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20/100) had significantly better final visual acuity than the eyes with poor preoperative vision «20/ 200) .93 Recurrences of CNV were successfully treated with laser photocoagulation and thereby did not affect the final visual outcome. Similarly, a retrospective review of 67 eyes that had surgical removal of subfoveal CNV caused by POHS demonstrated that the ingrowth site of subfoveal CNV could be identified in the majority of eyes, and that a significant number of eyes with subfoveal CNV have an, extrafoveal ingrowth site. The eyes with an extrafoveal ingrowth site have a favorable visual prognosis after surgical removal of CNV. If the ingrowth site is subfoveal or not identifiable, the visual prognosis after surgery is guarded. 125 In another retrospective study, visual recovery after submacular surgery in POHS was associated with postoperative perfusion of the subfoveal choriocapillaris. 126 The best-corrected visual acuity was an improvement of at least two Snellen lines in 71 % of the perfused and 14% of nonperfused eyes. It remains to be seen if the development of techniques to maintain or re-establish perfusion of the subfoveal choriocapillaris after surgery could improve visual outcome in these eyes. 126 Another retrospective study demonstrated that the ingrowth site of subfoveal CNV was a predictor of visual outcome after submacular surgical excision of CNV. 125 If the ingrowth site of subfoveal CNV was extrafoveal, the surgical removal of CNV was favorable, but if the ingrowth site of CNV was subfoveal or not identifiable, the visual prognosis was guarded. 125 Subretinal microsurgery is still in its infancy and going through its developmental stages. Initial encouraging results have not been consistently reproduced. Appropriate case selection and surgical timing of intervention to maximize visual benefits from submacular surgery still need to be defined. Several points need to be considered before deciding on subretinal or subfoveal surgery to remove CNV in POHS. First, all surgeons have stressed the importance of choosing the prospective patients very carefully. Submacular surgery is not for all patients with POHS, or perhaps even for most. Initial results of surgical removal of CNV in age-related. maculopathy have not been impressive. 51 Patients may need replacement of their nonfunctioning or barely functioning RPE cells along with removal of subfoveal neovascular membrane. Second, surgical removal of subretinal or subfoveal neovascular membranes is followed by a high recurrence rate and the results do not outweigh the results of other therapeutic modalities, especially laser photocoagulationY Third, and finally, a confounding point is the spontaneous regression of neovascular membranes in some patients with POHS,particularly in the young who happen to be good candidates for surgery.51 A randomized, controlled, prospective, multicenter tri(il, the Submacular Study Trial (SST) was organized to evaluate subfoveal surgery for POHS. Specifically, this study evaluates subfoveal surgery and compares it to ob-
CHAPTER 28:
rnll:;.;;zI'Jluy.m:;lIJ
OCULAR HISTOPLASMOSIS SYNDROME
servation for the treatment of eyes with POHS and subfoveal CNV. Histopathologic and ultrastructural findings of surgically excised CNV from patients who had undergone submacular surgery demonstrated fibrovascular tissue, fibrocellular tissue, or hemorrhage in all cases. Vascular endothelium and RPE were the most common constituents of the CNV.61,127-129
Complications Surgery
of SubmacularlSubretinal
CNV secondary to POHS often arises from focal defects in Bruch's membrane and proliferates anterior to the RPE.124 This type of membrane may be removed with preservation of the underlying RPE and choriocapillaris requisite to restoring visual function. 130 Submacular surgerycarries all the risks of vitrectomy surgery. Retinal detachment, retinal tears without detachment, endophthalmitis, subretinal hemorrhage, cataract formation, and premacular fibrosis have been reported as complications of submacular surgery.130 Recurrent neovascularization after subretinal surgery is a common problem. Recurrence should be differentiated from persistence of CNV because of incomplete removal of CNV membranes. Early recognition of persistent or recurrent CNV may allow laser photocoagulation in. CNV away from the fovea for better visual prognosis. 131 Subfoveal recurrence is the most difficult to manage, making it an ideal clinical mode~ for testing antiangiogenic agents 131 because laser treatment of subfoveal CNV destroys the fovea and is not recommended. 132 Younger patient age and the absence of previous laser photocoagulation are factors associated with a favorable visual prognosis after submacular surgery to remove subfoveal CNV.133 As discussed previously, the ingrowth site of subfoveal CNV in POHS has been associated with visual prognosis after submacular surgical removal of CNV. Eyes with an extrafoveal ingrowth site have a favorable visual prognosis after the surgical removal of the CNV. If the ingrowth site is subfoveal or not identifiable, the visual prognosis after submacular surgery is guarded. 125 Despite good results, the appropriate management of patients with POHS and subfoveal CNV remains controversial.
Amphotericin B It is presumed that the ocular histoplasmosis syndrome is caused by previous exposure to the fungus H. capsulatum. Because no organisms have been identified in human histopathologic specimens and none are found in the animal model 6 weeks after infection,lO the use of antifungal amphotericin B has no role in the treatment of POHS or reactivated macular lesions.
CONCLUSIONS Although many questions remain unanswered concerning the cause of ocular histoplasmosis, the epidemiologic, immunologic, experimental, and histopathologic data and evidence make a fairly compelling case that the fungus H. capsulatum is the causative agent for the constellation of ocular lesions that is clinically recognized as POHS. On the basis of these data and evidence, it has been proposed to call the entity ocular histoplasmosis and
drop the term presumed. Nevertheless, the syn.drome of ocular lesions is still called presumed ocular histoplasmosis syndrome. Since the efficacy of laser photocoagulation in treating extrafoveal and juxtafoveal CNV lesions is proven in controlled clinical trials, there is some hope for the patients suffering from POHS. The high-risk patients who have lost vision in one eye are encouraged to self-monitor their reading vision and regularly use an Amsler grid chart with each eye independently. This is recommended to detect new patches of neovascularization that may arise, either in the eye already affected or in the fellow good eye. I"aser treatment is then recommended. Further research is needed to better understand the pathophysiologic process that results in CNV and to develop animal models to explore potential antiangiogenic drugs to intervene in that process.
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LA~SMlOSliS SYNDROME
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CHAPTER 28: PRESUMED OCULAR HISTOPLASMOSIS SYNDROME
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82.
83.
84.
85.
86.
87.
88. 89.
90. 91.
92. 93.
94.
95.
96.
97. 98.
99.
100.
101.
102.
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103. Davidorf FH: The role of T-IJ1liphocytes in the reactivation of presumed ocular histoplasmosis sCars. Int Ophthalmol Clin 1975;15:111-124. 104. Smith RE. Natural history and reactivation studies of experimental ocular histoplasmosis in a primate model. Trans Am Ophthalmol Soc 1982;80:695-757. 105. Smith RE, Macy JI, Parrett C, Irvine J: Variations in acute multifocal histoplasmic choroiditis in tlle primate. Invest Ophthalmol Vis Sci 1978;17:1005-1018. 106. Aronson SB, Fish MB, Pollycove M, Coon MA: Altered vascular permeability in ocular inflammatory disease. Arch Ophthalmol 1971 ;85:455-466. 107. Gamble CN, Aronson SB, Brescia FB: Experimental uveitis: 1. The production of recurrent immunologic (Auer) uveitis and its relationship to increased uveal vascular permeability. Arch Ophthalmol 1970;84:321-330. 108. Kaplan HJ, Waldrep JC: Immunologic basis of presumed ocular histoplasmosis. Int Ophthalmol Clin 1983;23:19-31. 109. Gwin RM, Makley TAJr, Wynlan M, et al: Multifocal ocular histoplasmosis in a dog and cat. J Am Vet Med Assoc 1970;176;638-642. 110. Foster CS, Sonntag HG: Essentials of microbiology in uveitis. In: Kraus-Mackiw E, 0' Connor GR, eds: Uveitis: PatllOphysiology and Therapy, 2nd ed. Stuttgart, Georg Thieme Verlag, 1986, pp. 29-46. Ill. Jester JV, Smith RE: Subretinal neovascularization after experimental ocular histoplasmosis sY1ldrome. Retina 1987;7:1-8. 112. Hayreh SS, Cullen JF: Atypical minimal peripapillary choroidal colobomata. Br J Ophthalmol 1972;56:86-96. 113. Wise GN, Henkind P, Alterman M: Optic disc drusen and subretinal hemorrhage. Trans Am Acad Ophthalmol Otolaryngol 1974;78:212-219. 114. Bird AC, Grey RHB: Photocoagulation of disciform macular lesions witll krypton laser. Br J Ophthalmol 1979;63:669-673. 115. Sabates FN, Lee KY, Ziemianski MC: A comparative study of argon and krypton laser photocoagulation in tlle treatment of presumed ocular histoplasmosis syndrome. Ophthalmology 1982;89:729-734. 116. Yassur Y, Gilad E, Ben-Sira I: Treatment of macular subretinal neovascularization with the red-light krypton laser in presumed ocular histoplasmosis syndrome. Am J Ophthalmol 1981;91:172176. 117. Cummings HL, Rehmar AJ, Wood VV], Isernhagen RD: Long-term results of laser treatment in the ocular histoplasmosis syndrome. Arch Ophthalmol 1995;113:465-468. 118. Fine SL, Wood VV], Singerman LJ, et al: Laser treatment for subfoveal neovascular membranes in ocular histoplasmosis syndrome: Results of a pilot randomized clinical trial. Arch Ophthalmol 1993;111:19-20. 119. Gass JDM: Choroidal neovascular membranes-Their visualization and treatment. Trans Am Acad Ophthalmol Otolaryngol 1973;77:310-320. 120. Shah SS, Schachat AP, Murphy RP, et al: The evolution of argon laser photocoagulation scars in patients with tlle ocular histoplasmosis syndrome. Arch Ophthalmol 1988;106:1533-1536. 121. LimJI, Schachat AP, Conway B: Macular hole formation following laser photocoagulation of choroidal neovascular membranes in a patient with presumed ocular histoplasmosis (letter). Arch Ophthalmol 1991;109:1500-1501. 122. Schlaegel TF: Treatment of the POHS. In: Schlaegel TF, ed. Ocular Histoplasmosis. New York, Raven Press, 1977, pp 209-259. 123. Schlaegel TF: Corticosteroids in the treatment of ocular histoplasmosis. Int Ophthalmol Clin 1983;23:111-123. 124. Gass JDM: Biomicroscopic and histopathologic consideration regarding tlle feasibility of surgical excision of subfoveal neovascular membranes. AmJ Ophthalmol 1994;118:285-298. 125. Melberg NS, Thomas MA, Burgess DB: The surgical removal of subfoveal choroidal neovascularization: Ingrowth site as a predictor of visual outcome. Retina 1996;16:190-195. 126. Akduman L, Del Priore LV, Desai VN, et al: Perfusion of the subfoveal choriocapillaris affects visual recovery after submacular surgery in presumed ocular histoplasmosis syndrome. Am J Ophthalmol 1997;123:90-96. 127. Grossniklaus HE, Green WR: Histopathologic and ultrastructural findings of surgically excised choroidal neovascularization. Submacular surgery trials research group. Arch Ophthalmol 1998; 116:745-749. 128. Makley TA, Craig EL, Worling K: Histopathology of ocular histoplasmosis. Int Ophthalmol Clin 1983;23:1-18.
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Acknowledgments I wish to thank Malika Singh and Mani Singh for their support in completing this chapter.
I Elisabeth M. Messmer
Infectious chorioretinitis/endophthalmitis is defined by the pi'esence of actively replicating organisms within· the eye, associated with a variable degree of inflammation. VVhen the organisms are introduced into the eye from outside the body (e.g., at the time of ocular surgery or trauma) the infection is termed exogenous. An infection resulting from septic embolization (from extraocular sources) is termed endogenous. Fungal organisms, such as Candida species, are observed in endogenous and, less frequently, in exogenous ocular infections. 1 Intraocular candidiasis may produce a choroiditis and/ or retinitis that may break through to the vitreous and cause endophthalmitis. Candida chorioretinitis is defined as the presence of focal, deep, white, infiltrative, chorioretinal lesions with no evidence of direct vitreal involvement except a diffuse vitreous haze. Candida endophthalmitis is defined as (1) Candida chorioretinitis with extension of the surrounding inflammation into the vitreous, or (2) a vitreous abscess manifesting as intravitreal fluff balls. 2
In 1877, Grawitz was probably the ,~rst author to report ocular candidiasis in animal experiments. He injected C. albicans into the vitreous of rabbits, causing vitreous opacities and small, white preretinal "structures."3 The initial pathologic description of endogenous ocular candidiasis in humans was reported in 1943 by Miale." In 1958, Van Buren pltblished the first clinical report of a patient with multiple myeloma who developed Candida chorioretinitis. 5 Prior to the availability of adequate therapy, treatment for eyes with endophthalmitis was limited to minimizing the cosmetic deformity that resulted as the intravitreal abscess pointed and discharged its liquefied intraocular contents. 1 Almost all eyes with endophthalmitis evolved to complete blindness. Greater awareness of the disease entity, improvement of diagnostic tools, the development of new antifungal agents, alternative routes of antifungal administration, and refined surgical techniques contributed to a better functional outcome. Nevertheless, Candida endophthalmitis still carries a grave prognosis for the eye and, in cases of endogenous endophthalmitis, is even a marker for poor patient survival.
According to the results of the National Nosocomial Infections Surveillance System surveys conducted through 1992, Candida has become the fourth most common iSQlate recovered from blood cultures in the United States. 6 Rates of candidemia have also increased substantially in Europe. 7 Approximately half of all candidal infections occur in surgical intensive care units. 7 It has been~I"e ported that the species of Candida causing infection have shifted noticeably toward nonalbicans species. s, 9 DNA
typing has verified that transmission occurs from patient to patient and from health care worker to patient. 7 Among the numerous risk factors for endogenous candidiasis (including Candida endophthalmitis) are the use of antibiotics, indwelling catheters, hyperalimentation, cancer therapy, immunosuppressive therapy after organ transplantation, bone marrow transplantation, acquired immunodeficiency syndrome (AIDS), hospitalization in intensive care units, recent intra-abdominal surgery, candiduria, and colonization with Candida species. 7, 10-15 Ocular candidiasis has occurred as a complication of spontaneous abortion,16 as the only initial manifestation of pacemaker endocarditis,17 and after intravenous anesthesia with propofol,1s Candida endophthalmitis represents one of the most serious and increasingly common ocular complications of intravenous drug abuse. 15, 19-21 Fungal infection may result from contamination of the drug, syringes, needles, or the cotton used to filter the drug before intravenous injection. 20 , 21 Systemic fungal infections, especially candidiasis, have been increasingly encountered among high-risk neonatal patients. Candida sepsis was reported to occur in 3% to 4% of premature infants with a birthweight of under 1500 g.22,23 Further risk factors include extended antibiotic therapy, prolonged parenteral nutrition or use of fat emulsions, chronic artificial ventilation, and prior surgery.22, 24---27 In neonates with positive blood, urine, cerebrospinal fluid, or stool cultures of Candida albicans, Chen observed candidal meningitis in 55% and Candida endophthalmitis in 46% of infants. 28 Candida endophthalmitis, however, was also reported in otherwise healthy adults. 29 , 30 Exact numbers concerning the annual incidence of Candida endophthalmitis are not available. Fungal organisms, however, account for more than half of cases of endogenous endophthalmitis, with Candida albicans being responsible for 75% to 80% of cases. 31 , 32 Risk factors for exogenous Candida endophthahnitis include trauma and ocular surgery, especially cataract extraction with intraocular lens implantion 33-38 and perforating keratoplasty.39-42 Fungal endophthalmitis, especially that caused by candidal infection, is a frequent complication reported to occur in 9.9% to 45% of hospitalized patients with candi.. demia. lO , 11,43,44 In a study by Brooks, patient age, sex, underlying diseases, presence of Foley catheters, bacteremia, white blood cell count, use of multiple antibiotics, hyperalimentation, or surgery did not differ between the candidemic patients with and without Candida endophthalmitis. Moreover, groups were similar in number of sites colonized with yeast and species of Candida recovered. Io In a prospective multicenter study, Donahue and coworkers examined 118 patients with candidemia adequately treated with antifungal therapy. Candida chorioretinitis was seen in only 9% of patients. No patient was shown to progress to Candida ~ndophthalmitis.2
CHAPTER 29:
The presence of Candida endophthalmitis in ~ospita~ ized patients is an important indica~or of ~ystemIc.cand~ diasis, as evidenced by the pathologIc findmg of dIssemInated candidiasis in 78% of autopsy patients with Candida endophthalmitis. 29 The overall mortality of hospitalized patients with candidemia is high (53% to 61 %),12,13,45 with almost half the deaths occurring in the first week after candidemia begins. The mortality rate for patients with endogenous Candida eridophthalmitis is similarly high. Edwards and colleagues reviewed 76 cases of. Candida endophthalmitis and found an overall mortalIty of 50%.46 Menezes and associates reported an overall mortality rate of 77% of severely ill patients with Candida endophthalmitis, with an even higher mortality of 80% ~or intensive care patients. 12 Other authors found mortalIty rates ranging from 0% to 22% in their pa~ients ~th Candida endophthalmitis who were treated wIth vanous antifungal therapies with or without accompanying vitrectOlny or intravitreal antifungals. 13 , 29, 32, 47
CLINICAL CHARACTERISTICS Endogenous Candida Chorioretinitisl Endophthalmitis Ocular symptoms have been reported to be uncommon, especially in patients with peripheral chorioretinal Candida lesions or in moribund patients. Brooks noted the complete absence of visual symptoms even in patients with confirmed Candida endopht,llalmitis.lo Donahue and colleagues reported visual complaints in only 9 of .12 patients with ocular candidiasis. 2 ~atients wit~ Candzda endophthalmitis may complain of mIld ocular dIscomfort, red eye, floaters, and slowly progressing visu~l lo~s.2, 25, 48 Candida chorioretinitis, with focal, deep, whIte, Infiltrative chorioretinal lesions, is mainly bilateral, multiple (of;en including more than ten lesions), and predominantly observed in the posterior pole.2, 49 In 13 of 19. eyes with Candida chorioretinitis, additional fundus lesIOns, including nerve-fiber-Iayer infarcts, intraretinal hemorrhages, and white-centered hemorrhages (Roth spots), were present. 2 Whereas intraretinal hemorrhages ~r~ n?t usually the sole manifestation of intraocular candIdIasIs, nerve-fiber-Iayer infarcts and Roth spots are known to occur in hematogenously disseminated ocular infections. Moreover, Candida has been isolated from Roth spots,5,46 and therefore Roth spots could conceivably represent an early, nonspecific marker of Candida infection. 2 Neutropenia may inhibit the formation of typical Candida lesions in both animals and humans. 50 Candida endophthalmitis· presents as Candida chorioretinitis with extension of the surrounding inflaInmation into the vitreous, or vitreous abscess manifesting as intravitreal fluff balls. The vitreous opacities may be connected by strands producing a string-of.,.pearls appearance 15 (Fig. 29-1). Papillitis may be present. 48 Candida endophthalmitis follows a more indolent course than that of acute bacterial endophthalmitis. 25 Anterior segment pathology may include conjunctival hyperemia (only seen in 21 % of patients with ocular candidiasis by Donahue 2) anterior chamber cells, hypo. 2' -" '12 46 51 C orn eal . synec h·.c pyon, and postenor Iae .LOrmatIOn.
