Tuberculosis

Until the 1950s it was assumed that tuberculosis was by far the most common cause of uveitis.

This picture is outdated today, tuberculous uveitis is certainly a rarity in Europe and North America, but the incidence of new diseases is increasing. The resistance of the pathogens is growing, so that tuberculosis must certainly be considered much more frequently as a cause of uveitis.

  • INTRODUCTION

    After all, tuberculosis is still considered the world’s most common and most important systemic infectious disease, with 10 million new cases and almost 2 million deaths per year (WHO 2008). It can be assumed that about 1/3 of the world‘s population is infected, 95% of cases occur in developing countries. After years of declining incidence in Europe and North America until the end of the 1980s, the number of cases has risen continuously since the HIV epidemic began, so that tuberculosis is now also becoming a health problem in our country again.

    The prevalence of ocular tuberculosis is increasing in parallel to that of systemic infection. With less than 1% of infectious uveitis cases being attributed to tuberculosis in Europe and North America, even in larger centers. In Asia, especially in India, up to 10% of cases in the larger uveitis centers are classified as tuberculous, and incidences of 7 to 10.5% have been published for Japan and Saudi Arabia.

  • THE PATHOGEN AND ITS PREFERENCES

    The pathogen causing tuberculosis is the immobile acid-resistant Mycobacterium tuberculosis, an obligatory aerobic pathogen that is typically transmitted via droplet infection. The pathogen prefers oxygen-rich tissue. Lesions are typically found in the tip of the lung, in extrapulmonary infection in the choroid, which in relation to its volume is the tissue of the body with the best blood supply. After primary infection (primary TB), the infection usually enters an asymptomatic stage in healthy individuals (latent TB). The systemic spread of the pathogen can already occur at first contact, but in over 90% of cases extrapulmonary spread with pathogen dissemination occurs only secondarily as a result of a weakening of the immune system. Dissemination of tuberculosis (miliary tuberculosis) is found in patients with severe general diseases, malnutrition and cachexia, but especially in patients with immune deficiency. The classical risk groups include emigrants from epidemic areas and patients under immunosuppression and with HIV infection, as well as persons within medical professions.

  • CLINICAL PRESENTATION

    In 80% of the cases the disease remains limited to the lungs, in about 20% of the cases it spreads to other tissues. Interestingly, half of these patients show an unremarkable lung X-ray and every fifth patient has a negative tuberculin skin test. As mentioned above, patients with advanced HIV infection more often show extrapulmonary manifestations due to their immune deficiency. Only 10% of tuberculosis cases develop clinical symptoms, in half of the cases these occur within the first 1 to 2 years after infection. The majority of cases remain asymptomatic even in advanced infection, which explains the high spread of the infection. The typical triad of fever, night sweats and weight loss are observed in pulmonary and extrapulmonary manifestations, but is often absent in patients even with histologically confirmed ocular tuberculosis.

  • OCULAR TUBERCULOSIS

    Ocular changes caused by tuberculosis can be either primary and direct pathogen-related or secondary to the immune response in the tissue. Primary ocular tuberculosis is defined as infection as a result of primary penetration of the pathogens into ocular surface tissues; typically through the conjunctiva, cornea or sclera.

    Tuberculous uveitis is usually the result of secondary dissemination with hematogenic spread of the pathogen. In the anterior sections, anterior nodular scleritis, phlyctenular or interstitial keratitis with corneal infiltrates, anterior chamber irritation and iris granulomas or granulomatous anterior uveitis without focal lesions can be observed. However, the latter is almost always associated with posterior segment involvement. The “typical” tuberculous uveitis presents as a slowly progressive granulomatous panuveitis with anterior and posterior segment involvement. As well as speckled corneal fogging, iris nodules, posterior synechia and secondary glaucoma, but may occasionally also present as a non-granulomatous uveitis. Patients typically describe a slowly increasing visual disturbance, with increasing vitreous opacities and nebulae due to chronic macular edema. The most common clinical manifestation is a disseminating multifocal choroiditis with multiple discrete, yellowish impressive lesions from ½ to 1 ½ pd in diameter. Typically found mainly in the central choroid. In addition, papillary blurring, nerve fiber bleeding and a more or less severe granulomatous vitreous and anterior chamber infiltration may occasionally be seen. Quite rarely, on the other hand, solitary larger choroidal prominences, which can grow up to 5-papilla diameter, are observed with a surrounding serous detachment of the neuroretina and hard exudates (choroidal tuberculoma). It probably represents an early or special form of disseminating or miliary tuberculosis. Fluorescence angiographically, the choroidal foci show early hyper fluorescence and a secondary contrast agent pooling. Scarred lesions present as a fluorescence blockade with scar staning in the late phase. In ICG angiography the choroidal lesions appear hypo fluorescent in both early and late phase. Often, there are significantly more foci than are clinically apparent. Chronic tuberculous choroiditis can also sometimes manifest itself as serpiginous choroiditis, which is usually not very active and only very slowly progressive, as long as there is no advanced HIV infection. In the area of the retina, neuroretinal involvement will most likely result in peripheral retinal inflammation. Along with venous vessel occlusion, peripheral non-perfusion areas. However, only rarely with neovascularization and development of traction amotio. The picture of a unilateral peripheral occlusive retinal periphlebitis with recurrent vitreous hemorrhage, which typically occurs in young men and mostly without choroidal involvement, is known as Eales disease. It has been repeatedly attributed to ocular tuberculosis in recent years by detection of the pathogen from the vitreous and aqueous humor by PCR.

