Clinical usefulness of 18F-FDG PET/CT for initial staging and assessment of treatment efficacy in patients with lymph node tuberculosis.

INTRODUCTION: Few studies have evaluated the promising role of 18F-fluoro-2-deoxy-D-glucose positron emission tomography (PET) and PET/computed tomography FDG PET/CT in evaluating and monitoring treatment response in patients with lymph node tuberculosis (LNTB). The aim of this clinical investigation was to assess the clinical usefulness of FDG PET/CT for initial tuberculosis staging and to determine the prognostic value of the decrease of 18F-FDG uptake during antibiotic treatment in LNTB patients. METHODS: We retrospectively reviewed 18 cases of LNTB admitted at a single center from 2004 to 2014. Medical records of patients who underwent two FDG PET/CT (>6 months interval), at initial staging and at the end of therapy were reviewed to determine the impact of FDG PET/CT on initial management of LNTB and response to therapy. Statistical analysis was performed using linear mixed-effects model. RESULTS: Thirteen cases of disseminated LNTB and five cases of localized LNTB were included in the study. Initial FDG PET/CT allowed guided biopsy for initial diagnosis in 5 patients and identified unknown extra-LN TB sites in 9 patients. Visual analysis follow-up of FDG PET/CT showed a complete metabolic response in 9/18 patients (all of whom were cured), a partial response in 7/18 (5 of whom were cured) and no response in 2/18 (all of whom were not cured). The semi-quantitative evaluation of 18F-FDG intensity decrease based on the maximum standardized uptake value (SUVmax), compared to targeted estimated decrease allowed to predict correctly a complete response to treatment in 14/18 cases. CONCLUSION: FDG PET/CT allows an accurate pre-therapeutic mapping of LNTB and helps for early TB confirmation. The SUVmax follow up is a potential tool for monitoring the treatment response.

Expression profiling of lymph nodes in tuberculosis patients reveal inflammatory milieu at site of infection.

Extrapulmonary manifestations constitute 15 to 20% of tuberculosis cases, with lymph node tuberculosis (LNTB) as the most common form of infection. However, diagnosis and treatment advances are hindered by lack of understanding of LNTB biology. To identify host response, Mycobacterium tuberculosis infected lymph nodes from LNTB patients were studied by means of transcriptomics and quantitative proteomics analyses. The selected targets obtained by comparative analyses were validated by quantitative PCR and immunohistochemistry. This approach provided expression data for 8,728 transcripts and 102 proteins, differentially regulated in the infected human lymph node. Enhanced inflammation with upregulation of T-helper1-related genes, combined with marked dysregulation of matrix metalloproteinases, indicates tissue damage due to high immunoactivity at infected niche. This expression signature was accompanied by significant upregulation of an immunoregulatory gene, leukotriene A4 hydrolase, at both transcript and protein levels. Comparative transcriptional analyses revealed LNTB-specific perturbations. In contrast to pulmonary TB-associated increase in lipid metabolism, genes involved in fatty-acid metabolism were found to be downregulated in LNTB suggesting differential lipid metabolic signature. This study investigates the tissue molecular signature of LNTB patients for the first time and presents findings that indicate the possible mechanism of disease pathology through dysregulation of inflammatory and tissue-repair processes.

Erythropoietin-producing tubercle granuloma in a hemodialysis patient.

BACKGROUND: We describe a case of a fever of unknown etiology that was caused by a caseating tubercle granuloma which produced erythropoietin. To our knowledge, this is the first report of an erythropoietin- producing granuloma. CASE PRESENTATION: A 48-year-old Japanese man with a 5-year history of maintenance hemodialysis for diabetic nephropathy presented with an intermittent fever over a few months. During febrile periods he developed erythema nodosum on his legs. Computed tomography showed axillary lymph node enlargement and this was further corroborated by a gallium scan that revealed high gallium uptake in these nodes. A Mantoux test was positive and an interferongamma release assay for tuberculosis diagnosis was also positive. Lymph node tuberculosis was suspected and the patient underwent lymphadenectomy. Histological analysis of the lymph nodes revealed a caseating granuloma that showed positive results on an acid-fast bacteria stain and a Mycobacterium tuberculosis polymerase chain reaction test. After lymphadenectomy, however, the patient's hemoglobin levels rapidly decreased from 144 to 105 g/L, and this was further compounded by a decrease in serum erythropoietin from 223 mIU/mL to 10.7 mIU/mL by postoperative day 21. We suspected the tubercle to be a source of the erythropoietin and this was further confirmed by in situ hybridization. CONCLUSIONS: We report for the first time ectopic erythropoietin production by a tuberculous lymph node. Our observations are substantiated by a postoperative decline in his erythropoietin level and a clinical requirement for erythropoietin treatment.

