Interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review

A major challenge in tuberculosis control is the diagnosis and treatment of latent tuberculosis infection. Until recently, there were no alternatives to the tuberculin skin test (TST) for diagnosing latent tuberculosis. However, an alternative has now emerged in the form of a new in-vitro test: the interferon-gamma assay. We did a systematic review to assess the performance of interferon-gamma assays in the immunodiagnosis of tuberculosis. By searching databases, contacting experts and test manufacturers, we identified 75 relevant studies. The results suggest that interferon-gamma assays that use Mycobacterium tuberculosis-specific region of difference 1 (RD1) antigens (such as early secretory antigenic target 6 and culture filtrate protein 10) may have advantages over the TST, in terms of higher specificity, better correlation with exposure to M tuberculosis, and less cross-reactivity due to BCG vaccination and non-tuberculous mycobacterial infection. However, interferon-gamma assays that use RD1 antigens in isolation may maximise specificity at the cost of sensitivity. Assays that use cocktails of RD1 antigens seem to overcome this problem, and such assays have the highest accuracy. RD1-based interferon-gamma assays can potentially identify those with latent tuberculosis who are at high risk for developing active disease, but this requires confirmation. There is inadequate evidence on the value of interferon-gamma assays in the management of immunocompromised individuals, children, patients with extrapulmonary or non-tuberculous mycobacterial disease, and populations in countries where tuberculosis is endemic. Current evidence suggests that interferon-gamma assays based on cocktails of RD1 antigens have the potential to become useful diagnostic tools. Whether this potential can be realised in practice remains to be confirmed in well designed, long-term studies.     

Death associated with rifampin and pyrazinamide 2-month treatment of latent mycobacterium tuberculosis

We present the case of an elderly patient who died of fulminant hepatic failure in the course of receiving 2 months of treatment with pyrazinamide and rifampin for his latent tuberculosis. This 2-month course of treatment for latent tuberculosis is one of four options recently recommended by the Centers for Disease Control and Prevention. We discuss the safety of using this two-drug regimen to treat latent tuberculosis in stable elderly patients.     

Rifampicin plus pyrazinamide versus isoniazid for treating latent tuberculosis infection: a meta-analysis.

SETTING: Six trials from Haiti, Mexico, the U.S.A., Brazil, Spain, Zambia and Hong Kong. OBJECTIVE: To evaluate the efficacy and safety of rifampicin plus pyrazinamide (RZ) vs. isoniazid (INH) for the prevention of tuberculosis (TB) among persons with or without human immunodeficiency virus (HIV) infection. DESIGN: Meta-analysis of randomised controlled trials (RCTs) and quasi-RCTs that compared RZ for 2-3 months with INH for 6-12 months. Endpoints were development of active TB, severe adverse effects and death. Treatment effects were summarised as risk difference (RD) with 95% confidence intervals (CI). RESULTS: Three trials conducted in HIV-infected patients and three trials conducted in non-HIV-infected persons were identified. The rates of TB in the RZ group were similar to those in the INH group, whether the subjects were HIV-infected or not (HIV-infected patients: pooled RD = 0%, 95% CI -1-2, P = 0.89; non-HIV-infected persons: pooled RD = 0%, 95% CI -2-1, P = 0.55). There was no difference in mortality between the two treatment groups (HIV-infected patients: pooled RD = -1%, 95% CI -4-2, P = 0.53; non-HIV-infected persons: pooled RD = 0%, 95% CI -1-1, P = 1.00). However, both subgroup analyses showed that a higher incidence of all severe adverse events was associated with 2RZ than INH among non-HIV-infected persons (RD = 29%, 95% CI 13-46, P = 0.0005 vs. RD = 7%, 95% CI 4-10, P < 0.0001). CONCLUSION: RZ is equivalent to INH in terms of efficacy and mortality in the treatment of latent tuberculosis infection. However, this regimen increases the risk of severe adverse effects compared with INH in non-HIV-infected persons.     