FIGURE 29-1. "String of pearls" appearance to the vitreal exudates in a patient with endogenous Candida endophthalmitis. (See Color insert.)
involveInent may result in suppurative keratitis with perforation. 26 Patients with endogenous Candida endophthalmitisresulting from intravenou~ drug abuse may present .~th. n~ clinical or serologic eVIdence of systeInIc candIdIasIs, suggesting that ocular candidiasis may have been caus.ed by transient candidemia. Anterior uveitis a~'ld extensIve vitreous involvement are common, and patIents do not necessarily show associated retinal lesions. 15 , 19 This may result in part from the fact that these patients seek treatment late, when retinal lesions have either resolved or been obscured by pronounced vitreous involvement. 15 Ocular findings in children with endogenous Candida endophthalmitis may mimic other .ocu~ar disoI~ders. Clinch and associates observed a localIzed Intralentlcular candidal abscess presenting as an infantile cataract with associated endophthalmitis in a 6-month~old infant. 25 Shields and coworkers report a systemically healthy 12month-old boy who developed ocular candidiasis simulating retinoblastoma. 3o Hypopyon formation; synec~iae, and the absence of a distinct ocular mass WIth calCIfications on ultrasound and computed tomographic examinations should differentiate endophthalmitis from retinoblastoma in most cases. 30
Exogenous Post-traumatic
Endophthalmitis
Fungal endophthalmitis is a rare but devast~ting com~li cation of penetrating ocular trauma. ForeIgn matenal contaminating the wound, especially wood or other vegetable matter, may harbor fungi. 52 ,53 Mycotic endophthalmitis occurring after trauma is often caused by septate filamentous fungi (e.g., Fusarium solani and Aspergillus species). Yeasts are rarely isolated. 53 The signs of infection frequently are obscured by tissue damage and inflammation as a result of the injury. Therefore, diagnosis and initiation of treatment are often delayed. These factors co~tribute to the overall poor prognosis associated with traumatic fungal endophthalmitis. 53
Postoperative Candida endophthalmitis is a rare complication of intraocular surgery, but it represents a potentially catastrophic
CHAPTER 29: CANDIDIASIS
evenL Endophthalmitis caused by coagulase-negative Staphylococcus species and Propionibacteriu1TL acnes must be included in the differential diagnosis of indolent subacute or chronic cases of postoperative uveitis. Cataract Surgery. Several cases of non-Candida 54- 55 and Candida endophthalmitis34, 35, 57 have been reported to have occurred secondary to contaminated solutions. Stern and associates describe a large group of patients who developed Candida parapsilosis endophthalmitis 1 to 18 weeks after cataract surgery as a result of contaminated intraocular irrigating solutions. Patients developed indolent inflamluation with a fibrinopurulent anterior chamber exudate and vitreous snowball opacities. 34 Discontinuation of topical steroid therapy led to a dramatic increase in intraocular inflammation and ocular discOlufort in most patients. 34 Delayed-onset pseudophakic endophthalmitis caused by C. parapsilosis has been reported in three patients 1 to 23 months following cataract extraction with posterior chamber intraocular lens implantation. The patients exhibited keratic precipitates, a white intracapsular plaque thought to contain sequestered organisms within the capsule, stringy white infiltrates in the anterior vitreous adjacent to the capsular remnants, and a mild diffuse vitreitis. 33 Perforating Keratoplasty. Candida albicans endophthalmitis has been reported following penetrating keratoplasty.39-42 Postkeratoplasty fungal endophthalmitis may originate from the operative site, cOJl-taminated solutions, culture media, and contaminated donor tissue. Up to 27% of eyes suitable for corneal transplantation have been found to harbor fungi,58 and cultures of donor rims as well as corneal storage media were positive for Candida species in most of the reported cases of fungal endophthalmitis following perforating keratoplasty.39-41 Patients with postkeratoplasty Candida endophthalmitis typically present with mild to moderate pain, purulent discharge, conjunctival injection, multiple fluffy infiltrates at the graft-host interface, or endothelial plaques associated with vitreitis. 39-41
Treated chorioretinal lesions may heal either as a faint gliotic scar, or as a focal defect in the pigment epithelium. 49 However, if left untreated, vitreous invasion with irreversible sequelae may eventuate, producing a vitreoretinal abscess with retinal necrosis, vitreal organization, tractional retinal detachment, cyclitic membrane formation, or phthisis bulbi. 15 , 32, 49, 50, 59-51 Even in treated cases, premacular scars may reduce visual acuity permanendy.15, 40, 48, 49 Postinflammatory fibrovascular membranes puckeringor tractionally detaching the macula may be surgically removed. McDonald and coworkers report on four eyes undergoing pars plana vitrectomy and membrane peeling after Candida endophthalmitis. Postoperative visual acuity ranged from 1/200 to 20/25, depending on the degree of macular pathology and the presence and location of full-thickness retinal scars.50 In rare cases, choroidal neovascular membranes may develop following endogenous Candida endophthalrriitis. 52
IMMUNOLOGY Candida albicans is normally present as an intestinal saprophyte in 20% to 40% of healthy individuals. Other Candida species may also be found in the gastrointestinal tract, although in lower concentrations. 53 In situations of internal environmental change, such as results from chronic use of antibiotics, indwelling catheters, hyperaliluentation, immunosuppressive therapy, or recent intraabdominal surgery, Candida may become pathogenic.48 Animal studies 45 , 54 and human histopathologic evaluations 45, 54, 55 have demonstrated the ability of Candida to spread hematogenously to the choroid and retina. Species of Candida other than C. albicans that are encountered in human disease include C. tropicalis, C. parapsilosis, C. krusei, C. stellatoidea, C. guilliennondii, C. lusitaniae, C. glabrata, C. pseudotropicalis, and C. rugosa. 55 Immunocompromised patients with hematologic malignancies are particularly prone to develop non-albicans candidal infections. 57 The relative resistance of the eye to non-albicans candidal involvement has been demonstrated in a rabbit model of endophthalmitis by Edward and colleagues.58 While C. albicans caused endophthalmitis at an inoculum of 105 colony-forming units (cfu)/ml, 108 cfU/IUl of C. tropicalis and C. stellatoidea were necessary to cause chorioretinal lesions. However, these concentrations did not cause endophthalmitis. C. parapsilosis, C. guilliermondii, and C. krusei were not pathogenic to the eye at the doses studied.58 In humans, Candida species reported to cause endogenous endophthalmitis include C. albicans, C. tropicalis, C. stellatoides, C. parapsilosis, and C. krusei. 31 Contradictory data are available in humans with respect to the incidence of endophthalmitis caused by different Candidal species. One study found that disseminated C. tropicalis was associated with a higher rate of endophthalmitis than was C. albicans (23% versus 6%) .59 Most other studies report the opposite, with the highest rate of endophthalmitis in C. albicans fungemia. 2, 10, 32, 43, 51, 55 In patients with intraocular candidiasis, C. albicans was the most common species isolated from blood (58 %), followed by C. tropicalis (14%), C. (Torulopsis) glabrata (14%), C. parapsilosis (9%), and other species (7%) in a study by Donahue. 2 Mter infection, Candida may persist in ocular tissues for a long time. C. albicans was isolated from a rhesus monkey eye 110 days after intravascular inoculation. 70 The reasons for the susceptibility of the retina to Candida infections compared with other organs are unclear. Fungal virulence may relate to the ability of the organism to produce pseudohyphae from blastospores that lodge in the deep capillary plexus of the retina and in the choriocapillaris. The production and localization of various phospholipases in the growing fungal buds suggest that phopholipid-rich tissues such as the retina and choroid may provide a substrate for yeast filamentation. 71 Much of the tissue destruction observed in fungal infection may be not so much the direct consequence of invasion but rather the effect of mediators of inflammation induced by the organisms. 72 The histopathologic examination of ocular Candida lesions may demonstrate a cOlubination of an acute nec-
CHAPTER 29: CANDIDIASIS
rotIzmg process and a chronic granulomatous reaction by histiocytes and round cells occurring primarily in the choroid. 26 , 46, 48, 49, 73 Colonies of Candida, identified by their characteristic budding pseudohyphae, may be found in the choroid, the retinal pigment epithelium, and Bruch's membrane. Extension into the subretinal space and into the retina occurs secondarily.48, '19 Retinal involvement is usually accompanied by a macrophage response in the overlying vitreous. 49 The internal limiting membrane of the retina provides no barrier to the spread of C. albicans, and if the lesion remains untreated, vitreous invasion may occur. 49 Vitreous lesions are composed largely of neutrophils, macrophages, and epitheloid cells, but they may also harbor Candida organisms. 15 , 46, 73, 74 In adults, immune responses to Candida organisms include monocytic and neutrophilic phagocytosis, along with intracellular killing of fungal organisms. 75 In addition, serum factors and lymphocytic function, particularly T lymphocytes, are important. The patient's immune status and the health of the affected eye modify the immune response to Candida. Moreover, the frequent use of corticosteroid eyedrops in the early postoperative period may mitigate signs and symptoms of infection. 40 Newborn infants are probably at higher risk for the development of Candida infections because of their normally deficient host immune system and the reduced killing ability of their leukocytes. 76, 77
DIAGNOSIS Candida endophthalmitis shoul¢ be suspected in any patient with one of the known predisposing conditions. The presence of the characteristic white chorioretinal lesions or puff-balI-like vitreous opacities is highly suggestive in the appropriate clinical setting. Because of the lack of clinical or laboratory parameters to distinguish between candidemic patients with and those without endophthalmitis, Brooks recommends early ophthalmoscopic examinations. In his experience, follow-up examinations are often helpful to the clinician in guiding antifungal therapy.1O Blood, urine, indwelling catheters, and any potential source of infection should be cultured. Additional examinations and tests are helpful in confirming the final diagnosis of ocular candidiasis.
Nonocular Cultures The significance of candidemia remains problematic. Positive fungal blood cultures may represent skin contamination without candidemia, true but transient candidemia without deep tissue invasion, or candidemia with deep tissue invasion. 43 A presumptive diagnosis of ocular candidiasis may be made if Candida is cultured from a source other than the eye (e.g., blood, urine, cerebrospinal fluid) in the presence of typical ocular lesions.Unfortunately, blood cultures are frequently negative in systemic candidiasis.73, 78
Antibody Testing The value of Candida antibody testing in serum as an aid in the early diagnosis of disseminated candidiasis remains questionable. Various methods of antibody determination with rather low sensitivity and specificity, including immunodiffusion, counterelectrophoresis, and latex agglutina-
tion (LA), have been employed. 79-82 According to Gentry and colleagues, LA is the most sensitive test for antibody determination. 79 LA titers are, however, rarely of benefit in predicting the presence of endophthalmitis in ocular candidiasis. 43 Mathis and associates observed a significant difference in the local production of specific antibodies in the anterior chamber between patients with Candida endophthalmitis and controls. They even report a correlation between the severity of uveitis and antibody titers. 83
Antigen Testing Determination of Candida antigen titers can offer significant clinical advantages to the treating physician. Some studies have shown relatively high sensitivity and specificity of antigen detection tests for invasive disease caused by Candida species. 84 Parke and coworkers demonstrated antigen titers indicative of disseminated disease in three of four patients with endogenous Candidaendophthalmitis. 43 In a study by Bailey and colleagues, however, all five patients with Candida endophthalmitis had a negative LA test for serum antigen. 85 Antigen titers may prove to be more sensitive than antibody titers, especially in immunocompromised patients, who are incapable of mounting an adequate antibody response to Candida.
Anterior Chamber Tap and Vitreous Aspiration Henderson and coworkers confirmed the diagnosis of candidiasis in 62% of eyes with vitreous aspiration, but they found anterior chamber aspiration to be a poor diagnostic technique. l l Axelrod and PeYInan succeeded in culturing Candida after aspiration from the vitreous in only one of six untreated rabbit eyes exogenously inoculated with Candida, although abundant organisms were demonstrated in all eyes microscopically after enucleation. 87 A random, or even a directed, aspiration can fail to produce positive Candida cultures or smears because of the sequestration of the organisms within large-diameter inflammatory nodules. 15 Thus, vitrectomy may be the only procedure that can reliably obtain Candida from an infected vitreous.
Pars
Vitrectomy
The goal of vitrectomy in eyes with Candida endophthalmitis is to confirm the presumptive clinical diagnosis and remove the intravitreal fungal mass and inflammatory debris while delivering safe and therapeutic doses of antibiotics to the infected eye. Diagnostic vitrectomy is especially valuable in a subgroup of patients with presumed localized intraocular infection without clinical or cultural evidence of disseminated disease. 32 A vitreous infusion suction cutter is necessary to remove formed vitreous for suspected fungal infection. One recOlnmended technique consists of culturing the harvested vitreous specimen under sterile operating room conditions. Samples, diluted by the irrigating solution, are passed through a disposable membrane filter system.88 Specimens are inoculated onto Sabouraud's agar, blood agar, and liquid brain-heart infusion with gentamicin at room temperature for fungal isolation. For rapid diagnosis, slides are prepared for GraIn staining, Giemsa staining, and modified Grocott's methenamine-silver (GMS)
CHAPTER 29: CANDIDIASIS
stain, and Cellufluor or Ca1cofluor white techniques for the identification of fungal elements. If retinoblastoma is a consideration, fine-needle biopsy, rather than vitrectomy, should beperformed. 30
DIAGNOSIS The differential diagnosis of Candida chorioretinitis includes necrotizing retinopathies caused by herpes viruses such as cytomegalovirus (CMV) , herpes simplex virus (HSV) , and varicella-zoster virus (VZV) , and the acute retinal necrosis syndrome (Table 29-1). Protozoan infections such as toxoplasmic retinochoroiditis or nematode infections (e.g., Toxocara canis) may simulate candidal chorioretinitis. Bacterial endophthalmitis and fungal uveitis caused by organisms other than Candida (e.g., Aspergillus sp., Cryptococcus neoformans, Histoplasma capsulatum, Blastomyces dermatitidis) must be differentiated from ocular candidiasis. Choroidal granulomas (e.g., in ocular sarcoidosis) may mimic candidal chorioretinitis. Retinoblastoma and large cell lymphoma must be included in the differential diagnosis of ocular candidiasis. Even cottonwool spots may be confused with chorioretinal infection by Candida; however, their eventual regression over 5 to 8 weeks, depending on the underlying diagnosis, facilitates their diagnosis.
TREATMENT Endophthalmitis is a potentially devastating disease that requires aggressive management. Although the incidence of serious infections caused by Carcdida species is rising rapidly, the most appropriate management strategies for such infections remains severely limited because large controlled studies of the various approaches have not been performed. 68 The mainstay of treatment for Candida endophthalmitis has been a combination of systemic and intravitreal amphotericin B with or without pars plana vitrectomy.18, 49,51,61,68 Newly developed triazole compounds, such as fluconazole, are very promising agents for the therapy of systemic and ocular candidiasis. 89 - 93 Moreover, the removal of precipitating factors such as intravenous lines is extremely important.
Amphotericin B
Amphotericin· B was discovered in 195694 and was first used for the treatment of ocular candidiasis in 1960. 95 It acts by binding to cell membrane sterols, resulting in the leakage of cellular constituents and ultimately the death of the organism. 96 It is not absorbed by the gastrointestinal tract and must therefore be given intravenously. The TABLE 29-1. DIFFERENTIAL DIAGNOSIS OF OCULAR CANDIDIASIS Bacterial endophthalmitis Viral retinopathies (CMV, HSV, VZV) Acute retinal necrosis Toxoplasmic retinochoroiditis Toxocara canis chorioretinitis Aspergillosis Cryptococcosis
Histoplasmosis Blastomycosis Sarcoidosis Retinoblastoma Large cell lymphoma Cotton-wool spots
CMV, cytomegalovirus; HSV, herpes simplex virus; VZV, varicella-zoster/virus,
maximum recommended dose is 0.5 to 1.0 mg/kg/day for an average daily dose of 40 to 50 mg. Therapy should continue until the retinal lesions disappear completely or become small and/or are replaced by fibrous tissue. 32 Although amphotericin B is effective against a wide range of fungal pathogens, its systeluic use in treating fungal endophthalmitis is severely limited by poor ocular penetration. 97 ,98 Persistent intraocular infection has been reported in spite of an adequate course of treatment when the vitreous is involved. 15, 49 An additional drawback of systemic amphotericin B therapy is the wide spectrum of toxic side effects encountered, ranging from nausea, vomiting, and malaise, to anemia and renal failure. Moreover, a minimum dose of 750 to 1000 mg of amphotericin B is required for cure of candidal endophthalmitis. 15 , 46, 89 Systemically administered antimycotics are important not only to treat endophthalmitis but also in the treatment of systemic infections. 16, 32 If evidence of systeluic candidiasis is present, intravenous amphotericin B should be administered. For severe systemic infections, a combination of intravenous amphotericin B and another antifungal drug (e.g., flucytosine) is recommended by some authors because of their synergistic effect. 2o ,99 However, the increased risk of bone marrow suppression or diarrhea as a complication of the simultaneous use of these drugs must be weighed against the potential benefit. 99 The potential toxicity of amphotericin B has led to the development of lipid-associated preparations, including liposomal amphotericin B, amphotericin B colloidal dispersion, and amphotericin B lipid complex. These preparations are less nephrotoxic, but higher systemic doses than those of conventional amphotericin B are needed to achieve the same effect in invasive fungal infections.100-102 The efficacy of lipid-associated formulations of amphotericin B in the treatment of ocular candidiasis is under investigation. Studies have shown that amphotericin B can be delivered to the eye in effective concentrations by direct intravitreal injection. Doses of 5 and 10 /-Lg amphotericin B injected intravitreally into eyes of healthy rabbits did not cause retinal toxicity clinically, microscopically, or by electroretinography.103 The safety of intravitreal injection of amphotericin B in humans has been demonstrated in several case reports in which histopathologic confirmation of a cured infection, absent retinal toxicity, and normal electroretinograms following intravitreal amphotericin B injection are described. 34, 104, 105 A 10-/-Lg dose into a human eye would theoretically provide a concentration of 2.5 /-Lg/ml, which is effective against most fungal pathogens. 103 When there is no extraocular evidence of candidemia or candidiasis, local ocular treatment with intravitreal amphotericin B may be all that is required. 32
Flucytosine In an effort to avoid the toxicity of systemic amphotericin B administration, recent studies have evaluated the use of alternate systemic therapy with fluorinated pyrimidine (flucytosine) or imidazole compounds including ketoconazole or fluconazole .18, 32, 51, 73, 89-93, 99 Flucytosine is selectively taken up by susceptible fungi and deaminated to 5-fluorouracil, which blocks DNA and RNA synthesis. The suggested oral dose is 50 to 150 lUg/
zr
CHAPTER 29: CANDIDIASIS
kg/ day in four divided doses. It shows excellent oral absorption and ocular penetration, and it is active against C. albicans. 73 , 106 Systemic administration is relatively risk free, but bone marrow and liver toxicity can occur. Because of a significant incidence of primary resistance during therapy, flucytosine should not be used alone in disseminated disease.99
Imidazole derivates Imidazole derivates act by inhibiting membrane sterols in C. albicans; they have good antifungal activity, absorption, and ocular penetration with minimal toxicity. 107, lOS Fluconazole shows improved permeability into the vitreous compared to ketoconazole. It is the only antifungal that penetrates into cerebrospinal fluid. However, candidal resistance was reported in cases treated with imidazole compounds, and a patient developed Candida endophthalmitis while receiving fluconazole for the management of candidal pyelonephritis. l09 In a rabbit model, intravenous amphotericin B was superior to intravenous fluconazole in the treatment of Candida endophthalmitis. 110 Fluconazole appeared to be efficacious in treating endophthalmitis after 10 to 17 days of therapy, but this salutary treatment effect was lost by day 24, and fluconazole failedto eradicate C. albicans from the rabbit eyeYo Brod and colleagues, however, successfully treated five patients with systemic flucytosine (2 g every 6 hours), or ketoconazole (200 to 400 mg/d) in association with intravitreal amphotericin B injection. 32 They recommend this regimen especially for pat~nts without evidence of disseminated disease. 32 Christmas and Smiddy treated their patients suffering from endogenous Candida endophthalmitis with oral fluconazole (200 mg/d) and vitrectomy without intravitreal injection of antifungals. They also report clearance of infection and improvement of visual acuity in all six patients. 92 The successful use of oral fluconazole in a dosage of 200 to 800 mg PO daily for 2 to 4 months as the only treatment for endogenous Candida endophthalmitis has also been reported. IS, 73, S9-91 Other imidazole derivates, such as itraconazole, miconazole, and econazole, are also effective anticandidal substances, and they show good ocular penetration. Ill, 112 They are used in the treatment of keratomycosis,113-117 but therapeutic experience in the Inanagement of Candida chorioretinitis and endophthalmitis with these drugs is limited and anecdotal. 11S
Corticosteroids Intraocular and systemic corticosteroids have been suggested as a useful adjunctive treatment in cases of fungal endophthalmitis. 20 , 51, 119, 120 However, controversial opinions exist concerning their use in Candida endophthalmitis. Steroids may potentiate systemic candidiasis, but they may attenuate the inflammatory response in ocular candidal infection and may prevent vision-threatening sequelae.
