AIOS – Narsing A. Rao Award
Dr. Bhagya Sudheer, B16378, Dr.Rathinam Sivakumar R, Dr. Prajna Lalitha
Sudheer Bhagya, Sivakumar Rathinam, Prajna Lalitha, Arya Lalan Kumar,
Introduction:
Ocular tuberculosis is an extra pulmonary dissemination of Mycobacterium tuberculosis primarily from the lungs. Although ocular presentation is relatively less common than the pulmonary disease, the ocular manifestations present clinically with or without pulmonary involvement. The diagnosis and treatment of ocular tuberculosis is challenging. This is mainly due to the overlapping clinical presentations, lack of systemic evidence of disease, and difficulty in obtaining ocular tissues samples.
Examination of enucleated eyes with confirmed histopathological diagnosis of Intraocular tuberculosis ( IOTB) have revealed the paucibacillary nature of the disease, thus explaining the lack of mycobacterial culture positivity from the ocular fluid. Even the clinical signs of IOTB have wide variation in anatomic location, morphological appearance, and ancillary investigations. The lack of diagnostic criteria and gold standard tests carries a potential risk of either under or over diagnosis. Undiagnosed, TB uveitis carries high visual morbidity, whereas overzealous treatment with anti- TB drugs, in the absence of infection, carries a significant risk of systemic side effects.
Nucleic acid amplification techniques such polymerase chain reaction (PCR) has emerged as a powerful tool for rapid and accurate detection of the mycobacterial genome, with a high specificity and a variable sensitivity. PCR can be performed with a very small sample size, hence being helpful for ocular fluids.
The recent guidelines for the diagnosis of IOTB include clinical, radiological, laboratory tests such as a positive PCR, and response to treatment with anti-tubercular drugs. Due to the high specificity of PCR, a positive test with a good clinical treatment response can confirm the diagnosis.
The purpose of our study was to assess the diagnostic utility of nested MTB PCR in clinically suspected tubercular uveitis and to determine its correlation with treatment.
Methodology:
A retrospective, observational case study was performed on patients with a positive MTB PCR on ocular fluid analysis from April 2012 to March 2015 at the Aravind Eye Hospital in Madurai, India. Diagnosis of IOTB was based on clinical features suggestive of ocular tuberculosis including granulomatous keratic precipitates, hypopyon, iris, disc and or choroid granulomas, active vasculitis, choroiditis and healed chorioretinal scars along blood vessels. These ocular findings were included in the diagnostic criteria for IOTB. Moreover, patients were also selected if there was no response to oral steroids. All patients had to have a minimum follow-up of 6 months to be eligible for this study.
Patient records were reviewed for demographic data, disease course including past history of tuberculosis and treatment received, immune status, laboratory investigations such as complete blood count, purified protein derivative (PPD) skin test, and serum angiotensin converting enzyme (ACE), radiological tests including computerized tomography (CT) scan of the thorax and/ or ultrasonography (USG) of the abdomen to investigate active foci of TB. The disease course and treatment received prior to ocular sampling, best corrected visual acuity (BCVA), intraocular pressure (IOP), anterior and posterior segment findings, polymerase chain reaction (PCR) results, post paracentesis treatment and response to treatment were also reviewed and analysed.
The anti-tubercular treatment (ATT) for the initiation phase (first 2 months) included four drug therapies: rifampicin, isoniazid, pyrazinamide, and ethambutol. The continuation phase (following 4 months) consisted of two drugs therapy: rifampicin and isoniazid. The dose for each drug was calculated based on body weight.
BCVA was recorded using the log MAR chart and the initial and final visual acuity was compared for all patients.
Determination of the site of ocular fluid/tissue sampling was based on clinical exam and site of intraocular inflammation anterior chamber paracentesis was done in 14 patients, vitreous tap in 28 and vitreous biopsy in the remaining 14 patients. The procedure was performed under sterile precautions in the operation theatre.
PCR analysis was performed according to previously published protocols.The main outcome measure was the correlation of the PCR results with the clinical features and response to antitubercular therapy. The response was assessed with the improvement in the final visual acuity and disappearance of vitreous haze. The frequency of management change (defined as any change in treatment strategy directly attributable to PCR findings) was also analyzed.
