Effect of Filarial Infection on Immune Responses in Latent Tuberculosis
Condition: Mycobacterium Infections; Tuberculosis; Filariasis; Latent Tuberculosis
MeSH terms: Infections; Communicable Diseases; Tuberculosis; Mycobacterium Infections; Latent Tuberculosis; Filariasis
Study type: Observational

Summary: 
      Background:

      - Lymphatic filariasis is an infection that is caused by small, thread-like worms. It is
      spread by mosquitoes, and causes fever, chills, and headaches. If untreated, it can also
      cause elephantiasis, a condition that leads to swelling of the arms, legs, breasts, and
      scrotum. Treatment can eliminate the worms from the blood and reduce the risk of developing
      elephantiasis. Researchers want to study people with latent tuberculosis (TB) who may or may
      not be infected with filariasis. This study will look at the way that people with latent TB
      fight infection with these worms.

      Objectives:

      - To study how the immune systems of people with latent TB react to filarial infection.

      Eligibility:

      - Individuals between 18 and 65 years of age who have latent TB and may or may not have
      filarial infection.

      Design:

        -  Participants will be screened with a physical exam and medical history. They will
           provide a blood and stool sample to test for infection.

        -  Participants who do not have lymphatic filariasis but have another kind of intestinal
           worm will be treated for the parasite. This will be their last study visit.

        -  Participants who have latent TB and lymphatic filariasis will be treated with the
           standard treatment for the disease. They will come back for a second visit 6 months
           later, and will provide another blood sample.
    

Detailed description: 
      Tissue-invasive helminth parasites infect close to 500 million people worldwide and are
      associated with strong T helper (Th)2 responses and regulatory networks that downregulate
      potentially protective Th1 responses. The two common tissue invasive helminth parasites are
      Wuchereria bancrofti, that causes lymphatic filariasis and Strongyloides stercoralis, that
      causes stronyloidiasis. Previous studies have shown that the intestinal helminth coinfection
      is accompanied by lowered in vitro production of interferon-gamma and elevated production of
      interleukin 10 in individuals with active pulmonary tuberculosis (TB). Our team has recently
      shown that co-existent filarial TB infections down-regulate Th1 and Th17 responses, which are
      necessary for protection against active TB.

      The current study will compare immune responses to mycobacterial antigens in individuals with
      latent tuberculosis (LTBI+) and concomitant helminth infection (Hel+), including those with
      filarial (Fil+) and strongyloides (STR+) infection versus those with LTBI+ without
      concomitant helminth infection (Hel-). Immune responses to mycobacterial antigens from
      co-infected individuals will also be evaluated before and after treatment for helminth
      infection. Individuals (n=4000) will sign a screening consent prior to undergoing any study
      procedures. Every participant will have their medical history collected and will undergo a
      physical exam and a tuberculin 2TU purified protein derivative (PPD) skin test; women of
      childbearing potential will also undergo a urine pregnancy test, and those with positive test
      results will be excluded from the study. Individuals with positive PPD skin test results (>
      or = 5 mm) and no symptoms of active TB will have their blood drawn (5 mL) as part of the
      screening procedures to confirm LTBI+ status, evaluate circulating filarial antigenemia,
      determine Strongyloides status by ELISA, measure hematocrit levels, and for storage of serum
      samples; those with PPD skin test results less than or equal to 5 mm will be excluded from
      the study. Individuals with positive symptoms for TB will also be excluded from the study,
      but sputum will be collected from them, and those with positive smears will be referred for
      treatment. Individuals will be matched for age, gender, and geographic location, and they
      will be assigned to one of two groups, LTBI+ Hel+ (n=100) or LTBI+ Hel- (n=100).

      Within 3 months of screening, individuals will be asked to sign an on-study consent and will
      undergo a second blood draw (10 mL) for immunological investigations and storage of serum
      samples; women of childbearing potential will undergo a repeat urine pregnancy test, and
      those with positive test results will be excluded from further study. Stool samples will also
      be collected for microscopic evaluation of ova and parasites. LTBI+ Fil+ individuals will be
      treated with a single standard dose of albendazole (400 mg) and single standard dose of
      diethylcarbamazine citrate (300 mg), which are available through the National Programme for
      the Elimination of Lymphatic Filariasis in India. LTBI+ STR+ individuals will be treated with
      a single standard dose of ivermectin (12mg) and a single standard dose of albendazole
      (400mg). These individuals will be asked to return 6 months after treatment to undergo a
      third blood draw (10 mL) for additional immunological investigations and storage of serum
      samples. LTBI+ Hel-individuals who test positive for other intestinal helminth infection will
      be treated with a single standard dose of albendazole (400 mg).
    

Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        The screening will be a community-based study in South India. Study participants will be
        recruited from villages in the Kancheepuram District, where approximately 6% of the
        population tests positive for circulating filarial antigens [31]. PPD skin test reactivity
        in this population is virtually 100% to PPD-B (battery) and 60% to 70% to PPD-S (standard)
        by age 24, and the incidence of active TB is about 4 per 1000 individuals [31]. While the
        rate of positivity of the tuberculin skin test to the 2TU PPD test is not known,
        significant deviation in the percent positivity from skin tests using 1TU is not expected
        based on findings reported elsewhere [32]. However, we are revising the @@@screening sample
        number on the basis of preliminary data from the current study that shows that the
        prevalence of latent TB in this population is around 25% and filariasis is around 1%. In
        addition, preliminary data from these areas show that the prevalence of Stronglyloides
        infection is around 10%.
      
Keywords: T Cells; Immune Responses; Mycobacterial Antigens; Tissue-invasive Helminth Parasites; Cytokines