Role of Vitrectomy Pars plana vitrectomy offers several theoretical advantages to the treatment of Candida endophthalmitis. In addition to obtaining vitreous biopsy to correctly identify the organism, vitrectomy physically removes a large mass of
invading organisms, thereby fulfilling the general surgical criteria of incision and drainage of an abscess. Huang and coworkers demonstrated that intravitreal amphotericin B combined with vitrectomy was more effective in reducing vitreous opacification than was the use of intravitreal amphotericin B alone in a rabbit model of exogenous Candida endophthalmitis. 121 In 1976, Snip and Michels reported the successful use of pars plan vitrectomy and intravitreal amphotericin B in the management of endogenous Candida endophthalmitis in a patient. 122 Furthermore, it has been shown that infected eyes treated with vitrectomy and intraocular antibiotics have a surprisingly greater number of negative cultures 1 week later than do those treated with intraocular antibiotics alone. 123 Vitrectomy also removes the scaffold on which fibrotic traction bands might develop, resulting in secondary traction retinal detachment. 12'1 Moreover, vitreous, as a potential barrier to the diffusion of large molecules such as amphotericin B, is eliminated. 122 Amphotericin clearance and toxicity in vitrectomized versus nonvitrectomized eyes was studied by Doft and coworkers 125 and Baldinger and colleagues. 126 The most rapid decay in amphotericin concentration from the vitreous cavity occurred in aphakic vitrectomized eyes, with a half-life of 1.4 days compated to aphakic normal eyes (4.7 days) and phakic Candida infected eyes (8.6 days). Therefore, readministration of intravitreal amphotericin may be necessary 3 to 4 days following vitrectomy if clinically indicated. 32 , 125 Toxicity of amphotericin was not increased in vitrectomized eyes?26 Pars plana vitrectomy and injection of intravitreal amphotericin B should be considered for moderate to severe vitreous involvement in an eye with presumed ocular candidiasis. Most authors reserve surgery for patients with a visual acuity of 20/400 or less, or when the fundus cannot be visualized due to severe vitreous involvement. 72 The best timing for surgical therapy, however, is still not known. It may well be that early vitrectomy combined with intravitreal injections of amphotericin B offers the best chance for functional improvement. 124 The role of intraocular lens removal or exchange remains controversial in the management of exogenous Candida endophthalmitis following cataract surgery.34, 35, 37 Successful sterilization of the vitreal cavity does not require routine intraocular lens removal, although recurrences are possible. 34, 35 Stern and colleagues recommend introcular lens explantation only when clinical response to pars plana vitrectomy and intravitreal alnphotericin B is inadequate. 34 In cases where white plaque lesions are present at the posterior lens capsule, a large capsulectomy is warranted. 33 Single case reports have been published on the treatment of Candida endophthalmitis in children. In contrast to adults, intravenous infusions with amphotericin B, sometimes combined with flucytosine without vitrectomy, seem to be effective in these cases. 27 , 2S, 127 Having been treated with systemic antifungals alone, 11 premature infants demonstrated minimal residual ocular pathology.127 This may be due to the newborns' immature immune system resulting in less vitreous reaction and postinflammatory sequelae.
Prophylaxis The ultimate goal is to prevent disease. Prophylactic administration of oral nystatin can reduce fungal coloniza-
CHAPTER 29: CANDIDIASIS
tion and infection in very low birthweight infants. 128 The risk of systemic candidiasis can be minimized in patients by. following good antibiotic use principles. Indwelling intravascular devices and indwelling bladder catheters should be avoided when possible. 99
PROGNOSIS Although rare, spontaneous resolution of endogenous Candida endophthalmitis has been reported.129-131 Usually, the outcome of candidal endophthalmitis is dependent on four main factors: the virulence of the organisms, the duration of the inflammatory response, the prompt diagnosis, and correct management. 39 Moreover, the functional result depends on the extent and site of involvement of the chorioretinal lesions. 25 , 27 In recent publications, . final visual acuity following endogenous Candida endophthalmitis ranged from no light perception and phthisis to 20/15. 19 ,20,32,73 In five cases with less than 2 months between onset of sYlnptoms and initiation of antifungal therapy, four had a final visual acuity of 20/50 or better, but none of the patients with a delay of more than 2 months had a visual acuity better than 20/80. 32 Another important factor in determining the final visual outcome is the presence of intercurrent complications such as retinal detachments. 32 Depending on the time to diagnosis and appropriate therapy, visual acuity after postsurgical Candida endophthalmitis ranges from 20/25 to phthisis with no light perception. Reasons for bad visual acuity following postsurgical Candida endophthalmitis ~inc1ude graft failure, secondary glaucoma, pupillary membrane, and macular scars. 33 ,38-41 Infantile Candida endophthalmitis seems to have a good ocular prognosis for children treated promptly with systemic antifungal therapy.127
CONCLUSIONS Ocular candidiasis is one of the infectious causes of uveitis. The presence of Candida endophthahnitis is a good indicator of a systemic fungal infection that carries a high mortality in seriously ill patients in intensive care units. 12 Since many of these patients may have negative blood cultures despite extensive visceral involvement, the ophthalmologic examination is an important adjunct in the diagnosis of systemic candidiasis,12 and serial ophthalmic examinations are an objective measure of therapeutic response. 2 As in any infectious uveitis, steroids can suppress inflammation, but eventually the ocular problem deteriorates. A high index of suspicion is necessary to trigger a decision and to proceed to diagnostic vitrectomy in patients with Candida endophthalmitis. A stepladder approach in treatment of ocular candidiasis may be useful. Mild cases of Candida chorioretinitis without evidence of systemic disease may be managed with oral azole derivates alone, whereas advanced cases of Candida endophthalmitis and patients with candidemia need systemic antifungals and intravitreal amphotericin B injections combined with pars plana vitrectomy.
References 1. Weissgold DB, D'Amico DJ: Rare causes of endophthalmitis. Int Ophthalmol Clin 1996;36:163-177.
2. Donahue SP, Greven CM, ZuravlefflJ, et al: Intraocular candidiasis in patients with candidemia. Clinical implications derived from a prospective multicenter study. Ophthalmology 1994; 101: 13021309. 3. Grawitz P: Beitrage zur systematischen Botanik der pflanzlichen Parasiten mit experimentellen Untersuchungen i\ber die durch sie bedingten Krankheiten. Virchows Arch Path Anat 1877;70:546588. 4. Miale JB: Candida albicans infection confused with tuberculosis. Arch Pathol Lab Med 1943;35:427-437. 5. Van Buren JM: Septic retinitis due to Candida albicans. AMA Arch Pathol 1958;65:137-146. 6. Jarvis VVR: Epidemiology of nosocomial fungal infections, with emphasis on Candida species. Clin Infect Dis 1995;20:1526-1530. 7. Edwards JE: International conference for the development of a consensus on the management and prevention of severe candidal infections. Clin Infect Dis 1997;25:43-59. 8. Wingard JR: Importance of Candida species other than C. albicans as pathogens in oncology patients. Clin Infect Dis 1995;20:115125. 9. Pfaller MA: Nosocomial candidiasis: Emerging species, reservoirs, and modes of transmission. Clin Infect Dis 1996;22:S89-94. 10. Brooks RG: Prospective study of Candida endophthalmitis in hospitalized patients with candidemia. Arch Intern Med 1989;149:22262228. 11. Henderson DK, Edwards JE, Montgomerie JZ: Hematogenous Candida endophthalmitis in patients receiving parenteral hyperalimentation fluids. J Infect Dis 1981;143:655-661. 12. Menezes AV, Sigesmund DA, Demajo WA, et al: Mortality of hospitalized patients with Candida endophthalmitis. Arch Intern Med 1994;154:2093-2097. 13. Wey SB, Mori M, Pf(lller MA, et al.: Hospital-acquired candidemia: The attributable mortality and excess length of stay. Arch Intern Med 1988;148:2642-2645. 14. Coskuncan NM, Jabs DA, Dunn JP, et al: The eye in bone marrow transplantation. VI. Retinal complications. Arch Ophthalmol 1994;112:372-379. 15. Aguilar GL, Blumenkrantz MS, Egbert PR, McCulley JP: Candida endophthalmitis after intravenous drug abuse. Arch Ophthalmol 1979;97:96-100. 16. Haskjold E, Lippe von der B: Endogenous Candida endophthalmitis. Report of two cases. Acta Ophthalmol 1987;65:741-744. 17. Shmuely H, Kremer I, Sagie A, et al: Candida tmpicalis multifocal endophthalmitis as the only initial manifestion of pacemaker endocarditis. AmJ Ophthalmol 1997;123:559-560. 18. Daily MJ, Dickey JB, Packo KH: Endogenous Candida endophthalmitis after intravenous anesthesia with propofol: Arch Ophthalmol 1991;109:1081-1084. 19. Sugar HS, Mandell GH, Shalev J: Metastatic endophthalmitis associated with injection of addictive drugs. Am J Ophthalmol 1971;71:1055-1058. 20. Elliott JH, O'Day DM, Gutow GS, et al: Mycotic endophthalmitis in drug abusers. AmJ Ophthalmol 1979;88:66-72. 21. Vastine DW, Horsley W, Guth SB, Goldberg MF: Endogenous Candida endophthalmitis associated with heroin use. Arch Ophthalmol 1976;94:1805. 22. Baley JE, Kliegman RM, Fanaroff AA: Disseminated fungal infections in very low-birth-weight infants: Clinical manifestations and epidemiology. Pediatrics 1984;73:144-152. 23. Johnson DE, Thompson TR, Green TP, et al: Systemic candidiasis in very low-birth-weight infants « 1.500 grams). Pediatrics 1984;73:138-143. 24. Weese-Mayer DE, Fondriest DW, Brouillette RT, et al: Risk factors associated with candidemia in the neonatal intensive care unit: A case-control study. Pediatr Infect DisJ 1987;6:190-196. 25. Clinch TE, Duker JS, Eagle RC, et al: Infantile endogenous Candida endophthalmitis presenting as cataract. Surv Ophthalmol 1989;34:107-112. 26. Michelson PE, Rupp R, Efthimiadis B: Endogenous Candida endophthalmitis leading to bilateral corneal perforation. Am J Ophthalmol 1980;80:800-803. 27. Palmer EA: Endogenous Candida endophthalmitis in infants. Am J Ophthalmol 1980;89:388-395. 28. Chen JY: Neonatal candidiasis associated with meningitis and endophthalmitis. Acta PaedJap 1994;36:261-265.
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57. McCray E, Rampell N, Solomon SL, et al: Outbreak of Candida parapsilosis endophthalmitis after cataract extraction and intraocular lens implantation. J Clin Microbiol 1986;24:625-628. 58. White JH: Fungal contamination of donor eyes. Br J Ophthalmol 1969;53:30. 59. EdwardsJE, Mongomerie JZ, Foos RYet al: Experimental hematogenous endophthalmitis caused by Candida albicans. J Infect Dis 1975;131:647-657. 60. McDonald RH, Bustros de S, Sipperley JO: Vitrectomy for epiretinal membrane with Candida chorioretinitis. Ophthalmology 1990;97:466-469. 61. Wolfensberger TJ, Gonvers M: Bilateral endogenous Candida endophthalmitis. Retina 1998;18:280-281. 62. Beebe WE, Kirkland C, Price J: A subretinal neovascular membrane as a complication of endogenous Candida endophthalmitis. Ann Ophthalmol 1987;19:207-209. 63. Cohen R, Roth FJ, Delgado E, et al: Fungal flora of the normal human small and large intestine. N EnglJ Med 1969;280:638-641. 64. Hoffmann DH, Waubke TH: Experimentelle Untersuchungen zur metastatischen Ophthalmie mit Candida albicans. Graefes Arch Ophthalmol 1961;164:174-196. 65. Edwards JR, Lehrer RI, Stiehm ER, et al: Severe candidal infections: Clinical perspective, immune defense mechanisms, and current concepts of therapy. Ann Intern Med 1978;89:91-106. 66. Joshi N, HamoryBH: Endophthalmitis caused by non-albicans species of Candida. Rev Infect Dis 1991;13:281-287. 67. Horn R, Wong B, Kiehn TE, Armstrong D: Fungemia in a cancer hospital: Changing frequency, earlier onset, and results of therapy. Rev Infect Dis 1985;7:646-655. 68. Edwards JE, Mongomerie JZ, Ishida K, et al: Experimental hematogenous endophthalmitis due to Candida: Species variation in ocular pathogenicity. J Infect Dis 1977;135:294-297. 69. McDonnell Pj;.McDonnell JM, Brown RH, Green WR: Ocular involvement in patients with fungal infections. Ophthalmology 1985;92:706-709. 70. Green MT, Jones DB, Gentry LO: Endogenous Candida endophthalmitis in the primate. Invest Ophthalmol Vis Sci 1978;17(s):229. 71. Wilhelmus KR: The pathogenesis of endophthalmitis. Int Ophthalmol Clin 1987;27:74-81. 72. Okada AA, D'Amico DJ: Endogenous endophthalmitis. In: Albert DM, Jakobiec FA, eds: Principles and Practice of Ophthalmology, vol 5. Philadelphia, W.B. Saunders, 1994, pp 3120-3126. 73. Robertson DM, Riley FC, Hermans PE: Endogenous Candida oculomycosis. Report of two patients treated with flucytosine. Arch Ophthalmol 1974;91 :33-38. 74. Cohen M, Edwards JE, Hensley TJ, Guze LB: Experimental hematogenous Candida albicans endophthalmitis: Electron microscopy. Invest Ophthalmol Vis Sci 1977;16:498-511. 75. Baley JE, Annable WL, I\liegman RM: Candida endophthalmitis in the premature infant. Pediatrics 1981;98:458-461. 76. Dossett JH: Microbial defenses of the child and man. Deficient host mechanism of the newborn. Pediatr Clin North Am 1972;19:355-372. 77. Xanthou M, Valassi-Adam E, Kintsonidou E, Matsaniotis N: Phagocytosis and killing ability of Candida albicans by blood leukocytes of healthy term and preteI'm babies. Arch Dis Child 1975;50:72-75. 78. Bielsa I, Miro JM, Herrero C, et al:Systemic candidiasis in heroin abusers. Cutaneous findings. IntJ Dermatol 1987;26:314-319. 79. Gentry LO McNitt TR, Kaufman L: Use and value of serologic tests for the diagnosis of systemic candidiasis in cancer patients: A prospective study of 146 patients. Curl' Microbiol 1978;1:239-242. 80. Meckstroth KL, Reiss E, Keller ]W, Kaufman L: Detection of antibodies and antigenemia in leukemic patients with candidiasis by enzyme-linked immunosorbent assay. J Infect Dis 1981;144:24-32. 81. Filice G, Yu B, Armstrong D: Immunodiffusion and agglutination tests for Candida in patients with neoplastic disease: Inconsistent correlation of results with invasive infections. J Infect Dis 1977;135:349-357. 82. Stickle D, Kaufman L, Blumer SO, McLaughlin DW: Comparison of a newly developed latex agglutination test and an immunodiffusion test in the diagnosis of systemic candidiasis. Appl Microbiol 1972;23:490-499. 83. Mathis A, Falecaze F, Bessieres MH, et al: Immunological analysis of the aqueous humour in Candida endophthalmitis. II: Clinical study. BrJ Ophthalmol 1988;72:313-316.
