Prevalence and risk factors of paradoxical tuberculosis associated immune reconstitution inflammatory syndrome among HIV-infected patients in Beijing, China.

BACKGROUND: In this study, we aimed to describe the prevalence, clinical presentation and risk factors of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) cases in China. METHODS: We performed a descriptive analysis of demographic and clinical data of HIV/TB coinfected patients receiving ART at Beijing Ditan Hospital between January 2014 and October 2018. RESULTS: Of 199 patients included, 45 (22.6%) developed paradoxical TB-IRIS, and 19 (9.5%) TB-IRIS cases presented miliary TB. The pre-ART CD4 count lower than 50 cells/mm3 was found to be significantly associated with development of TB-IRIS. Similarly, patients with higher than 4-fold increase in CD4 cell count after antiretroviral therapy (ART) had significantly higher odds of having TB-IRIS. When patients aged 25-44 years were utilized as the control group, youths (< 25 years old) were more likely to have miliary TB. No significant difference was observed in the intervals from initiation of ART to IRIS presentation between miliary and non-miliary group. CONCLUSIONS: In conclusion, our data demonstrate that approximate one quarter of patients coinfected with TB and HIV develop paradoxical TB-IRIS after initial of ART therapy in China. Lower baseline CD4 count and rapid increase in CD4 count are the major risk factors associated with the occurrence of paradoxical TB-IRIS.

Programmed death-1+ T cells inhibit effector T cells at the pathological site of miliary tuberculosis.

Optimal T cell activation is vital for the successful resolution of microbial infections. Programmed death-1 (PD-1) is a key immune check-point receptor expressed by activated T cells. Aberrant/excessive inhibition mediated by PD-1 may impair host immunity to Mycobacterium tuberculosis infection, leading to disseminated disease such as miliary tuberculosis (MTB). PD-1 mediated inhibition of T cells in pulmonary tuberculosis and TB pleurisy is reported. However, their role in MTB, particularly at the pathological site, remains to be addressed. The objective of this study was to investigate the role of PD-1-PD-ligand 1 (PD-L1) in T cell responses at the pathological site from patients of TB pleurisy and MTB as clinical models of contained and disseminated forms of tuberculosis, respectively. We examined the expression and function of PD-1 and its ligands (PD-L1-PD-L2) on host immune cells among tuberculosis patients. Bronchoalveolar lavage-derived CD3 T cells in MTB expressed PD-1 (54·2 ± 27·4%, P ≥ 0·0009) with significantly higher PD-1 ligand-positive T cells (PD-L1: 19·8 ± 11·8%; P ≥ 0·019, PD-L2: 12·6 ± 6·2%; P ≥ 0·023), CD19+ B cells (PD-L1: 14·4 ± 10·4%; P ≥ 0·042, PD-L2: 2·6 ± 1·43%; not significant) and CD14+ monocytes (PD-L1: 40·2 ± 20·1%; P ≥ 0·047, PD-L2: 22·4 ± 15·6%; P ≥ 0·032) compared with peripheral blood (PB) of MTB and healthy controls. The expression of PD-1 was associated with a diminished number of cells producing effector cytokines interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-2 and elevated apoptosis. Locally accumulated T cells were predominantly PD-1+ -PD-L1+ , and blocking this pathway restores the protective T cell response. We conclude that M. tuberculosis exploits the PD-1 pathway to evade the host immune response by altering the T helper type 1 (Th1) and Th2 balance at the pathological site of MTB, thereby favouring disease dissemination.

Severe Paradoxical Reaction During Treatment of Disseminated Tuberculosis in a Patient With Neutralizing Anti-IFNγ Autoantibodies.

Interferon-gamma (IFNγ) neutralizing autoantibodies are associated with disseminated nontuberculous mycobacterial infections. We report a previously healthy Thai woman with disseminated tuberculosis and high-titer IFNγ-neutralizing autoantibodies, who developed a severe inflammatory reaction during anti-tuberculosis treatment. IFNγ contributes to host control of tuberculosis but appears inessential for tuberculosis paradoxical reactions.

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).

Recruitment of Th1 effector cells in human tuberculosis: hierarchy of chemokine receptor(s) and their ligands.

