7.2 Tuberculosis Diagnosis, DOTS Protocol & Infection Control

7.2 Tuberculosis Diagnosis, DOTS Protocol & Infection Control

Quick Answer: Tuberculosis (TB) is a chronic granulomatous infectious disease caused by the acid-fast bacillus Mycobacterium tuberculosis. Transmitted through microscopic airborne droplet nuclei, it predominantly affects the pulmonary parenchyma but can disseminate to cause extrapulmonary disease. The cardinal symptoms warranting immediate screening in Ghana include a persistent cough lasting $\ge 2\text{ weeks}$, hemoptysis, drenching night sweats, unexplained weight loss, and low-grade evening fevers. The Ghana National TB Programme (NTP) utilizes GeneXpert MTB/RIF as the primary rapid diagnostic tool to confirm infection and detect rifampicin resistance within 2 hours. Standard treatment for new drug-susceptible pulmonary TB entails a 6-month Directly Observed Therapy Short-Course (DOTS) regimen: 2 months of Intensive Phase with RHZE (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol) followed by 4 months of Continuation Phase with RH (Rifampicin, Isoniazid). Strict infection control demands airborne isolation, natural cross-ventilation, and N95 respirators.

---

Etiology, Transmission, and Pathophysiology

Mycobacterium tuberculosis is an obligate aerobe, non-motile, non-spore-forming rod-shaped bacterium. Its cell wall is uniquely composed of mycolic acids, complex branched-chain fatty acids that create a waxy, lipid-rich barrier comprising up to 60% of the bacterial cell envelope. This waxy envelope confers resistance to drying, chemical disinfectants, humoral immune lysis, and standard Gram staining, necessitating acid-fast staining (Ziehl-Neelsen or Auramine-O fluorochrome).

                      TUBERCULOSIS PATHOGENESIS PATHWAY
                                      |
         Inhalation of Droplet Nuclei (1-5 um) into Alveoli
                                      |
         Alveolar Macrophage Ingestion & Incomplete Digestion
         (Mycolic acid inhibits phagolysosomal fusion)
                                      |
         Intracellular Bacillary Proliferation & Cell Lysis
                                      |
         Migration to Regional Hilar Lymph Nodes
         [Ghon Focus + Hilar Lymphadenopathy = GHON COMPLEX]
                                      |
         Cell-Mediated Immunity Activation (CD4+ Th1 Cells)
         Release of IFN-gamma and TNF-alpha
                                      |
         Macrophage Differentiation into Epitheloid Histiocytes & Langhans Giant Cells
         Formation of Caseating Granuloma (Tubercle)
                                      |
                 +--------------------+--------------------+
                 |                                         |
        [IMMUNOCOMPETENT HOST]                  [IMMUNOCOMPROMISED HOST]
                 |                                         |
         Fibrosis & Calcification               Caseous Necrosis Liquefaction
           (Ranke Complex)                     Erosion into Bronchial Wall / Cavitation
                 |                                         |
         LATENT TB INFECTION (LTBI)             ACTIVE PULMONARY / MILIARY TB
      (Viable dormant bacilli within                 (Unrestrained replication
            granuloma; 90%)                             and transmission; 10%)

Transmission Dynamics

Transmission occurs when a patient with active pulmonary or laryngeal TB coughs, sneezes, speaks, or spits, expelling tiny aerosol droplets. The liquid evaporates rapidly, leaving behind microscopic droplet nuclei (1 to 5 micrometers) containing 1 to 3 viable bacilli. Due to their small aerodynamic diameter, droplet nuclei bypass the mucociliary escalators of the upper airway and penetrate into terminal respiratory bronchioles and alveoli.

Primary Infection to Caseating Granuloma

1. Phagocytosis and Immune Evasion: Alveolar macrophages engulf the bacilli, but M. tuberculosis blocks phagosome-lysosome fusion by releasing cell-wall glycolipids (such as lipoarabinomannan) and sulfatides. The bacilli replicate uninhibited inside the macrophage cytoplasm, eventually lysing the host cell.
2. Ghon Complex Formation: Bacilli spread via draining lymphatics to hilar and mediastinal lymph nodes. The primary subpleural parenchymal lesion (Ghon focus) combined with regional lymph node involvement constitutes the Ghon complex.
3. Granuloma Construction: Two to four weeks post-infection, host adaptive cell-mediated immunity activates. CD4+ T-helper 1 (Th1) lymphocytes recognize mycobacterial antigens presented by dendritic cells and secrete Interferon-gamma (IFN-$\gamma$) and Tumor Necrosis Factor-alpha (TNF-$\alpha$). These cytokines activate macrophages, inducing their transformation into epithelioid histiocytes and multinucleated Langhans giant cells. Activated histiocytes aggregate around the bacillary core, surrounded by an outer cuff of CD4+ and CD8+ lymphocytes and fibroblasts, forming a caseating granuloma (tubercle).
4. Latent vs. Active Tuberculosis: In approximately 90% of immunocompetent individuals, the granuloma successfully encapsulates the infection; the core undergoes central avascular caseous necrosis, dehydrates, and undergoes fibrocalcification (forming a radiographically visible Ranke complex). Bacilli remain dormant within this hypoxic barrier, creating Latent TB Infection (LTBI)—patients are asymptomatic, have negative sputum tests, and cannot transmit disease. However, in immunocompromised patients (such as those with HIV or malnutrition), cell-mediated containment fails. The caseous core liquefies, cavitates, and erodes into adjacent airways, causing Active Tuberculosis Disease.

