TuberculosisNCT04052022
Paradoxical Tuberculosis Reactions in Patients Without HIV Infection
An observational study of Tuberculosis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 3 sites in 2 countries.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 99 years
- Conditions the study is for
- Tuberculosis
- How many people
- 140 participants
- Where
- 3 sitesin 2 countries
- Study dates
- 20 Dec 2019to 30 Apr 2029
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 99 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Participants will be recruited from clinics in the surrounding Washington, DC area for the NIH site; and from clinics in Mexico for the foreign site
Who may be able to join
- Suspected Paradoxical Reaction Group Criteria:
- Aged greater than or equal to 18 years.
- 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.
Show all 19Show fewer
- 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.
- 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.
- Willingness to allow storage of blood or tissue samples for future research.
- Ability of participant to understand study requirements and give informed consent.
- 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:
- Aged greater than or equal to 18 years.
- Diagnosed with confirmed (microbiologically or with molecular methods) or suspected (clinical plus or minus histologic diagnosis) TB.
- Presenting 2 to 4 months after starting ATT to match timing of paradoxical reactions.
- Willingness to allow storage of blood or tissue samples for future research.
- Ability of participant to understand study requirements and give informed consent.
- 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).
Who cannot join
- Individuals in either group who meet any of the following criteria will be excluded from study participation:
- HIV infection. (Individuals with HIV infection may be eligible for a separate study exclusively evaluating persons living with HIV.)
- Pregnant or breastfeeding.
- Uncontrolled psychiatric disease, substance use, or inappropriate conduct unsuitable for a research study.
- Malignancy requiring imminent or ongoing treatment including radiation, chemotherapy, or immunotherapy.
- Debilitating or chronic conditions that would limit ability to participate in the study.
- 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.
Trial locations and contacts
3 sites in 2 countries. Contact the study team or a site near you to ask about taking part.
3 sites in 2 countries
Mexico2 sites, 2 recruiting
- Recruiting
Mexican Emerging Infectious Diseases Clinical Research Network (LaRed) INCMNSZ
Mexico City, 14080
Luis Ponce de Leon Garduno, Not Listed ext. 55 54870900, luis.ponceg@incmnsz.mx
- Recruiting
Mexican Emerging Infectious Diseases Clinical Research Network (LaRed) INER
Mexico City, 14080
Norma Angelica Tellez Navarrete, Not Listed ext. 55 54871700, norma.tellez@gmail.com
United States1 site, 1 recruiting
- Recruiting
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR), 800-411-1222 ext. TTY8664111010, prpl@cc.nih.gov
About this study
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.
Read more
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 either the NIH Clinical Center or the Mexico Clinic sites 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 at the NIH site only. 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.
Read the 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 a multisite, international observational study intended to improve understanding of the pathogenesis of paradoxical response to treatment in TB-infected patients who do not have HIV. Each site will 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.
- Conditions
- Tuberculosis
- Keywords
- Auto-Antibody Production, Host Genetic Predisposition, Immune Reconstitution Inflammatory Syndrome, Biomarkers, Pathogenesis, Natural History
- Medical subject headings
- Tuberculosis, Immune Reconstitution Inflammatory Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| 1 | Patients with TB who have already initiated treatment and are suspected to have paradoxical reactions | |
| 2 | Patients with TB who have already initiated treatment without signs of paradoxical reactions (control) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Immunologic and radiographic responses of TB patients with suspected paradoxical reactions.
Characterize immunologic and radiographic responses of TB patients with suspected paradoxical reactions.
Measured: Throughout study
Secondary outcomes (1)
Biomarkers and/or microbiologic burden correlate with paradoxical TB reactions.
Determine whether biomarkers and/or microbiologic burden correlate with paradoxical TB reactions.
Measured: Throughout study
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Aug 2019
- Study start20 Dec 2019
- Primary completion30 Apr 2029 (estimated)
- Study completion30 Apr 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for TuberculosisStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 140 participants (estimated)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Maura M Manion, M.D., Principal investigator, National Institute of Allergy and Infectious Diseases (NIAID)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04052022
- Sponsor's protocol ID
- 190133
- Other IDs
- 19-I-0133
- Status last verified
- 29 Oct 2026
- First submitted
- 8 Aug 2019
- Last updated
- 2 Nov 2026
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: No plan at this time.
Study at a glance
From the registry record, last updated by the sponsor on 2 Nov 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Paradoxical Tuberculosis Reactions in Patients Without HIV Infection
- ClinicalTrials.gov ID
- NCT04052022
- Acronym / sponsor ID
- 190133
- Conditions
- Tuberculosis
- Keywords
- Auto-Antibody Production, Host Genetic Predisposition, Immune Reconstitution Inflammatory Syndrome, Biomarkers, Pathogenesis, Natural History
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 140 participants (estimated)
- Lead sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
- Study start
- 20 Dec 2019 (actual)
- Primary completion
- 30 Apr 2029 (estimated)
- Study completion
- 30 Apr 2029 (estimated)
- First posted
- 9 Aug 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 either the NIH Clinical Center or the Mexico Clinic sites 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 at the NIH site only. 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.
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 a multisite, international observational study intended to improve understanding of the pathogenesis of paradoxical response to treatment in TB-infected patients who do not have HIV. Each site will 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 design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 1 | – | –Patients with TB who have already initiated treatment and are suspected to have paradoxical reactions |
| 2 | – | –Patients with TB who have already initiated treatment without signs of paradoxical reactions (control) |
Who may qualify
- Ages
- 18 to 99 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Participants will be recruited from clinics in the surrounding Washington, DC area for the NIH site; and from clinics in Mexico for the foreign site
Key inclusion criteria (19 listed)
- Aged greater than or equal to 18 years.
- 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:
- 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.
- Willingness to allow storage of blood or tissue samples for future research.
- Ability of participant to understand study requirements and give informed consent.
Key exclusion criteria (7 listed)
- Individuals in either group who meet any of the following criteria will be excluded from study participation:
- HIV infection. (Individuals with HIV infection may be eligible for a separate study exclusively evaluating persons living with HIV.)
- Pregnant or breastfeeding.
- Uncontrolled psychiatric disease, substance use, or inappropriate conduct unsuitable for a research study.
- Malignancy requiring imminent or ongoing treatment including radiation, chemotherapy, or immunotherapy.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Immunologic and radiographic responses of TB patients with suspected paradoxical reactions.
Time frame: Throughout study
Characterize immunologic and radiographic responses of TB patients with suspected paradoxical reactions.
1 secondary outcome
Biomarkers and/or microbiologic burden correlate with paradoxical TB reactions.
Time frame: Throughout study
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Nov 2026.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: No. No plan at this time.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Maura M Manion, M.D. principal investigator
National Institute of Allergy and Infectious Diseases (NIAID)
3 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Tuberculosis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 3 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 19 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 2 Nov 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Mexico, United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Mary E McLaughlin, R.N. ((301) 435-8001, mmclaughli@niaid.nih.gov), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Immunologic and radiographic responses of TB patients with suspected paradoxical reactions. (time frame: Throughout study). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Nov 2026.