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Lethal disseminated tuberculosis in patients under biological treatment – two clinical cases and a short review

Tumour necrosis factor (TNF)-α inhibitors are highly used in Romania for the treatment of autoimmune disorders, such as rheumatoid arthritis (RA), psoriasis, inflammatory bowel diseases, and ankylosing spondylitis. Biological therapy using TNF-α inhibitors is very effective but is associated with an increased risk of opportunistic infections, including active tuberculosis. Here, two cases are presented of patients with RA and psoriasis under biological therapy who developed very aggressive forms of disseminated tuberculosis, with a rapid progression to death. The authors conclude that patients undergoing biological therapy require thorough evaluation prior to initiating treatment, followed by continuous and rigorous monitoring by a multidisciplinary team during biological treatment, particularly in countries with a high incidence of tuberculosis.


Introduction
The use of tumour necrosis factor (TNF)-a inhibitor therapy in patients diagnosed with autoimmune diseases, such as rheumatoid arthritis (RA) and psoriasis, has proven highly effective in suppressing the pathologic inflammation responsible for specific symptoms and joint damage, but is associated with a decrease in host defence against opportunistic infections, including active tuberculosis (TB). [1][2][3][4] All anti-TNF drugs are associated with an increased risk of TB reactivation in patients positive for latent TB infection, with a lower risk associated with etanercept, 5,6 and a consistent number of cases have also been reported from countries with a low TB incidence (less than 20 per 100 000 population per year). 7 Cases of tuberculosis have been described in patients with known RA even before starting biological therapy, particularly in countries with high incidence of TB. 8 Only a few cases with rapid progression to death due to disseminated forms of TB have been reported to date, however. 9,10 Romania has a relatively high incidence of TB (70 per 100 000 inhabitants), 11 and like other countries, biological treatment is frequently used, thus, monitoring of the adverse effects of this therapy must be very rigorous, multidisciplinary, and well established in active national guidelines. The tuberculin skin test (Statens Serum Institut, Copenhagen, Denmark) and QuantiFERON-TB Gold in-tube assay (Cellestis Ltd, Carnegie, Victoria, Australia) are used in Romania to screen for latent TB infection.
Here, two cases are presented of patients with RA and psoriasis, treated using biological therapy, who developed very aggressive forms of disseminated tuberculosis. These cases are presented due to the unusual clinical features, unexpected severity, and fast progression to death.

Case reports
Approval to publish the present findings was provided by the Ethics committee of the Clinical Pneumology Hospital of Constanta (Case 1) and the Ethics committee of the Clinical Infectious Diseases Hospital of Constanta (Case 2) and each patient provided written informed consent on admission to hospital.

Case 1
A 72-year-old female patient was admitted to the First Internal Medicine Department of Constanta County Clinical Emergency Hospital in December 2015, for fever, chills, severe asthenia, productive cough, polyarthralgia, with symptomatology that had worsened over the previous 3 days. Medical  Bacteriological examination of blood culture was sterile and sputum samples were negative for pyogenic bacteria, fungi, and acid-fast bacillus. Standard chest X-ray ( Figure 1) showed multiple micronodular and nodular pale opacities, disseminated in both lungs. The investigations were extended using thoracic computed tomography (CT) and revealed a bronchopneumonic aspect, mediastinal lymphadenopathy (between 12 and 20 mm), and straight lymph node calcifications ( Figure 2). Antibiotic and antifungal treatment was initiated, comprising 1 g ceftazidinum twice daily and 400 mg/250 ml moxifloxacin once daily, plus 200 mg fluconazole once daily, all administered intravenously (i.v.). On day 4 of treatment, ceftazidinum was replaced with 1 g meropenem i.v., three times daily, and the treatment continued for a further 10 days, while previous treatment remained the same for the entire treatment duration. This treatment regimen was without good patient progression. Abdominal ultrasound, performed on the first day of hospitalization and repeated on day 5 due to poor patient progression, indicated     12 Physical examination did not reveal pathological signs. Biological tests were without significant or specific abnormalities: normal haemogram, fibrinogen, alanine transaminase, aspartate aminotransferase, creatine kinase-muscle/brain, creatinine, and urea, but elevated ESR (68 mm/h), blood glucose (195 mg/dl) and troponin level (199.2 mg/l). Myocardial infarction was excluded, but the patient's general condition deteriorated during hospitalization, the level of consciousness decreased, and fever with signs of meningeal irritation appeared five days following hospital admission. She was diagnosed with acute meningoencephalitis with a Glasgow coma scale score of 6 and was admitted to the Intensive Care Unit. Analyses of cerebrospinal fluid (CSF) revealed: intense positive Pandy's reaction (þþþþ), 235 cells/ml (85% polymorphonuclear leukocytes and 15% lymphocytes), increased albumin (132 mg/dl), hypoglycorrhachia (glucose, 0.31 g/l) and hypochlorrhachia (chloride, 9.20 mmol/l [6.35 g/dl]). Bacteriological examination showed the CSF to be positive for acid-fast bacillus (Ziehl-Neelsen staining), positive for TB nucleic acid using GeneXpert (Cepheid, Sunnyvale, CA, USA) with no detection of rifampin resistance, and positive for M. tuberculosis in liquid culture, tested using the BD BACTEC TM MGIT TM system. Chest X-ray showed a miliary TB pattern (not shown). The patient was confirmed as a new case of disseminated TB in a patient recently treated with infliximab for psoriasis. Specific anti-TB chemotherapy with four first-line drugs, as in the previous case (5 mg/kg/day isoniazid, 10 mg/kg/day rifampicin, 30 mg/kg/day pyrazinamide and 25 mg/kg/day ethambutol), oral administration, was started. Three days following initiation of treatment for TB, the patient presented upper digestive haemorrhage exteriorized by melena. Despite all aggressive treatment, the patient died with cardiorespiratory failure after 16 days of hospitalization.

