Miliary Tuberculosis and its complications | Medical Science Optional Notes for UPSC PDF Download

Introduction

• Miliary Tuberculosis: Miliary tuberculosis is characterized by the existence of numerous small tuberculous granulomas in various organs, each about the size of millet seeds.
• Hemoptysis: Hemoptysis, or coughing up blood, is a complication associated with secondary tuberculosis.
• Bronchopleural Fistula: The formation of a bronchopleural fistula occurs when a subpleural cavity ruptures into the pleural space. This can lead to tuberculous empyema and pneumothorax.
• Tuberculous Laryngitis: Tuberculous laryngitis is a complication associated with secondary tuberculosis.
• Intestinal Tuberculosis: Complications of secondary tuberculosis also include involvement of the intestines, leading to intestinal tuberculosis.

Miliary tuberculosis

• Definition: Massive lymphohematogenous spread of Mycobacterium tuberculosis bacilli originating from either a pulmonary or extrapulmonary focus, involving multiple organs, and characterized by very small granuloma lesions measuring 1-2 mm.
• Epidemiology: This condition accounts for approximately 20% of all extrapulmonary tuberculosis cases.
• Etiology: The onset may occur 2-5 months after the initial infection or even years later. Pulmonary involvement is the most common.
• Diagnosis: Chest X-ray reveals multiple, small, nodular densities of uniform size scattered throughout the lungs, often resembling a "millet seed" appearance.
• Commonly Affected Organs: Besides the lungs, other frequently affected organs include the central nervous system, choroid, skin, liver/spleen (resulting in hepatosplenomegaly), kidneys, and adrenal glands.

Tuberculosis-Diagnosis

Chest X-ray Findings in Tuberculosis

• Primary Tuberculosis Infection:
  • Cavitation is infrequent in primary tuberculosis.
  • Hilar lymphadenopathy is common.
  • Pleural effusions may occur.
  • Ghon complex, representing the sequelae of primary tuberculosis infection, can be observed.
• Reactivated Disease:
  • Reactivated tuberculosis often presents with upper lobe cavitary lung lesions.
• Sputum Microscopy with Acid-Fast Stain (Ziehl-Neelsen Stain):
  • Provides rapid results but lacks sensitivity.
  • Cannot differentiate between M. tuberculosis and nontuberculous mycobacteria.
• Culture (Gold Standard):
  • Utilized for species identification, sensitivity testing, and the identification of potential resistances.
  • The culture process may take up to six weeks, making it impractical for initial therapy planning.
  • Examples of culture media include Lowenstein-Jensen agar.

Nucleic Acid Amplification Tests (NAATs) as Primary Diagnostic Tools

• Xpert MTB/RIF Assay:
  • This fully automated, real-time nucleic acid amplification technology, performed on the GeneXpert® diagnostic platform, is the preferred first-line diagnostic test.
  • The Xpert MTB/RIF assay provides rapid confirmation of all types of tuberculosis, simultaneously detecting TB and rifampin resistance in less than 2 hours.
  • Its application has minimal biosafety and training requirements.
  • Recommended by the World Health Organization (WHO) for use worldwide as the initial diagnostic test in all individuals with signs or symptoms of active TB.
  • It is also suggested as the primary diagnostic test for people living with HIV in whom TB is suspected and as the initial test for suspected TB meningitis when applied to cerebrospinal fluid (CSF).
  • The sensitivity of this test is approximately 98% among AFB-positive cases and around 70% among AFB-negative specimens.
• New Xpert MTB/RIF Ultra Assay (Ultra):
  • The Xpert MTB/RIF Ultra assay represents a new technology, exhibiting an overall sensitivity 5% higher than the original Xpert MTB/RIF assay.
  • The greatest sensitivity increases are observed among smear-negative, culture-positive cases (an increase of 17%) and among HIV-infected individuals (an increase of 12%).
  • Notably, "trace calls," which indicate the detection of nonviable bacilli or fragments, require evaluation considering risk/benefit considerations.
• TD-LAMP Assay:
  • The TD-LAMP assay utilizes loop-mediated isothermal amplification (LAMP) technology, amplifying DNA at a constant temperature.
  • This assay is relatively simple to use and can be interpreted through a visual display.
  • It demands minimal laboratory infrastructure and has limited biosafety requirements.

