Diagnosis and Treatment of Tuberculosis

Tuberculosis (TB) is a granulomatous disease caused by the Mycobacterium tuberculosis complex. TB most commonly affects the lung, but it can affect almost any organ.

HIV/AIDS and TB are common causes of death from infectious disease and are particularly prevalent in sub-Saharan Africa.

The diagnosis of pulmonary tuberculosis (TB) should be suspected in patients with:

• Relevant clinical manifestations:
  • Cough lasting >2 to 3 weeks
  • Lymphadenopathy
  • Fevers
  • Night sweats
  • Weight loss
• Relevant epidemiologic factors:
  • History of prior TB infection or disease
  • Known or possible TB exposure
  • Past or present residence in or travel to an area where TB is endemic

Patients being evaluated for pulmonary tuberculosis who pose a public health risk for transmission should be admitted and isolated with airborne precautions.

The diagnosis of pulmonary tuberculosis is definitively established by:

• Isolation of M. tuberculosis from a bodily secretion (e.g., culture of sputum, bronchoalveolar lavage, or pleural fluid) or tissue (pleural biopsy or lung biopsy).

Additional diagnostic tools include:

• Sputum acid-fast bacilli (AFB) smear
• Nucleic acid amplification (NAA) testing

A positive NAA test (with or without AFB smear positivity) is considered sufficient for diagnosis of tuberculosis.

Radiographic studies are important supportive diagnostic tools.

The approach to diagnosis of tuberculosis begins with:

• A history and physical examination to assess the patient's risk for TB

Patients meeting clinical criteria should undergo:

• Chest radiography

If imaging suggests TB of the lungs or airways, three sputum specimens should be submitted for:

• AFB smear
• Mycobacterial culture
• NAA testing

The specimens should be obtained via cough or induction at least eight hours apart and include at least one early-morning specimen.

In addition, a tuberculin skin test (TST) or interferon-gamma release assay (IGRA) should be performed. These are tools designed for diagnosis of TB infection; a positive result supports (but cannot be used to establish) a diagnosis of active TB disease, and a negative result does not rule out active TB disease.

In HIV-infected patients with CD4 counts <100 cells/mm3, mycobacterial cultures of blood and urine should also be performed (in addition to the above studies).

Establishing a definitive laboratory diagnosis of TB may not be possible in some circumstances. No specific bacteriologic confirmation is ever established in at least 15 to 20 percent of patients with a clinical diagnosis of TB. In such cases, a presumptive clinical diagnosis may be based on:

• Epidemiologic exposure
• Physical findings
• Radiographic findings
• Positive TST or IGRA
• Analysis of sputum or bronchoscopy specimens
• Histopathology

In the setting of high clinical suspicion for tuberculosis, initiation of empiric therapy based on these findings is appropriate.

• TB is a global problem
• ¼ of world infected
• Of which about 10 million develop dx yearly
• about 1.5 million deaths
• Affects both males and females
• All age groups are at risk but mostly affects adults in their most productive years

Global report 2019 on Nigeria:

• Nigeria ranked 1st in Africa and globally 6th among 30 high TB burden countries
• Among the 14 countries in the world with triple high burden of TB, TB/HIV, and DR-TB
• 429,000 Nigerians have TB yearly

• Presumptive TB now preferred to TB suspect: symptoms and signs of TB
• Clinically diagnosed case of TB: no bacteriological confirmation but diagnosed and treated for TB by a clinician or other medical practitioner. Includes those diagnosed on CXR, suggestive histology and EPTB without lab confirmation
• Definite case of TB: bacteriologically confirmed by smear microscopy, culture, or WHO-approved rapid diagnostics

Clinical features: history and examination

• Related directly to TB
• Complications

History

Typical symptoms of TB may include:

• General: fever, lethargy, anorexia, weight loss, enlarged and tender lymph nodes
• Pulmonary: cough (usually chronic), sputum (initially dry, then purulent or blood-stained), breathlessness, pleuritic chest pain
• Extra-pulmonary: genitourinary (urinary symptoms), musculoskeletal (joint pain), neurological (headache, reduced GCS, focal neurology), cardiac (chest pain), gastrointestinal (abdominal pain, bloating), rash

Other important areas to cover in the history include:

• Past medical history: HIV or other immunosuppressive condition, chronic conditions such as diabetes
• Drug history: immunosuppressive medications including steroids
• Social history: occupation, alcohol or drug dependence, homelessness, country of birth and travel history
• TB contacts: nature and duration of contact

Pulmonary Complications:

• Hemoptysis (coughing up blood)

  Have you experienced coughing up blood or blood-streaked sputum?

