protein or leukocyte count plus clinical signs or symptoms consistent with neurosyphilis in the absence of any other known cause for these abnormalities. Positive CSF serology and pleocytosis are found much more commonly in HIV-infected patients who have ocular syphilis than in HIV-negative patients who do not have ocular syphilis.

Differential diagnosis

●Uveitis: sarcoidosis.

●Necrotizing retinitis: herpetic retinitis, cytomegalovirus retinitis.

●False-positive serologic tests for syphilis: other spirochetal infections (e.g. Lyme disease), malaria, leptospirosis, leprosy, measles, tuberculosis, chronic liver disease, connective tissue disease and blood transfusions.

TREATMENT

Parenteral penicillin is the preferred treatment for all stages of syphilis. The route, dosage, and length of treatment depend on the stage of the infection. Treatment of HIV-infected patients is discussed separately. Below are the United States Center for Disease Control recommendations. For pregnant women and neonates, see Congenital syphilis.

Primary and secondary syphilis

●Penicillin G benzathine at 2.4 million units IM in a single dose.

●For penicillin-allergic (non pregnant) patients, doxycycline

100 mg PO b.i.d. or tetracycline 500 mg PO q.i.d. for 14 days.

Late latent syphilis, tertiary syphilis and syphilis of unknown duration

●Penicillin G benzathine at 2.4 million units IM weekly for 3 weeks.

●For Penicillin-allergic (non pregnant) patients are treated with doxycycline 100 mg PO b.i.d. or tetracycline 500 mg PO q.i.d. for 14 days for early latent and 28 days for late latent infection; data regarding the efficacy of non penicillin regimens are scarce.

●Treatment of latent syphilis is intended to prevent occurrence or progression of late complications.

Neurosyphilis and syphilitic eye disease

●Aqueous crystalline penicillin G 3.0 to 4.0 million units IV every 4 hours is administered for 10–14 days (total of 18–24 million units per day) (penicillin G benzathine does not achieve treponemicidal levels in the CSF).

●Penicillin-allergic (nonpregnant) patients are treated with doxycycline 100 mg PO b.i.d. or tetracycline 500 mg PO q.i.d. for 2 weeks for early latent and 4 weeks for late latent infection; data regarding the efficacy of nonpenicillin regimens are scarce.

Complications

The Jarisch–Herxheimer reaction is an acute self-limited systemic febrile reaction accompanied by headache, myalgia, tachycardia, hyperventilation, and mild hypotension that occurs within 1 to 2 hours and lasts 12 to 24 hours after any effective therapy for syphilis. It can occur in any stage of syphilis (10% to 25%) but is particularly common in secondary syphilis (70% to 90%). It may also induce early labor or cause fetal distress in pregnant women. This should not prevent or delay therapy; patients should be warned of this reaction before treatment. The Jarisch–Herxheimer reaction is self-limited and can be symptomatically treated with aspirin every 4 hours for 24 to 48 hours. Treatment with prednisone is warranted in cardiovascular syphilis and neurosyphilis because the reaction may be catastrophic in these patients.

●Bilateral interstitial keratitis is the classic and most common finding (10% of patients), occurring in persons 5 to 20 years of age. There is associated anterior uveitis, which is followed by endothelial edema leading to a generalized corneal edema. The cornea is then invaded by superficial and deep blood vessels from the periphery that appear to push a faint opacity in front of them. The blood vessels can form to meet a ‘salmon patch’ and the inflammation then subsides, leaving clear branching ‘ghost vessels’ around a translucent scar anterior to Descemet’s membrane.

●Chorioretinitis appearing as a bilateral salt-and-pepper granularity of the fundus.

●Pseudoretinitis pigmentosa.

●Secondary glaucoma may develop due to chamber angle damage from the initial anterior segment inflammation.

Other antibiotic therapy

There have been reports about the possible efficacy of ceftriaxone, and azithromycin in infectious syphilis. The human clinical studies on ceftriaxone have been limited, and the initial positive reports with azithromycin have been followed by several reports on treatment failures. Therefore, neither therapy is generally recommended at this time.

Congenital syphilis

ETIOLOGY/INCIDENCE

The transmission of T. pallidum from an untreated or inadequately treated mother to her fetus may occur at any stage of pregnancy and is especially common in untreated primary or secondary syphilis. The lesions of congenital syphilis may become apparent anytime after the first trimester up to early adolescence. Congenital syphilis causes fetal or perinatal death in 10% to 40% of the infants affected.