Donor‐derived tuberculosis (TB): isoniazid‐resistant TB transmitted from a lung transplant donor with inadequately treated latent infection

Donor‐derived tuberculosis (TB) is an increasingly recognized complication of solid organ transplantation. We report a case of isoniazid‐resistant pulmonary TB in a lung transplant recipient. The patient acquired the infection from the lung donor who was previously empirically treated with isoniazid for latent TB. The case highlights the caveat that, while adequate treatment of latent TB with isoniazid is presumed, meticulous screening of donors is required.     

Latent tuberculosis infection: recommendations for preventive therapy in adults in Germany

The immunologic mechanisms of latent tuberculosis (TB) infection are complex and hitherto not completely understood. The lifelong risk of an immunocompetent individual of developing active TB after infection with M. tuberculosis is 5-10 % and highest during the first two years after infection. Various factors may considerably increase the risk of developing active TB, e. g., immunosuppressive disease or immunosuppressive medication. However, the development of active TB may be avoided by preventive chemotherapy, the therapy of choice being isoniazid over a 9-month period. Alternative treatment regimens may be indicated in special cases, but it must be borne in mind that the efficacy of these regimens has not been studied sufficiently while they seem to be less well tolerated than isoniazid monotherapy. The tuberculin skin test is still the only sufficiently documented method to detect latent infection with M. tuberculosis which is also suitable for routine application. This test today should be performed exclusively as described by Mendel and Mantoux. Its sensitivity and specificity depend on the prevalence of tuberculosis infection. It should therefore be restricted to individuals at increased risk of latent TB infection. When interpreting the tuberculin skin test, it is necessary to know whether an individual belongs to one of the defined risk groups or has an elevated risk of developing active TB. Among the risk groups are individuals who may have been infected recently with M. tuberculosis (contacts of contagious TB patients) or in whom other factors increase their risk of developing active TB. The indication for chemotherapy for latent TB infection must be based on a careful individual risk-benefit analysis and, besides patient compliance, requires full information of the patient and careful monitoring during therapy. Before initiating treatment, active TB must always be excluded by the proven methods.     

Enumeration of T cells specific for RD1-encoded antigens suggests a high prevalence of latent Mycobacterium tuberculosis infection in healthy urban Indians

Knowledge of the prevalence of latent Mycobacterium tuberculosis infection is crucial for effective tuberculosis control, but tuberculin skin test surveys have major limitations, including poor specificity because of the broad antigenic cross-reactivity of tuberculin. The M. tuberculosis RD1 genomic segment encodes proteins, such as early secretory antigenic target (ESAT)-6, that are absent from M. bovis bacille Calmette-Guérin (BCG) and most environmental mycobacteria. We recently identified circulating ESAT-6-specific T cells as an accurate marker of M. tuberculosis infection. Here, interferon-gamma-secreting T cells specific for peptides derived from ESAT-6 and a second RD1 gene product, CFP10, were enumerated in 100 prospectively recruited healthy adults in Bombay (Mumbai), India. Eighty percent responded to >/=1 antigen, and many donors had high frequencies of T cells that were specific for certain immunodominant peptides. In contrast, of 40 mostly BCG-vaccinated, United Kingdom-resident healthy adults, none responded to either antigen. This study suggests an 80% prevalence of latent M. tuberculosis infection in urban India.     

Rifampin plus pyrazinamide-induced hepatitis requiring hospitalization in a 30-y-old male with latent tuberculosis

The case of a 30-y-old male with latent tuberculosis who developed chemical hepatitis requiring hospitalization after 50 d of treatment with rifampin and pyrazinamide is reported. This case justifies the CDC guidelines that were updated on 31 August 2003 advising against the use of this brief regimen for patients with latent tuberculosis due to its risk for hepatotoxicity.     