• Pleural effusion (accumulation of fluid around the lungs)

  Have you had any chest pain or difficulty breathing, especially when lying down?

• Pulmonary fibrosis

  Have you noticed any changes in your breathing pattern or shortness of breath?

• Pneumothorax (collapsed lung)

  Have you ever had sharp chest pain that worsens with deep breathing?

• Chronic obstructive pulmonary disease (COPD)

  Do you experience chronic cough, wheezing, or shortness of breath?

• Bronchiectasis (damage to the airways)

  Do you have frequent respiratory infections or cough up large amounts of sputum?

Extrapulmonary Complications:

• Lymphadenitis (swollen lymph nodes)

  Have you noticed any lumps or swelling in your neck, underarms, or groin?

• Spinal tuberculosis (Pott's disease)

  Have you experienced back pain, especially at night or with movement?

• Tuberculous meningitis (infection of the membranes covering the brain and spinal cord)

  Have you had severe headaches, nausea, vomiting, or neck stiffness?

• Tuberculous pericarditis (inflammation of the membrane around the heart)

  Have you experienced chest pain that worsens when lying flat or with deep breathing?

• Tuberculous osteomyelitis (bone infection)

  Have you had bone pain, especially in your spine or hips?

• Genitourinary tuberculosis (infection of the kidneys, bladder, or genital organs)

  Have you experienced pain or discomfort while urinating, blood in the urine, or lower abdominal pain?

• Gastrointestinal tuberculosis (intestinal infection)

  Have you had abdominal pain, changes in bowel habits, or unexplained weight loss?

Systemic Complications:

• Malnutrition

  Have you experienced unintentional weight loss, decreased appetite, or fatigue?

• Anemia

  Have you noticed weakness, fatigue, or pale skin?

• Weight loss

  Have you lost weight unintentionally, and if so, how much in the past few months?

• Fatigue

  Do you feel unusually tired, even after resting?

Night sweats

Do you experience drenching sweats at night, often waking you up?

• Immune reconstitution inflammatory syndrome (IRIS)

  Have you experienced new or worsening symptoms after starting tuberculosis treatment?

Reproductive Complications (for females):

• Menstrual irregularities

  Have you noticed any changes in your menstrual cycle or missed periods?

• Infertility

  Have you been trying to conceive without success, or have you had any fertility treatments?

• Pregnancy complications

  Have you had any complications during pregnancy, such as preterm labor or low birth weight?

Complications Related to Co-existing Conditions (e.g., HIV):

• Opportunistic infections

  Have you had frequent infections, such as pneumonia, thrush, or skin infections?

• Immune suppression

  Have you experienced recurrent illnesses or slow wound healing?

Complications of Drug Therapy:

• Hepatotoxicity (liver damage)

  Have you noticed yellowing of the skin or eyes, dark urine, or abdominal pain?

• Nephrotoxicity (kidney damage)

  Have you had any changes in urination, swelling in your legs, or back pain?

• Ototoxicity (hearing loss)

  Have you experienced ringing in the ears, dizziness, or difficulty hearing?

• Peripheral neuropathy (nerve damage)

  Have you noticed tingling, numbness, or weakness in your hands or feet?

• Ocular toxicity (eye problems)

  Have you experienced blurred vision, eye pain, or changes in color vision?

• Hypersensitivity reactions

  Have you had any skin rash, itching, or difficulty breathing after taking medication?

The Walgren's timetable of TB: it was published by Walgren in 1984, it provides useful guide to the time sequence for development of various manifestations of the disease.
Time	Manifestation
3-8 weeks, average 6 wks Early manifestations	Incubation period Evidence of primary lesion and phenomena accompanying primary infection (erythema nodusum, phyectenular conjunctivitis)
Usually within 3 months	Military TB, TB meningitis
Usually 1 year	Pleural effusion
Usually 3 years	Bone and joint lesions
Usually within 5 years	Progressive pulmonary disease
After 5 years	Renal tuberculosis (urogenital)

More on Wallgren Timetable

Manifestation of TB in children can be predicted based on the Wallgren Timetable highlighted below:

• Pulmonary tuberculosis - within a few months of primary infection.
• Miliary and meningeal tuberculosis - 2-6 months.
• TB adenitis - 3-9 months.
• Bones and joints - several years.
• Renal and genital tuberculosis - may take over a decade.

Pulmonary lesions occurring as a result of reactivation of a dormant focus previously established in the body lakes a number of years after primary infection.