Diagnostic usefulness of a T-cell-based assay in patients with miliary tuberculosis compared with those with lymph node tuberculosis.

Forty-three patients with miliary tuberculosis were evaluated for diagnostic usefulness of enzyme-linked immunospot (ELISPOT) assay. Among noninvasive rapid tests available within 3-5 days, ELISPOT had the highest sensitivity (93%), compared with acid-fast bacilli stain (sputum, 32% and bronchoalveolar lavage, 7%), Mycobacterium tuberculosis polymerase chain reaction (sputum, 53% and bronchoalveolar lavage, 36%), and tuberculin skin test (22%). In comparison with 44 patients with lymph node tuberculosis, the sensitivity of the ELISPOT assay in patients with miliary tuberculosis (93%) was as high as in those with lymph node tuberculosis (95%, P = .63), whereas the sensitivity of the tuberculin skin test was substantially lower in patients with miliary tuberculosis (22%) than in those with lymph node tuberculosis (73%, P < .001).

Tuberculous lymphadenitis: FDG PET and CT findings in responsive and nonresponsive disease.

PURPOSE: No data is available on the different FDG PET and CT findings in the lymph nodes (LN) of patients with HIV and tuberculosis (TB) who respond compared with those who do not respond to anti-TB treatment by 4 months after initiation of TB treatment. These findings were the focus of our study. METHODS: PET/CT scans performed at 4 months after initiation of TB treatment in 20 consecutive HIV patients were analysed. SUVmax values were obtained for all regions of LN involvement. The diameter of the LNs was measured and the CT enhancement (LNs showing peripheral rim enhancement with central low attenuation, PRECLO, in comparison with homogeneously involved LNs) and the calcification patterns of involved LNs assessed. The relationship between the PET and CT findings and the clinical outcome, response or nonresponse, was evaluated. RESULTS: FDG PET identified 91 sites of LN involvement, 20 of which were not identified by CT. SUVmax values were significantly higher in nonresponders (8 patients, SUVmax 11.2 ± 4.0, mean ± SD) when compared to responders (12 patients, SUVmax 2.6 ± 2.3; p = 0.0001). In ROC analysis (AUC 0.952) a cut-off value of 4.5 for SUVmax yielded a sensitivity and specificity of 95% and 85% for discriminating nonresponding from responding LNs. LNs were significantly larger in nonresponders (1.9 ± 0.4 cm) than in responders (1.4 ± 0.4 cm; p = 0.0001); the AUC in the ROC analysis was 0.76. PRECLO LNs were significantly larger (2.2 ± 0.3 cm) than homogeneous involved LN basins (1.5 ± 0.4 cm) and LN basins with calcification (1.4 ± 0.5 cm; p = 0.001). Using the presence of at least one LN basin with PRECLO as a criterion for nonresponse, responders could be separated from nonresponders with a sensitivity of 88% and a specificity of 66%. CONCLUSION: LNs responding to TB treatment could be differentiated from nonresponding LNs with a sensitivity and specificity of 95% and 85% using a SUVmax cut-off value of 4.5 and a sensitivity and specificity of 88% and 66% using the presence of at least one LN basin with PRECLO.

SOCS in situ expression in tuberculous lymphadenitis in an endemic area.

