**7. Endogenous fungal endophthalmitis (EFE)**

Fungi can lead to infection of the posterior chamber through hematogenous spread; in fact, this represents the most frequent cause of EFE [186, 187]. Most cases of fungal endogenous endophthalmitis have a predisposing systemic risk factor. Common risk factors for EFE include recent hospitalization, systemic surgery, indwelling catheter, broad-spectrum antibiotic use, steroids, parenteral nutrition, cytotoxic therapies, and gastrointestinal disease [186]. Lower abdominal procedures, including genitourinary procedures (e.g. uterine curettage, urinary tract dilation, lithiasis removal), and toe-nail extraction due advanced onychomycosis have been implicated with EFE [188]. Most cases of fungal endogenous endophthalmitis have a predisposing systemic risk factor [189]. Diagnosis of EFE is frequently missed, as these characteristic findings might mimic non-infectious uveitis and orbital cellulitis [190]. In the pediatric population, common misdiagnoses are orbital cellulitis, congenital glaucoma, conjunctivitis, and retinoblastoma [191]. Misdiagnosis rates range from 16% to 63% [4, 191].

Patients who experience misdiagnosis can experience a delay in diagnosis (mean of 13 days) [186, 192], but familiarity with the clinical features of EFE can aid in avoiding this. Patients frequently complain of blurry or decreased vision (77%), redness (49%), eye pain (34%), floaters (26%), and photophobia (12%) [192]. Systemic symptoms also include frequently mild and relapsing fever, scalp lesions, and other pain [193]. In a study that examined 65 eyes with EFE found most eyes to have diffuse anterior and posterior segment inflammation (71%), followed by focal posterior inflammation (28%) and focal anterior segment inflammation (2%) [186]. Eyes with EFE can have some characteristic exam findings that can help in establishing a proper diagnosis. For example, eyes with EFE from *Candida spp*. typically will have one or more creamy, white chorioretinal lesions most commonly found in the posterior pole [194]. These lesions tend to be less than 1 mm in diameter with an overlying vitritis. Moreover, fluffy white vitreous opacities connected by strands of inflammatory material ("string of pearls") can be noted [194]. Also, EFE from *Aspergillus* can have a characteristic macular chorioretinal lesion that can be associated with a gravitational layering of inflammatory exudates (pseudohypopyon) either in the preretinal or subretinal space [195].

Due to their systemic nature in immunocompromised patients, cases are more likely to be bilateral compared to other causes of endogenous endophthalmitis, but the majority are still unilateral [196]. Unlike bacterial causes, EFE is less associated with a known focal systemic lesion. About 44% of patients with EFE from *Candida* spp. had no known focal lesion [29]. However, patients frequently present with a history of IVDU, chemotherapy, DM, abdominopelvic procedures and renal failure. Mold infections, caused by organisms such as *Aspergillus*, commonly occur with a history of iatrogenic immunosuppression, corticosteroid use, neutropenic patients, or solid organ transplantation [188, 189, 196, 197]. It is rare for patients with AIDS or IVDU to have *Aspergillus* endophthalmitis [197], and those patients are more likely to have a history of pulmonary aspergillosis or disseminated aspergillosis [196].

An accurate diagnosis of the causative agent is essential to the treatment of EFE. Culture positivity for *Candida* spp. EFE rates range from 45% to 74% in the immunocompromised, perhaps leading to more frequent misdiagnosis in this population. PCR is increasingly becoming the gold standard diagnostic tool for the identification of EFE infections: Identification has been reported to be up to 100% compared to 37.5% in traditional culture techniques [198, 199]. However, PCR does experience the same pitfalls in the diagnosis of fungal infections as it does for EBE. Prompt diagnosis with PCR and intervention with early vitrectomy and/or chorioretinal biopsy have improved patient visual outcomes [200].