29: 84. Fung JC, Donta ST, Tilton RC: Candida detection system (CANDTEC) to differentiate between Candida albicans colonization and disease. J Clin Microbiol 1986;24:542-547. 85. Bailey ]W, Sada E, Brass C, Bennett JE: Diagnosis of systemic candidiasis by latex agglutionation for serum antigen. J Clin MicrobioI 1985;21:749-752. 86. Henderson DK, EdwardsJE, Ishida K, et al: Experimental hematogenous Candida endophthalmitis: Diagnostic approaches. Infect Immun 1979;23:858-862. 87. Axelrod AJ, Peyman GA: Intravitreal amphotericin B treatment of experimental fungal endophthalmitis. Am J Ophthalmol 1973;76:584-588. 88. Forster RK, Abbott RL, Gelender H: Management of infectious endophthalmitis. Ophthalmology 1980;87:313-319. 89. Alder ME, Vellend H, Neely DM, et al: Use of fluconazole in the treatment of candidal endophthalmitis. Clin Infect Dis 1995;20:657-664. 90. Laatikainen L, Tuominen M, Dickhoffvon K: Treatment of endogenous fungal endophthalmitis with systemic fluconazole with or without vitrectomy. AmJ Ophthalmol 1992;113:205-207. 91. LuttrullJK, Wan WL, Kubak BM, et al: Treatment of ocular fungal infection with oral fluconazole. Am J Ophthalmol 1995;119:477481. 92. Christmas NJ, Smiddy WE: Vitrectomy and systemic fluconazole for treatment of endogenous fungal endophthalmitis. Ophthalmic Surg Lasers 1996;27:1012-1018. 93. Del Palacio A, Cuetara MS, Ferro M, et al: Fluconazole in the management of endophthalmitis in disseminated candidosis of heroin addicts. Mycoses 1993;36:193-199. 94. Gold W, Stout HA, Pagano JF, Donovick R: Amphotericins A and B: Antifungal antibiotics produced by a streptomycete: 1. In vitro studies. In: Welch H, Marti-Ibanez F, eds: Antibiotics Armua119551956. New York, Medical Encyclopedia, 1956, p 579. 95. Louria DB, Dineen P: Amphotericin B in the treatment of disseminated moniliasis. JAMA 1960;174:273-279. 96. Medoff G, Kobayashi GS: Strategies in the treatment of systemic fungal infections. N EnglJ Med 1980;30f.145-155. 97. Green WR, Bennett JE, Goos RD: Ocular penetration of amphotericin B. A report of laboratory studies and a case report of postsurgical cephalosporium endophthalmitis. Arch Ophthalmol 1965;73:769-775. 98. Fisher JF, Taylor AT, Clark J, et al: Penetration of amphotericin B into the human eye. J Infect Dis 1983;147:164. 99. Behlau I, Baker AS: Fungal infections and the eye. In: Albert DM, Jakobiec FA, eds: Principles and Practice of Ophthalmology, vol 5. Philadelphia, W.B. Saunders, 1994, pp 3030-3037. 100. Presterl E, Graninger W: New aspects in the treatment of systemic mycoses. Wien Klin Wochenschr 1998;110:740-750. 101. Ng TT, Denning DW: Liposomal amphotericin B (AmBisome) therapy in invasive fungal infections. Evaluation of United Kingdom compassionate use data. Arch Intern Med 1995;155:10931098. 102. Kruger W, Strockschlader M, Russmann B, et al: Experience with liposOll1al amphotericin B in 60 patients undergoing high-dose therapy and bone marrow or peripheral blood stem cell transplantation. Br J Haematol 1995;91:684-690. 103. Axelrod AJ, Peyman GA, Apple DJ: Toxicity ofintravitreal injection of amphotericin B. AmJ Ophthalmol 1973;76:578....583. 104. Stern GA, Fetkenhour CL, O'Grady RB: Intravitreal amphotericin B treatment of Candida endophthalmitis. Arch Ophthalmol 1977;95:89-93. 105. Ho PC, O'Day DM: Candida endophthalmitis and infection of costal cartilages. Br J Ophthalmol 1981;65:333-334. 106. Bennett JE: Chemotherapy of systemic mycoses. N Engl J Med 1974;290:30-32. 107. Debryne D, Ryckelynck J: Pharmacokinetics of fluconazole. Clin Pharmacokinet 1993;24:10-27.
108. O'Day DM, Foulds G, Williams TE, et al: Ocular uptake of fluconazole following oral administration. Arch Ophthalmol 1990;108:1006-1008. 109. Nomura J, Ruskin J: Failure of therapy with fluconazole for candidal endophthalmitis. Clin Infect Dis 1993;17:888-889. 110. Filler SG, Crislip MA, Mayer CL, Edwards JE: Comparison of fluconazole and amphotericin B for treatment of disseminated candidiasis and endophthalmitis in rabbits. Arltimicrob Agents Chemother 1991 ;35:288-292. Ill. Savani DV, Perfect JR, Cobo LM, Durack DT: Penetration of new azole compounds into the eye and efficacy in experimental Candida endophthalmitis. Antimicrob Agents Chemother 1987;31:610. 112. Van Cutsem J: Oral, topical and parenteral antifungal treatment with itraconazole in normal and in immunocompromised animals. Mycoses 1989;32S:14-34. 113. Mohan M, Panda A, Gupta SK: Management of human keratomycosis with miconazole. Aust N ZJ OphthalmoI1989;17:295-297. 114. Ball MA, Rebhun WC, GaarderJE, Patten V: Evaluation ofitraconazole-dimethyl sulfoxide ointment for treatment of keratomycosis in nine horses. J Am Vet Med Assoc 1997;211:199-203. 115. Arocker-Mettinger E, Huber-Spitzy V, Haddad R, Grabner G: Keratomycosis caused by Candida albicans. Klin Monatsbl Augenheilkd 1988;193:192-194. 116. Gupta SK: Efficacy of miconazole in experimental keratomycosis. Aust N ZJ OphthalmoI1986;14:373-376. 117. Thomas PA: Mycotic keratitis-an underestimated mycosis. J Med Vet Mycol 1994;32:235-256. 118. Airas KA, Nikoshelainen J: Haematogenous Candida endophthalmitis after abdominal surgery. Acta Ophthalmol Copenh 1987; 65:450-454. 119. Schulman JA, Peyman GA: Intravitreal corticosteroids as an adjunct in the treatment of bacterial and fungal endophthalmitis. Retina 1992;12:336-340. 120. Coats ML, Peyman GA: Intravitreal corticosteroids in the treatment of exogenous fungal endophthalmitis. Retina 1992;12:46-51. 121. Huang K, Peyman GA, McGetrick J: Vitrectomy in experimental endoph thalmi tis: 1. Fungal infections. Ophthalmic Surg 1979; 10:84-86. 122. Snip RC, Michels RG: Pars plana vitrectomy in the management of endogenous Candida endophthalmitis. Am J Ophthalmol 1976;82:699-704. 123. Cottingham AJ, Forster RK: Vitrectomy in endophthalmitis. Arch Ophthalmol 1976;94:2078-2081. 124. Barrie T: The place of elective vitrectomy in the management of patients with Candida endophthalmitis. Graefes Arch Clin Exp Ophthalmol 1987;225:107-113. 125. Doft BH, Weiskopf J, Nilsson-Ehle I, Wingard LB: Amphotericin clearance in vitrectomized versus nonvitrectomized eyes. Ophthalmology 1985;92:1601-1605. 126. Baldinger J, Doft BH, Burns SA, Johnson B: Retinal toxicity of amphotericin B in vitrectomized versus non-vitrectomized eyes. Br J Ophthalmol 1986;70:657-661. 127. Armable WL, Kachmer ML, DiMarco M, DeSantis D: Long-term follow-up of Candida endophthalmitis in the premature infant. J Pediatr Ophthalmol Strabismus 1990;27:103-106. 128. Sims ME, Yoo Y, You H, et al: Prophylactic oral nystatin and fungal infections in very-Iow-birthweight infants. Am J Perinatal 1988;5:33-36. 129. Horne MJ, Ma MH, Taylor RF, et al: Candida endophthalmitis. Med J Aust 1975;1:170-172. 130. Dellon AL, Stark WJ, Chretien PB: Spontaneous resolution of endogenous Candida endophthalmitis complicating intravenous hyperalimentation. Am J Ophthalmol 1975;79:648-654. 131. Servant JB, Dutton GN, Ong-Tone L, et al: Candidal endophthalmitis in Glaswegian heroin addicts: Report of an epidemic. Trans Ophthalmol Soc U K 1985;104:297-308.
Richard R. Tamesis
Coccidioidomycosis is a disease produced by the soil fungus Coccidioides immitis. It is also called the San Joaquin Valley fever or valley fever. C. immitis is a dimorphic fungus, which means that it occurs in two forms: (1) growing as a mold with septate hyphae in soil and in culture, and (2) as a nonbudding spherule in host tissue. 1 It is identified by its appearance and by the formation of segmented arthrospores. The fungus grows in the topsoil layers in semiarid areas of the Western Hemisphere. Infection is caused by inhalation of airborne arthrospores that have been dislodged from the soil. The arthrospores form thick-walled spherules inside the host that then rupture and release endospores that spread locally and disseminate.
HISTORY Coccidioidomycosis affecting the external eye and orbit has been described since 1896, when the disease was first reported in the United States. 2 In 1948, Levitt reported what he believed to be a case of intraocular coccidioidomycosis in a patient with pulmonary coccidioidomycosis. 3 However, it was not until 1967, when Hagele reported a patient with endophthalmitis caysed by C. immitis, that a case of intraocular coccidioidorllycosis was confirmed by histopathology and culture before enucleation or death of the patient. 4
EPIDEMIOLOGY
c. immitis is endemic in the region known as the lower Sonoran Life Zone, which includes the San Joaquin Valley region of California and the Southwestern United States. The disease also occurs in the arid regions of Mexico, Central America, and parts of South America. In semiarid climates, winters with heavy rain, followed by hot, dry, dusty periods, favor the rapid multiplication of the arthroconidia. The seasonal occurrence of primary coccidioidomycosis increases during the summer and fall in the Southwestern United States, corresponding to the dusty time of the year.. Severe drought followed by heavy rainfall was identified as a factor associated with a 19911993 epidemic of coccidioidomycosis in California. 5 ,6 Outbreaks have also occurred following earthquakes, dust storms, and archeological excavations. 7- 9 Filipinos, blacks, Native Americans, Mexican Americans, and immunocompromised individuals such as the elderly population, neonates, and those with the acquired immunodeficiency syndrome (AIDS) are at higher risk for developing the disease. lO , 11 Meningitis, lymphadenopathy, and diffuse pulmonary disease are more commonly found in these patients. CLINICAL CHARACTERISTICS The lungs, skin, and central nervous system are most commonly affected in patients with coccidioidomycosis. Approximately 40% of infected individuals are symptom-
atic. 12 The vast majority of symptomatic patients present with a mild upper respiratory tract infection or a pneumonitis characterized by fever, cough, night sweats, and malaise approximately 3 weeks after exposure to the organism. Erythema nodosum or multiforme may appear anywhere from 3 days to 3 weeks after the onset of symptoms. Disseminated infection occurs in less than 1 % of patients with pulmonary coccidioidomycosis. 13 Ocular coccidioidomycosis is rare, even in disseminated disease, and can present as (1) intraocular disease producing iridocyclitis, choroiditis, and chorioretinitis, which can affect one or both eyes; and (2) external disease consisting of blepharitis, keratoconjunctivitis, phlyctenular conjunctivitis, granulomatous conjunctivitis, episcleritis, and scleritis, as well as optic atrophy, extraocular nerve palsies, and orbital infection. 2 , 14-16 Posterior segment involvement can manifest in four different ways: (1) diffuse choroiditis often associated with widely disseminated (and preterminal) systemic disease, (2) large, juxtapapillary choroidal infiltrates with variable involvement of the overlying retina that may be associated with retinal edema and hemorrhage, (3) spherical opacities of the macula or posterior pole at the level of Bruch's membrane and sensory retina associated with macular edema and exudates, and most commonly as (4) small, peripheral chorioretinal scars with central hypopigmentation resembling presumed ocular histoplasmosis scars. 17, 18 Vitreous cells and perivascular sheathing may also be present with posterior segment disease. About half of all patients present primarily with a granulomatous iridocyclitis without posterior segment involvement. Iris nodules containing the fungus may be seen. Spherules of C. immitis can be demonstrated from anterior chamber taps and iris biopsies in these patients. Although ocular coccidioidomycosis generally occurs in patients with disseminated disease, there are reports of intraocular coccidioidomycosis occurring in otherwise apparently healthy individuals. 19- 21
C. immitis produces pyogenic, granulomatous, and mixed reactions. 22 Polymorphonuclear leukocytes suppurate around infecting conidia and inside granulomas when the spherules rupture and release endospores. A granulomatous reaction develops around the developing spherules, which can be found inside foreign body giant cells. Fibrosis, necrosis, and calcification can occur. Intact cell-mediated immunity serves to limit further extension of these foci and is essential for the host to eliminate this organism. Patients deficient in cell-mediated immunity such as those with AIDS are at risk for developing the chronic and disseminated forms of the disease and may require prolonged therapy. They typically have high titers of complement-fixing anticoccidioidal antibodies with no delayed-type hypersensitivity on skin testing.
CHAPTER 30: COCCIDIOIDOMYCOSIS
Distribution of the endospores via the ophthalmic artery to. the short posterior ciliary and central retinal arteries can result in miliary retinal and choroidal granulomas. Choroidal granulomas are confined Inainly to the middle and large vessel layers. 23 Retinal granulomas are centered in the distribution of the central retinal artery. Anterior segment lesions demonstrate zonal granulomatous inflammation that can involve the uvea and angle structures.
DIAGNOSIS Patients living in endemic areas who show the characteristic chorioretinal lesions should be suspected of having the disease whether or not they have active intraocular inflammation. Chest x-ray studies may show pneumonitis or characteristic "coin lesions." Biopsy of skin lesions can be especially important in identifYing the organism in disseminated coccidioidomycosis. Confirmation of the diagnosis is generally based on histopathologic, cultural, or molecular evidences of C. im1Jlitis. The spherules are 30 to 60 fJum in size and appear flattened rather than globular. 24 They are refringent on direct examination and stain with periodic acid-Schiff. Theendospores are oval in shape. Culturing for the organism can be very dangerous because the mycelial form is highly infectious and requires special handling. Aqueous and vitreous biopsies can be examined directly for the organism by means of the Papanicolaou stain. 25 Iris biopsies of lesions and nodules can also help establish the diagnosis of ocular G,Occidioidal infection rapidly. Immunologic evidence for the diagnosis includes a positive serologic test for anticoccidioidal antibodies in serum, cerebrospinal fluid, vitreous, or aqueous by (1) detection of anticoccidioidal IgM using immunodiffusion, enzyme immunoassay (EIA) latex agglutination, or tube precipitin, or (2) detection of a rising titer of anticoccidioidal IgG by immunodiffusion, EIA, or complement fixation. 26 Serum IgM antibodies appear 1 to 3 weeks after the onset of symptoms in 75% of cases of primary infection and disappear within 4 months. 27 Three months after onset, 50% to 90% of the patients with symptomatic primary infections have complement-fixing serum IgG anticoccidioidal antibody. This antibody may last for 6 to 8 months, although it may occasionally persist longer at low levels even after the infection resolves successfully. A fourfold rising titer is of grave prognostic significance and indicates advanced disease. A falling titer indicates improvement. Negative serologic tests do not exclude the diagnosis of coccidioidomycosis, particularly if chronic pulmonary disease is present. A valid diagnosis of coccidioidal infection can be made by skin test conversion with the mycelial phase antigen coccidioidin (1:100 dilution) from negative to positive after the onset of clinical signs and symptoms. Spherulin (1:100 dilution), a parasitic phase antigen, may be a more sensitive reagent in detecting delayed hypersensitivity and is just as specific a coccidioidin. The antigen is applied intradermally (0.1 ml). Thirty-six hours is the optimal reaction time, although the readings are usually taken at 24 and 48 hours. Induration greater than 5 mm in diameter is considered a positive reaction. A positive skin test
indicates previous exposure or active disease and usually occurs a week after the developinent of symptoms in about 80% of patients. A negative skin reaction does not rule out coccidioidomycosis. Almost all symptomatic patients are positive a month after the onset of sYlnptoms. Anergy is common in disseminated disease. There is a low degree of cross reactivity with histoplasmosis and blastomycosis. 28 Positive skin tests do not affect serologic testing, although a positive coccidioidin skin test may induce antibodies that cross react with histoplasmin. 29 Skin testing is important primarily in assessing the cellular immunity status of a patient with documented coccidioidal disease and as an epidemiologic tool.
The cornerstones of therapy for coccidioidomycosis at the present time are amphotericin B and the triazoles fluconazole and itraconazole. The advantages of the triazoles over amphotericin B include oral administration and relative nontoxicity. Fluconazole is effective in treating progressive pulmonary and disseminated coccidioidomycosis. 30 There are, however, no comparative trials comparing amphotericin B to the triazoles in the treatment of coccidioidomycosis, and the triazoles are not currently approved by the U.S. Food and Drug Administration for the treatment of this disease. Miconazole has not been proved to beeffective.in treating intraocular coccidioidomycosis. 3! . Amphotericin B is the treatment of choice for coccidioidomycosis. It is administered intravenously at a dose of 1 mg/kg body weight per day. A total dose of 500 mg to 1500 mg can be given. Intraocular amphotericin B (5 fJug/0.1 ml) is administered during vitrectomy for suspected fungal endophthalmitis. Amphotericin B, however, has poor ocular and central nervous systeln penetration, retinal toxicity associated with intravitreal injection, and potentially serious dose-limiting systemic side effects. Fluconazole (Diflucan) is the drug of choice for coccidioidal meningitis. Oral administration results in high concentrations in the cerebrospinal fluid, the aqueous, vitreous, retina, and choroid. 32 , 33 It is given orally at a dose of 400 to 800 mg/day. It can be substituted for amphotericin B, but cases of treatment failure have been reported. 34 Intraocular coccidioidomycosis has been successfully treated using fluconazole as the primary agent. 35 The authors of that report believe that alnphotericin B should be reserved for patients who fail initial treatment with oral fluconazole. Itraconazole (Sporanox) has also been used in the treatment of coccidioidomycosis, and it has a response rate of 60% to 80%.36,37 It is taken orally at a dose of 200 mg twice daily. Its role in treating ocular coccidioidomycosis is unclear, although it has been used successfully in a uveitis patient with iris-biopsy confirmed coccidioidomycosis. 2! Acute treatment of progressive pulmonary and extrapulmonary coccidioidomycosis should be followed by long-term maintenance therapy because of a reported high relapse rate after treatment with both amphotericin B and the triazoles. 38 , 39 Fluconazole (200 to 400 mg daily), weekly amphotericin B, or itraconazole may be effective. Patients with meningitis and those with the
CHAPTER 30: COCCIDIOIDOMYCOSIS
acquired immunodeficiency syn.drome with progressive or disseminated coccidioidomycosis should continue with maintenance therapy for life. Complications of intraocular coccidioidomycosis include posterior synechiae, cataracts, scleral thinning and staphyloma formation, and secondary glaucoma. The posterior segment lesions can involve the macula and the optic nerve, with devastating consequences to the vision. Epiretinal membranes and serous retinal detachment can occur. Even with aggressive antifungal therapy, the eye can become hypotonous and painful and require enucleation.