The number of reported cases of congenital syphilis in the US rose between 1984 to 1991, reaching a peak of 100 cases per 100,000 live born infants. This increase paralleled the rise of primary and secondary syphilis, which were usually associated with the practice of trading sex for drugs. Fortunately, there has been a steady overall decline of incidence since then reaching a nadir of 11.2 cases per 100,000 live born infants

DIAGNOSIS

Laboratory findings

●Confirmed congenital syphilis is defined by the Centers for Disease Control and Prevention as that occurring in an infant in whom T. pallidum is identified by dark-field microscopy.

●Presumptive congenital syphilis is defined as that occurring in an infant whose infected mother went untreated or was inadequately treated during pregnancy or an infant or a child who has a reactive treponemal test for syphilis plus

(1) any evidence of congenital syphilis on physical examination, (2) evidence of congenital syphilis on long-bone radiographs, (3) a reactive CSF VDRL, (4) elevated CSF cell or protein count without other cause, (5) quantitative nontreponemal serologic titer 4-fold higher than the mother’s titer (with both drawn at birth), or (6) reactive test for FTA- ABS-19S-IgM antibody.

●Serologic tests in both infants and mothers may be negative if the syphilis was acquired near the end of the pregnancy.

●Maternally acquired antibodies will decrease during the first year of life.

Differential diagnosis

●Other congenital infections (cytomegalovirus, rubella, toxoplasmosis), acquired syphilis (in cases of sexual abuse).

HIV is a member of the lentivirus family. There are two types of HIV: Type 1 (worldwide) and Type 2 (west Africa). HIV is a human retrovirus with RNA genome with reverse transcriptase enzyme.

Three routes of human transmission of HIV have been described: sexual, blood-borne and mother-infant.

COURSE/PROGNOSIS

HIV has the ability to cause an insidious and progressive deterioration of the host’s immune function, leading to profound immunossupression. Central to the immunopathogenesis of the HIV is its interaction with the CD4 molecule in the helper/ inducer subset of T-lymphocytes. As CD4 T-lymphocytes play a key role in the induction of most immunologic responses, HIV-induced damage of the CD4 T lymphocyte population results in the abolition of a wide range of immune functions, ultimately leading to extreme immunosupression manifested by opportunistic infections and neoplasms pathognomonic for AIDS.

than in the rest of sub-Saharan Africa. National HIV data, though, hide much higher levels of infection in parts of countries, as Nigeria illustrates. Southern Africa, unfortunately, offers only slight hints of possible future declines in HIV prevalence.

The AIDS epidemic is affecting women and girls in increasing numbers. Globally, just under half of all people living with HIV are female. Women and girls make up almost 57% of all people infected with HIV in sub-Saharan Africa, where a striking 76% of young people (aged 15–24 years) living with HIV are female. In most other regions, women and girls represent an increasing proportion of people living with HIV, compared with five years ago.

DIAGNOSIS

HIV-infected individuals whose CD4 T lymphocyte count is less than 200 cells/mL is classified as having AIDS. The presence of one of the specified indicator diseases (e.g. cytomegalovirus diseases, encephalopathy, candidiasis, etc.) is also diagnostic of AIDS, regardless of the CD4 T-lymphocyte count.

EPIDEMIOLOGY

The AIDS pandemic enters its 24th year and the total number of people living with the human immunodeficiency virus (HIV) rose in 2004 to reach its highest level ever: an estimated 39.4 million (35.9 million–44.3 million) people are living with the virus. From this total, 4.9 million (4.3 million–6.4 million) people acquired HIV in 2004. The global AIDS epidemic killed 3.1 million (2.8 million–3.5 million) people in the past year.

The number of people living with HIV has been rising in every region, compared with two years ago, with the steepest increases occurring in East Asia, and in Eastern Europe and Central Asia. The number of people living with HIV in East Asia rose by almost 50% between 2002 and 2004, an increase that is attributable largely to China’s swiftly growing epidemic. In Eastern Europe and Central Asia, there were 40% more people living with HIV in 2004 than in 2002. Accounting for much of that trend is Ukraine’s resurgent epidemic and the ever-growing number of people living with HIV in the Russian Federation.

Sub-Saharan Africa remains by far the worst-affected region, with 25.4 million (23.4 million–28.4 million) people living with HIV at the end of 2004, compared to 24.4 million (22.5 million–27.3 million) in 2002. Just under two thirds (64%) of all people living with HIV are in sub-Saharan Africa, as are more than three quarters (76%) of all women living with HIV.