Discussion
Incidence of RA in Romania is approximately 1% of the general population, and incidence of psoriasis is approximately 2%. 12 In these population groups, the prevalence of latent TB infection remains unknown. In patients diagnosed with RA and psoriasis, TNF-a blockers are initiated only in patients who are unresponsive to conventional treatment, and after careful exclusion of latent TB infection. 2,3,12,13 Romanian guidelines stipulate that prior to administration of biological treatment, the patient should follow an algorithm to identify latent TB infection, and chemoprophylactic treatment should be administered for 9 months in patients who have a positive tuberculin skin test, (tuberculin skin test, 10 mm, and without signs of active disease). 11 Despite pretreatment evaluation, it is well known that the use of TNF-a inhibitor therapy is associated with an increased risk of active TB. [12][13][14][15] The current report presents the cases of two female patients, both over 65 years old, with a long history of RA and psoriatic arthritis, who were diagnosed with TB after starting biological treatment, despite both being confirmed negative for latent TB infection prior to initiation of treatment. Neither of the cases had been recently exposed to TB, making it difficult to support an exogenous reinfection mechanism for TB. The possibility of a false-negative tuberculin skin test and negative QuantiFERON-TB Gold assay need to be taken into consideration, due to immunosuppression caused by disease or chronic anterior immunosuppressive therapy, 16,17 making the reactivation of postprimary TB lesions more feasible. Moreover, use of the tuberculin skin test is more controversial for a patient with psoriasis due to the possibility of overdiagnosis or ambiguous results. 18 Despite the fact that in many national guidelines the tuberculin skin test remains the firstline tool to screen for latent TB infection in patients with psoriasis, it is recommended that the QuantiFERON-TB Gold test is also performed, either before or on the same day as the Mantoux test, to increase the accuracy of diagnosis. 18 Unusual clinical features in adults with disseminated pulmonary and extrapulmonary TB (peritoneal and meningitis), may delay diagnosis for 5 to 15 days, leading to an increased risk of mortality (authors' personal experience). In Romania, meningitis is more frequently observed as a complication of primary TB in infants and is a very rare complication in adults. 19 Knowing the paucibacillary character of serositis, the present authors consider that the positive acid-fast bacillus smear for CSF (case 2) and positive GeneXpert and liquid culture for M. tuberculosis for ascites (case 1) reflect the severity of the disease. Published studies report a positive rate for acid-fast bacillus smear in TB meningitis of between 37 and 58%. 20,21 For both cases reported in the current study, death was considered to be related to disseminated TB, and it is unclear whether the occurrence of superior digestive haemorrhage aggravated the patients' prognosis. The anti-TB treatment cannot be directly associated with this haemorrhage complication, as administration was intravenous in case 1, and the complication preceded the start of treatment in case 2.
Medical professionals should be aware of the unusual pattern of TB in patients undergoing biological treatment. 22 For example, extrapulmonary or disseminated tuberculosis are more frequently observed in patients treated with TNF-a inhibitors. 7,23 A review of 70 cases of TB that developed after treatment with infliximab showed an increased proportion of extrapulmonary TB (56% versus 18%) and disseminated diseases (18% versus 2%), when associated with a severe immunosuppression status (including HIV positivity). 22 The four deaths out of 70 patients in this study were related to TB, 22 however, in patients receiving biological treatment, very few deaths related to TB have been reported in the literature. 9,10 The number of TB cases has been reported in the literature to be higher for infliximab than adalimumab, 22,24 however, two studies (one French and one English) reported that the incidence of TB was higher for adalimumab. 5,6 The interval from starting anti-TNF-a treatment until TB onset was 6 months in the present first case (treated with adalimumab), which was shorter than in a published study reporting median time to TB onset of 18.5 months for 11 patients treated with adalimumab, 6 and was more comparable with timeframes reported for patients treated with infliximab. 3,22,25 Clinical deterioration despite specific anti-TB treatment has been reported in cases of RA treated with adalimumab, due to a paradoxical reaction involving the lungs, with acute respiratory failure attributed to the recurrence of disease in the absence of biological treatment. 23,26,27 The onset of paradoxical reaction is considered one month after TB diagnosis and treatment. 23,27 In the present cases, it is difficult to maintain that death was attributed to a paradoxical reaction, because it occurred soon after starting the anti-TB treatment (7 days for case 1, and 3 days for case 2), but after 4 weeks from the last dose of adalimumab and 8 weeks from the last dose of infliximab. Unfortunately, procalcitonin level, a possible diagnostic and prognosis marker for paradoxical reaction, 23 was not tested in either case. The moment of restarting therapy with TNF-a inhibitors during or following the end of anti-TB treatment differs between guidelines. It is possible to restart after 2 months, 28 but it is mandatory to pay close attention to TB evolution during follow-up. 29 In conclusion, because of the high endemic value of TB in Romania, 30 and given the severe forms presented by these cases, there is ongoing discussion as to whether or not chemoprophylaxis with isoniazid should be provided in all cases before anti TNF-a treatment, even if the first screening excludes latent TB infection. In addition, old age, female sex, long history of autoimmune disease, and association of other comorbidities, such as diabetes, digestive haemorrhage, and HIV infection, could be risk factors for developing disseminated and lethal forms of TB during biological treatment with infliximab and adalimumab. Etanercept may be a more beneficial anti-TNF-a treatment given its relatively low incidence rate of TB, for patients in which this therapy is mandatory. 31 In cases at high risk of TB reactivation, the choice of a non-anti-TNF targeted biologic is advisable. 31 Declaration of conflicting interest