Selective recruitment of IFN-γ biased Th1 effector cells at the pathologic site(s) determines the local immunity of tuberculosis (TB). We observed the enrichment of CXCR3, CCR5 and CD11a(high) T cells in the peripheral blood, pleural fluid and bronchoalveolar lavage of TB pleural effusion (TB-PE) and miliary tuberculosis (MTB) patients respectively. CXCR3(+)CCR5(+) T cells were significantly high at the local disease site(s) in both the forms of TB and their frequency was highest among activated lymphocytes in TB-PE. Interestingly, all CCR5(+) cells were invariably positive for CXCR3 but all CXCR3(+) cells did not co-express CCR5 in pleural fluid whereas the situation was reverse in bronchoalveolar lavage. These CXCR3(+)CCR5(+) cells dominantly produced IFN-γ in response to Mycobacterium tuberculosis antigen. In vitro chemotaxis assay indicates dominant role of RANTES and IP-10 in the selective recruitment of CXCR3(+)CCR5(+)cells at the tubercular pathologic sites.

The correlation between CD4+ T-lymphocyte count and tuberculosis form in TB-HIV coinfected patients in Indonesia.

AIM: to find whether there is a correlation between CD4+ count and TB form in TB-HIV Coinfected patients in Indonesia. METHODS: this is a cross-sectional study of the TB-HIV patients at National HIV Center POKDISUS, Cipto Mangunkusumo Hospital in 2008-2011. We classified TB form as pulmonary TB, extrapulmonary TB, milliary TB, and combination form. The data were analyzed by Spearman and lambda correlation test. We also did partial correlation test to eliminate some counfounding factors, including demography and clinical characteristics, that had been determinated before. RESULTS: there were 122 TB-HIV patients (aged median 31 [18-34], 80% male) included in this study. The most common TB form was pulmonary TB (71.2%), then extrapulmonary TB (7.4%), the combined type (18.9%), and milliary TB (2.5%). Median of CD4+ count was 40 cells/mL (IQR 17.5-100.6). There was a very weak correlation between CD4+ count and TB form in TB-HIV patients in Indonesia (r=0.185; p=0.042). The other factor that also showed a significant correlation to TB form is HIV staging (r=0.289; p=0.001). After adjusting those factors, we found an increase on correlation between CD4+ count and TB form (r=0.353; p=0.000). CONCLUSION: there was a correlation between CD4+ count and TB form in TB-HIV patients in Indonesia, but in a very weak correlation.

Life-threatening disseminated tuberculosis as a complication of TNF-α blockade in an adolescent.

Life-threatening disseminated tuberculosis developed in a 17-year-old girl who was treated with the TNF-α blocker adalimumab for refractory SAPHO syndrome. The patient presented to the emergency department with dyspnea and somnolence and within 2 h developed the clinical picture of a septic shock. In addition to this unusual presentation, she showed a complicated course with increasing cerebral granuloma formation in spite of adequate antimycobacterial treatment. Immune reconstitution after discontinuation of TNF blockade may contribute to this "paradoxical reaction." Possible implications for screening, diagnosis, and treatment of tuberculosis in children and adolescents receiving anti-TNF treatment are discussed.

FoxP3+ regulatory T cells suppress effector T-cell function at pathologic site in miliary tuberculosis.

RATIONALE: The inadequacy of effector T-cell response in containment of tubercle bacilli is believed to result in the development of disseminated forms of tuberculosis (TB), such as miliary tuberculosis (MTB). Regulatory T cells (Treg) plausibly play a critical role in the immunopathogenesis of disseminated TB by suppression of effector immune response against Mycobacterium tuberculosis at the pathologic site(s). To understand the role of Treg cells in disseminated tuberculosis, we studied the frequency and function of Treg cells derived from the local disease site specimens (LDSS) of patients with TB pleural effusion and MTB as clinical models of contained and disseminated forms of disease, respectively. OBJECTIVES: To (1) enumerate the frequency of Treg cells in bronchoalveolar lavage (BAL) fluid of patients with MTB and compare with that of peripheral blood, (2) study the role of Treg cells in suppression of local T-cell response, and (3) study the selective recruitment of Treg cells at the local disease site(s). METHODS: Flow cytometry, reverse transcriptase polymerase chain reaction, and 3-(4,5-dimethylthythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT)-based cell proliferation assay. MEASUREMENTS AND MAIN RESULTS: Frequency of Treg cells (CD4(+)CD25(+)FoxP3(+)) was significantly higher in LDSS in MTB along with higher levels of FoxP3 mRNA. Importantly, FoxP3(+) Treg cells obtained from the BAL of patients with MTB predominantly produced IL-10 and could suppress the autologous T-cell proliferation in response to M. tuberculosis antigen. CONCLUSIONS: Our results highlight the importance of Treg cells in suppression of effector immune response and their influence on bacillary dissemination, disease manifestation, and severity.

A Rare Manifestation of Tuberculosis in a Renal Transplant Patient: A Case Report.

