**4. Bacterial forms of retinitis**

#### **4.1 Tuberculosis**

#### *4.1.1 Epidemiology*

The WHO reports that more than 2 billion people are affected worldwide by tuberculosis [62]. Extrapulmonary tuberculosis occurs in 20%, and ocular tuberculosis develops from 3.5 to 5.1% of infected people. Patients with HIV often develop a generalization of the specific inflammation process, caused by *Mycobacterium tuberculosis* [63**–**65].

#### *4.1.2 Clinical features*

Ocular tuberculosis has no direct relation to the clinical manifestations of pulmonary tuberculosis; moreover, up to 60% of patients with extrapulmonary variants of tuberculosis do not have affected lungs [66]. According to the results of Collaborative Ocular Tuberculosis Study (COTS) [62, 67], the manifestations of tuberculosis with retinal involvement can be divided into a few different forms:

1. Tubercular posterior uveitis (TPU), the inflammation affects retina and/or the choroid. 2. Tubercular panuveitis (TBP), the inflammation affects anterior chamber, vitreous body and retina/choroid. 3. Tubercular retinal vasculitis (TRV), phlebitis, or arteritis with or without vessel occlusion.

Choroidal tubercles can be characterized as the most common intraocular manifestation of TPU. Choroidal tubercles are disseminated ill-defined, oval, grayish-white or yellowish deep lesions, mostly localized in the posterior pole, they show early hypofluorescence and late staining on fluorescein angiography [68]. Choroidal tubercles may develop itself to choroidal tuberculomas, which present a solitary mass with overlying retinal folds or retinal detachment. These may be located anywhere in the choroid and can be misdiagnosed as intraocular tumors or subretinal abscesses [62].

TRV can be described as perivenular cuffing with thick exudates, with or without retinal hemorrhages, focal choroiditis lesions, and moderate vitritis. Because of occlusive nature, TRV leads to peripheral capillary nonperfusion and retinal or optic disc neovascularization. These processes can be complicated by vitreous hemorrhage, traction retinal detachment, iris neovascularization, and neovascular glaucoma [68, 69]. These clinical sings are not very specific for a tuberculous etiology; other ocular pathologies, such as sarcoidosis or ocular infection with Toxoplasma, can also produce similar clinical forms.

#### *4.1.3 Diagnostics*

The interferon-γ release assay (IGRA) indicates a latent or active tuberculosis and quantifies interferon-γ released by sensitized T cells when they were exposed to *M. tuberculosis* peptide antigens. IGRA has some advantages in the diagnostics of the ocular tuberculosis, because it allows to overcome the limitations of tuberculin skin test. The early secretory antigen target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10) are not present in the Bacille Calmette-Guérin vaccination strains and non-tuberculous mycobacterium species and provide increased specificity of IGRA versus skin tests [70]. There are two available IGRA test systems: the QuantiFERON-TB Gold Plus (QFT-Plus, Qiagen, Hilden, Germany) and the T-SPOT.TB (Oxford Immunotec, Abingdon, UK) [70, 71].

Some clinical particularities need to be considered, before the antitubercular therapy (ATT) is initiated. The usually applied cutoff values (0.35 IU/ml) for QFT were shown to be too low in the setting of uveitis and may lead to overtreatment [72]. A cutoff value of 2.00 IU/ml was proposed instead, based on receiver operating characteristic (ROC) curve analysis, which showed that a threshold of 2.00 IU/ml had 84% sensitivity and 87% specificity for successful ATT in patients with ocular tuberculosis. Moreover, the best option for optimizing the routine screening, based on QFT, is to adjust the cutoff value on local endemicity and epidemiological data [73]. An analysis conducted by Agrawal and colleagues suggests that QFT levels alone cannot adequately separate tuberculosis-positive and -negative patients among patients with clinical signs suggestive of ocular tuberculosis [74]. Thus, if QFT is used as a routine diagnostic tool, its results cannot be taken and interpreted without context. Even negative IGRA test results should be interpreted with caution because they do not exclude the diagnosis.

The nucleic acid amplification enables diagnostics of ocular tuberculosis without the need to detect acid-fast bacilli, which are rarely presented in ocular samples. The quantitative real-time PCR uses fluorescent probes for fast detection and quantification of *M. tuberculosis* load in the sample. The advantage of this procedure is a decreased rate of contamination [75]. Multi-targeted PCR simultaneously amplifies multiple gene targets to achieve a higher diagnostic sensitivity. The sensitivity and specificity of PCR methods were estimated and documented by [71], and sensitivity was ranging from 37.7 to 85.2% and specificity was at a level of 90**–**100%. The MTBDRplus assay, which was performed on vitreous fluid samples, could detect rifampicin and isoniazid resistance, confirmed by rpoB and katG gene sequencing [76]. Larger studies must be planned and performed to validate the accuracy and reliability of modern PCR methods [67]. PCR is considered a reliable method, and clinicians should evaluate negative results in correlation with clinical findings, an expected clinical response to ATT supports the PCR results [77].