重庆市一起学校肺结核聚集性疫情调查分析

目的: 对重庆市一起学校肺结核疫情进行调查和分析,为强化学校结核病防控工作提供思路和建议。方法: 采用描述性流行病学方法,对重庆市2020年12月至2021年5月一起学校肺结核疫情进行流行病学调查和分析。采用症状筛查、结核菌素皮肤试验(tuberculin skin test,TST)和胸部X线摄片(简称“胸片”)开展肺结核筛查,并对接触者开展流行病学调查。结果: 在确诊1例病原学阳性肺结核病例(指示病例)后,经过4次接触者筛查及1次随访检查,检出8例活动性肺结核患者和42例结核分枝杆菌潜伏感染者。校内8例学生患者均集中在指示病例所在班级,该班肺结核罹患率为12.7%(8/63),病原学阳性者占2/8,结核分枝杆菌潜伏感染者34例,潜伏感染率为61.8%(34/55),均全部完成预防性治疗。指示病例所在班级学生发病风险和感染风险均高于其他班级(RR=27.6,95%CI:13.5~56.4)。校内8例学生肺结核患者中,男生6例,女生2例,年龄分布以15岁组最多(6例)。因首次接触者筛查胸片质量差,未能及时发现学生患者,导致后续因症就诊发现3例患者。2例学生潜伏感染者因未规范服药,在预防性治疗期间转为肺结核患者。 结论: 本次肺结核疫情聚集性明显,筛查质量低、未能规范完成预防性治疗是疫情蔓延的重要原因。在处置学校肺结核疫情时,应提高筛查质量,根据流行病学调查情况充分考虑窗口期问题,保证预防性治疗的规范性和完成率。     

Tuberculous peritonitis during infliximab therapy

Reactivation of tuberculosis is a severe side effect of anti-TNF treatment. Especially extrapulmonary forms of tuberculosis may occur, which are difficult to diagnose. The diagnosis may be obtained by a thorough search for Mycobacterium tuberculosis. We describe two patients who developed tuberculous peritonitis after infliximab therapy that was prescribed for treatment of rheumatoid arthritis. These cases illustrate that tuberculous peritonitis has a nonspecific clinical manifestation and that Mycobacteria can be difficult to find in ascites fluid. For this reason, tuberculostatic therapy has to be started in case of clinical suspicion. Before starting infliximab therapy, the patient must be thoroughly screened for the presence of (latent) tuberculosis.     

Corticosteroids and immunosuppressive therapy influence the result of QuantiFERON TB Gold testing in inflammatory bowel disease patients

IntroductionLatent tuberculosis infection is detected by the tuberculin skin test before treating with anti-Tumour-Necrosis factor alpha (anti TNFα) reagents. More accurate are Interferon gamma release assays (IFNγ release assays) to identify patients with latent tuberculosis. Because of a positive control in this assay, it is possible to identify those patients in which a result of tuberculosis testing is not available due to a lack of stimulation capacity of lymphocytes (indeterminate result). Patients suffering from IBD are often treated with immunosuppressive agents, which may influence the results of tuberculosis testing.AimThe aim is to investigate the influence of immunosuppressive agents on the outcome of IFNγ-release assay.Methods50 consecutive patients were documented before introducing anti-TNF-treatment in this single centre study between April 2009 and April 2010. Data of INFγ release assay for latent tuberculosis, skin test and laboratory data and current medication were enrolled.ResultsFor the period of one year data of 45 consecutive patients was available for statistical analysis. 24 patients out of 45 (corresponding to 53.3%) received at least low doses of corticoid treatment and 27 patients out of 45 (corresponding to 60.0%) received immunosuppressive agents. 13 patients out of 45 (corresponding to 28.9%) had an indeterminate result of the QuantiFERON test. A correlation between the indeterminate result and combination therapy of corticosteroids was found. The concomitant therapy of immunosuppressive agents lead to a lower IFN release but no significance was found.ConclusionsSteroid treatment and further combination therapy with immunosuppressive agents lead to a high risk of indeterminate QuantiFERON test.     

