Paradoxical Reactions in Non Immuno-compromized Patients With Extrapulmonary Tuberculosis (PARATB)

Paradoxical Reactions During Anti-mycobacterial Treatment of Extrapulmonary Tuberculosis in Non Immuno-compromized Patients : Clinical, Radiological et Immunological

Tuberculous paradoxical reactions (PR) are immune reactions occurring during the course of antituberculous treatment and leading to a worsening of tuberculous symptoms after an initial improvement. This phenomenon has very extensively studied in HIV infected patients where it corresponds to the so called IRIS (immune reconstitution syndrome). However, it laso occurs in non immuno-compromized patients, especially those with extra-pulmonary localization of tuberculosis. The aim of the study is to look for risk factors of paradoxical reaction in non immuno-compromized patients with extra-pulmonary tuberculosis. The investigators will consider clinical, radiological and biological variables, including specific immune and genetic markers. Our secondary goals are to estimate the incidence of PR, describe their natural history; characterize the type of immune response they correspond to, and look for better diagnostic tools.The immunological characterization and the finding of predictive factors of PR, especially the genetic ones will allow a better understanding of biological mechanisms that lead to their occurrence during extra-pulmonary tuberculosis treatment. The establishment of predictive criteria could permit a better surveillance of at risk patients for a rapid treatment, or even a prevention of PR. The establishment of new diagnostic criteria at the time of PR could avoid numerous invasive diagnostic procedures, surgery and/or useless prolongation of antibiotic treatment.

Study Overview

• Status: Completed
• Conditions: Extrapulmonary Tuberculosis
• Intervention / Treatment: Genetic: Genetic analysis; Radiation: Body scan (CERVICO THORACO ABDOMINAL) + Cranian IRM; Other: Immunologic analysis; Other: QuantiferonTB Gold test

Detailed Description

Primary objective :

Search for predictive factors of tuberculous paradoxical reaction (PR), with assessment of clinical, radiological and biological factors.

Secondary objectives :

• Descriptive study of PR : incidence, clinical and radiological presentation, clinical course ; characterization of mycobacteria strains- Search for genetic predictive factors of PR
• Characterization of the specific immune antigene response during PR et analysis of different cell subsets implicated in peripheral blood and locally- Characterization of the anti-bacterial immune response before and after antituberculous treatment
• Preliminary search for new diagnosis criteria including clinical, biological (immune and genetic) and radiological factors.Methodology : Multicentric cohort study for a total of 5 years (4 years of enrolment and one year of follow-up, with biological collection for scientific purpose

Inclusion Status of patients (determined by a validation comity at M6)

• PR+ : PR with clinical symptoms
• rPR : pure radiological PR
• PR- : absence of RP after 6 months of treatment Development of the study

Primary outcome :

- Association between PR+ occurrence and clinical, biological and radiological factors harvested at the diagnosis of tuberculosis..

Secondary outcomes :

• Association between PR+ and rPR
• occurrence and the above quoted factors.- Descriptive study : clinical, biological, and radiological presentation of PR+ and rPR, characterization of isolated BK strains in PR+ patients
• Immunological study in 20 PR+ patients and 20 RP- : 20 patients per group will allow a 80% power to detect, by means of bilateral Mann-Whitney test with alpha=5%, any difference in the count of specific cells corresponding to at least one standard deviation of the primary immunological outcome
• controls: variation between tuberculosis diagnostic and either PR time or M2 (in absence of PR), of the specific cells, macrophages, dendritic cells, gamma-delta lymphocytes, NK et CD4 cells counts
• Preliminary search for diagnostic criteria that can be used at the time of PR occurrence: variation between D0 and the PR of clinical, biological, radiological immunological et genomic of PR+ patients.
• Evolution specific and non specific immune response of mycobacterial antigen at tuberculosis diagnosis during tuberculosis treatment and after. Sample size calculation
• prognostic study : Patients will be recruited and followed until the achievement of a 20 PR+ sample. The investigators will have to analyze 200 patients.