PROGNOSIS Despite systemic antifungal therapy, meningeal involvement carries a grave prognosis. 4 0-41 In patients with AIDS, less than half respond to treatment, and the mortality rate can climb as high as 70% in those patients with diffuse pulmonary disease. 42 The prognosis of ocular coccidioidomycosis ultimately depends on the location and severity of the ocular lesions, as well as on prompt diagnosis and treatment of the systemic disease. In general, intravenous and intraocular amphotericin B can sterilize most cases of ocular coccidioidomycosis. However, the prognosis for patients with isolated anterior segment coccidioidomycosis is poor, with the majority requiring enucleation owing to blindness and pain. 21
CONCLUSIONS Coccidioidomycosis must be considered in the differential diagnosis of ocular inflammatory disease, especially in patients who have lived in or traveled through endemic areas. The absence of serologic evidence for coccidioidomycosis and lack of systemic manifestations do not rule out the diagnosis of coccidioidal infection. Biopsies of intraocular lesions, including vitreous and aqueous taps, provide rapid diagnosis and may be the most efficient method of facilitating appropriate treatment. Guidelines for therapy have not been clearly established owing to the rarity of the disease. Intravenous amphotericin B is the treatment of choice, although the triazoles such as fluconazole hold promise as a better tolerated form of treatment. The role of intraocular injections of amphotericin B in treating intraocular coccidioidomycosis is unclear, although it is given in suspected cases of fungal endophthalmitis. Patients may require prolonged systemic therapy to prevent relapse and require close collaboration between the ophthalmologist and infectious disease specialists. The prognosis for isolated anterior segment disease is poor, and the majority of these eyes may ultimately require enucleation.
References 1. Bennett JE: Coccidioidomycosis and paracoccidioidomycosis. In: Isselbacher Ig, Braunwald E, Wilson JD, et al (eds): Harrison's Principles of Internal Medicine. New York, McGraw-Hill Book Company, 1994, pp 857-858. 2. Rodenbiker HT, Ganley JP: Ocular coccidioidomycosis. Surv Ophthalmol 1980;24:263-290. 3. Levitt JM: Ocular manifestations in coccidioidomycosis. Am J Ophthalmol 1948;31:1626-1628.
4. Hagele AJ, Evans DJ, Larwood TR: Primary endophthalmic coccidioidomycosis. Report of a case of exogenous primary coccidioidomycosis of the eye diagnosed prior to enucleation. In: Aiello E (ed): Coccidioidomycosis. Tucson, University of Arizona Press, 1967, pp 37-39. 5. CDC: Update: Coccidioidomycosis-California, 1991-1993. MMvVR 1994;43:421-423. 6. Pappagianis D: Marked increase in cases of coccidioidomycosis in California: 1991, 1992, and 1993. Clin Infect Dis 1994;19(Suppl 1):Sl4-18. 7. Schneider E, Hajjeh RA, Spiegel RA, et al: A coccidioidomycosis outbreak following the Northridge, California, earthquake. JAMA 1997;277:904-908. 8. Flynn NM, Hoeprich PD, Kawachi MM, et al: An unusual outbreak of windborne coccidioidomycosis. N EnglJ Med 1979;301:358-361. 9. Werner SB, Pappagianis D, Heindl I, et al: An epidemic of coccidioidomycosis among archeology students in Northern California. N Engl J Med 1972;286:507-512. 10. Galgiani IN: Coccidioidomycosis: Changes in clinical expression, serological diagnosis, and therapeutic options. Clin Infect Dis 1992;14(Suppl 1) :S100-S105. 11. Granoff DM, Libke RD: Coccidioidomycosis in children. In: Feigin RD, Cherry JD (eds): Textbook of Pediatric Infectious Diseases. Philadelphia, WE Saunders Company, 1981, pp 1488-1500. 12. Drutz DJ, Cadanzaro A: Coccidioidomycosis. Am Rev Resp Dis 1978;117:559-585. 13. Ampel NM, Wieden MA, Galgiani IN: Coccidioidomycosis: Clinic update. Rev Infect Dis 1989;11:897-911. 14. Maguire LJ, Campbell RJ, Edson RS: Coccidioidomycosis with necrotizing granulomatous conjunctivitis. Cornea 1994;13:539-542. 15. Fusaro RM, Bansal S, Records RE: Some unusual periorbital dermatoses. Ann Ophthalmol 1988;20:391-393. 16. Mark AS, Blake P, Atlas SW, et al: Gd-DTPA enhancement of the cisternal portion of the oculomotor nerve on MR imaging. AJNR AmJ Neuroradiol 1992;13:1463-1470. 17. Blumenkranz MS, Stevens DA: Endogenous coccidioidal endophthalmitis. Ophthalmology 1980;87:974-984. 18. Lamer L, Paquin F, Lorange G, et al: Macular coccidioidomycosis. Can J Ophthalmol 1982;17:121-123. 19. Zakka KA, Foos RY, Brown ~. Intraocular coccidioidomycosis. Surv Ophthalmol 1978;22:313-321. 20. Rodenbiker HT, Ganley JP, Galgiani IN, et al: Prevalence of chorioretinal scars associated with coccidioidomycosis. Arch Ophthalmol 1981;99:71-75. 21. Moorthy RS, Rao NA, Sidikaro Y, et al: Coccidioidomycosis iridocyclitis. Ophthalmology 1994;101:1923-1928. 22. Irvine AR Jr: Coccidioidal granuloma of the lid. Trans Am Acad Ophthalmol Otolaryngol 1968;72:751-754. 23. Glasgow BJ, Brown HH, Foos RY: Miliary retinitis in coccidioidomycosis. AmJ Ophthalmol 1987;104:24-27. 24. Gori S, Scasso A: Cytologic and differential diagnosis of rhinosporidiosis. Acta Cytologica 1994;38:361-366. 25. Warlick l\tLA, Quan SF, Sobonya RE: Rapid diagnosis of pulmonary coccidioidomycosis. Cytologic vs potassium hydroxide preparations. Arch Intern Med 1983;143:723-725. 26. CDC. Coccidioidomycosis-Arizona, 1990-1995. JAMA 1997; 277:104-105. 27. Stevens DA: Coccidioides immitis. In: Mandell GL, Douglas RG Jr, Bennett JE (eds): Principles and Practice of Infectious Diseases. New York, John Wiley & Sons, Inc., 1985, pp 1485-1493. 28. Chick EW, Baum GL, Furculow ML, et al: Scientific Assembly statement. The use of skin tests and serologic tests in histoplasmosis, coccidioidomycosis, and blastomycosis, 1973. Am Rev Respir Dis 1973;108:156-159. 29. Pappagianis D, Zimmer BL: Serology of coccidioidomycosis. Clin Microbiol Rev 1990;3:247-268. 30. Catanzaro A, Galgiani IN, Levine BE, et al: Fluconazole in the treatment of chronic pulmonary and nonmeningeal disseminated coccidioidomycosis. Am J Med 1995;98:249-256. 31. Blumenkranz MS, Stevens DA: Therapy of endogenous fungal endophtllalmitis. Arch Ophthalmol 1980;98:1216-1220. 32. Tucker RM, Williams PL, Arathoon EG, et al: Pharmacokinetics of fluconazole in cerebrospinal fluid and serum in human coccidioidal meningitis. Antimicrob Agents Chemotller 1988;32:369-373. 33. O'Day DM, Foulds G, Williams TE, et al: Ocular uptake of flucona-
CHAPTER. 30: COCCIDIOIDOMYCOSIS
34. 35.
36. 37.
38.
zole following oral administration. Arch Ophthalmol 1990;108: 1006-1 008. Evans TG, Mayer J, Cohen S, et al: Fluconazole failure in the treatment of invasive mycoses. J Infect Dis 1991;164:1232-1235. LuttruU JK, Wan WL, Kubak BM, et al: Treatment of ocular fungal infections with oral fluconazole. Am J Ophthalmol 1995;119:477481. Graybill JR, Stevens DA, Galgiani IN, et al: Itraconazole treatment of coccidioidomycosis. AmJ Med 1990;89:282-290. Tucker RM, Denning DW, Dupont B, et al: Itraconazole therapy for chronic coccidioidal meningitis. Ann Intern Med 1990; 112:108-112. Dewsnup DH, Galgiani IN, Graybill JR, et al: Is it ever safe to stop
39.
40.
41. 42.
azole therapy for Coccidioides immitis meningitis? Arm Intern Med 1996;125:304-310. Oldgfield EG III, Bone WD, Martin CR, et al:Prediction of relapse after treatment of coccidioidomycosis. Clin Infect Dis 1997;25:12051210. Bouza E, Dreyer JS, Hewitt WL, et al: Coccidioidal meningitis: An analysis of thirty-one cases and review of literature. Medicine 1981;60:139-172. Kafka JA, Cataranzo A. Disseminated coccidioidomycosis in children. J Pediatr 1981;98:355-361. Fish DG, Ampel NM, Galciani IN, et al: Coccidioidomycosis during human immunodeficiency virus infection: A review of 77 patients. Medicine (Baltimore) 1990;69:384-391.
Katerina Havrlikova-Dutt
Cryptococcosis is a systemic infection caused by the saprophytic fungus Cryptococcus neoformans. It is known to affect mainly immunocompromised patients, although it can cause disease in an immunocompetent individual as well. Pulmonary and central nervous system (CNS) involvement make up the majority of cases. Cryptococcosis is the most common mycotic infection of the CNS, and ocular involvement occurs in 40% of patients with cryptococcal meningitis. 1 C. neoformans is a round, encapsulated yeastlike fungus that reproduces by budding. Staining with India ink and Wright's stain shows a large capsule surrounding a cell that has a single bud attached to a narrow bud base.
EPIDEMIOLOGY
c. neoformans is a worldwide saprobe, found in pigeon feces, pigeon nesting places, and contaminated soi1,2 Despite the high concentration of fungus in pigeon feces, the birds are not infected. 3 There is evidence that the disease occurs after the organism is aerosolized and inhaled. 4 Transmission from animals to humans or between humans has not been documented, although a case of cryptococcal endophthalmitis a~quired through a corneal transplant from a donor with active cryptococcosis has been reported. 5 There has also been a case report describing Cryptococcus laurentii keratitis spread by a rigid gaspermeable contact lens in a patient with onychomycosis. 6 Cryptococcosis is relatively rare in an immunocompetent host, but in patients with acquired immunodeficiency syndrome (AIDS), it is the fourth most common cause of life-threatening infections. 7 It can also be seen in other immunocompromised patients such as diabetic patients on long-term corticosteroids or individuals with polyarteritis nodosa, lymphoma, systeluic lupus erythematosus, Hodgkin's disease, organ transplant recipients, or other systemic diseases treated with immunosuppressive agents. CHARACTERISTICS Systemic involvement in cryptococcosis varies widely and includes meningitis, pneumonia, mucocutaneous lesions, multiple skin lesions, pyelonephritis, endocarditis, hepatitis, prostatitis, and ocular infection. In the population of patients with AIDS, C. neoformans is an important pathogen producing not only a variety of CNS and neurophthalmic complications (chronic meningitis being the most common) but also devastating disseminated systemic disease. Ocular manifestations are thought to arise via optic nerve extension from central nervous system involvementS, 9 but it appears that intraocular involvement can occur via hematogenous spread as well. 10 Ophthalmic manifestations of cryptococcosis include papilledema, optic neuropathy, chiasmal involvement, optic atrophy, cranial nerve palsies, nystagmus, internuclear ophthalmoplegia, choroiditis, retinis, uveitis, inflamma-
tory iris mass, keratitis, conjunctival granuloma, limbal nodules, phthisis bulbi, periorbital necrotizing fasciitis, orbital infection, exogenous endophthalmitis, and endogenous endophthalmitis. In most patients ocular involvement is associated with meningitis. Specifically, the ocular involvement usually follows meningitis, but a case of endogenous cryptococcal endophthalmitis without a preceding meningeal infection has been documented. The most common intraocular manifestation is chorioretinitis. The earliest sign is focal or multifocal choroiditis, in which yellowish to white, subretinal, slightly elevated lesions one fifth to one optic disc diameter in size are usually observed. Choroiditis is followed, in rapid succession, by inflammation of the retina, vitreous, and if the condition is left untreated, the anterior segment. Endogenous cryptococcal endophthalmitis was first reported in 1948,11 and since then, approximately 15 cases have been reported in the literature. 12- 2o The earliest symptom is blurred vision, followed by redness, pain, photophobia, flqaters, ocular injection, and profound visual loss. Patients with concomitant cryptococcal meningitis also suffer from headaches and nausea. Ophthalmic findings include injection, anterior chamber cell and flare, mutton fat keratic precipitates, posterior synechiae, yellow or white chorioretinal lesions, retinal perivascular sheathing, subretinal exudate or localized serous retinal detachment, vitreous cells, severe vitreous inflammation with fluffy exudates, preretinal or vitreous abscesses, retinal detachment, and phthisis bulbi. 12- 20 The outcome in cryptococcal endophthalmitis is generally rather poor, including blindness or enucleation. Because cryptococcosis affects mostly ilumunocompromised patients, the inflammation typical of uveitis in an immunocompetent individual may be lacking. It is important to keep in mind that primary choroidal lesions in patients with AIDS may herald severe systemic disseminated disease. Funduscopic examination may detect disseminated cryptococcal disease before other clinical manifestations, thereby allowing prompt institution of effective therapy. 10
C. neoformans is a budding, spore-forming yeast yielding yellow-tan colonies on culture media. Four serotypes (A, B, C, and D) have been identified based on capsular polysaccharide antigen determination with immunofluorescence or agglutination. Types A and D are most COlUmonly pathogenic: 21 Infection occurs via inhalation into the moist environment of the lungs, where the yeast enlarges and starts to bud. A thick polysaccharide capsule forms around each cell. This capsule is immunologically inert and provides protection from phagocytic cells, thus the inflammatory response to infection is variable. Hematogenous spread to the brain leads to cystic clusters of cryptococci associated with minimal inflalumatory re-
CHAPTER 31: CRYPTOCOCCOSIS
sponse. Neutrophils are first to home to the infected area, followed by the monocytes that predominate in the later inflammatory infiltrate. 22 Neutrophils and monocytes can ingest and kill cryptococci in vitro by using the myeloperoxidase-peroxide-halide system 23 or the neutrophil cationic proteins. 24 Encapsulated C. neoformans may be sufficiently large to preclude phagocytosis, but they can still be surrounded and killed by "rings" of lTIaCrOphages. 25 Macrophage activation requires functional, sensitized T cells. Natural killer cells,26 anticryptococcal antibodies,27 and T cells may all be involved in the host defense response.
DIAGNOSIS The diagnosis of cryptococcosis requires a high degree of suspicion and is often presumptive, depending on the clinical context. Definitive diagnosis requires identification of the organism in culture from infected tissue, blood, or body fluids. There are usually no abnormalities in routine blood tests. If signs of meningitis are present, cerebrospinal fluid (CSF) analysis, including cryptococcal antigen testing and fungal culture, should be performed. When the CNS is involved in immUnOCOlTIpetent patients, the CSF is almost always abnormal with an elevated opening pressure, elevated protein, hypoglycorrhachia at 50%, and 20 to 600 leukocytes/mm3 with lymphocyte predominance. In severely immunosuppressed patients, there are minimal to no abnormalities of the CSF. India ink smears of the CSF have positive results for cryptococcus in 50% of patients. Solution ID'ay be contaminated by nonpathogenic cryptococci; other fungi or artifacts may be mistaken for cryptococci as well. Centrifuged CSF specimens should be cultured on several different occasions, because negative results do not rule out the disease. Cryptococcal polysaccharide capsular antigen may be detected in the CSF or serum of 90% of patients with meningoencephalitis. 28 The antigen is detected by latex agglutination; false-positive results may occur in the presence of rheumatoid factor. Anticryptococcal antibodies are also detectable in healthy persons, so culture of cryptococcus remains the definitive diagnostic test. Cryptococcal serology and fungal cultures of blood, sputum, or urine are often helpful in patients with disseminated disease. 2 If the results of these tests are negative and clinical suspicion still exists, diagnostic vitreous tap, vitrectomy,24 fine-needle abscess biopsy,16 or eye wall biopsy29 can be performed.
DIAGNOSIS Multifocal choroiditis due to Pneumocystis carznzz cannot be distinguished from cryptococcocal uveitis by clinical examination alone. A history of P. carinii pneumonia and the use of aerosolized pentamidine in patients with AIDS should suggest the former diagnosis. Other opportunistic infections in AIDS patients, including toxoplaslTIosis, cytomegalovirus, and herpes simplex virus, all of which primarily infect the retina, should be excluded in cases of suspected C. neofonnans endophthalmitis. Tuberculosis, sarcoidosis, intraocular lymphoma, and uveitis caused by other fungal organisms should also be considered in the differential diagnosis.
Cryptococcal meningitis is usually fatal without systemic antifungal therapy, and even with treatment, the relapse rate is about 50% in patients with AIDS. Fluconazole (200 to 400 mg/ day) has been used as a long-term oral maintenance therapy in an attempt to prevent such recurrences. 22 ,29 Combined therapy with oral flucytosine (25 to 35 mg q, 6 h PO) and intravenous amphotericin B (0.4 to 0.6 mg/day) has been recommended as the treatment of choice for patients with disseminated or meningeal cryptococcosis. Oral fluconazole has been successful in some patients with AIDS, as well as others who cannot tolerate the renal toxicity and bone marrow suppression of the combined therapy. 23, 30 Treatment of endogenous cryptococcal endophthalmitis may require a combination of systemic antifungal agents, intravitreous amphotericin B, and pars plana vitrectomy. Patients with cryptococcosis should be evaluated every few months for at least 1 year after therapy, even if they are asymptomatic. The CSF, urine, and sputum should be cultured repeatedly. The outcome for an immunocompetent patient treated for a localized pulmonary infection is usually very good. The outcome for. immunocompromised patients can vary depending on a variety of factors. The mortality rate of immunocompromised patients who do not have AIDS and who have been treated for cryptococcal meningitis is approximately 25%. When predisposing factors- such as lymphoreticular malignancy or corticosteroid therapy are present, the mortality rate is 55%. After the initial treatment with amphotericin B, 20% to 25% of patients relapse. Of those cured, 40% suffer significant permanent sequelae, such as visual loss, cranial nerve palsies, lTIotor impairment, personality changes, and decreased mental function. The prognosis for patients with AIDS is very poor, because these patients are rarely completely cured. The treatment regimen is directed toward suppressing inflammation without interfering with treatment of concomitant diseases. 2 Despite its ubiquity throughout the world, C. neoformans is an uncommon cause of systemic or ocular disease in the immunocompetent patient. However, in the immunosuppressed host, particularly those individuals afflicted with AIDS, this fungus has become an important pathogen, producing potentially devastating CNS, ocular, and systemic disease. Diagnosis requires a high degree of clinical acumen in the correct clinical context, and despite aggressive treatment with systemic and/or intraocular antifungal agents, the prognosis is guarded. Nevertheless, early diagnosis and treatment of cryptococcosis can not only preserve the patients vision, but may also be life-saving, particularly in the managelTIent of patients with AIDS.
References 1. Lesser RL, Simon RM, Leon H, et al: Cryptococcal meningitis and internal ophthalmoplegia. Am J Ophthalmol 1979;87:682.