上海市中心城区某幼儿园一例肺结核患者密切接触者筛查情况分析

目的 分析上海市中心城区某幼儿园1例肺结核患者密切接触者筛查情况,为完善托幼机构结核病防控提供依据。方法 分别于2019年2月15日和2019年3月14日对2019年1月14日确诊的上海市中心城区某幼儿园1例肺结核教职工的128名密切接触者进行流行病学筛查,包括肺结核疑似症状筛查、结核分枝杆菌潜伏感染检测[γ干扰素释放试验(interferon-γ releaseassays,IGRA)]、胸部X线摄片或CT检查,以及痰涂片和痰培养;并对不同特征密切接触者(性别、卡介苗接种情况、有无疑似肺结核症状、近期呼吸系统疾病就诊史、暴露等级)的潜伏感染情况进行分析。结果 128名密切接触者中,幼儿107名(83.59%),教职工21名(16.41%)。疑似肺结核症状阳性率为5.47%(7/128),其中幼儿为5.61%(6/107),教职工为4.76%(1/21)。两次筛查中,共125名密接者(3名幼儿拒绝检测)进行了IGRA检测,阳性者11例(8.80%),包括幼儿4例(3.20%),教职工7例(5.60%)。肺结核的检出率为0.78%(1/128),总潜伏感染率为8.06%(10/124;排除1例确诊和3名未进行IGRA检测的幼儿),其中幼儿的潜伏感染率[2.91%(3/103)]明显低于教职工[33.33%(7/21)],差异有统计学意义(χ²=21.773,P=0.000)。7例潜伏感染教职工进行了3、6、12个月末的胸片随访,3例潜伏感染幼儿进行了3个月的预防性抗结核药品干预治疗;经1年随访观察均无续发结核病患者。单因素分析显示,接种卡介苗者的潜伏感染率[5.13%(6/117)]与未接种者(4/7)比较,差异有统计学意义(Fisher精确概率法,P=0.001);高暴露等级者的潜伏感染率[17.07%(7/41)]明显高于中暴露等级者 [3.61%(3/83)],差异有统计学意义(χ²=5.012,P=0.025)。结论 应加强托幼机构教职员工健康体检,积极行IGRA检测筛查结核病患者密切接触者,尤其是无卡介苗接种史和高暴露者。对结核分枝杆菌潜伏感染者行预防性服药或胸片随访对防止续发肺结核有重要意义。     

Application and problems of quantiFERON TB-2G for tuberculosis control programs--(2) clinical use of quantiFERON TB-2G

BACKGROUND: QuantiFERON TB-2nd Generation (QFT) is an accurate tool for detecting tuberculosis infection regardless of past history of BCG vaccination. In Japan, QFT test was recognized for diagnostic tool on April 2005, and adopted officially on January 2006. Tuberculosis Society issued Guideline for using QFT-2G on May 2006. PURPOSE: This article describe the usefulness and remarks in clinical use on diagnosis and system for detection of tuberculosis infection among staff in NHO Tokyo Hospital that has 100 beds for tuberculosis. METHOD: (1) QFT test for 403 definite diagnosed tuberculosis patient before tuberculosis treatment or within 7 days chemotherapy in NHO Tokyo Hospital. Seventy-four patients have immunosuppressive diseases such as diabetes mellitus, malignant disease, using corticosteroid or immunosuppressor and HIV+ including overlap diseases. QFT result was analyzed by immunosuppressive diseases and by age for 329 patients who have no immunosuppressive diseases. (2) For control of tuberculosis infection of staff, QFT test is used in 3 situation. One is baseline QFT for staff who are shifted to tuberculosis ward from non-tuberculosis ward and new employee, 2nd is following up for staff who work at tuberculosis ward, and 3rd is contact investigation for staff who work at non-tuberculosis ward. Tuberculin skin testing and baseline QFT were done for 92 staff on April 2006, 2 were shifted to tuberculosis ward from non-tuberculosis ward and 90 were new employee. RESULT: (1) Among 403 definite diagnosed tuberculosis patient before tuberculosis treatment or within 7 days chemotherapy, QFT positive rate was 78.7%. Among 74 patients who have immunosuppressive diseases such as diabetes mellitus, malignant disease, using corticosteroid or immunosuppressor and HIV+ including overlap diseases, QFT positive rate was 58-70%. Among 329 patients who have no immunosuppressive diseases, QFT positive rate was 88-89% in thirties and forties, 69% in sixties and 63% in nineties. QFT-2G test for 134 previously treated tuberculosis cases who are not suffered from active tuberculosis, 49 cases (37%) were positive, 27 cases (20%) were intermediate and 58 cases (43%) were negative. Instructive three cases were reviewed. Suspicion of tuberculosis relapse with QFT negative case was M. avium-intracellulare disease. Suspicion of M. avium-intracellulare disease rather than tuberculosis by X-ray and CT with QFT positive case was tuberculosis. A case with small nodule on CT with QFT positive was adenocarcinoma. (2) Tuberculin Skin Testing and baseline QFT for 92 staff, 4 were QFT positive. Compared with Tuberculin Skin Testing more than 29 mm in erythema, QFT positive rate was 9% and more than 9 mm in induration, QFT positive rate was 7%. By following up QFT test for staff working at tuberculosis ward, 2 staff, one nurse and one helper, were diagnosed tuberculosis infection. As to contact investigation, one nurse was diagnosed tuberculosis infection. CONCLUSION: Although QFT is a very excellent tool for detecting tuberculosis infection, on clinical diagnosis, it is important to mind that QFT depends on clinical condition especially immunosuppressive diseases, aging and past infection. We cannot diagnose or exclude active tuberculosis by QFT result. This is a useful assistant tool on clinical diagnosis.     