---

Clinical Presentation and High-Risk Case Finding

Active tuberculosis is characterized by an insidious clinical onset progressing over weeks to months. The Ghana NTP utilizes the following clinical symptom triad as the cornerstone of facility-based intensified case finding:

Pulmonary Tuberculosis Manifestations

• Cough: Persistent, productive or dry cough lasting $\ge 2\text{ weeks}$, initially dry and hacking, progressing to purulent sputum production.
• Hemoptysis: Expectoration of blood-streaked sputum or frank blood resulting from erosion of cavitary lesions into bronchial blood vessels (Rasmussen's aneurysm).
• Systemic B-Symptoms:
  • Drenching Night Sweats: Profuse diaphoresis waking the patient and requiring clothing changes.
  • Low-Grade Evening Pyrexia: Chills and diurnal fever spikes occurring late in the afternoon or evening.
  • Unexplained Weight Loss & Anorexia: Progressive cachexia ("consumption") mediated by high circulating levels of TNF-alpha (cachectin).
  • Chest Pain & Dyspnea: Dull, aching pleuritic chest discomfort from subpleural granulomatous inflammation.

Extrapulmonary Tuberculosis (EPTB)

Extrapulmonary disease accounts for approximately 15-20% of TB cases in Ghana, occurring with high frequency in individuals with advanced HIV disease:

• TB Lymphadenitis (Scrofula): Most common EPTB form; painless, matted, rubbery cervical lymph node enlargement that may form cold abscesses and discharging sinus tracts.
• Pleural TB: Exudative pleural effusion presenting with pleuritic chest pain, dullness to percussion, and decreased breath sounds.
• Tuberculous Spondylitis (Pott's Disease): Infection of thoracic/lumbar vertebral bodies leading to disc collapse, localized back pain, gibbus deformity, and lower extremity paraplegia.
• Tuberculous Meningitis: Subacute basilar meningitis manifesting with headache, neck stiffness, cranial nerve palsies (especially CN VI), lethargy, and rising intracranial pressure.
• Miliary TB: Hematogenous dissemination producing widespread microscopic granulomas throughout lungs, liver, spleen, and marrow, appearing as diffuse 1-2 mm "millet-seed" nodules on chest radiography.

---

Diagnostic Modalities

Accurate, rapid diagnosis is essential to halt community transmission. The diagnostic algorithm in Ghana incorporates molecular assays, microscopy, and radiography:

---

Ghana National TB Programme (NTP) DOTS Protocol

Ghana adopts the World Health Organization Directly Observed Therapy Short-Course (DOTS) strategy. DOTS requires a trained healthcare worker, treatment supporter, or family member to directly witness the patient swallow every dose of medication. Fixed-Dose Combination (FDC) tablets are standard to reduce pill burden and prevent monotherapy-induced drug resistance.

Standard 6-Month Regimen for New Pulmonary TB (2RHZE / 4RH)

                    STANDARD 6-MONTH DOTS REGIMEN (2RHZE / 4RH)
                                        |
    +-----------------------------------+-----------------------------------+
    |                                                                       |
[INTENSIVE PHASE: 2 MONTHS (2RHZE)]                  [CONTINUATION PHASE: 4 MONTHS (4RH)]
    Duration: 8 consecutive weeks                        Duration: 16 consecutive weeks
    Daily administration of 4 drugs:                     Daily administration of 2 drugs:
    - Rifampicin (R)                                     - Rifampicin (R)
    - Isoniazid (H)                                      - Isoniazid (H)
    - Pyrazinamide (Z)                                   -
    - Ethambutol (E)                                     -
    Goal: Rapidly destroy multiplying bacilli,           Goal: Eliminate dormant persister bacilli,
    render patient non-infectious (< 2 weeks),           sterilize tissues, and achieve permanent cure
    prevent emergence of drug resistance                 without post-treatment relapse

• Intensive Phase (First 2 Months - 2RHZE): Daily administration of Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol. This intensive combination rapidly kills actively dividing bacilli, resolves clinical symptoms, achieves early sputum conversion (smear negativity), and prevents selection of resistant mutants.
• Continuation Phase (Subsequent 4 Months - 4RH): Daily administration of Rifampicin and Isoniazid for 16 weeks. This phase eliminates semi-dormant "persister" bacilli nestled within necrotic caseous tissue, sterilizing the lesions and preventing post-treatment relapse.