#### *4.1.4 Therapy*

The role of ATT by ocular tuberculosis remains controversial, and there is no international agreement on therapeutic protocols and duration of the ATT [78**–**82]. Evidence shows efficacy of ATT in reducing the rate of disease recurrences [83].

Results derived from a meta-analysis of 28 studies, which evaluated the effect of ATT on the ocular outcome of 1917 [80] patients, demonstrate that 84% of patients treated with ATT did not experience relapse of inflammation during the follow-up. The role of oral corticosteroids and immunosuppression agents is also still controversial, and there is no agreement on their efficacy in patients with tubercular uveitis treated with ATT [80]. Recent studies show a success of local therapy in the management of tubercular uveitis as an optional adjunctive anti-inflammatory therapy [82, 84, 85].

#### *4.1.5 Prognosis*

There is no evidence-based data about long-time prognosis. A low treatment failure rate was shown to occur in patients with tuberculous uveitis treated with ATT. Patients with TBP complicated by vitreous and choroidal involvement had a higher risk of treatment failure [74].

### **4.2 Ocular syphilis**

Syphilis caused by the spirochete bacterium *Treponema pallidum* has an ability to mimic different diseases due to its variety of clinical manifestations.

#### *4.2.1 Epidemiology*

The CDC in the United States reported 7.5 cases of primary and secondary syphilis per 100,000 population in 2015; 54% of patients were males, who have practiced sex with other males [86]. The syphilis co-infection of HIV patients ranges from 20% to 70% [87]. Statistical analysis estimates that HIV-positive individuals have an 86 times higher risk of syphilis [63]. Male gender was found to be the only statistically significant risk factor for the development of ocular syphilis; ocular syphilis was seen in 9.5% of men as compared with 1.5% of women [87].

#### *4.2.2 Clinical features*

Retinal manifestations of ocular syphilis include following constellations [87]: 1. Chorioretinitis; 2. Necrotizing retinitis; 3. Retinal vasculitis; 4. Retinal vasculitis; 5. Vitritis; 6. Exudative retinal detachment.

Chorioretinitis with vitritis is the most usual finding in syphilitic posterior uveitis and involves the posterior pole and mid-periphery. The inflammatory lesions are initially small, between one-half to one in disc-diameter, but they can become large and confluent [88**–**90]. The affection of the retina or choroid is usually seen in secondary syphilis, and approximately half of the patients with ocular syphilis experience bilateral involvement [91].

Acute syphilitic posterior placoid chorioretinitis (ASPPC) is a rare manifestation of ocular syphilis [92]. ASPPC is characterized by yellowish, placoid, outer retinal lesions, usually located at or near the macula, with a faded center and stipulation of the retinal pigment epithelium. Such lesions can be seen as the result of active specific inflammation of the chorioretinal complex (choriocapillaris-pigment epithelialretinal photoreceptor complex). The inflammation can be triggered by dissemination and direct invasion of *T. pallidum*, which causes occlusion of the choriocapillaris or sedimentation of soluble immune complexes, which cause an inflammation of the vessel wall or both of these pathogenetic inflammation ways [92]. Two cases of acute

zonal occult outer retinopathy (AZOOR) were reported in which syphilis was identified as the underlying disease [93]. AZOOR presents with a sudden onset of photopsia and scotoma, which are related to loss of outer retinal sectors function. Fundoscopy can be normal in the early phase of the disease.

Necrotizing retinitis is a seldom complication of ocular syphilis and can mimic acute retinal necrosis [94**–**96]. Usual clinical features of retinitis associated with ocular syphilis are presented by retinal lesions, which tend to heal with minimal disruption of the retinal pigment epithelium [97]. Vasculitis involves retinal arteries, arterioles, capillaries, and veins [98]. The fundus fluorescein angiography can be complex and demonstrates perivascular exudation and fibrosis, occlusive vasculitis [93, 99], isolated or focal retinal vasculitis, which can simulate branch retinal vein occlusion [100, 101].

#### *4.2.3 Diagnostics*

The screening tests used for syphilis diagnostics are enzyme immunoassays (EIA) and chemiluminescent immunoassays (CIA), which detect antibodies to treponemal antigens. If positive, a non-treponemal test, rapid plasma reagin (RPR) or Venereal Diseases Research Laboratory (VDRL) test for cardiolipin antibodies should be performed [87]. The *T. pallidum* hemagglutination assay (TPHA) or *T. pallidum* particle agglutination test (TPPA) detects specific treponemal antibodies. Some of HIV-positive patients can show non-reactive serological results. This phenomenon can be avoided by testing diluted serum [87].