Statistics:
The demographic and treatment variables are presented with frequency, percentage and medians. Mean (SD) along with the range was given for continuous variables. A non-parametric test, Wilcoxon-Signed Rank test was used to analyze the ordinal variable (BCVA). The p value <0.05 was considered statistically significant. All statistical analysis was done by statistical software STATA 11.1 (Texas, USA).
Results:
A total of 85 patients underwent PCR testing for IOTB. Among these, 56 patients had follow up for 6 months. The demographics and the clinical features of the patients are shown in Table 1. The mean age of the patients was 38 years (12 to 73 years) with a slight female preponderance (males 21, 37.5%; females 35, 62.5%). Uveitis was unilateral in 40 (55.5%) eyes and bilateral in 32 eyes (44.4%). Past history of tuberculosis was present in 14 (25%) patients, all of whom received the complete course of the four drug regimen of anti- tubercular treatment (10 patients who had pulmonary TB received 6 months of ATT and the remaining 4 had extra pulmonary TB and received 9 months to 1 year of ATT).
Initial visual acuity of 6/60 or worse was seen in 37 (52.9%) patients. The mean IOP was 13.94 (± 4.81) mmHg. There were 31 (55.35%) patients who had an acute episode of uveitis and 25 (44.64%) patients with chronic uveitis. Recurrence was seen in 8 patients. Anterior, intermediate, posterior, and pan uveitis was found in 10 (13.9%), 9 (12.5%), 17 (23.6%), and 36 (50%) eyes respectively. In the 10 eyes which had presented with anterior uveitis, hypopyon was present in 5 eyes and iris granulomas in 3 eyes. Scleritis with pan uveitis and scleritis with anterior uveitis was seen in 3 (5.35%) and 1 (1.4%) eye, respectively.
The significant posterior segment findings were vitritis 67 (93.1%) eyes, choroidal granulomas 10 eyes (13.9%) either solitary or multiple, disc granulomas 4 eyes (5.6%), exudative vasculitis 13 (18.1%), and chorioretinal scars along the blood vessels 14 eyes (19.4%). Retinitis was the presenting clinical feature in 20 eyes (35.7%). Choroiditis, exudative retinal detachments, and cystoid macular edema were also present. Ophthalmic exam details are described in Table 2.
The PCR results were positive for MTB in 24 (42.8%) patients among whom 16 (51.61%) had acute uveitis and 8 (32.5%) had chronic uveitis. Looking at the PCR results among the different clinical presentation we found it is positive in 5 (50%) patients with anterior uveitis, 3 (33.3%) patients with intermediate uveitis, 5 (29.4%) patients with posterior uveitis, 9 (25%) patients with pan uveitis and 1 (100%) patient with scleritis with anterior uveitis and 1 (33.3%) patient with scleritis with pan uveitis. PCR results were negative in 32 (57.1%) patients.
Twenty-six patients were started on ATT and the MTB PCR results were positive in 16 of these patients. On analysing the clinical response to treatment we found that all these patients had showed a positive response to ATT at the end of 6 months with complete resolution of inflammation and a 2 line improvement in vision. In the remaining 10 patients whose PCR was negative only 6 showed responses to treatment and the other 4 had to be switched to antiviral therapy with oral steroids. After a change in the treatment all 4 patients had complete resolution of the disease.
Among the 30 patients who did not receive ATT initially, 22 were MTB PCR negative and 8 were MTB PCR positive. Of the 22 PCR negative patients, only 2 were given an ATT trial as these patients had shown no response to immunosuppresants they were receiving and had a necrotic PPD with an elevated ESR. At the end of 6 months these 2 patients had a complete resolution of symptoms with ATT. Whereas in the 8 patients whose PCR was positive, 6 were started on ATT and had response to therapy, whereas among the remaining 2, 1 had clinical features strongly suggestive of ARN and thus was started on antivirals and the other was a known case of VKH on methotrexate thus a change to mycophenolate mofetil brought the disease under control.
The number of patients who had a change in their initial treatment after MTB PCR results were 25. Among these 25, eight patients received ATT after the analysis; these patients were initially treated with oral steroids and or oral antivirals. Four patients had a change from their original therapy of ATT to antivirals and had PCR for MTB which was negative. In the rest of the 13 patients, 5 received antivirals, 4 oral steroids, 2 anti-toxoplasma therapy and 2 immunosuppressants. One patient (no.35) who received oral steroids at one month follow-up had developed a retinal detachment of the affected eye, and had undergone pars plana vitrectomy with silicon oil injection, with an attached retina and a BCVA of 6/60 at 6 months follow-up.
