Immune Responses to Mycobacterium Tuberculosis (Mtb) in People With Latent Tuberculosis Infection With or Without Concomitant Helminth Infection
| Status: | Recruiting |
|---|---|
| Conditions: | Infectious Disease, Infectious Disease, Infectious Disease |
| Therapuetic Areas: | Immunology / Infectious Diseases |
| Healthy: | No |
| Age Range: | 18 - 70 |
| Updated: | 4/21/2016 |
| Start Date: | August 2014 |
| End Date: | January 2030 |
| Contact: | Nicole C Holland-Thomas, R.N. |
| Email: | hollandnc@mail.nih.gov |
| Phone: | (301) 402-5969 |
Longitudinal Study of Immune Responses to Mycobacterium Tuberculosis (Mtb) in Subjects With Latent Tuberculosis (TB) Infection(LTBI) With or Without Concomitant Helminth Infection
Background:
Tuberculosis (TB) is a severe disease and a major cause of death in many people worldwide.
It is caused by a bacteria that enters through the lungs and can spread elsewhere in the
body. People with latent TB have the bacteria that lie dormant but can become active and
cause disease. These people are offered treatment to prevent development of active TB.
Worldwide, a lot of people with LTBI also have a parasitic worm called a helminth that can
stay in the gut or the blood. These parasites can affect the immune system and cause
diseases like TB to become worse. Researchers want to see how helminth infection makes it
harder for people to fight TB infection.
Objectives:
- To study how the immune system of people with latent tuberculosis infection (LTBI) acts to
prevent development of active TB. Also, to study how helminth infection might affect this
immune response.
Eligibility:
- Adults age 18 70 with LTBI as defined by an approved blood test called QuantiFERON TB
Gold.
- No evidence of infections like Hepatitis or HIV
- Pregnant subjects and subjects taking medications that suppress the immune system are
not eligible.
- Have not received prior treatment for LTBI. Participants might be still eligible if
prior treatment for active TB has been received
Design:
Screening phase:
- Participants will be screened with medical history, physical exam, and blood tests for
other infections/conditions which might affect the immune system. They will have testing for
active TB i.e. blood testing as well as testing of their spit, scans and X-rays.
Baseline phase:
- Only eligible participants will be entered into the study.
- Participants will have interviews, medical history, and physical exam.
- Blood will be drawn from an arm vein for testing.
- Participants will collect stool samples at home for 3 days in a row to test for
helminth infection..
- Participants may have apheresis. Blood cells are removed by needle. They pass through a
separator machine which returns everything but the cells back to the participant.
- Participants may have procedures at the start and end of the study that let researchers
look into the lungs and collect cells.
Study phase, about 2 years:
- All participants will be offered treatment for LTBI which lasts 6-9 months.
- Participants being treated for LTBI will have about 11 study visits. They will visit
monthly for 9 months while on treatment, then 6 and 12 months after treatment.
- Participants not eligible/refusing treatment for LTBI will be made aware of active TB,
then have 3 other visits, about 6, 12, and 24 months after the baseline visit.
- Participants who have helminth infection will receive appropriate treatment.
- All participants will have blood drawn at each visit.
Tuberculosis (TB) is a severe disease and a major cause of death in many people worldwide.
It is caused by a bacteria that enters through the lungs and can spread elsewhere in the
body. People with latent TB have the bacteria that lie dormant but can become active and
cause disease. These people are offered treatment to prevent development of active TB.
Worldwide, a lot of people with LTBI also have a parasitic worm called a helminth that can
stay in the gut or the blood. These parasites can affect the immune system and cause
diseases like TB to become worse. Researchers want to see how helminth infection makes it
harder for people to fight TB infection.
Objectives:
- To study how the immune system of people with latent tuberculosis infection (LTBI) acts to
prevent development of active TB. Also, to study how helminth infection might affect this
immune response.
Eligibility:
- Adults age 18 70 with LTBI as defined by an approved blood test called QuantiFERON TB
Gold.
- No evidence of infections like Hepatitis or HIV
- Pregnant subjects and subjects taking medications that suppress the immune system are
not eligible.
- Have not received prior treatment for LTBI. Participants might be still eligible if
prior treatment for active TB has been received
Design:
Screening phase:
- Participants will be screened with medical history, physical exam, and blood tests for
other infections/conditions which might affect the immune system. They will have testing for
active TB i.e. blood testing as well as testing of their spit, scans and X-rays.
Baseline phase:
- Only eligible participants will be entered into the study.
- Participants will have interviews, medical history, and physical exam.
- Blood will be drawn from an arm vein for testing.
- Participants will collect stool samples at home for 3 days in a row to test for
helminth infection..
- Participants may have apheresis. Blood cells are removed by needle. They pass through a
separator machine which returns everything but the cells back to the participant.
