Paradoxical Tuberculosis Reactions in Patients Without HIV Infection

Background:

Most people with tuberculosis (TB) feel better after starting treatment. But for some people, the opposite happens. They may feel better at first, but then suddenly get worse. This is a paradoxical reaction. Researchers want to better understand what causes this reaction and what happens after someone has it.

Objective:

To learn about paradoxical reactions to TB treatment.

Eligibility:

Adults 18 and older diagnosed with confirmed or suspected TB and currently on treatment for at least 2 weeks, with or without signs/symptoms of a paradoxical inflammatory reaction.

Design:

Participants will be screened with a physical exam and medical history. They will give blood and urine samples.

Eligible participants will visit the NIH Clinical Center 3 times over 6 to 18 months. Each visit will take 7 hours to complete; visits may be scheduled over more than 1 day. Participants may have more visits if their TB symptoms change.

Participants will give blood, urine, and sputum samples. They will have adverse event assessments. They will have 2 to 3 positron emission tomography/computed tomography (PET/CT) scans. PET/CT scans make pictures of the inside of the body. For this, participants will lie on a table that slides into a donut-shaped scanner. They will get a small amount of radioactive dye through an IV, which is a small plastic tube placed in a vein in the arm using a needle.

Participants may have optional apheresis. For this, blood is taken from a needle in one arm. White blood cells are separated from the rest of the blood. The rest of the blood is returned through a needle in the other arm.

Study Overview

• Status: Recruiting
• Conditions: Tuberculosis

Detailed Description

Paradoxical reaction in non-HIV tuberculosis (TB) is a clinical and/or radiologic worsening of a patient s pre-existing TB while receiving anti-TB medications. This phenomenon has been clinically well described for many years and is thought to occur in 10%-25% of HIV-negative patients starting treatment for TB. Paradoxical reactions are diagnosed by excluding other possible causes for worsening of TB signs and symptoms, such as a second infection or treatment failure. However, challenges in culturing TB can complicate early diagnosis of paradoxical reactions.

This is an observational study intended to improve understanding of the pathogenesis of paradoxical response to treatment in TB-infected patients who do not have HIV. We plan to follow up to 20 patients with TB who have already initiated or have previously completed treatment and are suspected to have paradoxical reactions, as well as about 40 patients taking TB treatment without signs of paradoxical reactions (controls). All participants will have regular study visits for clinical assessments, blood and sputum collections, positron emission tomography-computed tomography (PET/CT) scans, and optional leukapheresis. Radiography and laboratory evaluations will be performed to identify biomarkers, clinical signs, and molecular explanations for paradoxical reactions. Better understanding of characteristics of paradoxical reactions will assist in earlier diagnosis or even prediction.

• Study Type: Observational
• Enrollment (Estimated): 70

Contacts and Locations

• Study Contact: Name: Maura M Manion, M.D.; Phone Number: (301) 312-2103; Email: maura.manion@nih.gov
• Study Contact Backup: Name: Frances J Galindo, R.N.; Phone Number: (301) 761-6657; Email: galindofj@niaid.nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR); Phone Number: TTY8664111010 800-411-1222; Email: prpl@cc.nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Participants will be recruited from clinics in the surrounding Washington, DC area.

Description

• INCLUSION CRITERIA:

Suspected Paradoxical Reaction Group Criteria:

1. Aged greater than or equal to 18 years.

2. Diagnosed with confirmed (microbiologically or with molecular methods) or suspected (clinical plus or minus histologic diagnosis) TB and currently on ATT for a minimum of 2 weeks, or have completed ATT, with at least 2 of the following signs/symptoms of a paradoxical inflammatory reaction:

   • Recrudescent symptoms of TB after initial clinical improvement.
   • Change in physical exam after initial clinical improvement suggestive of new inflammatory process (e.g., lymphadenopathy or new findings on pulmonary exam).
   • Worsening radiographic evidence of disease after initiation of treatment, as compared with imaging prior to or earlier in treatment.
   • Laboratory evidence of acute inflammatory response, including the development of leukocytosis (white blood cell count > 10,000 cells/microL) or a change of C-reactive protein (CRP) > 5 mg/L compared to prior laboratory values.
   • Worsened organ function after initial clinical improvement.
3. The above sign/symptom(s) cannot be explained by a newly acquired infection, clinical course of a previously recognized infectious agent, side effects of the ATT, the presence of drug resistance, or any other condition except for paradoxical reaction.
4. Willingness to allow storage of blood or tissue samples for future research.
5. Ability of participant to understand study requirements and give informed consent.
6. Has a primary care physician and is being followed by the local Department of Health for their TB (or has plans to arrange after enrollment if enrolled early in course from inpatient transfer).

Control Group Criteria:

1. Aged greater than or equal to 18 years.
2. Diagnosed with confirmed (microbiologically or with molecular methods) or suspected (clinical plus or minus histologic diagnosis) TB.
3. Presenting 2 to 4 months after starting ATT to match timing of paradoxical reactions.
4. Willingness to allow storage of blood or tissue samples for future research.
5. Ability of participant to understand study requirements and give informed consent.
6. Has a primary care physician and is being followed by the Department of Health for their TB (or has plans to arrange after enrollment if enrolled early in course from inpatient transfer).

EXCLUSION CRITERIA:

Individuals in either group who meet any of the following criteria will be excluded from study participation:

1. HIV infection. (Individuals with HIV infection may be eligible for a separate study exclusively evaluating persons living with HIV.)
2. Pregnant or breastfeeding.
3. Uncontrolled psychiatric disease, substance use, or inappropriate conduct unsuitable for a research study.
4. Malignancy requiring imminent or ongoing treatment including radiation, chemotherapy, or immunotherapy.
5. Debilitating or chronic conditions that would limit ability to participate in the study.
6. Emergent or urgent clinical conditions not due to studied disease of interest requiring immediate treatment that would be unsuitable for a research study. These patients would be transferred to an emergency room and able to rescreen when condition has been stabilized.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
1; Patients with TB who have already initiated treatment and are suspected to have paradoxical reactions, as well as patients taking TB treatment without signs of paradoxical reactions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunologic and radiographic responses of TB patients with suspected paradoxical reactions.	Characterize immunologic and radiographic responses of TB patients with suspected paradoxical reactions.	Throughout study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarkers and/or microbiologic burden correlate with paradoxical TB reactions.	Determine whether biomarkers and/or microbiologic burden correlate with paradoxical TB reactions.	Throughout study

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Maura M Manion, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2019
• Primary Completion (Estimated): April 30, 2029
• Study Completion (Estimated): April 30, 2029

Study Registration Dates

• First Submitted: August 8, 2019
• First Submitted That Met QC Criteria: August 8, 2019
• First Posted (Actual): August 9, 2019

Study Record Updates

• Last Update Posted (Actual): April 18, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: April 16, 2024

More Information

Terms related to this study

• Keywords: Natural History; Biomarkers; Pathogenesis; Auto-Antibody Production; Host Genetic Predisposition; Immune Reconstitution Inflammatory Syndrome
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Urogenital Diseases; Genital Diseases; HIV Infections; Tuberculosis
• Other Study ID Numbers: 190133; 19-I-0133

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: .No plan at this time.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No