The epidemics in sub-Saharan Africa appear to be stabilizing generally, with HIV prevalence at around 7.4% for the entire region. But such a summary perspective hides important aspects. First, roughly stable HIV prevalence means more or less equal numbers of people are being newly infected with HIV and are dying of AIDS. Beneath the apparent constancy of steady prevalence levels lie devastating realities-especially in southern Africa, which accounts for one third of all AIDS deaths globally. Second, the epidemics in Africa are diverse, both in terms of their scale and the pace at which they are evolving. There is no single ‘African’ epidemic. Some urban parts of East Africa display modest declines in HIV prevalence among pregnant women, while in West and Central Africa prevalence levels have stayed roughly steady at lower levels

Clinical signs and symptoms

An infectious mononucleosis-like syndrome (recognized as acute retroviral syndrome), develop in more than 50% of HIVinfected persons. This is observed 3 to 6 weeks after exposure and resolves spontaneously.

Laboratory findings

Detectable antibody to HIV develops in the overwhelming majority of infected individuals within 6 months of exposure. The enzyme-linked immunosorbent assay (ELISA) is used for screening. Western blot, immunofluorescent antibody studies, p24 antigens determinations, qualitative DNA PCR studies, viral cultures and other techniques are used to evaluate suspected false-positive and false-negative test results.

Ophthalmologic disorders

Until potent antiretroviral therapy (ART) became available, the most common retinal manifestation of immunodeficiency in advanced AIDS was CMV retinitis.

Retinitis is the most common manifestation of CMV disease in adult individuals with AIDS. Before the era of potent antiretroviral therapy (ART), 16.5% to 34% of HIV-infected individuals eventually had reactivation of latent infection and development of clinically apparent CMV end-organ disease.

Epidemiologic data regarding AIDS and CMV retinitis changed dramatically following the introduction of potent antiretroviral drugs (ARV) in the late 1990s. Several classes of antiretroviral drugs are currently available, including nucleoside reverse-transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors; the latter target viral proteases involved in the assembly of new viral particles rather than the viral genome. Any combination of three or more antiretroviral drugs, or a combination containing one protease inhibitor and one non-nucleoside reverse transcriptase inhibitor, are considered ART.

The use of ART has been associated with reduced HIV replication and an increase in CD4+ T-lymphocyte counts, as well as a marked increase in survival. A reduced incidence of opportunistic infections, and a drop in newly diagnosed cases of CMV retinitis by 55% to more than 90%, were also observed.

TREATMENT

Ocular

Topical broad-spectrum antibiotics, such as 10% sulfacetamide eye drops, four times daily, may be used to prevent secondary bacterial infection. Use of topical corticosteroids may predispose an already compromised cornea to develop microbial keratitis and such practice should be discouraged. In the majority of patients, infection is short in duration, self-limiting, and free of significant ocular sequelae.

Park SW, Lee CS, Jang HC, et al: Rapid identification of the coxsackievirus A24 variant by molecular serotyping in an outbreak of acute hemorrhagic conjunctivitis. J Clin Microbiol 43(3):1069–1071, 2005.

Wadia NH, Irani PF, Katrak SM: Neurological complications of a new type of conjunctivitis. Lancet 1:350–352, 1973.

Wairagkar NS, Gogate SS, Labhsetwar AS: Investigation of an epidemic of acute haemorrhagic conjunctivitis in Pune, India. J Commun Dis 31(1):41–43, 1999.

PREVENTIVE MEASURES

AHC is transmitted mainly by infected eye-to-hand-to-eye contact. Fomites, contaminated instruments, public washing facilities and swimming pools may be implicated in transmission. Careful hand washing, sterilization of ophthalmic instruments, avoiding contact with infected patients may prevent the transmission.

COMMENTS

AHC is an extremely contagious, symptomatic and highly visible ocular disease that occurs in epidemics. Prolonged visual disability does not occur and patients recover with remarkably few sequelae. Because of the relatively benign course of the disease, over treatment with topical antibiotics and corticosteroids should be avoided.

REFERENCES

Asbell PA, de la Pena W, Harms D, et al: Acute hemorrhagic conjunctivitis in central America: first enterovirus epidemic in the western hemisphere. Ann Ophthalmol 17:205–209, 1985.