- Participants may have procedures at the start and end of the study that let researchers
look into the lungs and collect cells.
Study phase, about 2 years:
- All participants will be offered treatment for LTBI which lasts 6-9 months.
- Participants being treated for LTBI will have about 11 study visits. They will visit
monthly for 9 months while on treatment, then 6 and 12 months after treatment.
- Participants not eligible/refusing treatment for LTBI will be made aware of active TB,
then have 3 other visits, about 6, 12, and 24 months after the baseline visit.
- Participants who have helminth infection will receive appropriate treatment.
- All participants will have blood drawn at each visit.
Mycobacterium tuberculosis (Mtb) infection remains an important cause of morbidity and
mortality worldwide. A problem for eradication efforts is the large reservoir of ~2 billion
people with latent tuberculosis (TB) infection (LTBI) and poor understanding of factors
leading to active disease progression. Helminth infections geographically overlap with Mtb
and induce significant immune-mediated modulation. Although CD4+T cells producing IFN-gamma
and TNF-alpha have been implicated in protective immunity to TB, a detailed description of
the evolution of protective and immunomodulatory responses in LTBI is lacking. Additionally,
there is incomplete understanding of how the immunomodulation caused by helminth
co-infection affects such responses.
This protocol will attempt to fill this knowledge gap through comprehensive longitudinal
immunological analyses of two populations of subjects with LTBI, with or without concurrent
helminth infection (HEL+ and HEL- respectively). In both groups, venipuncture and possibly
apheresis will be performed to understand protective and modulatory T cell and
monocyte/macrophage responses. Subjects will receive treatment for helminth infection and
treatment for LTBI will be offered according to current standard of care guidelines. Two
groups of subjects within the LTBI group will be offered bronchoscopy and lavage --- (a)
those with structural lung damage from prior treated/healed tuberculosis and (b) those with
recent prolonged exposure (greater than or equal to 3 months) to a household contact with
active TB.
The primary objective is to evaluate CD4+ T cell responses and regulatory T cell responses
in HEL+ and HEL- subjects with LTBI at the time of diagnosis (baseline). HEL+ subjects will
then receive treatment for parasitic infection and both groups (HEL+ and HEL-) will be
offered LTBI treatment. Evolution of the baseline TB-specific immune responses on and after
LTBI treatment will then be studied. Additionally, baseline immune responses to mycobacteria
will be contrasted in the HEL+ group with all time points post treatment for helminth
infection. A secondary objective is to evaluate the immune phenotype and functionality of
tissue resident immune cells obtained by bronchoalveolar lavage in subjects with LTBI and
structural lung damage from prior treated/healed pulmonary tuberculosis as well as subjects
with recent prolonged TB exposure from an active TB case irrespective of helminth infection
status.
An exploratory objective is to evaluate if there are subsets of subjects within the LTBI
group (irrespective of helminth infection status) who have stable pool of long lasting
antigen-specific IL-2 only producing CD4+ central memory T cells and changes to this pool
after receiving LTBI treatment.
mortality worldwide. A problem for eradication efforts is the large reservoir of ~2 billion
people with latent tuberculosis (TB) infection (LTBI) and poor understanding of factors
leading to active disease progression. Helminth infections geographically overlap with Mtb
and induce significant immune-mediated modulation. Although CD4+T cells producing IFN-gamma
and TNF-alpha have been implicated in protective immunity to TB, a detailed description of
the evolution of protective and immunomodulatory responses in LTBI is lacking. Additionally,
there is incomplete understanding of how the immunomodulation caused by helminth
co-infection affects such responses.
This protocol will attempt to fill this knowledge gap through comprehensive longitudinal
immunological analyses of two populations of subjects with LTBI, with or without concurrent
helminth infection (HEL+ and HEL- respectively). In both groups, venipuncture and possibly
apheresis will be performed to understand protective and modulatory T cell and
monocyte/macrophage responses. Subjects will receive treatment for helminth infection and
treatment for LTBI will be offered according to current standard of care guidelines. Two
groups of subjects within the LTBI group will be offered bronchoscopy and lavage --- (a)
those with structural lung damage from prior treated/healed tuberculosis and (b) those with
recent prolonged exposure (greater than or equal to 3 months) to a household contact with
active TB.
The primary objective is to evaluate CD4+ T cell responses and regulatory T cell responses
in HEL+ and HEL- subjects with LTBI at the time of diagnosis (baseline). HEL+ subjects will
then receive treatment for parasitic infection and both groups (HEL+ and HEL-) will be
offered LTBI treatment. Evolution of the baseline TB-specific immune responses on and after
LTBI treatment will then be studied. Additionally, baseline immune responses to mycobacteria
will be contrasted in the HEL+ group with all time points post treatment for helminth
infection. A secondary objective is to evaluate the immune phenotype and functionality of
tissue resident immune cells obtained by bronchoalveolar lavage in subjects with LTBI and
structural lung damage from prior treated/healed pulmonary tuberculosis as well as subjects
with recent prolonged TB exposure from an active TB case irrespective of helminth infection
status.
