Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04930978 |
| Other study ID # |
2020 041 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
June 21, 2021 |
| Est. completion date |
June 20, 2024 |
Study information
| Verified date |
November 2023 |
| Source |
Tuberculosis Research Centre, India |
| Contact |
SUBASH BABU, PhD |
| Phone |
04428369500 |
| Email |
sbabu[@]icerindia.org |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the
Coronavirus disease (COVID-19). Tuberculosis (TB) is the foremost cause of infectious deaths
globally. In 2025, an additional 1.4 million TB deaths could occur as direct consequence of
the COVID-19 pandemic. It is postulated that individuals with latent or active TB are more
susceptible to SARS-CoV-2 disease and that COVID-19 disease rate is high in patients with
active TB, although the evidence is still scarce. TB and SARS-CoV-2 are both infectious
diseases which primarily attack the alveolar region of the lungs and share common symptoms.
SARS-CoV-2 disease can induce innate and adaptive immunity, but uncontrolled inflammatory
innate immunity and impaired adaptive immune responses may be associated with severe tissue
damage, both locally and systemically. People with coinfection (COVID-19 and TB disease)
might potentially have impaired protective immune responses and treatment outcomes,
specifically as far as anti-tuberculosis treatment is concerned. However, very little is
known about the immunological underpinnings in this interface between TB and COVID-19 on the
effect of SARS-CoV-2 disease on disease severity, response to treatment and treatment
outcomes in pulmonary tuberculosis. Investigators hypothesize that altered immunity due to
prior or present asymptomatic disease with SARS-CoV-2 virus can lead to altered immune
responses and systems biology, increased severity and altered treatment outcomes in TB
disease.
The main objective of the study would be to evaluate the baseline differences in immune cells
populations immune cell responses at baseline and at the time of treatment (2nd month) and
end of treatment. Further, Investigators would be evaluating the changes in proteomic
profiles in a subset of these individuals. In addition, immunological assays examining
differences in T cell populations, measuring levels of various cytokines and by
immunophenotyping as well as other immune parameters related to innate and adaptive responses
will be performed to enhance the understanding of the immunological cross-talk between active
TB patients with or without SARS-CoV-2. The secondary objective would be to study the
clinical features, disease severity, mycobacterial burden and treatment outcomes in a cohort
of SARS-CoV-2 infected (asymptomatic PCR or Antibody+) and non-infected patients with active
pulmonary TB.
Description:
Coronavirus disease (COVID-19) is a new respiratory infectious disease caused by severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to the family coronaviridae
with wide spreading in humans and animals. This virus is enveloped and contains
positive-sense, single-stranded RNA with approximately 31 kb of genome size and so far, is
considered as the largest known RNA viruses. The COVID-19 infected individuals exhibit low to
modest symptoms (cough, fever, and respiratory distress) and transmitted mainly by
respiratory droplets. However, around 15% of infected individuals proceed to severe pneumonia
and approximately 5% of them progress to acute respiratory distress syndrome (ARDS), septic
shock and/or multiple organ failure. Transmission of SARS-CoV-2 occurs through the means of
coughing and sneezing, touching the mouth, nose, eyes, close personal contact and touching a
virus-contaminated object. SARS-CoV-2 disease can induce both the arms of innate and adaptive
immunity, but uncontrolled inflammatory innate immunity and weakened adaptive immune
responses might be associated with destructive tissue damage, both locally and systemically.
Patients with severe COVID-19 exhibited decrease of lymphocytes, and the elevation of IL-6,
IL-10 and C-reactive protein. The SARS-CoV-2 is a global pandemic threat. Currently, as on
August 5, the total number of COVID-19 cases is approximately 18,354,342 with 696147 deaths
were reported worldwide and 216 countries are affected. In India, approximately 1,908,254
individuals were infected and 39795 deaths occurred due to COVID-19. SARS-CoV-2 disease is
often associated with unconstrained immune response, caused by the hyperactivation of
monocytes, macrophages and elevated neutrophils. Both, humoral (production of IgG, IgM,
neutralising antibodies and reduced memory B cells) and cell mediated (CD4+, CD8+ and
cytotoxic markers) immunity is required for defense against COVID-19. In addition, the
activation of Th1 / Th17 cells might induce the exacerbation of the inflammatory response.
Tuberculosis (TB) is one of the most important infectious diseases around the world.