Tuberculosis and biologics in rheumatology: A special situation

India has a huge patient burden of rheumatic diseases (RDs) including rheumatoid arthritis. The use of biologics has transformed the treatment paradigm for RD; however, biologic treatment‐related infections (especially tuberculosis [TB]) are an area of potential concern for TB‐endemic nations like India. Anti‐tumor necrosis factor (TNF) therapy impairs the physiological TNF‐mediated signaling and may cause reactivation and dissemination of latent TB infection (LTBI). Careful screening is, thus, crucial in RD patients who are about to commence anti‐TNF treatment. To date, there is no consensus available for the screening, evaluation and treatment of LTBI as well as on the drug dosage and duration regimen (monotherapy or combination therapy) in the Indian population. An evidence‐based algorithm for LTBI screening and management in RD patients undergoing biologic disease‐modifying anti‐rheumatic drug therapy is suggested in this review for Indian rheumatologists. The proposed algorithm guides physicians through a step‐wise screening approach, including medical history, tuberculin skin test, interferon gamma release assay, chest radiograph and management of LTBI with isoniazid therapy or its combination with rifampicin. Further, the provided algorithm can aid the national bodies (such as National TB Control Program) in formulating recommendations for LTBI in this high‐risk population.     

Fluoroquinolones for the treatment of latent Mycobacterium tuberculosis infection in liver transplantation

Solid organ transplantation(SOT)is the best treatment option for end-stage organ disease.Newer immunosuppressive agents have reduced the incidence of graft rejection but have increased the risk of infection,particularly due to the reactivation of latent infections due to opportunistic agents such as Mycobacterium tuberculosis.Active tuberculosis(TB)after SOT is a significant cause of morbidity and mortality.Most cases of posttransplant TB are secondary to reactivation of latent tuberculosis infection(LTBI)due to the effects of long-term immunosuppressive therapy.Risk minimization strategies have been developed to diagnose LTBI and initiate treatment prior to transplantation.Isoniazid with vitamin B6 supplementation is the treatment of choice.However,liver transplantation(LT)candidates and recipients have an increased risk of isoniazid-induced liver toxicity,leading to lower treatment completion rates than in other SOT populations.Fluoroquinolones(FQs)exhibit good in vitro antimycobacterial activity and a lower risk of drug-induced liver injury than isoniazid.In the present review,we highlight the disease burden posed by posttransplant TB and summarize the emerging clinical evidence supporting the use of FQs for the treatment of LTBI in LT recipients and candidates.     