Physical Examination

Pulmonary Tuberculosis

Physical examination findings of pulmonary tuberculosis include:

• Appearance of the Patient
  • Cachexia
  • Pallor
• Vitals
  • Tachypnea
  • Tachycardia
  • Fever
• Lungs
  • Decreased breath sounds
  • Rales
  • Rhonchi
  • Bronchial breath sounds

Some patients with active tuberculosis may have a normal physical examination, so further testing should be performed to confirm the diagnosis.

Extra-Pulmonary Tuberculosis

Extra-pulmonary tuberculosis may also include some of the physical findings of pulmonary tuberculosis such as fever, cachexia, tachypnea, tachycardia, and may be associated with an active pulmonary infection.

Extra-Pulmonary Location
Extra-Pulmonary Location	Additional Physical Examination Findings
Tuberculous Lymphadenitis	Cervical lymph node enlargement
Skeletal Tuberculosis	Low back pain, stiffness, tenderness, joint swelling and erythema, limited range of motion.
Central Nervous System Tuberculosis	Altered mental status, CN palsy (specially CN VI), papilledema, hemiparesis, hemiplegia, and nuchal rigidity.
Tuberculosis Peritonitis	Diffuse abdominal tenderness, ascites, fever.
Tuberculous Pericarditis	Tachycardia, pulsus paradoxus and hypotension (in cardiac tamponade), jugular venous distension with a prominent Y descent, Kussmaul's sign, pleural dullness, pericardial knock, pericardial rub, distant heart sounds, hepatomegaly, ascites, and ankle edema.
Renal Tuberculosis	Costo-vertebral angle tenderness (in UTI), lower abdominal tenderness (in obstructive uropathy), findings of renal insufficiency.

Diagnostic Tools for Tuberculosis (TB)

• To confirm diagnosis
• Molecular assays (LPA, Xpert MTB/RIF assay etc): Xpert MTB/RIF or Xpert ultra is recommended as initial test* in all forms of TB rather than smear microscopy/culture and phenotypic DST
• TB culture and DST

Radiographic Imaging

• Chest Radiography:
  • Initial approach for suspected TB.
  • Useful for evaluating symptomatic patients with appropriate risk factors.
  • Active TB may not be distinguished from inactive disease based on radiography alone.
  • Classic presentations: upper or lower lobe focal infiltration with or without cavitation.
  • Atypical presentations in advanced HIV disease: lobar or segmental infiltration, miliary lesions, pleural effusions.
• Chest Computed Tomography (CT):
  • More sensitive than plain radiography for identifying early or subtle parenchymal and nodal processes.
  • Reserved for precise resolution when needed or for suspected alternative diagnosis.
• Magnetic Resonance Imaging (MRI):
  • Demonstrates intrathoracic lymphadenopathy, pericardial thickening, pericardial, and pleural effusions.

Microbiologic Testing

• Sputum Acid-Fast Bacilli (AFB) Smear
• Rapid and inexpensive.
• Less sensitive than nucleic acid amplification (NAA) or culture.
• Diminished sensitivity in HIV-infected patients.
• Common techniques: carbolfuchsin methods, fluorochrome procedure.
• Mycobacterial Culture
• Gold standard for detection of TB.
• Detects as few as 10 bacteria/mL.
• Required for drug susceptibility testing and species identification.
• Types: egg-based, agar-based, liquid media, or automated systems.
• Drug Susceptibility Testing (DST)
• Conventional (phenotypic) culture-based testing: Gold standard for drug-resistant TB diagnosis.
• Molecular testing: Provides genotypic information and faster turnaround time.

Molecular Tests

• Probe-Based (NAA) Tests:
  • Amplify specific nucleic acid sequences.
  • Examples: Amplified MTD, Xpert MTB/RIF.
  • Detect TB and some drug resistance mutations.
  • Rapid diagnosis, especially in AFB smear-positive specimens.
• Sequence-Based Assays:
  • Provide genetic identity of mutations for greater accuracy.
  • Examples: Pyrosequencing, Sanger sequencing, Next-generation sequencing.
  • Investigational, not FDA approved.
• Other Assays:
  • MTBDR (Mycobacterium Tuberculosis Drug Resistance) Platforms:
    • MTBDRplus: Detects rifampin and isoniazid resistance mutations.
    • MTBDRsl: Detects resistance to fluoroquinolones and injectable agents.
  • Xpert MTB/RIF Assay:
    • Molecular beacon assay for TB and rifampin-resistance mutations.
    • Rapid and accurate, provides results in 2 hours.
  • Xpert MTB/RIF Ultra Assay:
    • Improved sensitivity compared to Xpert MTB/RIF.
    • Not FDA approved, available for research use only.
  • Urine LAM Antigen Detection in HIV Infection:
    • Urine-based detection of lipoarabinomannan (LAM) assay.
    • Additional test for diagnosis of TB in HIV-infected patients.
    • Recommended for seriously ill patients with signs and symptoms of TB and low CD4 counts.