Centers for Disease Control and Prevention (CDC): Acute hemorrhagic conjunctivitis outbreak caused by coxsackievirus A24–Puerto Rico, 2003. Morb Mortal Wkly Rep 53(28):632–634, 2004.

Dalapathy S, Lily TK, Madhavan HN: Development and use of nested polymerase chain reaction for identification of adenovirus from conjunctivitis. J Clin Virol 11:77–84, 1998.

Dussart P, Cartet G, Huguet P, et al: Outbreak of acute hemorrhagic conjunctivitis in French Guiana and West Indies caused by coxsackievirus A24 variant: phylogenetic analysis reveals Asian import. J Med Virol 75(4):559–565, 2005.

Hung TP, Sung SM, Liang HC, et al: Radiculomyelitis following acute haemorrhagic conjunctivitis. Brain 99(4):771–790, 1976.

Kew OM, Nottay BK, Hatch MH, et al: Oligonucleotide fingerprint analysis of enterovirus 70 isolates from the 1980 to 1981 pandemic of acute hemorrhagic conjunctivitis: evidence for a close genetic relationship among Asian and American strains. Infect Immun 41(2):631–635, 1983.

Kono R: Apollo 11 disease or acute hemorrhagic conjunctivitis: a pandemic of a new enterovirus infection of the eyes. Am J Epidem 101(5):383– 390, 1975.

Kono R, Miyamura K, Tajiri E, et al: Neurologic complications associated with acute hemorrhagic conjunctivitis virus infection and its serologic confirmation. J Infect Dis 129(5):590–593, 1974.

Lin KH, Takeda N, Miyamura K, et al: The nucleotide sequence of 3c proteinase region of the coxsackievirus A24 variant: comparison of the isolates in Taiwan in 1985–1988. Virus Genes 5:121–131, 1991.

Lu YY, Yan JY, Feng Q, et al: A novel enterovirus associated with acute hemorrhagic conjunctivitis. Complete genome data. NCBI-GenBank Accession numbers: AY876913, AY876912. Online. Available at: http:// www.ncbi.nlm.nih.gov, 29 Apr 2005.

5 ASPERGILLOSIS 117.3

Mark D. Sherman, MD

Anaheim Hills, California

Aspergillosis is a generic term indicating infection by a member of the saprophytic fungus Aspergillus. Approximately 21 of the 900 species and subspecies of Aspergillus have been associated with human disease. Aspergillus spp. are commonly isolated from soil, vegetation, grains, airway systems and decaying organic matter. The spectrum of human disease caused by Aspergillus spp. includes allergic reactions, colonization of debilitated tissue without invasion, invasive destruction of specific organs and disseminated disease. Infection most commonly results from inhalation of spores. The respiratory system is the most common site of infection. Disseminated aspergillosis may involve the skin, central nervous system, brain, kidney and bone. Less common manifestations of aspergillosis include otomycosis, corneal ulcers, endophthalmitis and nasoorbital disease.

ETIOLOGY/INCIDENCE

Aspergillus fungi can be found in most parts of the world. Aspergillosis is a major cause of fungal infection in both tropical and temperate climates. Infection is more common in individuals where contamination is more likely, such as with grain farmers and breeders of poultry. Orbital involvement is most commonly a result of spread from the paranasal sinuses. Corneal involvement requires direct inoculation such as occurs during ophthalmic surgery or occurs as a complication of contact lens wear or other local insult. Corneal involvement is more likely in individuals with compromised ocular defenses or pre-existing corneal disease. Keratomycosis caused by Aspergillus spp. accounts for almost 50% of all reported cases of oculomycosis. Endogenous Aspergillus endophthalmitis is associated with disseminated Aspergillus. Individuals at greatest risk are those who are intravenous drug abusers, immunosuppressed, or recipients of organ transplants. Aspergillus causes an occlusive vasculitis in the retina and choroid. Hyphae can penetrate the walls of the blood vessels to infect contiguous structures such as the vitreous and sclera.

COURSE/PROGNOSIS

The therapy of Aspergillus infections is often complicated by a delay in diagnosis, the previous use of corticosteroids and the long-term use of antifungal medications. Aspergillosis

requires intensive and aggressive treatment. Orbital aspergillosis has a poor prognosis for maintaining useful vision and a poor prognosis for life. Despite extensive debridement and antifungal treatment, Aspergillus spp. can reappear in previously involved tissues, especially when vascular invasion has occurred. The prognosis for Aspergillus endophthalmitis is similarly poor. Successfully treated Aspergillus keratomycosis may require later penetrating keratoplasty for visual rehabilitation.

false-positive results could occur if the specimen remains unnecessarily exposed.