• Study Type: Observational
• Enrollment (Actual): 135

Contacts and Locations

Study Locations

• France
  • Paris, France, 75015
    • Georges Pompidou Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Extra-pulmonary tuberculosis

Description

Inclusion Criteria:

• Extrapulmonary tuberculosis, with associated pulmonary localization or not
• Treatment started less than 5 days ago
• Negative HIV serology
• Social insurance
• Age >= 18- Foreseeable follow-up of at last one year
• Signed Free Inform Consent

Exclusion Criteria:

• HIV infection
• immuno-suppressive treatment (including corticosteroids > 10 mg /d prednisone equivalent, however patients with corticotherapy could be included during the phase 2 of the study)
• central neurological system tuberculosis and tuberculous pericarditis - pure pulmonary tuberculosis
• multiresistant tuberculosis
• pregnancy or breast feeding

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
1:paradoxical reaction negative (RP-); control group with tuberculosis but without paradoxical reaction	Genetic: Genetic analysis; identification of candidates genes by a differential analysis of the whole transcriptome of the peripheral leucocytes of 20 PR+ patients and 20 RP- controls, at D0, D15, M2,;; Genetic association analysis: comparison of allelic distributions of SNPs (diallelic markers) within the candidate genes, between PR+ and PR- patients, in the whole cohort. One supplementary ACD tube of 5 ml à D0, D15, M2, PR+, for RNA extraction.; Radiation: Body scan (CERVICO THORACO ABDOMINAL) + Cranian IRM; at day 0, Month 2, paradoxical reaction, end of treatment, read by an independent radiologist; Other: Immunologic analysis; For patients included until 20 PR+ : blood puncture of 4 ACD tubes of 10 ml, 1 EDTA tube of 7,5 ml et 1 heparinate lithium tube of 7,5ml at D0, D15, M2, and M6 and at the time of an potential RP+
1:paradoxical reaction negative (RP+); group with tuberculosis and paradoxical reaction	Genetic: Genetic analysis; identification of candidates genes by a differential analysis of the whole transcriptome of the peripheral leucocytes of 20 PR+ patients and 20 RP- controls, at D0, D15, M2,;; Genetic association analysis: comparison of allelic distributions of SNPs (diallelic markers) within the candidate genes, between PR+ and PR- patients, in the whole cohort. One supplementary ACD tube of 5 ml à D0, D15, M2, PR+, for RNA extraction.; Radiation: Body scan (CERVICO THORACO ABDOMINAL) + Cranian IRM; at day 0, Month 2, paradoxical reaction, end of treatment, read by an independent radiologist; Other: Immunologic analysis; For patients included until 20 PR+ : blood puncture of 4 ACD tubes of 10 ml, 1 EDTA tube of 7,5 ml et 1 heparinate lithium tube of 7,5ml at D0, D15, M2, and M6 and at the time of an potential RP+; Other: QuantiferonTB Gold test; at M0, M2, M6 and in case of PR+.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Risk factors of paradoxical reaction	Risk factors of paradoxical reaction : clinical, radiological immune and genetic factors	at 6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Incidence and natural history of paradoxical reactions	during the first 6 months
Immune description of paradoxical reactions	during the first 6 months
Preliminary study of Diagnosis factors of paradoxical reaction	during the first 6 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Anne BOURGARIT, MD, PhD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): March 14, 2011
• Primary Completion (Actual): February 21, 2018
• Study Completion (Actual): February 21, 2018

Study Registration Dates

• First Submitted: November 27, 2010
• First Submitted That Met QC Criteria: December 2, 2010
• First Posted (Estimate): December 3, 2010

Study Record Updates

• Last Update Posted (Actual): May 28, 2021
• Last Update Submitted That Met QC Criteria: May 27, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Tuberculosis; Incidence; Risk factors; Natural history; Gene Expression Profiling; CT scan; Extrapulmonary; Paradoxical reaction; Immune system phenomena; Immune markers
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis
• Other Study ID Numbers: P081253; 2010-A00375-34 (Other Identifier: ID-RCB)