• Close contacts of persons known or suspected to have active disease
• Immunocompromised status (elderly, cancer)
• Drug abuse and alcoholism.
• People lacking adequate health care.
• Pre-existing medical conditions (diabetes mellitus, chronic renal failure).
• Immigrants from countries with higher incidence of TB.
• Institutionalization (long-term care facilities)
• Living in substandard conditions.
• Occupation (health care workers)
• Low socioeconomic status
• Crowded living conditions
• Diseases that weaken immune system like HIV
• People on immunosuppressant therapy
• Recent Tubercular infection within the last 2 years
• HIV infection
• Children exposed to high-risk adults
• Silicosis
• Prolonged corticosteroid therapy
• Low body weight (10% or more below ideal)
• Residents and employees of high-risk congregate settings

• Anatomical: pulmonary vs extrapulmonary
• History of previous Treatment: new vs previously treated (relapse viz true relapse or reinfection, failure & loss to follow up*, others**)
• HIV status: +ve, -ve, or unknown
• Drug resistance: mono, poly (other than MDR), MDR, XDR, RR (includes any form of RR e.g. mono, poly, MDR or XDR)

Treatment of New Drug-Susceptible TB Patients

• Essential (1st line) anti-TB drugs:
• 6 months treatment: 2HRZE/4HR now recommended over other options
• Daily dose throughout.
• If INH resistance is high, use HRE in the continuation phase
• TB Patients Kit

Treatment of Previously Treated Patients

• Efforts should be made to ensure culture and DST in all previously treated TB patients. DST for at least HR. This is to ensure appropriate treatment.
• Ideally, what is done depends on the survey results. If MDR is high in relapse and default, then MDR regimen is needed. If, on the other hand, MDR is low (for example, in those who failed previous treatment), then retreatment regimen is used with 1st line drugs.
• For our setting, empirical retreatment should be used after initial Xpert test if no RR while urgent steps should be taken to ensure DST becomes available for all previously treated patients.

• Monitor patients
• Clinically
• Laboratory-wise: usually for PTB
• Adverse drug reaction

Monitoring During Treatment

People who are being treated for LTBI must be monitored by a healthcare provider at least once per month to monitor for any signs of medication toxicity, such as liver injury. Minority women in the postpartum period may be at higher risk for side effects. Signs of liver injury may include unexplained tiredness, loss of appetite, nausea, vomiting, dark-colored urine, jaundice (yellowing of the skin or the white portion of the eye), fatigue, abdominal pain, or, rarely, unexplained bruises. Anyone who experiences one or more of these problems while taking any of these medications should stop their medication immediately and notify their healthcare provider.

In certain special cases, monthly monitoring may also include blood tests to monitor the function of the liver or blood counts.

Treatment Outcomes

• Cure
• Treatment completed
• Failure
• Loss to follow up
• Transferred out
• Died
• Treatment success

• Primary vs Secondary Resistance
• Mono vs Poly Resistance
• MDR/RR vs XDR

Treatment of Drug-Resistant TB

• Treatment of Rifampicin-sensitive INH-resistant TB (Hr-TB)
• Do not add streptomycin or other injectable agents to the regimen
• Treat with REZ and levofloxacin for 6 months
• MDR-TB/RR-TB
• A shorter all-oral bedaquiline-containing regimen of 9–12 months duration is recommended if the following are fulfilled:
• No previous treatment with second-line TB medicines used in this regimen for more than 1 month (except susceptibility confirmed)
• No resistance to fluoroquinolones: confirmed by DST
• No extensive TB
• No severe EPTB
• No pregnancy
• Patient not younger than 6 years
• Regimen: 6Beda + 4/6*Levo/Moxi, ethionamide, E, Z, H(high dose), Clofa, followed by 5Levo/Moxi, Clova, E, Z
• *given for 4 months but extend to 6 months if sputum smear still positive at the end of 4 months