Biologic therapy and infections

Biologic therapy is an important therapeutic arsenal in rheumatic diseases. Anti-TNF therapies affect host defenses against infections, since TNF mediates inflammation and modulates cellular immune responses. Cases of tuberculosis have been observed in patients treated with TNF antagonists, mainly due to the presence of latent or "dormant" tuberculosis infection (LTB1). Other microorganisms responsible for the infectious complications associated with biologic therapy are generally intracellular pathogens or pathogens that commonly exist in a chronic latent state: Mycobacterium sp., Listeria monocytogenes, Legionella sp., Brucella sp., toxoplasmosis and deep mycoses, that are normally held in control by cell-mediated immunity. Diagnosis may require a high index of suspicion and prompt acquisition of appropriate tissue samples for microscopic examination and microbiologic culture. Patients who develop a new infection while undergoing treatment with biologic therapy should be monitored closely. Administration of anti-TNF should be discontinued if a patient develops a serious infection or sepsis. The relationship between TNF-inhibition and infection risk remains unclear, many of the serious infections have occurred in patients on concomitant immunosuppressive therapy that, in addition to severe rheumatic diseases, could predispose them to infections, and most reports present low level of evidence. Nevertheless, prompt diagnosis and empiric therapy infections is necessary to prevent mortality.     

阿达木单抗治疗强直性脊柱炎致播散性结核病一例并文献复习

目的 探讨应用阿达木单克隆抗体(简称“单抗”)治疗强直性脊柱炎致播散性结核病的临床特点、诊治要点和治疗转归。 方法 回顾性分析福建省福州肺科医院2019年6月10日收治的1例应用阿达木单抗治疗强直性脊柱炎致播散性结核病的临床资料、诊治经过及随访情况,并进行文献复习。以“adalimumab”和“disseminated tuberculosis”为检索词对PubMed数据库进行检索,以“阿达木单抗”和“播散性结核病”为检索词通过万方数据库和中国知网对中文文献进行检索,检索时间截止到2019年9月,经过筛选剔除,共获取相关文献34篇,其中中文文献0篇,英文文献34篇。删去重复的文献并剔除可能为阿达木单抗以外的肿瘤坏死因子α(TNF-α)致播散性结核病及TNF-α致其他播散性疾病的报道,共筛选出具备详细病例资料的文献8篇,共获得8例患者,结合本研究收集的患者,对其临床特征、诊断和治疗情况进行分析。 结果 本例患者为男性,28岁。因“强直性脊柱炎”接受阿达木单抗治疗,治疗2个月后出现咳嗽、气促、腹胀、发热,入院后经胸部CT、胸膜活检及支气管镜等检查,诊断为“播散性结核病(双肺、右侧支气管、胸腔、腹腔、心包、纵隔淋巴结、锁骨上淋巴结、腹腔淋巴结、盆腔淋巴结、脾)”。给予“3H-R-Z-E/9H-R-E”方案治疗,辅以异烟肼支气管局部雾化吸入,行抗结核药物治疗后症状改善。治疗第5个月,CT复查提示“肺部病变减少,纵隔内部分淋巴结肿大较前缩小,增厚的支气管管壁较前变薄,管腔较前通畅,胸、腹腔积液明显吸收。截止到2019年12月,患者仍处于规则的抗结核药物治疗中。文献检索后获得8例患者,加上本例,共9例患者。其中,男3例,女6例;年龄9~75岁,平均年龄(50.44±25.19)岁。9例患者中,5例开始使用阿达木单抗治疗之前的结核病筛查试验结果为阴性,1例既往有抗结核治疗史,1例曾进行过预防性抗结核治疗,3例有与结核病患者的密切接触史。诊断明确行抗结核药物治疗后,5例患者转归良好。3例转归差,其中1例病情持续进展,并发消化道出血;1例颅内病灶持续进展;1例出现急性呼吸窘迫综合征,最终死亡。1例转归不明。 结论 阿达木单抗可致播散性结核病,准备接受阿达木单抗治疗的患者均应在用药前进行结核病筛查,治疗过程中应该警惕潜伏性结核感染转为活动性结核病及新发结核感染,停用阿达木单抗和及时行抗结核药物治疗是预后良好的关键。     

Philippine guidelines on the screening for tuberculosis prior to the use of biologic agents