  • DIAGNOSIS

    For the diagnosis of tuberculous choroiditis, the detection of active pathogens from body fluids is considered standard. In many cases of ocular tuberculosis this is not possible. The suspected diagnosis cannot be clinically confirmed. This is only possible by observance of, and response to, anti-tuberculosis therapy. The purified protein derivative or PPD test and the y-interferon test (e.g. QuantiFERON-TB Gold) confirm the presence of the infection but not its activity and thus support the diagnosis. Whereas a false positive reaction, e.g. after vaccination, cannot be excluded even in the case of a strongly positive tuberculin test. Regardless of the redness, the skin test is only considered indicative if an induration of at least 10 to 15 mm or an ulceration 48 to 72 hours after intradermal tuberculin injection can be detected. An infiltration of 15 mm or more in diameter is considered a positive test. However, false-negative test results in up to 25% are also to be expected in patients with acute diseases. Those include: immune insufficiency or defect, under steroid treatment, malnutrition and sarcoidosis. False-positive test results often occur in cases of infection with atypical mycobacteria and, as already mentioned, after immunization (BCG vaccination).

    Tuberculosis testing (PPD-test or QuaniFERON-test) should only be carried out in case of clinical suspicion of tuberculosis. This is because in non-risk patients the diagnostic probability speaks against routine tuberculosis diagnostics. Diagnostics should occur only if there are indications of a recent exposure to tuberculosis or if the PPD test is strongly positive. If this is the case, a systemic infectious clarification with lung x-ray, microbiology of sputum, urine and gastric juice aspiration (if necessary cervical lymph node biopsy) to detect acid-proof rods, is useful. However, the diagnosis of tuberculosis cannot be ruled out even if all these tests are negative. In these cases, if the suspicion still exists, a vitreous or chorioretinal biopsy to confirm the diagnosis by PCR is useful (eubacterial PCR (detection of ribosomal RNA) or sensitive detection of tuberculosis-specific DNA sequences). If a chorioretinal biopsy is performed, cytological or histological search for acid-proof rods should of course also be performed.

  • THERAPY

    Systemic antibiotic combination therapy is indicated in patients with uveitis whose tuberculosis tests were primarily negative and became positive secondarily. This occurs even if lung x-rays and other systemic diagnostics do not provide any evidence of tuberculosis. Typically, a triple to quadruple combination therapy is carried out as a long-term therapy because of the frequently existing resistance to isoniazid (INH). Due to the extremely low replication rates of mycobacteria, the duration of therapy should be at least 3 to 6 months in order to avoid the selection of multi-resistant tuberculosis bacteria. Patients with poor therapy compliance and HIV infection have the highest risk of selecting resistant TB strains. Step by step therapy starts with INH, rifampicin and pyrazinamide for 2 months followed by a 4 to 6-month maintenance phase, usually with INH and rifampicin. If resistance to these drugs is detected by PCR techniques or resistance testing when living pathogens are cultivated, ethambutol or streptomycin are given as additional therapy over 4 months.

    Therapeutic problems arise mainly in patients with suspected ocular tuberculosis who show a positive tuberculin test, but otherwise no evidence of systemic tuberculosis infection. In this case a therapy is clearly justified based on this strongly positive skin test. In addition, controlling spread of infection under the often additionally required systemic and local steroid therapy, with regular lung x-rays is necessary. Since long-term steroid therapy without accompanying antibiosis in active tuberculosis leads to a progressive worsening. This also with the choroidal lesions. If pulmonary x-rays cannot reliably rule out pulmonary tuberculosis and a long-term steroid therapy is planned, prophylaxis with INH should be carried out for 6 months to a year. Under Biologica therapy, in particular TNF blocker therapy (Remicade), an INH prophylaxis of tuberculosis dissection is necessary in case of a positive TB skin test. This prophylaxis should be installed at least 3 weeks prior to the start of Biologica therapy, as under TNF blockers latent tuberculosis reactivates quite frequently.

    The additional local therapy of ocular manifestations depends on the extent of the inflammatory activity and secondary problems such as synechia formation, vitreous opacity and macular edema. This also includes secondary glaucoma and often requires surgical intervention as soon as the infectious activity is under control. The ocular changes usually do not react noticeably to therapy for several months.

  • SUMMARY

    In summary, ocular tuberculosis is to be understood as part of the extrapulmonary manifestation of systemic tuberculosis, and thus a rare disease which accounts for about 0.6 to 1% of infectious uveitis cases in our latitudes. The problem in diagnostics is that the infection is often not detected and thus the suspected diagnosis cannot be definitively excluded or confirmed but can only be substantiated by the course of the disease and the response to therapy. Skin test and y-interferon test can be false positive and false negative. Half of the cases of ocular manifestations show an inconspicuous lung x-ray in the sense of an extrapulmonary tuberculosis manifestation. Due to its rarity, the diagnosis is often made late, often only after exacerbation under systemic steroids or immunosuppression. For this reason, patients with granulomatous choroidal lesions, in which tuberculosis cannot be excluded, should be very well controlled clinically if a long-term steroid or immunosuppressive therapy is planned. If the skin test is positive, INH prophylaxis should be started at least three weeks before a planned Biologica therapy.