Grouping of Drugs for Use in Longer MDR-TB/RR-TB Regimens

• Group A: levofloxacin or moxifloxacin, bedaquiline, and linezolid. Considered highly effective and strongly recommended for inclusion in all regimens unless contraindicated.
• Group B: clofazimine, and cycloserine or terizidone. Conditionally recommended as agents of second choice.
• Group C: ethambutol, delamanid, pyrazinamide, imipenem–cilastatin or meropenem, amikacin (or streptomycin), ethionamide or prothionamide, and p-aminosalicylic acid. Included in this group are all other medicines that can be used when a regimen cannot be composed with Group A and B agents. The medicines in Group C are ranked by the relative balance of benefit to harm usually expected of each.
• Other medicines that are not included in Groups A–C are: Kanamycin and capreomycin, Gatifloxacin and high-dose isoniazid, and thioacetazone, Clavulanic acid (except as a companion agent to the carbapenems)*
• Still on research: perchlozone, interferon gamma, sutezolid

Longer Treatment of MD/RR-TB

• In MDR/RR-TB patients on longer regimens, all three Group A agents and at least one Group B agent should be included to ensure that treatment starts with at least four TB agents likely to be effective, and that at least three agents are included for the rest of treatment if bedaquiline is stopped. If only one or two Group A agents are used, both Group B agents are to be included. If the regimen cannot be composed with agents from Groups A and B alone, Group C agents are added to complete it.
• Kanamycin and capreomycin are not to be included in the treatment of MDR/RR-TB patients on longer regimens.
• Bedaquiline should be included in longer multidrug-resistant TB (MDR-TB) regimens for patients aged 18 years or more.
• Bedaquiline may also be included in longer MDR-TB regimens for patients aged 6–17 years.
• Delamanid may be included in the treatment of MDR/RR-TB patients aged 3 years or more on longer regimens.
• Ethionamide or prothionamide may be included in the treatment of MDR/RR-TB patients on longer regimens only if bedaquiline, linezolid, clofazimine, or delamanid are not used, or if better options to compose a regimen are not possible. PAS also can only be used in such situations.
• Clavulanic acid should not be included in the treatment of MDR/RR-TB patients on longer regimens.
• In MDR/RR-TB patients on longer regimens:
• A total treatment duration of 18–20 months is suggested for most patients; the duration may be modified according to the patient’s response to therapy.
• A treatment duration of 15–17 months after culture conversion is suggested for most patients; the duration may be modified according to the patient’s response to therapy.
• A regimen containing amikacin or streptomycin requires an intensive phase of 6–7 months for most patients; the duration may be modified according to the patient’s response to therapy.

Special Issues in MDR/RR-TB Treatment

• Extrapulmonary TB and TB Meningitis:
• Use longer MDR-TB regimens.
• Treatment of MDR/RR-TB meningitis is best guided:
• by DST of the infecting strain
• by knowledge of the properties of TB medicines that cross the blood–brain barrier.
• Levofloxacin and moxifloxacin penetrate the CNS well.
• So also ethionamide/prothionamide, cycloserine/terizidone, linezolid, and imipenem–cilastatin. Seizures may be more common in children with meningitis treated with imipenem–cilastatin; thus, meropenem is preferred for meningitis cases and in children.
• High-dose isoniazid and pyrazinamide may be useful if the strains are susceptible.
• Amikacin and streptomycin penetrate the CNS only in the presence of meningeal inflammation.
• Culture-negative TB:
• Other durations of treatment may be appropriate for persons with culture-negative TB.
• If a longer regimen option is chosen, a total duration of 18–20 months of treatment is advised, and the response should be monitored by clinical parameters other than specimen bacteriology.
• Pregnancy:
• Amikacin, streptomycin, prothionamide, and ethionamide are usually contraindicated during pregnancy.
• HIV Infection:
• Regimen for MDR-TB does not usually differ substantially for PLHIV.
• Careful attention is needed to avoid certain drug–drug interactions (e.g., bedaquiline and efavirenz).
• Patients with Extensive TB Disease
• Duration of treatment post-culture conversion may be modified according to the patient’s response to therapy (e.g., culture conversion before 2 months of treatment).
• Other risk factors for treatment failure or relapse should also be considered.
• Patients on Regimens Without Amikacin/Streptomycin
• The length of treatment is determined by:
• Recommended total duration of the regimen used
• Time after culture conversion

• Emphasize the need to reduce burden of TB in HIV patients through the three I’s*
• Treatment of new case and retreatment case should be at least for the same duration as in HIV-negative individuals. It must be used daily throughout.
• ART should be initiated for all people living with HIV with active TB disease irrespective of CD4 cell count.
• TB treatment should be started first, followed by ART as soon as possible and within the first 8 weeks of starting TB treatment
• The recommended first-line ART regimens for TB patients are those that contain efavirenz (EFV), since interactions with anti-TB drugs are minimal.
• Complications include adverse effects, drug–drug interactions, and IRIS.

• In Pregnancy and Lactation
• In Liver Disease
• In Renal Failure