Tuberculosis-CBNAAT/Xpert MTB/RIF/Gene Expert

Latent TB-Diagnosis

Interferon Gamma Release Assay (IGRA)

• Definition: IGRAs are laboratory blood tests that measure the cell-mediated immune response by assessing T-cell release of interferon-gamma (IFN-γ). These tests are conducted in vitro, and their stimulation involves antigens specific to the Mycobacterium tuberculosis complex, such as early secreted antigenic target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10).
• Specificity Over PPD: IGRAs offer greater specificity than the Purified Protein Derivative (PPD) test for Mycobacterium tuberculosis. This specificity arises from the absence of ESAT-6 and CFP-10 in the genomes of most BCG vaccine strains and various non-tuberculous mycobacteria (NTM) species.
• Antigens Used: The antigens employed in IGRAs, ESAT-6 and CFP-10, contribute to their heightened specificity.
• Commercial IGRA Tests: Two widely used commercial IGRA tests are available in many countries: the QuantiFERON-TB Gold In-Tube (QFT) assay and the T-SPOT.TB assay.
• BCG Vaccine Strains and NTM: IGRAs are advantageous as they do not cross-react with BCG vaccine strains or most NTM species, enhancing their accuracy in detecting Mycobacterium tuberculosis infection.

Mantoux Test

• Delayed-Type Hypersensitivity Reaction: Infection with Mycobacterium tuberculosis leads to a delayed-type hypersensitivity reaction specific to antigenic components of the bacilli.
• Purified Protein Derivative (PPD):
  • The Mantoux test involves the intradermal administration of the purified protein derivative (PPD) of tuberculin.
  • The aim is to elicit a memory T cell response to mycobacterial antigens.
• Procedure: A 26-gauge needle and tuberculin syringe are employed to intradermally inject 0.1 ml of PPD into the volar aspect of the forearm.
• Interpretation:
  • Forty-eight to seventy-two hours after the injection, the induration diameter is measured transversely to the long axis of the forearm.
  • The measurement, recorded in millimeters, is used for interpretation.

Tuberculosis-Treatment

Directly Observed Treatment (DOT)

• Integral to DOTS Strategy: DOT is a crucial element of the DOTS strategy, ensuring the correct administration of the entire course of treatment with the right drugs, in appropriate doses, and at the prescribed intervals.
• Supervised Medication Intake: In DOT, a designated observer supervises and supports the patient in taking their prescribed medications.
• DOT Provider: The health worker or community volunteer responsible for administering DOT is referred to as the 'DOT Provider.'
• Non-Family DOT Provision: DOT can be facilitated by any individual other than the patient's family members.
• DOT Center: The 'DOT center' serves as the location for providing DOT, ensuring convenience for both the patient and the DOT provider.

DOTS Plus

• Definition: Traditionally, DOTS Plus encompasses DOTS programs incorporating components for the diagnosis, management, and treatment of Multi-Drug Resistant Tuberculosis (MDR-TB).
• Integration Guidelines (January 2010):
  • These guidelines advocate the comprehensive integration of DOTS and DOTS-Plus activities within the Revised National Tuberculosis Control Programme (RNTCP).
  • This integration aims to correctly identify and manage patients with MDR-TB in line with the recommendations outlined in the RNTCP DOTS Plus Guidelines from January 2010.

Components of DOTS Plus

• Political and Administrative Commitment: Emphasis on sustained commitment at both political and administrative levels.
• MDR-TB Diagnosis: Utilization of quality-assured culture and drug susceptibility testing (DST) for the accurate diagnosis of MDR-TB.
• Appropriate Treatment Strategies: Implementation of proper management conditions and treatment strategies employing second-line drugs.
• Uninterrupted Drug Supply: Ensuring a continuous and uninterrupted supply of quality-assured anti-TB drugs.
• Recording and Reporting System: Development of a recording and reporting system tailored for DOTSPus programs, facilitating performance monitoring and evaluation of treatment outcomes.