CHAPTER 31: CRYPTOCOCCOSiS 2. Behlau I, Baker AS: Fungal infections and the eye-cryptococcosis. In: Albert DM, Jakobiec FA, eds: Principles and Practice of Ophthalmology: Clinical Practice, 1st ed, Vol V. Philadelphia, WB Saunders, 1994, p 3045. 3. Littman ML, Walter JE: Cryptococcosis: Current status. Am J Med 1968;45:922. 4. Neilson JB, Fromtling RA, Bulmer GS: Cryptococcus neoformans: Size range of infectious particles from aerosolized soil. Infect Immun 1977;17:634. 5. Beyt BEJr, Waltman SR: Cryptococcal endophthalmitis after corneal transplantation. N Engl J Med 1978;298:825. 6. Ritterband DC, Seeder JA, Shah MK, et al: A unique case of C1yptococcus laurentii keratitis spread by a rigid gas-permeable contact lens in a patient with onychomycosis. Cornea 1998;17:115. 7. Eng RHK, Bishburg E, Smith SM, et al: Cryptococcal infections in patients witll the acquired immune deficiency syndrome. Am J Med 1986;81:19. 8. Eng RHK, Bishburg E, Smith SM, et al: Cryptococcal infections in patients witll tlle acquired immune deficiency syndrome. AmJ Med 1986;81:19. 9. Ofner S, Baker RS: Visual loss in cryptococcal meningitis. J Clin Neuroophthalmol1987;7:45. 10. Rostomian K, Dugel PD, Kolahdous-Isfahani A, et al: Presumed multifocal cryptococcal choroidopathy prior to specific systemic manifestation. Int Ophthalmol 1997;21:75. 11. Weiss C, Perry IH, Shevky MC: Infection of the human eye with Cryptococcus neofonnans (Torula histologica; Cryptococcus hO'lninis): A clinical and experimental study with a new diagnostic method. Arch Ophthalmol 1948;39:739-751. 12. Denning DW, Armstrong RW, Fishman M, et al: Endophthalmitis in a patient with disseminated cryptococcosis and AIDS who was treated 'with itraconazole. Rev Infect Dis 1991;13:1126. 13. Grieco MH, Freilich DB, Louria DB: Diagnosis of cryptococcal uveitis with hypertonic media. AmJ Ophtllalmol 1971;72:171. 14. Henderly DE, Liggett PE, Rao NA: Cryptococcal chorioretinitis and endophthalmitis. Retina 1987;7:75. 15. Hiles DA, Font RL: Bilateral intrf¥)cular cryptococcus Witll unilateral spontaneous regression: Report of a case and review of tlle literature. Am J Ophtllalmol 1968;65:98. 16. Hiss PW, Shields JA, Augsburger lJ: Solitary retrovitreal abscess as
17.
18. 19. 20.
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22.
23.
24. 25.
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27.
28. 29. 30.
the initial manifestation of cryptococcosis. Ophthalmology 1988;95:162. Malton ML, Rinkhoff JS, Doft BS, et al: Cryptococcal endophtllalmitis and meningitis associated with acute psychosis and exudative retinal detachment. AmJ Ophthalmol 1987;104:438. O'Dowd GJ, Frable ~: Cryptococcal endophthalmitis: Diagnostic vitreous aspiration cytology. Am J Clin Pathol 1983;79:382. Schields JA, Wright DM, Augsburger lJ, et al: Cryptococcal chorioretinitis. Am J Ophtllalmol 1980;89:210. Schulman JA, Leveque C, Coats M, et al: Fatal disseminated cryptococcosis following intraocular involvement. Br J Ophthalmol 1988;72:171. Diamond R: CryjJtococcus neofonnans. In: Mandell GC, Bennett JE, Dolin R, eds: Principles and Practice of Infectious Disease, 4tll ed. New York, Churchill-Livingstone, 1995, pp 2331-2340. Gadebush HH: Mechanisms of native and acquired resistance to infection with Cryptococcus neofonnans. CRC Crit Rev Microbiol 1972;1:311. Diamond RD, Root RK, Bennett JE: Factors influencing killing of Cryptococcus neofonnans by human leukocytes in vitro. J Infect Dis 1972;125:367. Ganz T, Selsted ME, Szklarek D, et al: Defensins: Natural peptide antibiotics of human neutrophils. J Clin Invest 1985;76:1427. Kalina M, KIetter Y, Aronson M: The interaction of phagocytes and the large-sized parasite, Cryptococcus neofonnans: Cytochemical and ultrastructural study. Cell Tissue Res 1974;152:165. Hidore MR, Murphy JW: Correlation of natural killer cell activity and clearance of Cryptococcus neoformans from mice after adoptive transfer of splenic nylon-wool-nonadherent cells. Infect Immun 1986;51:57. Nabavi N, Murphy JW: Antibody-dependent natural killer cell-mediated growtll inhibition of Cryptococcus neofonnans. Infect Immun 1986;51 :556. Benett JE, Bailey JW: Control for rheumatoid factor in the latex test for cryptococcosis. Am J Clin Pathol 1971 ;56:360. Peyman GA, Juarez CP, Raichand M: Full-thickness eye-wall biopsy: Long-term results in 9 patients. Br J Ophthalmol 1981;65:723. Golnik KC, Newman SA, Wispelway B: Cryptococcal optic neuropathy in the acquired immune deficiency syndrome. J Clin Neuroophthalmol 1991;11:96-103.
I Manolette Rangel Roque and C. Stephen Foster
Sporotrichosis is a chronic infectious disease caused by the filamentous branching fungus Sporothrix schenckii (Sporotrichum schenckii). It is characterized by subcutaneous, nodular granulomata, which are usually acquired by traumatic implantation through the skin. Ocular involvement ranges from simple conjunctivitis to fuhninant endophthalmitis.
The reported literature on sporotrichosis dates back to the turn of the 20th century. In 1809, Link, cited by Gordon,I described the genus Sporotrichum primarily as a saprophyte on wood. Schenck reported the first described clinical case in 1898. 2 He described a typical lesion occurring on a finger, followed by the formation of a nodular chain. As a result of his research, his name was attached to the organism. The first reported case of S. schenckii involving the eye or its adnexa was published in 1907 by Danlos and Blanc. 3 In that same year, DeBeurmann, Gougerot, and Laroche 4 cited a similar case with lid involvement. The first reported case of intraocular S. schenckii was published in 1909. 5 Morax then first isolated ocular S. schenckii in 1914. 6 In the 1940s, a large outbreak of nearly 3000 cases occurred in South African gold mines as a result of contaminated timber beams. 7 The latest reported case occurred in a patient with acquired immunodeficiency syndrome (AIDS) who had disseminated sporotrichosis with extensive cutaneous involvement. s
sippi rivers. This fungus is common in Mexico and Central America. It is a common saprophyte found in natural vegetation (soil,9-11 plants, thorns, wood, straw, reeds,7 etc.). There is a consequent high incidence of infection involving gardeners,I2 forestry workers,I3 agricultural workers, miners, meat packers, and sphagnum moss handlers. 14 Sporotrichosis also can be inoculated by insect stings, animal bites, and cat scratches, or by handling of contaminated fish. Pathogenic sporotricha have also been isolated from the hair of horses and other domestic animals and their excreta. I5
Mycology Sporothrix schenckii lives as a saprophyte on plants in many areas of the world. In nature and on culture at room temperature (25°C), the fungus grows as a beige-colored leathery mold that darkens to black with age (Figs. 32-1 and 32-2), but within host tissue or at 37°C on enriched media, it grows as a budding, cigar-shaped yeast (Fig. 32-3). It is identified by its appearance in mold and yeast forms I6 ,I7 (Figs. 32-4 and 32-5). The hyphae are 2 f-Lm in width; they are segmented and branched and produce oval conidia, which range from 2 to 6 f-Lm in longest diameter. IS
CLINICAL CHARACTERISTICS
Nonocular Disease
Sporothrix schenkii is distributed worldwide but is common in tropical or temperate regions. In the United States, the .majority of cases have been found in the Midwestern river valleys, especially those of the Missouri and Missis-
Lymphocutaneous infection is the most common form of sporotrichosis. 9, 10 At the site of entry (usually the hands), a small, painless, pink or purple, verrucous, nodular or ulcerative cutaneous lesion develops anytime from 1 week to several months later. It is a chronic subcutaneous nodular granuloma, usually with spreading lymphatic involvement, following trauma. The nodules may ulcerate and discharge a small amount of serosanguineous exudate.
FIGURE 32-1. Young colonies of Sporothrix schenckii remain white for some time at 25°C or when incubated at 37°C to induce its yeast phase. (Reprinted from http://Jungllsweb. utmb. edu/mycology/sporothrix. html, with permission from Medical Mycology Research Center, Depattment of Pathology, University of Texas Medical Branch.) (See color insert.)
FIGURE 32-2. Older colonies of Sporothrix schenckii turn black due to the production of dark conidia that arise directly from the hyphae. (Reprinted from http://fungusweb.utmb.edll/mycology/sporothrix.html, ,vith permission from Medical Mycology Research Center, Department of Pathology, University of Texas Medical Branch.) (See color insert.)
CHAPTER 32: SPOROTRICHOSIS
FIGURE 32-3. Sporothrixschenckii has a yeast form at 37°C. (Reprinted from http://fungusweb. utrnb.edu/mycology/sporothrix.htrnl, with permission from Medical Mycology Research Center, Department of Pathology, University of Texas Medical Branch.)
FIGURE 32-4. Conidia arising directly from the hyphae, and conidia arising on denticles from sympodial conidiophores are typical of Sporothrix schenckii. (Reprinted from http://fungusweb. utmb.edu/mycology/sj)orothrix.html, with permission from Medical Mycology Research Center, Department of Pathology, University of Texas Medical Branch.)
The primary lesion remains "fixed" in 23% of cases, without lymphatic involvement,19 originating from the extremities or the face, and persisting for years. These localized cutaneous lesions without lymphatic spread may appear nodular, crusted, weeping, or fungating or may resemble papillomata, folliculitis, or intertrigo. Sporotrichosis may be limited to the site of inoculation (plaque sporotrichosis) and manifests ctp a nontender, red, maculopapular granuloma, without associated systemic signs and symptoms. Disseminated sporotrichosis (lesions in more than one organ system) occurs after hematogenous 2o ,21 spread from a primary pulmonary or subcutaneous site, in an immunocompromised 22 host. When it occurs, it most commonly affects bones and joints. 9, 10 Reported manifestations of extracutaneous or disseminated sporotrichosis include fungal tendinitis, bursitis, arthritis, osteomyelitis, diffuse skin lesions, meningitis, ocular infection, and vocal cord granulomata. It has been observed in association
with corticosteroid use, sarcoidosis, diabetes mellitus, alcoholism, neoplasia, and AIDS.s, 22 Multifocal cutaneous sporotrichosis (skin infection beyond a single extremity) is extremely common in cases of dissemination. Except for a rilre primary pulmonary23 form of infection in which the organism is inhaled in endemic areas or by an immunocompromised host, sporotrichosis most commonly enters the body through the skin, usually in association with some episode of tralunatic implantation. Symptoms include the insidious onset of cough, sputum production, malaise, weight loss, low-grade fever, and occasional hemoptysis. A single, chronic, cavitary upper lobe lesion and hilar adenopathy are usually revealed on chest x-ray. 12 In the rare instance that the central nervous system is involved, focal or diffuse neurologic symptoms and headache and confusion may be present. An unusual case of lymphocutaneous sporotrichosis was seen in a man who engaged in self-tattooing of his
Conidiophore
Denticle
FIGURE 32-5. Sporothrix schenckii. (Reprinted from
Microconidia
http://www. asrnusa. org/edusrc/ library/ irnages/SMITH/ bnages/TMAGE1-ANJPG, with permission from Andrew G. Smith, M.D., and the AnIerican Society for Microbiology Instructional Library.)
"Fiowerettes", hyphae and conidia, diagnostic of Sporothrix
CHAPTER 32: SPOROTRICHOSIS
left foot. 24 He admitted to having mowed the lawn wearing only sandals on the same day that he tattooed his foot. Sporotrichosis can be seen in patients with other systemic illnesses. Three cases of coinfection with Leishmania have been described in Columbia. 25 The use of empirical treatments for leishmaniasis, such as poultices or puncturing of the lesion with thorns or wood splinters, was speculated to have caused the introduction of the Sporothrix. A woman with Cushing's disease presented with erysipeloid sporotrichosis. 26
Ocular Disease
In 1966, Alvarez and Lopez-Villegas 27 reported an ll-yearold mestizo boy with primary ocular sporotrichosis. The diagnosis was based on mycologic study of the biopsied left temporal bulbar conjunctiva. Conjunctival sporotrichosis may be a primary infection or may be secondary to involvement of the lid and face. The initial sign of infection in the skin of the eyelid is the appearance of a hard, spherical, movable, nontender nodule that later becomes attached to the skin. It is initially pink, then purple, and finally black and necrotic (sporotrichotic chancre). Multiple subcutaneous nodules appear along the course of the lymphatics draining the area. Numerous soft, yellow, granulomatous nodules, which may ulcerate, develop in the palpebral or bulbar conjunctiva of the involved eye. The conjunctival ulcers usually discharge a small amount of purulent material. Gross enlargement and occasional suppuration of preauricular and submandibular l)'lnph nodes occur. '0/ Most cases of ocular sporotrichosis· have an exogenous cause and are acquired through a traumatic injury to the conjunctiva,· cornea, or eyelids by a contaminated object. Witherspoon and associates 39 reported a case of exogenous S. schenckii endophthalmitis in a 13-year-old boy who was struck in his eye with a stick. They also reviewed previous cases of exogenous and endogenous ocular sporotrichosis, citing older reviews by Gordon in 1947, and Francois and Rysselaere in 1972. Most cases in the 1947 review were exogenous and involved the eyelids, conjunctiva, cornea, lacrimal excretory system, or orbit. But 14 of the 18 cases of intraocular sporotrichosis reported in the 1972 review were endogenous, resulting from disseminated sporotrichosis. The other 4 were cases of postoperative exogenous S. schenckii endophthahnitis following cataract surgery. Presenting s)'lnptoms in endogenous S. schenckii endophthalmitis include decreased vision, pain, and ocular redness. Most cases have signs of anterior segment inflammation, including granulomatous or nongranulomatous keratic precipitates, iris nodules, and hypopyon. Later sequelae may include posterior s)'l1.echiae, glaucoma, cataract, and phthisis bulbi. Posterior segment involvement may be manifested by choroiditis, vitritis, or a fluffy white retinal lesion. These latter cases of endogenous sporotrichosis can masquerade as idiopathic panuveitis or posterior uveitis; hence, it is important that the ophthalmologist keep in mind this and other causes of endogenous infectious uveitis. In 1993, Cartwright and coworkers 28 reported a 24year-old black male with S. schenckii endophthalmitis who presented without a history of trauma or systemic infec-
tion and was originally diagnosed with granulomatous uveitis that resulted in scleral perfo:ration. Most patients with endogenous S. schenckii endophthalmitis eventually require enucleation. One problem is that it is difficult to culture the organism from blood, urine, or intraocular fluids. Several cases in the Witherspoon study39 were not accurately diagnosed until enucleation had been performed. In addition, most of the previously reported cases occurred before amphotericin B or modern vitreoretinal surgical techniques were available. A recent case of endogenous S. schenckii endophthahnitis involved a 30-year-old man with AIDS and disseminated sporotrichosis. He had a granulomatous uveitis that worsened following topical and subconjunctival corticosteroid therapy. An aqueous aspirate was positive for S. schenckii, and the patient received treatment with intravitreous and intravenous amphotericin B. The patient's intraocular inflammation worsened despite negative repeat aqueous and vitreous cultures, and enucleation was eventually required.
PATHOLOGY Pathogenesis Traumatic implantation is the main mechanism for infection. Strains that multiply well at 25°C but poorly at 37°C can produce cutaneous lesions. Strains that multiply at both 25°C and 37°C are capable of producing lymphocutaneous or visceral disease. However, inhalation of spores is also known to cause a pulmonary form of disease.
Histopathology Histopathologic and electronmicroscopic examination of an eye with sporotrichosis reveals suppuration and granulomata, occasionally with caseating necrosis. Organisms morphologically compatible with S. schenckii have been demonstrated in the anterior chamber, vitreous cavity,29 retina,30 subretinal space, and retinal piglnent epithelium. 31 Additional histopathologic findings in other patients with S. schenckii endophthalmitis include a granulomatous necrotizing chorioretinitis 31 and intracellular fungi 32 within inflammatory cells. Scattered S. schenckii organisms with disrupted protoplasm 30 may occasionally be seen.
Immunology Historical attempts to demonstrate a positive reaction to the agglutination test have been dispelled by the fact that the spores have been similarly agglutinated by the serum of normal controls. S. schenckii can bind to fibronectin, laminin, and type II collagen; the organisms also show differences in binding capacity according to the morphologic form of the fungus. 33 The virulence of S. schenckii conidia may be determined by their cell wall composition. 34 Modern research has attempted to give the organism a molecular persona. Cell-mediated immunity is important in determining the extent of disease. S. schenckii is processed chiefly by the cellular limb of the immune system; therefore, the relative integrity of the cellular immune system will influence whether the disease remains localized or becomes disseminated.
CHAPTER 32: SPOROTRICHOSIS
The organism is rarely seen on direct examination of tissue. The positive diagnosis of sporotrichosis relies on the identification of the organism. 1 The most reliable means of identification is by culture. It grows well on Sabouraud's glucose agar or blood agar at 25°C. It is resistant to cycloheximide; therefore, Mycosel or Mycobiotic agar may be used for culture. Colony morphology is variable and may be white or pigmented, creamy, or shiny, depending on the strain and specimen type. Animal inoculation may also be performed for specific identification. S. schenckii can be very difficult to isolate frOlll blood, urine, or ocular fluid, thereby necessitating repeated diagnostic aqueous and vitreous aspiration and culture to isolate the organism. If there is another site of infection, such as a cutaneous lesion or fungal arthritis, biopsy or aspiration of that site with culture may be helpful. Careful examination of Gram's, periodic acid-Schiff, or Gomori methenamine silver stain, as well as immunofluorescence histologic studies of a tissue specimen, may reveal organisms, even when the cultures are negative. Also, specific serologic tests are available to identify antibodies to S. schenckii in blood or body fluid. Immunodiffusion, enzyme-linked immunosorbent assay (ELISA), or Western immunoblot testing can be performed on aqueous or vitreous fluid as well. Gallium and bone scans have been helpful in localizing areas of involvement in patients with disseminated sporotrichosis. Despite the well-known difficulties in determining an accurate and timely diagnosis, fine-needle aspiration cytology, l~ter confirmed by tissue biopsy and culture study, was performed and reported in 1999. 35
DIAGNOSIS Before the chain of lesions develops, there is nothing characteristic of the presentation that suggests sporotrichosis. Once the ulcers or chain of nodules appears, sporotrichosis should be suspected. All other causes of granulomatous lesions, however, should be investigated. Syphilis and tuberculosis may be ruled out on the basis of the clinical pictures and the specific lesions seen at biopsy and laboratory testing. Leprosy must also be excluded. In cases of conjunctival involvement, Parinaud's conjunctivitis should be considered and excluded. Other differentials worthy of consideration include causes of severe granulomatous inflammation such as sarcoidosis and fungal endophthalmitis caused by other organisms. The approach to treatment of sporotrichosis varies with the disease form. Administration of saturated solution of potassium iodide (SSKI) 1,36 is the treatment of choice for cutaneous disease. Oral potassium iodide is an effective, inexpensive treatment that has been the standard regimen for decades. Its antifungal effect is not well understood, and it has no direct effect on S. schenckii. It is taken orally in milk at an initial dose of 5 drops three times daily, increased by 4 to 5 drops per day up to 12 to 18 mllday12 (l drop equals 50 lull), or until signs of toxicity occur (e.g., lacrimation, salivation, parotid gland swelling, indigestion). When toxicity develops, the therapy should be stopped for a few days and restarted at a lower dose.