BACKGROUND: The immune response to Mycobacterium tuberculosis is complex and multifactorial, the cytokine system being a major factor in M. tuberculosis immunity. AIM: To analyze the immunohistochemical aspects of tuberculous lymph nodes in immunocompetent patients and search for associations between SOCS and cytokine expression in human tuberculous lymphadenitis. METHODS: Thirteen lymph nodes were assayed by immunohistochemistry for SOCS-1 and 3, STAT-3, RANTES, MIP-1-alpha, ICAM-1, IFN-gamma as well as CD45RO, CD20, CD34, CD68, trypsin and lysozyme. Additionally, the RT in situ PCR was performed for SOCS-1 and 3 mRNA detection. RESULTS: Decreased MIP-1 alpha expression together with reduced SOCS-3 (p=0.042), lysozyme (p=0.024) and CD45RO (p=0.05) was observed in the TB lymph nodes compared to the control lymph nodes. In conclusion, the lymphadenitis due to M. tuberculosis was associated with a downregulation of memory T cells (CD45RO), activated lysozymes and SOCS-3 compared to controls, which may play a role in the long-term bacterial replication and altered immune modulation characteristic of the disease.

Immunohistochemistry using a Mycobacterium tuberculosis complex specific antibody for improved diagnosis of tuberculous lymphadenitis.

The clinical and histological criteria used to diagnose lymphadenitis caused by Mycobacterium tuberculosis complex organisms have poor specificity. Acid-fast staining and culture has low sensitivity and specificity. We report a novel method for diagnosis of tuberculosis that uses immunohistochemistry to detect the secreted mycobacterial antigen MPT64 on formalin-fixed tissue biopsies. This antigen has not been detected in non-tuberculous mycobacteria. Polymerase chain reaction (PCR) for amplification of IS6110 from DNA obtained from the biopsies was used as a gold standard. Fifty-five cases of granulomatous lymphadenitis with histologically suspected tuberculosis obtained from Norway and Tanzania were evaluated. Four known tuberculosis cases were used as positive controls, and 16 biopsies (12 foreign body granulomas and four other non-granulomatous cases) as negative controls. With immunohistochemistry, 64% (35/55) and with PCR, 60% (33/55) of granulomatous lymphadenitis cases were positive. Using PCR as the gold standard, the classical tuberculosis histology had sensitivity, specificity, positive and negative predictive values of 92, 37, 60, and 81%, respectively, and immunohistochemistry had sensitivity, specificity, positive and negative predictive values of 90, 83, 86, and 88%, respectively. The observed agreement between PCR and immunohistochemistry was 87% (kappa = 0.73). Immunohistochemistry with anti-MPT64 antiserum is a rapid, sensitive, and specific method for establishing an etiological diagnosis of tuberculosis in histologic specimens. Immunohistochemistry has the advantages over PCR of being robust and cheap, and it can easily be used in a routine laboratory.

[Changes in blood coagulation affected by rifampicin administration].

OBJECTIVE: To study the characteristics of influence on coagulation by rifampicin (RFP) administration. METHODS: Seventy-three patients, ages between 10 and 65 years(mean age 30.3 years), with tuberculosis of neck lymphnode were treated with 2HRZS/10HRE. The prothrombin time, activity, fibrinogen, II: C, V: C, VII: C, IX: C and alanine aminotransferase concentration in each case were observed during the period of RFP administration. RESULTS: The prolongation of the PT and the reduction of the PA, FIB concentration in 48 cases were observed after 5-30 days following RFP administration. These changes depended on drug dosage and duration, especially the severe influence on coagulation were detected when the RFP were reused after the ALT normalized in seventh to tenth months. The ALT was (18 +/- 12) U/L in the tenth month, but the PT was (19.2 +/- 3.9) s and the FIB was (1.8 +/- 0.5) g/L respectively. CONCLUSIONS: Not only the coagulation factors II, VII, IX, X, but also I V, VI and VIII were affected by RFP. The coagulation test is more sensitive than ALT test in the evaluation of liver injury. RFP should be stopped when FIB less than 1 g/L in spite of ALT in normal range.

Prolonged elevations of soluble interleukin-2 receptors in tuberculosis.