Patient-wise boxes (PWB)

• Patient-Wise Boxes (PWB): Medications are provided in Patient-Wise Boxes (PWB), each containing the complete treatment course, and packaged in blister packs.
• Color Code for Categories: PWBs are color-coded to denote the treatment category (Red for CAT I, Blue for CAT II, and Green for CAT III).
• Two Pouches in Each PWB: Each PWB consists of two pouches: one for the intensive phase (A) and one for the continuation phase (B).
• Intensive Phase Blister Packs: For the intensive phase, each blister pack contains medications for a single dose.
• Continuation Phase Blister Packs: In the continuation phase, each blister pack contains a one-week supply of medication.
• Supervised Intensive Phase Doses: All doses during the intensive phase are administered under the direct observation of the DOT provider.
• Missed Dose Protocol in Intensive Phase: If a dose is missed during the intensive phase, the patient is contacted within one day. The missed dose is administered on the following day.
• Continuation Phase Administration: At least the first dose of the week in the continuation phase is taken under direct observation. Subsequent doses for the week are self-administered.
• Blister Pack Collection in Continuation Phase: During the next scheduled visit, the DOT provider collects the empty blister pack before providing the next weekly dose.
• Follow-Up for Missed Doses in Continuation Phase: If a dose is missed in the continuation phase, the patient is contacted and retrieved for treatment within a week.
• Retention of Empty Blister Packs: All empty blister packs, both from the intensive and continuation phases, are retained in the Patient-Wise Boxes (PWB).

Category I (red box)

• Indications:
  • Newly diagnosed with sputum smear-positive TB.
  • Seriously ill individuals with sputum smear-negative TB.
  • Seriously ill patients with extrapulmonary TB.
• Regimen:
  • 2(HRZE)3 for the intensive phase.
  • 4(HR) for the continuation phase.
• Extrapulmonary TB Conditions:
  • Meningitis.
  • Pericarditis.
  • Peritonitis.
  • Bilateral or extensive pleural effusion.
  • Spinal TB with neurological involvement.
  • Intestinal and genitourinary TB.
  • Co-infection with HIV.
  • All forms of pediatric extrapulmonary TB except lymph node TB and unilateral pleural effusion.
• Seriously Ill Sputum Smear-Negative TB Conditions:
  • Miliary TB.
  • Extensive parenchymal infiltration.
  • Co-infection with HIV.
• Sputum Smear-Negative Pulmonary TB Conditions:
  • Cavitations.
  • All forms of sputum smear-negative pulmonary TB except primary complex.

Category II (blue box)

• Indications:
  • Previously treated individuals with sputum smear-positive TB.
  • Cases of TB relapse.
  • Treatment after a previous default or failure.
• Regimen:
  • 2(HRZES)3 for the intensive phase.
  • 1(HRZE)3 for the continuation phase.
  • 5(HRE)3 for the entire treatment duration.

Category III (Green box)

• Indications:
  • Newly diagnosed cases with smear-negative TB.
  • Individuals with extrapulmonary TB who are not seriously ill.
• Regimen:
  • 2(HRZ)3 for the intensive phase.
  • 4(HR)3 for the continuation phase.

Mode of administration and follow up

Mode of Administration:

• Intensive Phase (IP):
  • Thrice weekly on specified days (Monday, Wednesday, Friday, or Tuesday, Thursday, Saturday).
  • Each dose is administered under direct observation.
• Continuation Phase (CP):
  • Thrice weekly on specified days (Monday, Wednesday, Friday, or Tuesday, Thursday, Saturday).
  • The first dose of the week is taken under direct observation.

Follow-Up Sputum Examination Schedule:

• First Follow-Up: Conducted at the end of the intensive phase in all categories.
• Second Follow-Up: Scheduled 2 months after starting the continuous phase.
• Final Follow-Up: Conducted at the end of the entire treatment period.

TB-Causes of Treatment failure

Doctors - Causes of TB Drug Treatment Failure

• Use of inappropriate guidelines.
• Non-compliance with established guidelines.
• Lack of guidelines altogether.

Drugs - Causes of Inadequate Treatment

• Poor quality of drugs.
• Irregular supply of drugs.
• Incorrect delivery, involving issues with dosage or drug combination.
• Use of unsuitable drugs due to drug resistance.

Patients - Causes of TB Drug Treatment Failure

• Insufficient information provided to patients.
• Limited financial resources for treatment and/or transportation.
• Real or perceived side effects of the drugs.
• Lack of commitment to adhere to the long course of drug treatment.
• Malabsorption issues.
• Social barriers impacting treatment adherence.