Local application of heat to the lesions may be helpful. A pustular, acneiform rash over the face and cape area of the trunk is not an infrequent finding, but it is not an indication to discontinue iodides; To avoid recurrence iodides should be continued for 4 to 6 weeks after clinical resolution. Disseminated or extracutaneous sporotrichosis is usually treated with intravenous amphotericin B (0.5 mg/ kg/ day). Flucytosine 37 has been effective in treating disseminated disease. Itraconazole is also very effective against both S. schenckii (in vitro) and disseminated sporotrichosis. Treatment with itraconazole has resulted in response rates of greater than 90%. As a result, itraconazole (200 mg once or twice daily) 17 is likely to become the drug of choice for both disseminated and nondisseminated forms of sporotrichosis, as most patients do not accept oral potassium iodide. 38 The patient presented by Witherspoon and associates 39 had exogenous S. schenckii endophthalmitis, and it was the first case to be successfully treated. The patient underwent pars plana lensectomy and vitrectomy, received topical amphotericin B, and had a repeat vitrectomy with injection of intravitreous amphotericin B. This was the first reported case of S. schenckii endophthalmitis treated with vitrectomy. The patient's vision improved frOlll light perception to 20/50. All previous cases of endogenous and exogenous S.schenckii endophthalmitis had resulted in enucleation. Successful treatment of endogenous S. schenckii endophthalmitis has not been reported.
PROGNOSIS Sporotrichosis in its cutaneous, lymphocutaneous, and mucocutaneous forms remits and relapses over years without therapy.12 Spontaneous cure has been reported in plaque sporotrichosis. 40 Most patients with sporotrichosis respond well to treatment, even when the disease has reached a fairly advanced state, provided that the deeper structures of the body are not yet involved. Involvement of the globe is evidence of deep invasion and indicates that the organism has reached the blood stream, unless a history has been elicited of direct perforation by the traumatizing and etiologic agent. 1
A high index of suspicion of the clinical entity of sporotrichosis is needed if a properly conducted early laboratory diagnosis is to be achieved. Positive diagnosis of sporotrichosis relies on identification of the organism. The most reliable means of identification is by culture. The treatment of choice for the cutaneous presentation is potassium iodide in its soluble form. For extracutaneous forms, aggressive treatment using systemic antifungal agents (amphotericin B and/or itraconzole), pars plana vitrectomy, and intravitreous amphothericin B is warranted.
References 1. Gordon DM: Ocular sporotrichosis. Arch Ophthalmol 1947;37:56. 2. Schenck BT: On refractory subcutaneous abscesses caused by a fungus, possibly related to the Sporotrochia. Bull Johns Hopkins Hosp 1898;9:286, as cited by Gordon DM: Ocular sporotrichosis. Arch Ophthalmol 1947;37:56. 3. Gordon DM: Ocular sporotrichosis. Arch Ophthalmol 1947;37:56.
CHAPTER 32: SPOROTRICHOSIS 4. DeBeurmann CL, Gougerot H, a11d Laroche: Gomme de 1£1 paupiere. Bull Mem Soc Med Hop Paris 1907;27:1046, as cited by Gordon DM: Ocular sporotrichosis. Arch Ophthalmol 1947;37:56. 5. DeBeurmann CL, Gouge-at H: Sporotrichose cachectisante martelle. Bllll Mem Soc Med Hop Paris 1909;26:1046, as cited in Duanes's Ophthalmology on CD-ROM. Philadelphia, LippincottRaven, 1996. 6. Morax V: Uveite sporotrichosique avec gomme sporotrichosique episclerale secondaire: Absence de route autre localization sporotrichosique decelable. Ann Ocul 1914;152:273, as cited in Duanes's Ophthalmology on CD-ROM. Philadelphia, Lippincott-Raven, 1996. 7. Mackenzie DWR: Subcutaneous mycoses. In: Stricldand GT, ed: Hunter's Tropical Medicine, 7th ed. Philadelphia, WB Saunders, 1991, pp 510-515. 8. Ware AJ, Cockerell q, Skiest DJ, Kussman HM: Disseminated sporotrichosis with extensive cutaneous involvement in a patient with AIDS. J Am Acad Dermatol 1999;40(2.2):350~355. 9. Wilson DE, Mann.IT, BennettJE, UtzJP: Clinical features of extracutaneous sporotrichosis. Medicine 1967;46:265. 10. Lynch PJ, Voorhees.IT, Harrell ER: Systemic sporotrichosis. Ann Intern Med 1970;73:23. 11. Chang AC, Destouet JM, Murphy WA: Musculoskeletal sporotrichoc sis. Skeletal Radial 1985;12:23. 12. Albert DM,Jakobiec FA, eds: Principles and Practice of Ophthalmology, on CD-ROM. Philadelphia, WB Saunders, 2000. 13. Powell KE, Talor A, Phillips BJ, et £11: Cutaneous sporotrichosis in forestry workers. Epidemic due to contaminated sphagnum moss. JAMA 1978;240:232. 14. Dixon DM, Salkin IF, Duncan RA, et £11: Isolation and characterization of Sporothrixschenchii from clinical and environmental sources associated with the largest U.S. epidemic of sporotrichosis, J Clin Microbial 1991;29:1106-1113. 15. McGrath H, Singer JI: Ocular sporotrichosis. Am J Ophthalmol 1952;35:102. 16. Pettit TH, EdwardsJEJr, Purdy EP, BullockJD: Endogenous fungal endophthalmitis. In: Pepose JS, Holland GN, Wilhelmus KR, eds: Ocular Infection and Immunity, 1st ed. Ml;ssouri, Mosby, 1996, pp 1278-1281. 17. Bennett JE: Miscellaneous mycoses and prototheca infections. In: Harrison TR, Resnick WR, Wintrobe MM, Thorn GW, et £11, eds: Harrison's Principles of Internal Medicine, 14th ed, on CD-ROM. New York, McGraw-Hill, 1998. 18. Rippon JW: The pathogenic fungi and the pathogenic Actinomycetes. In: Medical Mycology, 3rd eel. Philadelphia, WB Saunders, 1988. 19. BennettJE: Sporothrix schenchii. In: Pepoose JS, Holland GN, Wilhelmus KR, eds: Ocular Infection and Immunity. Missouri, Mosby-Year Book, 1996, p 1278. 20. Satterwhite TK, Kagler WV, Conklin RH, et £11: Dissemil1ated sporotrichosis. JAMA 1978;240:771. 21. Matthay RA, Greene WH: Pulmonary infections in the immunocom-, promised patient. Med Clin North Am 1980;64:529.
22. Bibler MR, Luber JH, Glueck HI, Estes SA: Disseminated sporotrichosis in a patient with HIV infection after treatment for acquired factor VIII inhibitor. JAMA 1986;256:3125. 23. Michelson E: Primary pulmonary sporotrichosis. Ann Thorac Surg 1977;24:83. 24. Bary P, Kuriata MA, Cleaver LJ: Lymphocutaneous sporotrichosis: A case report and unconventional source of infection. Cutis 1999;63(3) :173-175. 25. Agudelo SP, Restrepo S, Velez ID: Cutaneous New World leishmaniasis-sporotrichosis coinfection: Report of 3 cases. J Am Acad Dermatol 1999;40(6.1):1002-1004. 26. Kim S, Rusk MR, James WD: Eysipeloid sporotrichosis in a woman with Cushing's disease. J Am Acad Dermatol 1999;40(2.1) :272-274. 27. Alvarez RG, Lopez-Villegas A: Primary ocular sporotrichosis. Am J Ophthalmol 1966;62(1):150-151. 28. Cartwright MJ, Promersberger M, Stevens GA: Sporothrix schenchii endophthalmitis presenting as granulomatous uveitis. Br J Ophthalmol 1993;77:61-62. 29. Cassady JR, Foerster HC: Sporotrichum schenchii endophthalmitis. Arch Ophthalmol 1971;85:71. 30. Kurosawa A, Pollock SC, Collins MP, et £11: Sporothrix schenchii endophthalmitis in a patient with human immunodeficiency virus infection. Arch Ophthalmol 1988;106:376-380. 31. Font RL, Jakobiec FA: Granulomatous necrotizing retinochoroiditis caused by Sporotrichum schenhii: Report of a case including immunofluorescence and electron microscopical studies. Arch Ophthalmol 1976;94:1513. 32. Brod RD, Clarkson JG, Flynn HW Jr, et £11: Endogenous fungal endophthalmitis. In: Duane TD, Jaeger EA, eds: Clinical Ophthalmology, vol 3. Hagerstown, MD, Harper & Row, 1990. 33. Lima OC, Figueiredo CC, Pereira BA, et £11: Adhesion of the human pathogen Sporothrix schenchii to several extracellular matrix proteins. BrazJ Med BioI Res 1999;32(5):651-657. 34. Fernandes KS, Matthews HL, Lopes Bezerra LM: Differences in virulence of Sporothrix schenchii conidia related to culture conditions and cell-wall components. J Med Microbial 1999;48(2):195-203. 35. Zaharopoulos P: Fine-needle aspiration cytologic diagnosis of lymphocutaneous sporotrichosis: A case report. Diagn Cytopathol 1999;20(2):74-77. 36. Wescott BL, Nasser A, Jarolim DR: Sporothrix meningitis. Nurse Pract 1999;24(2):90, 93-94, 97-98. 37. Shelley WB, Sica PA JR: Disseminated sporotrichosis of skin and bone cured with 5-fluorocytosine: Photosensitivity as a complication. J Am Acad Dermatol 1983;8:229. 38. Wescott BL, Nasser A, Jarolim DR: Sporothrix meningitis. Nurse Pract 1999;24(2) :90, 93-94, 97-98. 39. Witherspoon DC, Kuhn F, Owens D, et £11: Endophthalmitis due to Sporothrix schenchii after penetrating ocular injury. Ann Ophthalmol 1990;22:385-388. 40. Bargman HB: Sporotrichosis of the nose with spontaneous cure. Can Med AssocJ 1981;124:1027.
Andrea Pereira Da Mala and Fernando Orefice
Toxoplasmosis is caused by the obligate intracellular protozoan Toxoplasma gondii. It has a universal distribution and a high serologic prevalence in all countries, but the incidence of Toxoplasma-induced disease is much lower. Although it affects humans and animals, the feline species is the only definitive host. Toxoplasmosis is the most common cause of posterior uveitis in the world,r-3 accounting for over 80% of the cases in some regions. 4,5 Recurrence of congenitally acquired toxoplasmosis,once blamed for almost all cases, is still the leading cause of Toxoplasma retinochoroiditis, but it is becoming increasingly clear that acquired ocular disease is more common than previously suspected. 6- 17 Although active Toxoplasma retinochoroiditis usually has a self-limiting course in immunocompetent patients, it can recur and lead to irreversible visual loss should ocular structures critical to good vision (the macula and the optic nerve) be involved. In the immunosuppressed host, Toxoplasma infection poses unique diagnostic and therapeutic challenges.
HISTORY Toxopla~ma gondii was discovered independently by two investigators in 1908. Alfonso Sp~endore in Brazil identified the organism in laboratory rabbits,18, 19 while Charles Nicolle and Louis Manceaux in Tunis observed the organism in the North Mrican rodent Ctenodactylus gondii. Nicolle and Manceaux named the parasite Toxoplasma gondii: Toxoplasma from the Greek word toxon, meaning arc, describing the small crescent shape of the parasites, and gondii from the animal in which it was found. 20 , 21 Both papers agreed in most of their observations, but it was Splendore who identified the schizogenous form of reproduction and the formation of true cysts. In the same year, Darling unwittingly described systemic toxoplasmosis at the Gorgas Hospital in PanalTIa. He reported a patient with acute myositis, but misdiagnosed it as sarcosporidiosis. Years later, Chaves-Carballo and Samuel reexamined the biopsy samples and concluded that the parasite was T. gondii. 22 Other reports followed, including Castellani (Ceylon, 1914) who attributed a case of fever and splenomegaly to a protozoan, which at the time he named Toxoplasma pyrogenes. 23 The first description of congenital toxoplasmosis with ocular involvement is attributed to JankCt. (Prague, 1923), who reported an II-month-old infant with hydrocephalus, microphthalmia, and a retinal "coloboma" in the macular region. Histopathologically, JankCt. identified an oval sporocyst containing numerous dark sporozoites within the outer layer of the choroid in this "colobomatous area. "24 The first photographic documentation of ocular toxoplasmosis was made in Brazil by Belfort Mattos in 1933 (Fig. 33-1). Acquired toxoplasmosis with ocular manifestations was not described until 1940, when Pinkerton and Weinman noted retinal lesions in a young adult with generalized disease. 25 Wilder demonstrated T. gondii
in stained sections of eyes with "intractable chorioretinitis." This resulted in a shift in the diagnostic mentality of posterior uveitis from tuberculosis being the most COlTImon agent to Toxoplasma as an important cause of posterior uveitis. 26 Diagnostic testing for toxoplasmosis was first attempted by Nicolau and Ravelo (1937), who used a complement fixation test to demonstrate the existence of anti- Toxoplasma antibodies. 27 However, their test proved to be of low reliability. The introduction of the Sabin-Feldman test in 1948 provided a sensitive and specific method for the detection of antibodies against T. gondii, allowing epidemiologic studies to be conducted. By 1960, toxoplasmosis was identified as the most common cause of posterior uveitis in the world. 28 It was not until 1970 that the feline species, primarily the domestic cat, was identified as the definitive host of T. gondii. 29 ,30
The Organism T. gondii is an obligate intracellular parasite that can be found in the host's tissues and body fluids, such as saliva, milk, semen, urine, and peritoneal fluid. The morphology of the T. gondii varies depending on the stage of the life cycle and habitat. It can present in three forms: the tachyzoite, bradyzoite, and sporozoite. The tachyzoite, also called trophozoite, is the infectious form responsible for the acute phase of the disease. It is approximately 3 by 7 /-Lm in length and 2 to 4 ~m in diameter, and it has the shape of a crescent. It was the form first observed by Nicolle and Manceaux that inspired the genus name Toxoplasma (Fig. 33-2). The tachyzoite, an obligate intracellular form, may enter the cytoplasmic vacuoles of any nucleated cell. It is mobile and quickly multiplies by endodyogeny until the cell ruptures, releasing more tachyzoites to infect other cells.
FIGURE 33-1. First photographic documentation of ocular toxoplasmosis. Taken by Waldemar Belfort Mattos, Brazil, 1933. (Courtesy of Rubens BelfOl~t Mattus Jr., M.D., Ph.D., UNIFESP, Brazil.)
CHAPTER 33: TOXOPLASMOSIS
FIGURE 33-2. Scanning electron photomicrograph of Toxoplasma 'gondii tachyzoites. (Courtesy of Rubens Belfort Mattos Jr., M.D., Ph.D., UNIFESP, Brazil.)
The tachyzoite encysts at the first sign of environmental stress such as the host immune response or the presence of antibiotic. The encysted form, known as the bradyzoite, begins to appear as soon as 1 week following infection. Bradyzoites divide slowly inside the cellular vacuole, which eventually becomes part of the cyst's capsule. The wall of a mature cyst is composed of a cOlubination of both host and parasitic components, so the bradyzoites are protected from the host's immune system. The cysts are very resistant and can remain dormant in "i' the host for years without tissue damageY Cysts have a predilection for tissues such as the retina, skeletal muscles, the central nervous system, and the heart, and they persist for the life of the host. They are approximately 10 to 100 fJvm in size and may contain up to 3000 bradyzoites (Fig. 33-3) .32 For reasons unknown, the cysts may rupture, causing reactivation of the disease and intense inflammation. Oocysts are produced only in the feline intestinal cells and are excreted in the feces. The oocyst is the most resistant form of the organism and may remain infectious
for up to 2 years in warm, moist soil. 32 They are oval and measure 10 to 12 fJvm in diameter. Within 1 to 21 days after shedding, the oocysts undergo sporulation and become mature, infective oocystS. 33 These mature forms contain two sporocysts, each of which contains four sporozoites. The ingestion of mature oocysts can cause infection in either an intermediate or the definitive host. Sporulation does not occur below 4°C or above 37°C, thus explaining the lower incidence of toxoplasmosis in areas with extreme temperatures.
life Cycle The life cycle of T. gondii is composed of two distinct phases: the asexual phase, which occurs in all hosts, and the sexual phase that happens only in the intestinal epithelium of the definitive host. Felines, especially domestic cats, are the only definitive host and they sustain both sexual and asexual reproduction. Humans and many other animals, such as cattle, pigs, sheep, and poultry, support asexual reproduction of T. gondii and constitute the intermediate host group.
FIGURE 33-3. Transmission electron photomicrograph of Toxoplasma gondii tissue cyst in mouse brain. (Courtesy of Fausto Araujo, Ph.D., United States.)