Cutaneous lesions in the presence of fever in patients undergoing immunosuppressive therapy are a diagnostic challenge and may represent manifestations of multiple diseases, such as fungal infections, nocardiosis, lymphoproliferative diseases, zoonosis, and tuberculosis. The authors report a case of a 66-year-old white man with chronic kidney disease since 2014 (chronic pyelonephritis) who had a renal transplant in the previous 6 months. Induction therapy was performed with thymoglobulin, and his current immunosuppression scheme included tacrolimus, mycophenolate mofetil, and prednisolone. The patient had no history of pulmonary tuberculosis. The patient presented with 2 cutaneous lesions, localized on the back and abdomen, that appeared to be firm, painful, subcutaneous, erythematous nodules with an approximately 5 cm diameter overlying an infected focus and purulent material inside. The patient also had a fever and fatigue. Blood analysis showed pancytopenia with an elevation of inflammatory markers and graft dysfunction. Tissue cultures and skin biopsy with histological analysis were performed. Histopathology of the lesion showed a nonspecific inflammatory infiltrate without granulomas, and acid-fast bacillus staining was negative. Nevertheless, serum QuantiFERON testing was positive. But polymerase chain reaction finally confirmed the presence of Mycobacterium tuberculosis, which confirmed the diagnosis of cutaneous tuberculosis. A chest computed tomography scan showed a lung pattern of miliary tuberculosis. The patient was treated with multidrug tuberculosis therapy, resulting in lesion clearance after 3 weeks. Tuberculosis is a serious infection, especially in high-risk patients, such as those in an immunocompromised state. The incidence of cutaneous tuberculosis is rare, but it should be considered in patients presenting with atypical skin lesions suggestive of an underlying infectious etiology.

Successful treatment of disseminated Acanthamoeba sp. infection with miltefosine.

We report on an HIV-negative but immunocompromised patient with disseminated acanthamoebiasis, granulomatous, amoebic encephalitis and underlying miliary tuberculosis and tuberculous meningitis. The patient responded favorably to treatment with miltefosine, an alkylphosphocholine. The patient remained well with no signs of infection 2 years after treatment cessation.

Paradoxical Reaction of Tuberculosis in a Heart Transplant Recipient During Antituberculosis Therapy: A Case Report.

INTRODUCTION: Tuberculous paradoxical reactions (PRs) are excessive immune reactions occurring after antituberculosis (TB) treatment and are commonly observed in immunocompromised hosts such as patients infected with the human immunodeficiency virus. CASE REPORT: We recently encountered a 63-year-old male heart transplant recipient who developed tuberculous PR after treatment for miliary TB. The patient had been receiving immunosuppressive therapy with cyclosporine and mycophenolate mofetil for over 15 years. The diagnosis of miliary TB was made based on the presence of intermittent fever and fatigue; thus, anti-TB treatments (isoniazid, levofloxacin, ethambutol, and pyrazinamide) were started, which led to rapid defervescence and regression of the granular shadow and pleural effusion. However, a new persistent fever and confused state developed 1 month after the anti-TB therapy was started. After excluding possible etiologies of the patient's symptom, a PR was suspected, and anti-TB drugs were continued; corticosteroids were added as anti-inflammatory agents. After that, he has shown a favorable course with long-term anti-TB chemotherapy. CONCLUSION: A PR should always be considered when the patients' symptoms of tuberculosis re-exacerbate after an appropriate anti-TB therapy. A PR commonly occurs in patients with various immunologic conditions including heart transplant recipients.

[Disseminated tuberculosis in a patient with overlap syndrome, challenges in preventing]. / Tuberculosis diseminada en una paciente con síndrome de sobreposición, retos en la prevención.

Patients with autoimmune rheumatic diseases are at increased risk for developing infections and these are associated with increased morbidity and mortality from these diseases, especially in patients with systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis and autoimmune inflammatory myopathies. The objective of this paper is to address the challenges in detecting latent tuberculosis in immunosuppressed patients and the initiation of prophylactic treatment because currently there are no well-defined guidelines indicating what action to take for detection and treatment; so far the available scientific evidence is scarce and some methodological shortcomings.

Los pacientes con enfermedades reumáticas autoinmunes tienen un elevado riesgo para el desarrollo de infecciones, y estas se asocian al incremento de la morbimortalidad de estas enfermedades, principalmente en pacientes con lupus eritematoso sistémico, artritis reumatoide, esclerosis sistémica y con miopatías inflamatorias autoinmunes. El objetivo de este trabajo es abordar los retos en la detección de tuberculosis latente en pacientes inmunosuprimidos y el inicio del tratamiento profiláctico ya que en la actualidad no existen lineamientos bien definidos que indiquen la conducta a seguir para su detección y tratamiento; por el momento la evidencia científica disponible es escasa y con algunas deficiencias metodológicas.