*Endogenous Endophthalmitis: Etiology and Treatment DOI: http://dx.doi.org/10.5772/intechopen.96766*

*Candida* spp. infections represent the most common cause of fungal endogenous endophthalmitis, with incidences ranging from 34–36% of cases of all EFE [29]. The *Candida* spp. are known to affect the eye and have a predilection toward the posterior segment [190, 196]. Reports show infection of *Candida* spp. after pacemaker implantation [196]. In immunocompromised patients, the most common cause of fungal endogenous endophthalmitis is *Candida* [199]. Infection with a new candida strain, *Candida dubliniensis*, has been noted in several countries. Although much less frequent than other *Candida* species, *C. dubliniensis* can present with fluconazole-resistance and no other systemic evidence for disseminated disease [201]. However, *C*. *dubliniensis* has better treatment outcomes compared to *C. albicans* [201]. Despite its low frequency in overall endophthalmitis cases, *Candida albicans* is the most common cause of endogenous endophthalmitis in pediatric populations worldwide. Risk of infection increases with a history of distant wound infection, meningitis, intravenous catheters, and UTIs [191, 202]. Common causes of pediatric fungal endophthalmitis include neonatal sepsis, poor hygiene, or an immunocompromised status [191]. Given the high rates of misdiagnosis in this population (63%), there is evidence that dilated ophthalmic examination of patients with invasive fungal disease and screening of at-risk children with evidence of fungal colonization has some therapeutic benefit [4, 191, 203].

The *Aspergillus* genus represents the second most common cause of fungal endophthalmitis (33%) [199]. Other common opportunistic fungi include *C. neoformans*, *Fusarium* spp*.*, *Scedosporium*, *Rhodotorula* spp., *Mucor* spp., *Alternaria* spp., *Acremonium falciforme Pneumocystis jiroveci*, and many other less prevalent fungal species [167, 196, 198, 204]. Microsporidum has also been implicated with posterior segment etiology [205].

Pathogenic dimorphic fungi have also been implicated in EFE. Unlike opportunistic causes, pathogenic dimorphic fungi are usually regionally restricted. These infections can cause endophthalmitis in both immunocompetent and immunocompromised hosts. EFE is primarily a result of a disseminated pulmonary infection [196, 206]. Examination of the eye for dimorphic fungi shows fluffy yellow/white aggregates with retinal hemorrhages. *Coccidiodies immitis*, *Blastomyces dermatitidis, Histoplasma capsulatum,* and *S. schenckii* have all been implicated as regional causes of EFE [167, 196, 198, 204]. Patients who are suspected of having systemic *C. immitis* and *Blastomyces* should undergo serial eye examination given its insidious nature, especially for immunocompromised patients [196, 207, 208]. *C. immitis* does not always present with signs of systemic infection, so visual cues such as vitreous opacities are beneficial to a systemic diagnosis [207]. Despite early diagnosis and prompt treatment, it is reported that 50% of patients who do not succumb to the disseminated infection undergo enucleation of the infected eye [196, 207–209]. The initial treatment of suspected EFE should be intravitreal and systemic antifungal agents followed by early surgical intervention [193]. Depending on the specific cause and duration of EFE, medications used for treatment include amphotericin B, systemic fluconazole (oral or IV), voriconazole, and caspofungin, with preference depending on sensitivity of the infection and side effect profile. Like EBE, a tapand-inject technique is recommended through the pars plana to collect a sample of the vitreous for culture followed by intravitreal injection of antifungals. Again, sometimes a chorioretinal biopsy may be required for identification of the fungus [171, 200, 210].

Treatment of endogenous fungal endophthalmitis in the eyes of pediatric population have shown favorable resolution with systemic and intravitreal antifungals, intravitreal steroids, and early surgical intervention. However, there is no specific guideline for dosing of pediatric patients with EFE with systemic and intravitreal antibiotics [192]. While patients with EFE have shown resolution of symptoms, as

noted, with systemic and intravitreal antifungal medications, eyes that present with poor vision or are refractory to injected antifungals should undergo vitrectomy [198]. Surgical intervention via early PPV has been proven to have therapeutic efficacy [199].

Of all the fungal causes, infections with *Candida* spp. have shown the best visual acuity outcomes. Results for eyes with *Aspergillus* EFE are not as favorable because of increased rates of macular scarring secondary to infection [211].

## **8. Endogenous protozoal endophthalmitis**

Protozoans, unicellular eukaryotic organisms, are a major cause of intraocular infections worldwide. Different protozoa have special animal hosts with varying routes of infection. Travel and dietary history as well as patient habits are important in establishing a diagnosis, since most transmission occurs through contaminated food and water sources in endemic areas. Protozoa such as *Giardia lamblia, Plasmodium falciparum, Acanthamoeba* spp., and *Toxoplasma gondii* can all present with intraocular manifestations; however, only toxoplasmosis is well established to cause endogenous endophthalmitis.