Direct detection can be carried out with dark-field microscopy, PCR, and immune histochemistry. Dark-field microscopy directly visualizes *T. pallidum* by investigation of clinical samples (exudates from chancres, condylomata lata, lymph node aspirates, etc.) [102]. The sensitivity and specificity of dark-field microscopy are approximately 90% and 100%, respectively [103]. PCR of vitreous aspirates can be used, for example, to diagnose atypical manifestations of ocular syphilis [104] and can also be used to identify drug resistance of *T. pallidum* [105, 106].

### *4.2.4 Therapy*

The current CDC guidelines recommend penicillin G as the drug of choice. Primary and secondary syphilis: benzathine penicillin G, 2.4 million units intramuscularly (i.m.) in a single dose. Early latent syphilis: benzathine penicillin G 2.4 million units i.m. in a single dose. Late latent syphilis: benzathine penicillin G 7.2 million units, as three doses of 2.4 million units i.m./week. Tertiary syphilis with normal CSF results: benzathine penicillin G 7.2 million units, as three doses of 2.4 million units i.m./week. Neurosyphilis and ocular syphilis: aqueous crystalline penicillin G 18**–**24 million units/day, as 3**–**4 million units i.v. every 4 h or continuous infusion for 10**–**14 days; or alternatively procaine penicillin G 2.4 million units i.m./days plus probenecid 500 mg orally 4× daily, both for 10**–**14 days. Systemic steroids have not been proven to have clinical benefits in the treatment of syphilis [107]. All patients with ocular or neurosyphilis should be screened for HIV. Highly effective treatment protocols to prevent neurosyphilis in patients with HIV and syphilis are still not available [108]. However, the antiretroviral therapy can improve clinical outcomes in patients with HIV and syphilis [87].

## *4.2.5 Prognosis*

After serological diagnosis, syphilis treatment is associated with good prognosis [109].

#### **4.3 Ocular manifestations of bartonellosis**

There are over 30 different Bartonella subspecies. *Bartonella henselae, Bartonella quintana,* and *Bartonella bacilliformis* are responsible for most infections in humans. This organism is a Gram-negative hematotropic pathogen, it affects erythrocytes and/ or endothelial cells. The clinical form can manifest as disseminated vascular proliferations throughout the body [110].

#### *4.3.1 Epidemiology*

Cats are the main reservoir, and over 90% of patients with Bartonella species infection have had a contact with a cat [111]. The clinical infection with Bartonella species has the term Cat-scratch disease (CSD) as a synonym. A multicenter retrospective study of CSD patients with ocular manifestations was performed between 1996 and 2015 [112]. Seasonal patterns were observed with ocular CSD [112]. Ocular bartonellosis has a broad age distribution [113]. In one clinical study, 141 of 3222 patients (4.4%) have had concomitant ocular manifestation of CSD [114].

#### *4.3.2 Clinical features*

The posterior segment manifestations of CSD include intermediate uveitis, optic neuritis, neuroretinitis, focal or multifocal retinitis and/or choroiditis, vascular occlusions, retinal vasculitis, granulomas, exudative retinal detachments, macular exudates, macular hole, white dot syndromes, angiomatous lesions, and acute endophthalmitis [115**–**117]. Patients may experience a varying severity of unilateral or bilateral visual loss and central scotoma. Neuroretinitis presents as optic disc swelling with serous retinal detachment, and macular exudation, which can be seen 2–4 weeks after the initial observation of optic disc swelling. The macular exudates can take a long time to resolve, up to 12 months [112].

#### *4.3.3 Diagnostics*

The diagnosis of CDS is based on the presence of the following clinical criteria [114]: 1. Contact with cats; 2. Positive skin test in response to CSD antigen; 3. Characteristic lymph nodes and lymphadenopathy not caused by other bacteria.

The best screening test for diagnostics of CSD is a serologic testing by either indirect fluorescence assay (IFA) or ELISA [118]. The IFA test has a sensitivity and specificity of 90% in immunocompetent patients and is the more commonly used diagnostic test [115, 119]. PCR is also a useful diagnostic test in particular by negative serology. PCR demonstrates a high specificity, but the sensitivity is lower than serology testing [119].

#### *4.3.4 Therapy*

Antibacterial therapy can be performed with the following antimicrobial drugs: doxycycline, macrolide antibiotics (clarithromycin, erythromycin, azithromycin), rifampicin, ciprofloxacin, ceftriaxone, and cotrimoxazole [111]. The usual therapy includes doxycycline 100 mg 2**×** per day for 4**–**6 weeks for immunocompetent patients and up to 4 months for immunocompromised patients. Younger patients can be treated with a macrolide antibiotic because of less long-term side effects [119].

Corticosteroids may be used as additional therapy component to antibiotic treatment with the aim to stop and control the inflammatory response. A multivariate logistic regression analysis has shown a significant improvement of visual acuity by a combination therapy (systemic corticosteroids and antibiotics) [112].