In order to determine whether tuberculosis is associated with elevated levels of soluble interleukin-2 receptors (SIL-2R), patients with both pulmonary (n = 12) and extrapulmonary (n = 8) disease were studied. SIL-2R were measured in sera using an enzyme-linked immunosorbent assay (ELISA). Prior to treatment, all 20 patients had levels of SIL-2R significantly greater than those of the 14 control subjects. Longitudinal study of patients with pulmonary disease revealed that levels of SIL-2R remained elevated in 11 of 12 patients after 2 months, and in four of six patients after 3 months of treatment. These findings suggest that tuberculosis is characterized by prolonged activation of the immune system despite optimal chemotherapy and that SIL-2R may distinguish active immunity from immunologic memory to this infection.

Eosinophil chemotactic factors from granuloma of Kimura's disease, with special reference to T lymphocyte-derived factors.

The granuloma of patients with Kimura's disease characterized by tissue and peripheral blood eosinophilia was reviewed with respect to eosinophil infiltration. An infiltrate of inflammatory cells with histiocytes and a sprinkling of eosinophils were observed in the fibrous stroma surrounding the newly formed vessels. Mast cells were rarely seen in the areas where eosinophils were grouped together. Three different eosinophil chemotactic factors (ECF) were isolated from the granulomas of Kimura's disease. They were termed as low molecular weight (LMW), intermediate molecular weight (IMW), and high molecular weight (HMW)-ECF according to the profile on gel filtration (LMW-ECF, about 500; IMW-ECF, about 12,500; HMW-ECF, 45,000-70,000). In terms of their activity when extracted from the granuloma, LMW-ECF and HMW-ECF seemed to be major natural mediators for the tissue eosinophilia, whereas IMW-ECF was a minor one. In an in vitro system, it was shown that granuloma lymphoid cells produce spontaneously at least two ECF having similar properties to LMW- and HMW-ECF, respectively. By analysis with monoclonal antibodies, granuloma T cells, probably OKT4-positive cells, were shown to be responsible for the production of those two ECF. It was thus suggested that prolonged synthesis of LMW- and HMW-ECF by OKT4-positive T cells plays a crucial role in the local eosinophilia of Kimura's disease.

Immunohistochemical localization and distribution of S-100 proteins in the human lymphoreticular system.

Immunohistochemical localization of S-100b protein and S-100ao protein in human lymphoreticular system was studied by using monospecific antibody directed against either the alpha subunit or beta subunit of S-100 protein. S-100b protein immunoreactivity was detected in Langerhans cells, interdigitating reticulum cells, and histiocytosis X cells, but not in ordinary macrophages and blood monocytes. In contrast, S-100ao protein immunoreactivity was detected in blood monocytes, macrophages of lymph node, alveolar macrophages of lung, and small numbers of Kupffer cells of liver. S-100ao immunoreactivity was also detected in epithelioid cells, Langhans giant cells, and foreign body giant cells. The present findings suggest that the presence of S-100ao protein in the cytoplasm is one of the characteristic features of cells in the human mononuclear phagocyte system. The detection of S-100b, but not S-100ao, immunoreactivity in Langerhans cells and interdigitating reticulum cells also suggests that they are independent of the monocyte-macrophage system. S-100ao protein may be a novel cytoplasmic marker for cells of the human monocyte-macrophage system.

[Modification of the koch bacillus by a material extracted from tuberculosis lesions]. / Modification du bacille de Koch par un matériel extrait de lésions de tuberculose.

Lymph node lesions of tuberculous cattle and swine gave, after disruption, centrifugation through 2.2 M sucrose, and ultrafiltration, a material that brings about, in vitro, modification of the tubercle bacilli or chromogenic mycobacteria into bacterial elements that are not acid fast, rapidly growing on nutritive agar supplemented with glycerol. The phenomenon is similar to that which the authors have previously described, using an inducing agent extracted from cultures of mycobacteria, called "endometallaxic conversion."

DNA synthesis in cells of human tuberculous lymph nodes.

DNA metabolism of cells of tuberculous lymph nodes was studied autoradiographically with 3H-thymidine injected directly into one of the afferent lymph vessels. The undifferentiated mononuclear cells showed the most intensive DNA synthesis, but a large number of epitheloid cells had also become labelled. The nuclei of the giant Langhans cells took no label.