Category IV (DOTS PLUS)-MDR TB

Multidrug-Resistant Tuberculosis (MDR-TB)

• Bacilli exhibit resistance to isoniazid and rifampin, which are the most potent bactericidal agents in managing tuberculosis.
• WHO Treatment Recommendation for MDR-TB:
  • In most patients, the WHO suggests the use of five drugs:
    • Inter-generation fluoroquinolone (e.g., moxifloxacin).
    • An injectable agent, such as the aminoglycosides amikacin or kanamycin, or the polypeptide capreomycin.
    • Ethionamide (or prothionamide).
    • Either cycloserine or PAS.
    • Pyrazinamide.
  • Ethambutol can be included.
• Treatment Duration:
  • The optimal duration is not precisely known.
  • A course of at least 20 months is recommended for previously untreated patients.
  • This includes the initial phase with an injectable agent, typically discontinued at 4 months after culture conversion.

Because the management of patients with MDR-TB is complicated by both social and medical factors, care of these patients is ideally provided in specialized centers.

Recent Advancements in MDR-TB Management
Bedaquiline/Delamanid Usage:

• Bedaquiline and Delamanid can now be employed in MDR-TB cases.
• This is applicable when it is challenging to formulate an effective WHO-recommended standard MDR-TB regimen due to:
• Known resistance issues.
• Intolerance to specific drugs.
• Non-availability of certain second-line drugs in the regimen.

XDR TB

• Definition:
  • Resistant to isoniazid and rifampin.
  • Resistance to any fluoroquinolone and at least one of three injectable second-line drugs (amikacin, kanamycin, or capreomycin).
• Treatment Challenges:
  • Limited treatment options.
  • Poor prognosis for patients with XDR-TB.
• Patient-Centered Approach:
  • Prioritize palliative and end-of-life care when all treatment options are exhausted.
  • Adhere to respiratory infection-control measures.
• Novel Regimen in South Africa:
  • A novel regimen consisting of pretomanid, bedaquiline, and linezolid.
  • High cure rate observed among XDR-TB patients in South Africa.
• Future Therapeutic Option:
  • Promising regimen with potential future importance.
  • Composed of pretomanid, bedaquiline, and linezolid.
• FDA Approval for New Oral Regimen (BPaL):
  • FDA-approved oral three-drug regimen for XDR-TB.
  • Combination of pretomanid, bedaquiline, and linezolid (BPaL regimen).
  • Approved in 2019 with a high efficacy rate of 90%.
  • Short treatment duration of six months.

Tubercular meningitis

• Incubation Period:
  • Approximately 2-8 weeks.
• Etiology:
  • Results from hematogenous spread of primary or post-primary pulmonary TB.
  • May also occur from the rupture of a subependymal tubercle into the subarachnoid space.
• Diagnostic Approach:
• Lumbar Puncture:
• Cornerstone of diagnosis.
• CSF Findings:
  • Lymphocytic leukocytosis.
  • Elevated protein content.
  • Low glucose concentration.
• AFB staining and culture of CSF.
• Real-time automated nucleic acid amplification (Xpert MTB/RIF assay) preferred for initial diagnosis with up to 80% sensitivity.
• Imaging:
  • CT and MRI may be utilized.
• Treatment:
  • Antituberculosis treatment.
  • Adjuvant glucocorticoid therapy with either dexamethasone or prednisolone.
  • Tapered over 6-8 weeks.

Tuberculosis-Repeats

Q1: Describe various laboratory methods used for the diagnosis of Pulmonary Tuberculosis. (1998)

Q2: Discuss the management of Multidrug Resistant Tuberculosis. (2005) 

Q3: What do you understand with the terms miliary tuberculosis and disseminated tuberculosis? What are the complications of the miliary tuberculosis? How will you diagnose and manage the case of a TBM? (2007)

Q4: A 35-year old male took Anti-TB Treatment (ATT) for 9 months with first-line drugs. His sputum is still positive for AFB. Discuss causes of treatment failure and his management now. (2009)

Q5: What are the multidrug-resistant tuberculosis (MDR-TB) and extensive drug resistant tuberculosis (XDR-TB) List the group of drugs used to treat MDR-TB. (2012)

Q6: Describe multi-drug resistance in tuberculosis. (2000)