We found 80% correlation with the PCR results and the treatment response. The sensitivity was 73.3% and specificity was 92.3% with positive and negative predictive values of 91.7% and 75% respectively (Table 3).
Discussion:
In our study we found a good clinical agreement between the PCR results of intraocular fluids to the treatment response in clinically suspected tuberculous uveitis. The PCR results strengthened our clinical diagnosis. The sensitivity and specificity of the test was 73.3% and 92.3%, respectively. All the patients receiving anti-tubercular treatment showed complete resolution of symptoms at the end of the study period.
The most common manifestation of intraocular TB seen is posterior and pan uveitis. In our study population panuveitis was the predominant clinical presentation. As tubercular uveitis is a granulomatous disease, 29 eyes of 56 patients had granulomatous KP’s at presentation. The most common clinical features associated with PCR positivity for MTB were hypopyon uveitis (4 out of 5), choroidal granulomas (5 out of 10) and vasculitis (5 out of 11). Hypopyon uveitis though a rare manifestation of the disease was seen in 5 of the eyes. Among them 4 had a positive PCR result for MTB.
The reported positivity for PCR in various studies ranges from 33.33% for tubercular retinal vasculitis to as high as 66.67% for granulomatous pan uveitis. PCR positivity was higher in those who presented with acute rather than with chronic form of uveitis. This may be due to the nature of the disease or the prior treatments the patient may have received.
Response to treatment is an important clinical sign for confirmation of diagnosis. All our patients received the initiation phase of ATT with 4 drugs and the maintenance phase with 2 drugs for a period of 6 to 9 months depending on the clinical severity of the case with tapering doses of oral steroids. As proven in previous studies the treatment helps in reducing the antigenic load in the ocular tissue and reduces the recurrences significantly. The response to ATT over 4-6 weeks is one of the diagnostic features of IOTB.
Diagnosis of IOTB needs a high degree of clinical suspicion with corroborative laboratory and radiological findings. Though smear and culture is the gold standard confirmatory test due to lack of sample, molecular diagnostic tests such as PCR has an important role. A positive PCR clinches the diagnosis whereas a negative test implies us to rely on our clinical diagnosis. An adequate clinical response to treatment is hence a valuable tool in these cases.
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TABLES:
| Table 1. DEMOGRAPHIC INFORMATION ANDCLINICAL FEATURES | |||||||||
| Mean Age | 38 Yrs (Range 12 to 73 yrs) | ||||||||
| 0-30 | 21 (37.5%) | ||||||||
| 31-60 | 30 (53.6%) | ||||||||
| >61 | 05 (8.9%) | ||||||||
| Gender | |||||||||
| Male | 21 (37.50%) | ||||||||
| Female | 35 (62.50%) | ||||||||
| Affected Eye | |||||||||
| Unilateral | 40 (71.4%) | ||||||||
| Bilateral | 16 (28.6%) | ||||||||
| Visual Acuity in Affected Eye | |||||||||
| ≥6/24(%) | 25 (35.7%) | ||||||||
| <6/24 – 6/60(%) | 08 (11.4%) | ||||||||
| <6/60 0R WORSE (%) | 37 (52.9%) | ||||||||
| Mean (SD) IOP in Affected Eye | 13.94 (±4.81) mmHg | ||||||||
| Duration | |||||||||
| Acute | 31(55.35%) | ||||||||
| Chronic | 25(44.64%) | ||||||||
| Anatomical type of Uveitis | |||||||||
| Anterior | 10 (13.9%) | ||||||||
| Intermediate | 09 (12.5%) | ||||||||
| Posterior | 17 (23.6%) | ||||||||
| Panuveitis | 36 (50%) | ||||||||
| Scleritis with AU | 01 (1.4%) | ||||||||
| Scleritis with Panuveitis | 03 (4.2%) | ||||||||