CHAPTER JJ: TOXOPLASMOSIS
The asexual cycle starts when a susceptible host ingests mature oocysts, tissue cysts contain bradyzoites, or tachyzoites are present in body secretions and raw meat. Tachyzoites that reach the stomach are destroyed by gastric acid, but. tachyzoites are very active and may penetrate the oral mucosa. Digestive enzymes break down the walls of both oocysts and tissue cysts, releasing sporozoites and bradyzoites. These organisms then enter cells of the intestinal tract and transform into rapidly multiplying tachyzoites that rupture the cells, releasing free tachyzoites. Extracellular tachyzoites or tachyzoites within leukocytes are transported throughout the body via the lymphatic system and bloodstream, and they can invade any organ or tissue. This initial infection characterizes the acute phase of the disease. Once infected, the host produces specific antibodies, which bind to the extracellular tachyzoites, initiating immune-mediated eradication of the free parasite. However, humoral immunity is ineffective against intracellular parasites and the cellular immune response is called upon to attack the parasitized cells, reducing intracellular multiplication and causing the tachyzoites to encystY When the immune system has eliminated the tachyzoites, symptoms disappear, and the chronic phase ensues. The sexual cycle takes place exclusively in the feline intestine, and it is unclear why this phase occurs only in members of the cat family. Cats may initially become infected by eating contaminated meat containing tissue cysts or by ingesting sporulated oocysts. In the cat's intestine, the tachyzoites invade the ~pithelial cells and start to multiply by schizogony. During this process, gametocytes are formed and fertilized to produce oocysts. The time interval between the infection and the appearance of oocysts in the feces depends on the form of the organism ingested and varies from 3 to 24 days. Excretion continues for up to 20 days, with shedding of as many as 12 million oocysts in a single day. In general, once a cat has cleared the initial infection it will not shed oocysts again. However, if the cat becomes infected with Isospora felis, recurrent oocyst shedding may occur. 34
Transmission The main mechanism of human infection is by ingestion of tissue cysts in raw or undercooked meat. In the United States, evidence of bradyzoites is seen in approximately 10% to 20% of lamb products and 25% to 35% of pork products, whereas the incidence in beef is only about 1%.35 Food may also be contaminated with oocysts, especially through dissemination by insects and by food handlers. The second important route of infection is contact with any material contaminated by infected cat feces, such as soil and cat litter. This may result in accidental ingestion or inhalation of oocysts. Infection may also be acquired through ingestion of unpasteurized goat's milk, raw eggs, or unwashed vegetables; transfusion of blood or leukocytes; organ transplantation; and laboratory accidents. 34--38 Transplacental transmission Inay occur if a woman is initially infected just before or during pregnancy. Women with positive serology before pregnancy have little or no chance of infecting their fetuses, although on rare occasions, women with chronic latent infection and per-
sistent parasitemia may have one or more affected children. 39 : 4o Reactivation of ocular toxoplasmosis during pregnancy does not increase the risk of congenital transmission in an immunocompetent woman,4l
As an obligate intracellular pathogen, T. gondii's reproductive success depends on its ability to penetrate host cells and evade cellular defenses. The tachyzoites actively secrete penetration-enhancing factors (PEFs) that interact with the cellular phospholipid bilayer and allow the organism to invade eukaryotic cells within 5 to 10 seconds. 42-44 During this active penetration, the tachyzoites become enveloped by part of the. cell membrane, inducing a new subcellular organelle, the parasitophorous vacuole. The tachyzoites induce molecular and morphologic changes in the parasitophorous vacuole, which prevent acidification and fusion with cellular lysozomes. 42 , 45-49 Maintenance of an alkaline pH (7.0 to 8.0) inside the vacuole is one of the main mechanisms that enable survival and replication of the tachyzoites. The activation of B cells and the humoral immune response is the first step toward control of the Toxoplas17w infection; this consists of the production of antiToxoplasma-specific immunoglobulin M (IgM), IgA, IgE, and IgG antibodies. Antibody binding to tachyzoites can result in lysis by the classical complement pathway, but more important, antibody-coated tachyzoites are unable to actively penetrate cells. Instead, these opsonized tachyzoites are recognized by phagocytic cells and are engulfed into phagolysosomes, resulting in destruction of the parasite. 49 ,50 Although the humoral response is important, it is not sufficient to eradicate the intracellular organism. Cellmediated immunity is the major mechanism involved in the resolution of the active disease,5l Indeed, a significant feature of the toxoplasmosis infection is the strong and persistent cellular immunity induced by the parasite. Evidence for the importance of cell-mediated immunity comes from immunocompromised patients in whom primary infection or reactivation of chronic T. gondii cysts often results in disseminated disease with a high mortality.52 The cellular immune response is characterized by activation of macrophages, natural killer (NK) cells, and T cells, and release of their cytokines. Macrophages are activated following phagocytosis of antibody-opsonized T. gondii, and they initiate the imlnune response by producing interleukin 12 (IL-12) and tumor necrosis factor alpha (TNF-a) .53,54 These monokines stimulate CD8 + T lymphocytes and NK cells to produce interferon-')' (IFN-')') .55 IFN-')' plays a key role in the immune response to T. gondii by enhancing the microbicidal activity of the macrophage. 55 ,56 Activated macrophages use toxic oxygen and nitrogen intermediates as well as products of arachidonic acid metabolism to enhance killing intracellular T. gondii. Other evidence suggests that IFN-')' Inay inhibit replication of Toxoplasma by tryptophan starvation in retinal pigment epithelial cells. 57 Monokines released by macrophages also stimulate CD4 + Th1 cells to produce IL2, which in turn activates cytotoxic T cells and NK cells to attack cells infested with T. gondii and free tachyzoites.
CHAPTER 33: TOXOPLASMOSIS TABLE 33-1. NAME
SAG1 SAG2 SAG3 GRA1 GRA2 GRA3 GRA4 GRA5 . ROP1 ROP2 MIC1 TUB1 TUB2
DTS1 NTP1
OF TOXOPLASMA GONDII GENES CLONED AND CHARACTERIZED THUS FAR OTHER NAMES
LOCALIZATION
KDA (SDS.PAGE)
REFERENCE
P30 P22 P43 P23, P27 P28
Surface Surface Surface Dense granule Dense granule Dense granule Dense granule Dense granule Rhoptry Rhoptry Micronemes Microtubules Microtubules
30 22 43 22, 23, 27 28, 28.5 30 40 21 60,60.5 54, 55 60
Secretory
63
172-175 173, 174, 176 173, 174, 177 178, 180 179,181-183 180, 184 180, 185 179, 186 183, 187 183, 188 189, 190 191 191 192 193, 194
P21 PEF P54, TG34 Alfa-tubulin Beta-tubulin DHFR NTPase
Modified from Joincr KA: Cell entry by Toxoplasma gondii: All paths do not lead to success. Res ImmunoI1993;144:34-38.
Conversely, stimulated CD4 + Th2 cells produce IL-4, IL5, and IL-I0, which modulate the activity of the cellmediated immune responses to prevent an excessive inflammatory response. 55 The inflammatory reactions in the eye are generally modified, because the eye is an immunologically privileged site; thus, the local ocular immune response tends to be suppressed to limit tissue damage. In the eye, inflammatory reactions are dominated by CDS + T cells and CD4 + Th2 cells due to constitutive expression of anti-inflammatory factors such as F~s, Fas ligand, and tumor growth factor beta (TGF-13).· T. gondii, however, seems to promote the production of factors, such as IFN-l' that abrogate this immune privilege. 55 , 58 The Toxoplasma organism has developed another strategy to evade host defenses. When tachyzoites encyst, the tissue cysts become invisible to the immune system, because the cyst wall incorporates cellular components derived from the host and thus is recognized as itself. Cysts may remain dormant for an indefinite period. Factors modulating the reactivation of cysts are poorly understood, but it seems· relatively clear that IFN-l' helps to prevent reactivation of chronic toxoplasmosis, possibly by inhibiting cyst rupture. 55 ,59 Immunosuppression, however (particularly the depletion of T-helper cells), allows the breakdown of tissue cysts and thus tachyzoite proliferation. Advances in the field of cellular biology of T. gondii have made possible the identification and purification of many cell surface antigens or secreted antigens from the tachyzoites (Table 33-1). The major surface antigen P30, for example, appears to have an important role in both immune and pathogenic mechanisms of the parasite. P30 may beinvolved in antibody-dependent, complement..,mediated lysis of the tachyzoites. 60 Another surface protein, p22, seems to be the target of cellular immune response,61 and the specific heat shock protein 70 (Hsp-70) may have an important role in the process of bradyzoite-tachyzoite conversion during the reactivation of chronic toxoplasmosis. 62
The T. gondii infection is one of the IllOSt common zoonoses in the world. 63 In all countries, a large percentage of
the population has chronic asymptomatic disease. The prevalence varies extensively in different regions, depending on socioeconomic, geographic, and climatic factors. A high prevalence is found in tropical areas close to sea level, and a lower prevalence is found in arid regions, in cold climates, and at high altitudes. These variations are related to environmental influences on the oocysts. In addition, the habit. of eating raw meat and the presence of the domestic cat greatly increase the incidence of Toxoplasma disease. The prevalence of seroconversion also increases with age. For example, in the United States, 5% to 30% of individuals 10 to 19 years old are seropositive, whereas up to 70% of those over age 50 years show serologic evidence of T. gondii exposure. 35 The general prevalence in the United States ranges from 30% to 70%.64-66 A comparison of positive serology for toxoplasmosis in different populations and geographic regions is shown in Table 33-2.
Congenital Toxoplasmosis Intrauterine toxoplasmosis infection deserves special at-, tention. Congenital infection has been estimated to affect 3000 infants born in the United States each year. 67 , 68 The prevalence of congenital disease parallels the rate of seropositivity (Table 33-3). Approximately 70% of women of child-bearing age in the United States are at risk of
TABLE 33-2. FREQUENCY OF POSITIVE SEROLOGY FOR TOXOPLASMOSIS IN DIFFERENT POPULATIONS POPULATION
Eskimos Navajo Indians England Finland Venezuela Austria Colombia United States Brazil France
POSITIVITY (%)
o 4
25 45 60 62 65 30-70 42-83 90
Modified from Orefice F, Bonfioli AA: Toxoplasmose. In: Orefice F, ed: Uveite clinica e cirurgica (in prelo). Rio de Janeiro, Brazil, Editora Cultura Medica, 1999; Orefice F, Belfort RJr: Toxoplasl11ose. In: Orefice F, Belfort R, eds: Uveitis. Sao Paulo, Roca, 1987.
CHAPTER 33: TOXOPLASMOSIS TABLE 33-3. PREVALENCE OF CONGENITAL INFECTION BY T. GONDII POPULATION
REFERENCE
Alabama England Scotland United States Czech Republic Australia Belgium Yugoslavia Switzerland Brazil France
Hunter et al, 1983 195 Jackson et aI, 1987]96 Williams et aI, 198p97 Alford, 1982]98 Palicka, 1982 199 Sfameni et aI, 1986200 Foulon et aI, 1984201 Logar et aI, 1992 202 Bornand, 1991 203 Camargo Neto, 197820 '1 Desmonts, 1983 205
CASES PER 1000 BIRTHS 0.12 0.07-0.25 0.46-0.93 1 1.6
2 2 3 3.5 4
7
contracting the disease,32 but the incidence of acquiring toxoplasmosis during pregnancy is only 0.2% to 1%.35 Among women who first contract toxoplasmosis during pregnancy, the chance of transplacental infection of the fetus is about 40%.69 The severity of congenital toxoplasmosis is inversely related to the time of gestational exposure. Vertical transmission is most frequent during the third trimester, when the fetus may be exposed to maternal blood. Fortunately, third-trimester infection usually results in a subclinical form of the disease. If, on the other hand, the infection occurs in the first trimester, it can result in spontaneous abortion or birth of an infant with severe disease. The transplacental infection rate is approximately 10% to 17% in the first trimester, 30% in the second trimester and 60% to 65% in the third trimester. 34, 41 Most auth~rities agree that transplacental transmission rates are lower if the mother receives treatment during pregnancy.70-73 However, a recent study claims that prenatal antibiotic therapy after toxoplasmosis infection during pregnancy has no impact on the fetomaternal transmission rate, but it does reduce the rate and severity of adverse sequelae among the infected infants. 74 Overall, retinochoroiditis is the most common manifestation of congenital infection, occurring in 70% to 90% of all cases. 64, 67 Most cases of congenital toxoplasmosis present as a subclinical or chronic infection. The newborn mayor may not have retinochoroidal scars (Figs. 33-4 and 33-5), intracranial calcifications (Fig. 33-6), or other sequelae of intrauterine infection. Mter months or even years, these children develop the signs and symptoms of central nervous system involvement, such as hydrocephalus or microcephalus, seizures, psychomotor retardation, development delay, and ocular disease with retinochoroidal lesions, strabismus, and blindness. The identification of subclinical infection is ilnportant, because early treatment improves the prognosis. 68 Some infants with congenital toxoplasmosis are born with clinical signs of active infection. They may present at birth with neurologic involvement or generalized disease, but the former is more frequent. The central nervous system involvement presents as encephalomyelitis, paralysis, meningismus, seizures, respiratory disturbances, hydrocephalus or microcephalus, intracranial calcifications, and failure to thrive. The generalized disease pre-
FIGURE 33-4. Typical wagon wheel appearance of a retinochoroidal lesion in congenital toxoplasmosis.
~ents with an exanthematous rash, petechiae, ecchymoses, ICterus, fever or hypothermia, anemia, lymphadenopathy, hepatosplenomegaly, pneumonitis, vOlniting, and c;liarrhea. This neonatal form is severe and patients frequently develop ocular ane}. neurologic sequelae even with treatment. The most common ocular sequelae are retinochoroidal scars, cataracts, microphthalmia, phthisis bulbi, strabismus, nystagmus, and optic atrophy. ?cca~ionally, the infant is normal at birth and develops actIve dIsease In the first few months of life. This form is more common in premature infants and results in severe disease, but it may also occur in full-term infants, in whom it is less severe.
Acquired Toxoplasmosis Typically, about 70% of immunocompetent patients who acquire toxoplasmosis are completely symptom free. Even when symptomatic, the disease is usually so mild and nonspecific that the diagnosis is difficult to make, and the condition is frequently unrecognized. The most common
FIGURE 33-5. Classic macular retinochoroidal lesion of congenital toxoplasmosis. (See color insert.)
CHAPTER 33: TOXOPLASMOSIS
manifestations IS variable, and ranges from days to years. 11-14. 17
Toxoplasmosis in Immunocompromised Patients
fiGURE 33-6. Contrast-enhanced CT scan demonstrating coarse intracranial calcifications, encephalomalacia and ventriculomegaly in congenital toxoplasmosis.
manifestation of acquired toxoplasmosis is l)Tlnphadenopathy affecting one or multiple lYJ-llph nodes. Cervical nodes are involved more frequently, followed by suboccipital, supraclavicular, axillary, inguinal, and mediastinal nodes. Involved lymph nodes are llsually bilateral, discrete, nontender, and nonsuppurative and they vary in firmness. About 20% to 40% of patients with lymphadenopathy also present with constitutional sYJ-llptoms resembling a mononucleosis-like illness. The sYJ-llptoms include headache, malaise, pharyngitis, fatigue, fever, and night sweats. A smaller proportion of sYJ-llptomatic patients may have a more florid picture including meningismus, meningoencephalitis, myalgias, arthralgias, abdominal pain, and a maculopapular rash that spares palms and soles. Acquired toxoplasmosis in an immunocompetent individual is usually benign and self-limiting, lasting about 2 to 4 weeks. However, malaise and lYJ-llphadenopathy may persist or recur in months. Rarely, the clinical manifestations may be very severe and include encephalopathy, pneumonitis, myocarditis, polymyositis, hepatitis, and splenomegaly, resulting in significant morbidity and even mortality. Acquired ocular toxoplasmosis was once thought to be relatively rare, as it was diagnosed only when the ocular disease occurred following an episode of acute symptomatic systemic disease. Because most acquired Toxoplasma disease is aSYJ-llptomatic, the true incidence of ocular toxoplasmosis in this setting is unclear, but current estimates range from 2% to 20%.3,7, S. 75 Evidence to support the hypothesis that acquired disease may often result in ocular toxoplasmosis comes from epidemiologiC studies demonstrating patients with elevated IgM and the frequentoccurrence of multiple siblings with ocular disease. 4, 5, S, 12, 15 When ocular disease occurs as a consequence of acquired toxoplasmosis, it can be simultaneous with the systemic disease or have a delayed onset. The time interval between the systemic disease and ocular
Immunocompromised patients are at increased risk for developing acute toxoplasmosis. The disease may be caused by reactivation of a chronic infection, or it may be an acquired infection. T. gondii causes a severe, fuhninant disease in immunocompromised individuals, including patients with human immunodeficiency virus (HIV) , transplant recipients, and, less frequently, l)Tlnphoma patients. 76 , 77 Toxoplasmosis in these individuals carries a poor prognosis and may be rapidly fatal if untreated. The parasite has an affinity for the central nervous system; consequently, the most common manifestation in patients with acquired immunodeficiency syndrome (AIDS) is intracranial involvement. Patients may present with diffuse neurologic dysfunction, seizures, or even focal neurologic signs due to encephalopathy, meningoencephalitis, and mass lesions. They also may develop multiple organ involvement, especially pneumonitis and myocarditis. Toxoplasma pneumonitis may be severe and rapidly progress to acute respiratory failure with hemoptysis, metabolic acidosis, hypotension, and occasionally disseminated intravascular coagulation. Ocular toxoplasmosis in AIDS patients is relatively uncommon and occurs in only about 1% to 3%,7s-s0 and of these cases up to 25% are thought to be the result of a newly acquired infection. s1 When Toxoplasma retinochoroiditis occurs in AIDS patients, it is frequently associated with encephalitis. In fact, 25% of AIDS patients with ocular toxoplasmosis also have intracranial involvement. Conversely, 10% to 20% of AIDS patients with intracranial toxoplasmosis also have ocular involvement. s2 One study found that, at autopsy, approximately 40% of all AIDS patients have intracranial Toxoplasma abscesses. 83 Thus, all AIDS patients who have ocular toxoplasmosis should undergo a complete neurologic evaluation, including computed tomography (CT) or magnetic resonance imaging (MRI) with contrast, and lumbar puncture. Unlike the situation in immunocompetent patients, most of the Toxoplasma retinal lesions in AIDS patients do not develop adjacent to old retinochoroidal scars. Instead, the lesions occur in a perivascular distribution, which suggests newly acquired infection or dissemination of parasites from other nonocular sites in the body.so, 81, S4 Retinochoroiditis in AIDS patients may have other atypical features, such as very large areas of severe confluent retinal necrosis,s5 as well as discrete single or multifocal lesions 79 , S6 and even bilateral active retinochoroiditis. 87 Ocular inflammation is variable and depends on the patient's lYJ-llphocyte count at the time of active disease. In general, AIDS patients who develop toxoplasmosis are still able to mount enough of a cellular immune response to produce the clinical findings of vascular sheathing, prominent vitritis, and intense anterior uveitis. 81 Ocular toxoplasmosis may follow a devastating course in AIDS patients, with inflammation extending into the orbit, causing orbital cellulitis and panophthalmitis. ss The clinical findings of Toxoplasma retinochoroiditis in AIDS patients may resemble a wide range of ocular
CHAPTER 33: TOXOPLASMOSIS
pathologies, and ocular ~oxo1?lasmo.sis shoL~ld always be suspected. The differentIal dIagnosIs may Include cytomegalovirus (CMV) retinitis, syphilitic retinitis, and progressive outer retinal necrosis (PORN). Howe:er,. toxoplasmosis retinochoroiditis :toes not ha:e. ~he sIgnI.ficant retinal hemorrhages seen In CMV retInItIs, nor IS the retinitis limited to the outer retinal layers, as in PORN. The utility of serologic testing in the diagnosis ~f AI~S patients for toxoplasmosis is que.stiona~le .. Ig