*Acanthamoeba* spp., typically associated with contact lens wear, trauma, and contaminated water exposure, can cause keratitis. Advanced stages can lead to corneal perforation and endophthalmitis; however, it is exogenous in nature secondary to direct corneal extension [212, 213]. Malaria, an infectious disease caused by *Plasmodium* and carried by *Anopheles* mosquitoes, leads to retinal ocular manifestation without any intraocular inflammation. Retinal findings, such as patchy retinal whitening and retinal hemorrhages, occur in severe cerebral malaria caused by *Palsmodium falciparum* but are secondary to microvascular obstruction and severe anemia [214, 215]. *Giardia lamblia*, the most common intestinal parasite worldwide, is acquired through ingestion of cysts from contaminated water [216]. Asymptomatic salt-and-pepper retinal degeneration is the most common ocular manifestation of giardiasis [217]. Only rare cases of retinal arteritis and anterior uveitis have been documented in the literature [218, 219]. Ocular sequalae of giardiasis is believed to occur as result of immune response to cross-reacting antigens or molecular mimicry rather than a direct invasion by the parasite [217, 220].

*Toxoplasmosis gondii,* a ubiquitous protozoan that infects roughly one third of the human population, is the most common cause of uveitis worldwide [221, 222]. Oocytes from cat (definitive host) feces infect humans (intermediate hosts) through consumption of contaminated water and undercooked meats (animals already infected) or from direct mishandling of domestic cat feces [223, 224]. In the past, all cases of ocular toxoplasmosis were believed to be reactivations of previous congenital infections; however, recent evidence has shown that most cases are in fact acquired postnatally [221, 225]. Congenital infection occurs when the mother is infected with the protozoa either just before conception or during gestation, which leads to vertical transmission through the placenta to the fetus. Fetal transmission only occurs if the mother is exposed to the parasite for the first time or to a novel strain [226]. Unless she is immunocompromised, a previously infected mother already possesses the immunity that protects her and the fetus from any new infection. Fetal infection during the first trimester will typically lead to a more severe form of congenital toxoplasmosis than later stages of pregnancy [227]. Retinochoroiditis is a common ocular manifestation, which may lead to blindness if left untreated [228]. Other extraocular clinical signs of congenital toxoplasmosis include seizures, sensorineural hearing loss, intracranial calcifications, microcephaly, and cognitive impairment. Prompt treatment of the newly infected mother

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with spiramycin has demonstrated a 60% reduction in congenital toxoplasmosis [229]. Moreover, prompt postnatal treatment of infants is also warranted. Infants who were treated after one year of life were more likely to develop new retinochoroidal lesions than patients who received earlier treatment (70% vs. 31%, respectively) [230]. It is important to note that clinical presentation of congenital toxoplasmosis can resemble congenital viral infections such as HSV, CMV, Zika virus, and rubella, which needs to be taken into consideration when making the diagnosis [228].

Other clinical classifications of toxoplasmosis include acquired cases in immunocompetent and immunocompromised patients. Toxoplasmosis is mainly asymptomatic in healthy patients. Painless cervical lymphadenopathy is the main clinical manifestation if symptoms do occur. Retinochoroiditis is also a common feature, since *Toxoplasma gondii* is the most common pathogen to infect the retina in immunocompetent patients [231]. Retinal lesions can present in acute or reactivation stages, and in the latter case, lesions are essentially similar whether the original infection was congenital or acquired [232, 233].

Retinochoroiditis is frequently subclinical but can result in retinal detachment and loss of vision [228, 234]. Other symptoms may include pain, photophobia and epiphora. Ophthalmic exam is vital in the diagnosis of retinochoroiditis, which typically presents as a focal white lesion with overlying vitritis. When vitritis is severe, a classic finding of "headlight in the fog" can be seen. Healed lesions become atrophic and develop a scar bordered with black pigment. Atypical lesions found in elderly and immunocompromised patients have distinctive characteristics including hemorrhages, multiple foci and features present in acute retinal necrosis (ARN) such as peripheral retinitis, vasculitis and vitritis [235, 236]. Early management of toxoplasmosis in immunodeficient patients is vital, as disseminated disease has 100% mortality if left untreated.