Aim: To develop practice guidelines in tuberculosis screening of patients and their households and close contacts, prior to the use of biologic agents. Method: A technical research committee formulated an evidence‐based draft, based on existing literature regarding the tests used in tuberculosis screening among immunocompromised patients. The evidence‐based draft was then circulated to an expert panel. An en banc meeting of the panelists was held and a consensus was declared if more than 50% agreed on a recommendation. Issues not resolved by consensus were discussed by correspondence and voted upon. The guidelines were presented in a public forum and feedback by stakeholders were reviewed and integrated into the final draft. Recommendations: 1. Patients for biologic therapy should be screened for latent and active tuberculosis prior to initiating treatment. 2. All patients who are candidates for biologic agents should be screened by tuberculin skin test for latent TB, and a chest radiograph for active tuberculosis. 3. Household and close contacts of candidate patients should be screened for active tuberculosis. 4. All household and close contacts of candidate patients should be screened for active TB using chest radiograph. 5. Treat latent and active tuberculosis according to local guidelines. 6. Delay treatment with biologic agents in patients with latent or active tuberculosis. 7. Administer tuberculosis prophylaxis to the patient for biologic therapy exposed to household contacts with active tuberculosis. Conclusion: These recommendations emphasize the importance of screening patients, household and close contacts for latent and active tuberculosis prior to initiating biologic therapy.     

Discriminating between latent and active tuberculosis with multiple biomarker responses

We sought to identify biomarker responses to tuberculosis specific antigens which could 1) improve the diagnosis of tuberculosis infection and 2) allow the differentiation of active and latent infections. Seventy subjects with active tuberculosis (N = 12), latent tuberculosis (N = 32), or no evidence of tuberculosis infection (N = 26) were evaluated. We used the Luminex Multiplexed Bead Array platform to simultaneously evaluate 25 biomarkers in the supernatant of whole blood samples following overnight stimulation using the Quantiferon(?) Gold In-Tube kit. We defined the response to stimulation as the difference (within an individual patient) between the response to the pooled tuberculosis antigens and the negative control. IP-10 response was significantly higher in tuberculosis-infected (active or latent) subjects compared to the uninfected group (p < 0.0001). Among the 25 parameters, expression levels of IL-15 and MCP-1 were found to be significantly higher in the active tuberculosis group compared to the latent tuberculosis group (p = 0.0006 and 0.0030, respectively). When combined, IL-15 and MCP-1 accurately identified 83% of active and 88% of latent infections. The combination of IL-15 and MCP-1 responses was accurate in distinguishing persons with active tuberculosis from persons with latent tuberculosis in this study.     

Multifocal progressive leukoencephalopathy occurring after refractory anemia and multiple infectious disorders consecutive to severe lymphopenia

Progressive multifocal leukoencephalopathy (PML) is related to central nervous system infection with JC virus (JCV). This leukoencephalopathy occurs in immunocompromised patients such as those with acquired immunodeficiency syndrome (AIDS) or lymphoid malignancies. We describe here a patient with myelodysplastic syndrome who developed several life-threatening infections including listeriosis, tuberculosis, and PML. Listeriosis and recurrence of tuberculosis preceded the occurrence of PML. Neurologic features associated with major ataxia, speech disorders, and PML were documented by cranial magnetic resonance imaging showing typical features in the cerebellum and proven by polymerase chain reaction (PCR) detection of JCV DNA in the cerebrospinal fluid. No specific treatment was decided because of progression toward acute myeloid leukemia. In this case, PML occurred with no susceptibility and without immunosuppressive treatment. Our case adds further support to the association between the impairment of T-cell immune responses and myelodysplastic disorders.     

Delayed response to anti-tuberculosis treatment in a patient on infliximab

The introduction of infliximab, an anti-TNF-alpha agent, in the treatment of rheumatic diseases has offered important therapeutic advances in recent years. The main adverse effect from the usage of this drug is susceptibility to infections, mainly reactivation of latent tuberculosis. We present a 23 year-old male with ankylosing spondylitis, who developed endobronchial and widespread pulmonary tuberculosis, 2 years after initiation of treatment with infliximab. The patient had already been treated for a positive PPD skin test with a 9-month prophylactic course of isoniazid. He was treated with a five drug anti-tuberculosis scheme but he showed an extremely slow therapeutic response with daily high fever, even 4 months after initiation of treatment. Seven months after beginning anti-tuberculosis therapy, bronchoscopy still revealed necrotic and inflammatory tissue at the site of the original lesions. This unusual clinical course of tuberculosis infection was attributed to immunosuppression due to the long-lasting anti-TNF-alpha action of infliximab.