Tuberculosis (TB), although largely a curable disease, still remains a major cause of
morbidity and mortality worldwide. According to the Global Tuberculosis Report 2019, there
are an estimated 10 million incident cases of tuberculosis and killed 1.2 million in 2018
globally. India accounts for 27% of all estimated incident cases worldwide. M. tuberculosis
(M.tb) infection could result in the activation of innate (monocytes, macrophages, dendritic
cells, neutrophils, mast cells) and adaptive (CD4+ and CD8+ T cells, cytotoxic markers)
immune response which are necessary for protection. Protective immunity against M.
tuberculosis is not completely understood but depends on a wide range of innate and adaptive
immune mechanisms. T cell-mediated immune responses are important in the host control of M.
tuberculosis infection. The ability of CD4+ T cells to produce gamma interferon, which
activates phagocytes to contain the intracellular pathogen, is central in protection. Indeed,
T helper 1 (Th1) cells and the gamma IFN that they produce are crucial for protection against
disease. This is evident from the increased risk of tuberculosis in individuals with
deficiencies in their IFNγ and interleukin 12 (IL 12; which promotes Th1 cell
differentiation) signalling pathways. Many other CD4+ T cell subsets, in addition to gamma
IFN producing Th1 cells, may also have a role; for example, IL 17-producing CD4+ T cells were
shown to mediate the recruitment of protective Th1 cells to the lung upon M. tuberculosis
challenge. Furthermore, increased frequencies of regulatory CD4+ T regulatory (Treg) cells
during active disease may ensure that the Th1 cell response is not excessive, and this would
help minimize lung damage in tuberculosis. The CD8+ T cell response to M. tuberculosis is
normally of a lower magnitude than the CD4+ T cell response; however, CD8+ T cells may
modulate phago¬cyte activity or produce molecules such as granulysin that may be directly
cytotoxic to the mycobacteria. Similarly, other cytokines, in addition to gamma IFN, may also
be crucial; for example, Tumour necrosis factor-alpha is important for establishing the
granuloma, which is a well-organized collection of innate and adaptive cells that forms to
contain the pathogen. Development of TB disease results from interactions among the
environment, the host, and the pathogen, and known risk factors include HIV coinfection,
immunodeficiency, diabetes mellitus, overcrowding, malnutrition, and general poverty.
The link between TB and COVID-19 is likely to be bi-directional. The temporary
immunosuppression induced by tuberculosis may increase the susceptibility of patients to
COVID-19, and COVID may, in turn, also increase susceptibility to TB. In 2025, an additional
1.4 million TB deaths could be occurred as direct consequence of the COVID-19 pandemic. The
COVID-19 disease rate was high in patients with active TB. TB and SARS-CoV-2 are both
infectious diseases which primarily attack the alveolar region of the lungs and share common
symptom patterns. Both CD4 and CD8 counts were severely reduced, and the surviving T cells
appeared to demonstrate "functional exhaustion". This T cell depletion and dysfunction may
exacerbate active TB. Published studies have reported that patients with TB and other viral
infections impede the host immune responses like induction of type I interferons by influenza
infection, lower mean of CD4+ and CD8+ T cells and increased viral elimination in sputum,
stool and suppression of cellular immunity. Recent studies have reported that cytokines seem
to play an important role in COVID-19 and TB, and their plasma levels associated with disease
severity. It is predicted that people with coinfection have impaired protective immune
responses and treatment outcomes, specifically in terms of anti-tuberculosis treatment.
Studies showed that SARS-CoV2 coexistent with TB resulted in a decreased absolute number of
CD4+ and CD8+ T cells and reduced antibody levels following SARS-CoV-2 recovery. SARS-CoV-2
with TB patients exhibited prolonged viral elimination from stools and sputum in comparison
without TB. Studies have demonstrated that SARS-CoV-2 disease stimulates increased cytokine
secretion, like interleukin-1 , gamma interferon, tumour necrosis factor- alpha,
interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-10 (IL-10), that ultimately leads to
severe inflammation and their plasma levels were linked with disease severity. However, only
limited information is available on the function of antigen-specific T cell-mediated immune
response to COVID-19 specifically upon coinfection with tuberculosis, since both the disease
primarily affects the lungs.
Limited studies have shown that influenza induces immune system hyperactivity and exacerbates
pulmonary tuberculosis, leading to worsening of pulmonary function. Respiratory viral
infections coexistent with TB delay the host immune responses and lead to more serious
clinical outcomes. Coinfection most probably exacerbates inflammation through heightened
secretion of cytokines and accelerates the development of severe acute respiratory syndrome
and also worsen the TB disease and its outcome. Hence, Investigators propose that
understanding mechanisms of immune regulation during SARS-CoV-2 disease may lead to the
development of better therapeutic strategies and the results of our fundamental studies may
inform future plans for clinical interventional studies. The main fundamental research
component of this study might identify clinical parameters and treatment methods and to
understand the immunological mechanism for the severity in coinfected SARS-CoV-2 and TB
patients.
Hypothesis: Investigators hypothesize that altered immunity due to present or prior
asymptomatic disease with SARS-CoV-2 virus could lead to altered immune responses and systems
biology, increased severity and altered treatment outcomes in TB disease.