Weight-Band Dosing of 4-Drug Fixed-Dose Combinations

FDC tablets containing Rifampicin (150 mg) + Isoniazid (75 mg) + Pyrazinamide (400 mg) + Ethambutol (275 mg) are administered daily according to adult weight categories:

• 25 to 39 kg: 2 tablets daily
• 40 to 54 kg: 3 tablets daily
• 55 to 69 kg: 4 tablets daily
• 70 kg and above: 5 tablets daily

These are WHO's current adult weight bands; always follow the dosing chart supplied by Ghana's National TB Programme with the tablets in use.

---

Adverse Drug Effects and Clinical Monitoring

Safe and effective TB therapy requires nurses to recognize, monitor, and manage drug-specific adverse effects across the standard regimen:

[!CAUTION] Antitubercular Drug-Induced Liver Injury (DILI): Rifampicin, Isoniazid, and Pyrazinamide are all potentially hepatotoxic. If a patient develops jaundice, dark tea-colored urine, persistent nausea, or transaminases rise to $> 3\times$ upper limit of normal with symptoms (or $> 5\times$ without symptoms), immediately discontinue all hepatotoxic medications. Once liver enzymes normalize, reintroduce agents sequentially under specialist supervision.

---

Multi-Drug Resistant Tuberculosis (MDR-TB)

Multi-Drug Resistant TB (MDR-TB) is defined as infection caused by M. tuberculosis strains exhibiting in vitro resistance to at least Isoniazid and Rifampicin, the two most potent first-line drugs. Resistance arises either through primary transmission of a resistant strain or acquired secondary resistance resulting from interrupted treatment, sub-therapeutic dosing, patient non-adherence, or poor drug absorption.

• Diagnostics: Detected rapidly via GeneXpert MTB/RIF (which uses rifampicin resistance as a surrogate marker for MDR-TB, as > 90% of rifampicin-resistant strains are also isoniazid-resistant) or line probe assays (LPA).
• Second-Line Management: WHO now recommends shorter all-oral regimens—for many patients a 6-month regimen of bedaquiline, pretomanid, linezolid and moxifloxacin (BPaLM)—with longer individualised regimens when needed. Key drug classes are diarylquinolines (Bedaquiline), oxazolidinones (Linezolid), fluoroquinolones (Levofloxacin or Moxifloxacin) and nitroimidazoles (Pretomanid, Delamanid). These patients are managed through specialised MDR-TB treatment centres.

---

Inpatient Ward Infection Prevention & Control (IPC)

Transmission of tuberculosis in Ghanaian healthcare settings represents a critical occupational and nosocomial hazard. Wards must strictly execute the hierarchy of IPC measures:

1. Administrative Controls (First & Most Critical Line of Defense):
   • Implement triage protocols: rapidly screen all coughing patients at the outpatient department (OPD) desk.
   • Promptly isolate presumptive and confirmed pulmonary TB cases in designated single rooms or well-demarcated isolation areas.
   • Enforce cough etiquette: provide surgical masks to coughing patients to capture large respiratory droplets at the source.
   • Collect sputum outdoors in open air or in specialized, well-ventilated sputum collection booths—never in enclosed bathrooms, corridors, or unventilated examination rooms.
2. Environmental and Engineering Controls:
   • Maximize natural cross-ventilation: keep large windows and doors on opposing walls open at all times to promote continuous air dilution. Natural cross-ventilation in tropical hospital wards can achieve $\ge 12$ to 20 air changes per hour (ACH), rapidly clearing suspended droplet nuclei.
   • Utilize ceiling fans directed to blow air across wards toward exterior open windows.
   • Where available, utilize shielded upper-room Ultraviolet Germicidal Irradiation (UVGI) fixtures to kill airborne mycobacteria.
3. Personal Respiratory Protection:
   • Healthcare personnel attending to infectious TB patients must wear fit-tested N95 or FFP2 particulate respirators, which filter out $> 95%$ of airborne particles down to 0.3 micrometers.
   • Standard paper or surgical masks provide barrier protection against fluid splashes but do not filter out droplet nuclei; surgical masks must be worn by the patient, while N95 respirators are reserved for healthcare providers.