| Anterior Segment Findings | |||||||||
| Granulomatous KP | 29 (40.3%) | ||||||||
| Nongranulomatous KP | 23 (31.9%) | ||||||||
| No KP | 20 (27.8%) | ||||||||
| AC Reaction | 67 (93.1%) | ||||||||
| Hypopyon | 05 (7.0%) | ||||||||
| PAS | 04 (7.14%) | ||||||||
| PS | 14 (25%) | ||||||||
| Iris Granulomas | 03 (4.2%) | ||||||||
| Cataract | 20 (27.8%) | ||||||||
| Pseudophakia | 14 (19.4%) | ||||||||
| Posterior Segment Findings | |||||||||
| CME | 20 (27.8%) | ||||||||
| Vitritis | 67 (93.1%) | ||||||||
| Retinitis | 20 (27.8%) | ||||||||
| Choroiditis | 10 (13.9%) | ||||||||
| Vasculitis | 13 (18.1%) | ||||||||
| Serous/Exudative RD | 10 (13.9%) | ||||||||
| Choroidal Granuloma | 10 (13.9%) | ||||||||
| Disc Granuloma | 04 (5.6%) | ||||||||
| Chorioretinal Scar | 14 (19.4%) | ||||||||
| Immune Status | |||||||||
| Immunosuppressants | 05 (8.9%) | ||||||||
| Uncontrolled DM | 01 (1.8%) | ||||||||
| HIV | 03 (5.4%) | ||||||||
| Past H/O TB | 14 (25%) | ||||||||
| CT Thorax Showing Evidence of TB | 07 (12.5%) | ||||||||
| Patients with PPD Test ≥ 15MM | 17 (30.4%) | ||||||||
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IOP = Intraocular pressure, AU = Anterior uveitis, KP = Keratic precipitate, PAS = Peripheral anterior synechiae, PS = Posterior synechiae, CME = Cystoid macular edema, DM = Diabetes mellitus, HIV = Human immunodeficiency syndrome, TB = Tuberculosis, CT = Computerised tomography, PPD = Purified protein derivative
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| TABLE 2. Describes the PCR results in different groups | |||||||||
| Total no of PCR Positivity for MTB | 24 (42.85%) | ||||||||
| No. Of PCR MTB + IN AC tap (N=14) | 08 (57.14%) | ||||||||
| No. Of PCR MTB + IN Vitreous tap (N=28) | 11 (39.28%) | ||||||||
| No. Of PCR MTB + IN Vitreous Biopsies (N=14) | 05 (35.71%) | ||||||||
| PCR Positivity | |||||||||
| Acute Uveitis (N=31) | 16 (51.61%) | ||||||||
| Chronic Uveitis (N=25) | 08 (32%) | ||||||||
| Anterior Uveitis (N=10 eyes) | 05 (50%) | ||||||||
| Intermediate Uveitis (N=9 eyes) | 03 (33.3%) | ||||||||
| Posterior Uveitis (N=17 eyes) | 05 (29.4%) | ||||||||
| Pan Uveitis (N=36 eyes) | 09 (25%) | ||||||||
| AU with Scleritis (N=1 eye) | 01 (100%) | ||||||||
| Pan Uveitiswith Scleritis (N=3 eyes) | 01 (33.3%) | ||||||||
| PCR MTB = Polymerase chain reaction Mycobacterium Tuberculosis, AC = Anterior chamber, AU = Anterior uveitis | |||||||||
| TABLE 3. Describes the correlation of the PCR results with the treatment response and the sensitivity and specificity of the PCR test | |||||||||
| Clinical response | No clinical response | Total | |||||||
| PCR + | 22 | 2 | 24 | ||||||
| PCR – | 08 | 24 | 32 | ||||||
| 30 | 26 | 56 | |||||||
| Sensitivity | Specificity | Positive Predictive value | Negative Predictive Value | ||||||
| 73.3% | 92.3% | 91.7% | 75% | ||||||
| TABLE 4.Analysis of the change in the treatment plan after PCR results | |||||||||
| Clinically suspected TB Uveitis and treatment initiated for MTB | 26 (46.42%) | ||||||||
| Anti TubercularTreatment (ATT) not started | 30 (53.57%) | ||||||||
| Change in initial Treatment | 25 (83.33%) | ||||||||
| No. of Patients started on ATT after PCR results | 8 (32%) (6 PCR +VE and 2 –VE) | ||||||||
| No. of Patients in whom ATT was stopped after PCR results | 4 (16%) (PCR –VE in all 4) | ||||||||
| No. of Patients in whom ATT was not started even after + PCR MTB result | 1 (4%) (Clinical picture of ARN) | ||||||||
| ATT = Anti tubercular therapy, PCR = Polymerase chain reaction, MTB = Mycobacterium Tuberculosis, ARN = Acute retinal necrosis | |||||||||