Recurrences of retinochoroiditis are common, roughly 80%, with a median interval of two years [237]. New lesions tend to occur at the border of an old, scarred lesion. Recurrences are more common after cataract extraction and in patients older than 40 years of age as well as in previously affected eyes [237–239]. Nevertheless, late sequelae and recurrences from congenital infection tend to be bilateral, more severe, and involve the macula, whereas acquired infections are usually unilateral, spare the macula, and are not associated with an old chorioretinal scar [228, 232, 240].

The diagnosis of toxoplasmosis is mainly clinical based on characteristic retinal lesions; however, serology can confirm the exposure to the protozoa. Various methods exist for detecting IgG and IgM immunoglobulins against *Toxoplasma gondii* such as immunocapture, immunoblot, immunosorbent agglutination, indirect immunofluorescence, enzyme-linked immunosorbent assays, and Chemiluminescence Immunoassay (CLIA) [241–243]. Each test has its own sensitivities and specificities which are beyond the scope of this chapter. Nevertheless, IgM antibodies indicate a primary infection and can be especially helpful in pregnant patients to determine whether infection occurred during or prior to pregnancy, while memory IgG antibodies demonstrate previous infection. IgM antibodies typically appears during the first week of infection and can remain detectable up to a year, while IgG appears approximately 2 weeks after the infection and typically remains detectable for life [244]. For example, patients with chronic and recurrent retinochoroiditis will typically only have IgG detected, whereas detection of both IgM and IgG typically indicates a primary and acute infection.

These serological tests only reveal previous exposure to *Toxoplasma gondii* and offer little insight into the mode of transmission. However, a new test using a protozoa-specific protein called *T. gondii* embryogenesis-related protein (TgERP)

can be useful in determining the original source of infection [245]. PCR amplification has also been successfully utilized in the diagnosis of toxoplasmosis and can be especially useful in atypical patient presentations. PCR is also beneficial in testing for congenital infections, since it offers earlier diagnosis and avoids the invasiveness of serum testing on fetuses by sampling amniotic fluid [228, 246]. PCR can also utilize CSF, urine, fetal, and placental tissue [228, 247]. Moreover, a newer test that utilizes similar general principles of PCR, known as loop-mediated isothermal amplification method (LAMP), might offer a cheaper and simpler alternative in confirming *Toxoplasma gondii* exposure [248].

There is a lack of evidence supporting the utility of routine antibiotic and steroid regimens in the treatment of acute retinochoroiditis [249]. Not all cases necessarily warrant treatment; for example, small lesions in the periphery that are not visionthreatening tend to be self-limited and will heal spontaneously in immunocompetent patients [250–252]. Most clinicians will treat patients with disease persisting more than one month and associated with reduced visual acuity. Other indications for treatment include lesions that are vision-threatening such as those affecting the macula or the optic nerve, lesions larger than one disc diameter, lesions in monocular patients, presence of multiple lesions, lesions associated with moderate to severe vitritis, active lesions over a large vessel, or lesions in immunocompromised patients [253]. The classic triple therapy comprises oral pyrimethamine, sulfadiazine, and prednisolone. Pyrimethamine is prescribed with folinic acid to prevent bone marrow toxicity (anemia). Alternative treatments include oral trimethoprimsulfamethoxazole (TMP-SMX), azithromycin, or clindamycin, all of which have shown favorable results [254–256]. Intravitreal treatment has also been studied for the treatment of ocular toxoplasmosis [257, 258]. Combined clindamycin and dexamethasone intravitreal injections were found to be comparable to a regimen of oral pyrimethamine and sulfadiazine [258–260]. Intravitreal TMP-SMX with dexamethasone also demonstrated benefit [261, 262]. Intravitreal injections can be favorable in pregnant patients due to their reduced systemic toxicity compared to oral medication [263, 264]. Photocoagulation around the foci of the scars and vitrectomy have also been performed; however, these studies are limited and did not show any preventive effect [265]. Fulminant ocular toxoplasmosis may occur with corticosteroid monotherapy, in which case vitrectomy may be warranted [266].