An exploratory objective is to evaluate if there are subsets of subjects within the LTBI
group (irrespective of helminth infection status) who have stable pool of long lasting
antigen-specific IL-2 only producing CD4+ central memory T cells and changes to this pool
after receiving LTBI treatment.
- INCLUSION CRITERIA
All subjects must meet the following criteria:
- Subjects must have 1 of the following:
- Untreated LTBI, defined as positive Quantiferon TB Gold assay; absence of active
TB disease as determined by history, physical examination, chest X-ray, and
negative sputum smear and culture for Mtb; and no history of prior treatment for
LTBI. OR
- Chronic inactive TB, defined as past history of documented or selfreported
active pulmonary TB for which treatment was received; current negative sputum
smear and culture for Mtb; and a positive result on the Quantiferon TB Gold
assay. These subjects will compose the treatment-induced LTBI group and will not
require treatment for LTBI.
- Age 18-70 years. Subjects over the age of 70 will not be included due to the
increased potential for immune senescence
- With or without clinical/microbiologic/serologic evidence of untreated concurrent
helminth infection
- Agree to have blood specimens stored for future studies
Subjects undergoing optional bronchoscopy and bronchoalveolar lavage must meet the
following additional inclusion criteria:
- Subjects must have 1 of the following:
- Documented or self reported history of prior treated TB with positive
Quantiferon TB Gold test and structural lung findings of chronic inactive
tuberculosis on radiologic imaging, defined as: a) calcified Ghon focus with or
without apical calcified nodules (Simon foci), b) parenchymal or pleural
calcification, and/or c) apical fibrosis and cavitary changes. OR
- History of recent prolonged (greater than or equal to 3 months) exposure to a
confirmed case of active TB disease.
- Able and willing to arrange to have another person drive them home after the
procedure
- Able and willing not to eat or drink anything for 6 hours prior and 2 hours after the
procedure
- Agree to have respiratory tract samples stored for future research
EXCLUSION CRITERIA
A subject will be excluded if they meet any of the following criteria:
- Presence of active TB disease
- Treatment for helminth infection within the past year
- Positive at screening for HIV, hepatitis B, and/or hepatitis C Cardiovascular
instability (Blood pressure: Systolic > 180 or < 90 mm/Hg or Diastolic > 100 or < 50
mm/Hg; pulse < 40 or > 110)
- Inadequate peripheral venous access
- Anemia (hemoglobin < 11 g/dL)
- Current use of corticosteroids or other immunosuppressive agents or documented
diagnosis of a primary immunodeficiency disorder
- Underlying heart disease, lung disease, bleeding disorder, or other conditions that,
in the judgment of the investigator, contraindicates apheresis
- Temperature greater than or equal to 38.5 degrees C or other clinical evidence of an
acute infection at screening
- Currently pregnant or breastfeeding
A subject will not be eligible for optional bronchoscopy and bronchoalveolar lavage if
they meet any of the following additional exclusion criteria:
- History of recent/acute clinically significant pulmonary compromise. This will be
defined by the following criteria:
- New lung infection or change in status of chronic lung infection or significant
new findings on chest X-ray or CT scan
- Asthma that is unstable or required emergent care, urgent care, hospitalization,
or intubation during the past two years, or that required the use of oral or
parenteral corticosteroids during the past two years
- Clinically significant reactive airway disease that does not respond to
bronchodilators
- Unstable chronic lung disease such as Chronic Obstructive Pulmonary Disease
(COPD) or pulmonary fibrosis
- History of pulmonary hypertension
- Requirement of supplemental oxygen at rest
- Unstable angina or uncontrolled heart failure or rhythm disturbance
- Significant kidney or liver disease
- Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy, or
platelet disorder requiring special precautions), significant bruising or bleeding
difficulties with IM injections or blood draws, or use of anticoagulant medications
- Use of platelet inhibitors including aspirin and NSAIDs within 7 days of procedure or
clopidogrel (Plavix [TM]) within 14 days of procedure or the inability to safely stop
platelet inhibitors for 7-14 days prior to procedures
- History of allergic reaction to lidocaine, sedative medications like Valium(TM) or
Versed (TM), or narcotic medications like morphine or fentanyl
- Any medical, psychiatric, social condition, occupational reason or other
responsibility that, in the judgment of the investigator, is a contraindication to
bronchoscopy and bronchoalveolar lavage or impairs a volunteer s ability to give
informed consent for the procedure
We found this trial at
2
sites
Silver Spring, Maryland 20902
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9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
Phone: 800-411-1222
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