●Gram’s, Giemsa, and GMS stains are better than KOH stains for detecting the branching septated hyphae that are typical of Aspergillus spp.

●Either Sabouraud’s media (Emmon’s modification) or blood agar will usually be positive within 48 hours.

●Blood cultures are routinely negative, even in fulminant cases.

DIAGNOSIS

Clinical signs and symptoms (ocular and periocular)

Eyelid

Lid edema may occur in association with deeper orbital involvement. A local chronic ulcerative granuloma may occur with direct inoculation.

Conjunctive

Chemosis occurs with orbital involvement. Conjunctivitis may occur with Aspergillus canaliculitis.

Cornea

Aspergillus keratomycosis may present with a foreign body sensation, pain, redness and decreased vision. The eye is usually severely inflamed. There may be a central or paracentral corneal abscess, diffuse keratitis and satellite lesions. There commonly is an intense anterior chamber reaction with hypopyon.

Lacrimal system

Canaliculitis, dacryocystitis and dacryoadenitis can occur.

Sclera

Scleritis is rare but may progress to perforation.

Orbit

Patients may present with slowly progressive, unilateral proptosis with or without pain. Later signs include decreased vision and changes in ocular motility. An orbital granuloma or abscess may form. Optic atrophy due to vascular compromise in the orbital apex has been reported.

Uveal tract

Multifocal choroiditis associated with vitreous cells and retinal vasculitis can occur.

Endophthalmitis

Patients may present with decreased vision, pain, and photophobia. Clinical signs include anterior chamber cells, hypopyon, vitreous cells or snowball opacities, serous or exudative retinal detachment, posterior ischemic optic neuropathy and central retinal artery occlusion.

Laboratory findings

●Aspergillus keratitis: six to eight scrapings with a Kimura spatula from the bed of the infection are needed for culture.

●In cases of suspected intraocular Aspergillus, intravitreal and anterior chamber aspirates should be concentrated by the use of a filter or by centrifugation before plating.

●Orbital biopsy material should be plated soon after collection because Aspergillus is a ubiquitous organism and

Differential diagnosis

●Fungal infection: Candida, Fusarium, Mucor, Coccidioides,

Blastomyces and others depending on geographic location and risk factors.

●Bacterial infection: orbital cellulitis, subperiosteal abscess, syphilis, M. tuberculosis, or atypical mycobacteria.

●Orbital inflammatory disease: orbital pseudotumor, Graves’ ophthalmopathy, sarcoidosis, Wegener’s granulomatosis, idiopathic sclerosing orbititis, polyarteritis nodosa, other collagen-vascular disorders.

●Neoplasm: metastases, lacrimal gland tumor, lymphoma, leukemia.

●Vascular disease: carotid-cavernous fistula, cavernous sinus thrombosis, varix.

TREATMENT

Systemic

●Systemic treatment should be prescribed in coordination with consultation from an infectious disease subspecialist.

●Amphotericin B (0.5 to 1.5 mg/kg/day) has been the mainstay of systemic therapy for disseminated aspergillosis. Amphotericin B has substantial and varied toxicity, which can limit its use. Newer therapies are now becoming available.

●Itraconazole (200 to 600 mg/day) has been reported to show effectiveness in some cases in which amphotericin B failed.

●The combination of amphotericin B with flucytosine (100 to 200 mg/kg/day) or rifampin (600 mg b.i.d.) has been reported to improve the clinical response.

●Other azole antifungal agents (fluconazole, miconazole, ketoconazole) have shown less effectiveness in the treatment of aspergillosis.

●The use of systemic steroids is controversial. They may be necessary in cases of visual loss and proptosis but should not be used until effective antifungal therapy has been started.

Local

●Natamycin (5% suspension) is the only commercially available topical formulation for the treatment of ocular aspergillosis (keratomycosis). It is effective for superficial corneal infections but less effective for deep stromal infection.

●Topical amphotericin B (0.05% to 0.15% eyedrops prepared from the intravenous formulation) can be used for cases of deeper keratomycosis or cases refractory to natamycin.

●Subconjunctival injection of amphotericin B (1 mg) has been described but may be associated with significant local toxicity.

●Successful therapy requires frequent and prolonged administration of medication. Hourly eyedrops may be necessary