Miliary tuberculosis: new insights into an old disease.

Miliary tuberculosis is a potentially lethal form of tuberculosis resulting from massive lymphohaematogeneous dissemination of Mycobacterium tuberculosis bacilli. The emergence of the HIV/AIDS pandemic and widespread use of immunosuppressive drugs has changed the epidemiology of miliary tuberculosis. Impaired cell-mediated immunity underlies the disease's development. Clinical manifestations are non-specific and typical chest radiographic findings may not be seen until late in the course of the disease. Atypical presentations--eg, cryptic miliary tuberculosis and acute respiratory distress syndrome--often delay the diagnosis. Several laboratory abnormalities with prognostic and therapeutic implications have been described, including pulmonary function and gas exchange impairment. Isolation of M tuberculosis from sputum, body fluids, or biopsy specimens, application of molecular methods such as PCR, and histopathological examination of tissue biopsy specimens are useful for the confirmation of diagnosis. Although response to first-line antituberculosis drugs is good, evidence regarding optimum duration of treatment is lacking and the role of adjunctive corticosteroid treatment is unclear.

Refractory polymyositis undergoing remission following antitubercular therapy.

Opportunistic infections pose a significant problem in patients receiving immunosuppressive therapy for autoimmune diseases. We present a case of a woman with polymyositis refractory to high-dose steroid and methotrexate, as a consequence of which she developed miliary tuberculosis. Her myositis went into remission after initiation of antitubercular therapy, in spite of bringing down the intensity of immunosuppression. This is the first reported case of myositis undergoing remission after treating intercurrent infection, and illustrates the complex relationship between autoimmune disease and host response to infection.

Acute renal failure on immune reconstitution in an HIV-positive patient with miliary tuberculosis.

Immune reconstitution syndrome following HAART in human immunodeficiency virus (HIV)-infected patients is characterized by inflammatory worsening of organ functions despite improvement in HIV surrogate markers of HIV infection. We describe a patient with miliary tuberculosis and urinary shedding of acid fast bacilli who developed acute renal failure 8 weeks after initiation of antituberculosis therapy and 6 weeks after initiation of HAART. The diagnostic workup and further course of disease implicated immune reconstitution syndrome as the cause of acute renal failure.

Spectrum of manifestations of Mycobacterium tuberculosis infection in primates infected with SIV.

To characterize the manifestations of coinfection with M. tuberculosis and SIV infection, we studied 12 SIV-infected rhesus monkeys, six of which were infected intrabronchially with a low dose of Mycobacterium tuberculosis H37Rv. In the six coinfected animals, M. tuberculosis antigen-stimulated lung and blood cells produced high concentrations of IFN-gamma but not IL-4 8-16 weeks after infection. Of the three coinfected animals with high levels of plasma viremia, two developed disseminated tuberculosis and the other died of bacterial peritonitis. Of three coinfected animals with moderate levels of plasma viremia, two had no clinical or radiographic evidence of tuberculosis or progressive SIV infection for 6 months after infection. At neuropsy, pulmonary granulomata were observed and acid-fast organisms or M. tuberculosis were present. These clinical, immunologic and pathologic findings are consistent with those in humans with latent tuberculosis infection (LTBI), and suggest that a model of LTBI in SIV-infected primates can be developed. Such a model will permit delineation of the immunologic and microbial factors that characterize LTBI in HIV-infected persons.

Differential cell analysis in bronchoalveolar lavage fluid from pulmonary lesions of patients with tuberculosis.

To obtain information on the cellular reactions to Mycobacterium (M) tuberculosis in the lung, we analyzed the cells in bronchoalveolar lavage (BAL) fluid from pulmonary lesions in comparison with those in BAL fluid from nonaffected regions of the lungs, and control lungs, and in peripheral blood of patients with tuberculosis. Neutrophils and lymphocytes were increased in number in BAL fluid from affected lesions of the lungs of patients with miliary tuberculosis and patients with active pulmonary tuberculosis compared with those in BAL fluid from control patients, but the number of alveolar macrophages was decreased in BAL fluid from tuberculous lesions. However, the numbers of these cells were not changed in the BAL fluid from nonaffected regions of the lungs of patients with active or inactive pulmonary tuberculosis. The numbers of lymphocytes were decreased and the numbers of monocytes were increased in peripheral blood from patients with miliary tuberculosis and with active tuberculosis, indicating inverse changes in the numbers of lymphocytes and monocytes in the peripheral blood to those in the BAL fluid of patients with tuberculosis. These results indicate characteristic redistributions of immune or inflammatory cells in response to infection with M tuberculosis and suggest that these changes are important for understanding the pathophysiology of pulmonary tuberculosis.