Overview
Tuberculosis (TB) is caused by Mycobacterium tuberculosis (MTB). It is one of the few pulmonary infections that can disseminate to other organs if not treated (or contained). It is spread by airborne particles which may be expelled through coughing, sneezing, singing, laughing or coughing. To become infected, only a small number of active TB bacilli need to be inhaled (these are spread by airborne particles known as droplet nuclei)
Routine screening for tuberculosis is not recommended for at-risk groups.
1/3 of the world’s population is infected with TB bacilli. Of these, 5 – 10% (of those not infected with HIV) will develop TB at some time in their life, with the majority developing active TB 1 – 2 years after acquiring the infection. In Kenya, there are 133,000 cases annually.
Definition of Terms
| Term | Definition |
|---|---|
| Pulmonary TB | TB of the lungs. 70-80% of patients have TB of the lungs, usually producing cough lasting ≥ 3 weeks |
| Active pulmonary TB | Sputum smear positive. Infectious and can be transmitted to others (including laryngeal TB). Each person with active TB can infect 10 – 15 people per year. Latent TB can become active TB. |
| Latent TB | TB bacteria are alive but inactive in the body. Patients have no TB symptoms and cannot spread TB to others. Usually has a positive skin test reaction. May develop TB later in life if they do not receive treatment for latent TB |
| Extrapulmonary TB | TB in any part of the body other than the lungs |
- Characteristics of Mycobacterium tuberculosis
- Contains mycoilic acid in the cell wall which makes it acid fast
- Obligate aerobe
- Non-motile
- Slow growing – divides every 18 – 24 hours and can be dormant for decades
- No exotoxins
- Transmission
- Person to person through respiratory droplets
- Inoculation
- Rare transplacental transmission
- Patient at risk of developing tuberculosis
- Alcoholics
- Immigrants (from endemic countries)
- Health-care workers
- Patients in nursing homes (weakened immune system)
- HIV/AIDS
- Patients using anti-TNF drugs (infliximab, adalimumab)
- Factors that affect the transmission of TB
- Concentration of infected respiratory droplets in the air
- Period of time exposed to contaminated air
- Factors that increase the risk fo progression from latent TB to active TB disease
- HIV (strongest risk factor among those with latent TB)
- Weakened immunity from poor nutrition, aging, stress etc.
- Immature immunity in babies and young children
- Poor health status seen in cancer, substance use and diabetes
Pathophysiology
Definition of terms
| Term | Definition |
|---|---|
| Primary tuberculosis | Infection of the lung parenchyma and regions around the hilum caused by inhalation of droplets. Characterised by caseating granulomas (langhan’s giant cells, lymphoctes and fibrosis) and calcifications. It can extend into the apex of the lungs to cause cavitation and co-infection with aspergillus |
| Ghon complex | First described by Anton Ghon (1866 – 1936). It is a non-pathognomic chest-radiograph finding of a pulmonary lesion with regional lymphadenopathy. The ghon focus (pulmonary lesion) is usually subpleural and predominantly in the upper part of the lower lobe and lower part of the middle or upper lobe due to better ventilation in this region and its |
| Ranke complex | A calcified ghon complex visible on chest radiograph |
| Post-primary tuberculosis | This is caused by reactivation of the gon complex or re-infection in endemic areas. It can progress to bronchoppneumonia or miliary tuberculosis |
| Miliary tuberculosis | Describes the “millet-like” morphologic presentation of disseminated tuberculosis within the lungs, gastrointestinal tract, peritoneum, lymph nodes, CNS and other organs. |
- Pathophysiology of pulmonary tuberculosis
- Entry into macrophages
- MTB enters macrophages via phagocytosis mediated by Mannose-binding lectin, and Type 2 complement receptor (CR3) among other
- Replication in macrophages
- MTB inhibits phagososme maturation and blocks formation of the phagloysosome → bacterium replication unchecked (protected from lysosome) → bacteremia and seeding of multiple sites (non-sensitised individuals, asymptomatic, mild-flu-like illness)
- Inhibition of phagolysosome function: Recruitement of Coronin to phagosome membrane → coronin activates calcineurin → inhibition of phagosome-lysosome fusion
- Innate immunity
- PAMPs (Lipoarabinomannan, Unmethylated CpG) made by MTB are recognized by TLR2 and TLR9 → initiate and enhance innate and adaptive immune response
- TLR2 activation → production of IL-12 by dendritic cells → TH1 differentiation
- Th1 response (Mounted 3 weeks after infection)
- MTB antigens enter draining lymph nodes → Antigen presentation to CD4+ T-cells → Differentiation to Th1 cells (IL-12, IL-18)
- TH1-mediated macrophage activation and killing of bacteria
- TH1 produce IFNy → activation of macrophages
- stimulation of phagolysosome maturation
- Stimulation of Inducible NOS to produce NO
- Mobilization of defensin against MTB
- Stimulation of autophagy (sequestration and destruction of damaged organelles and MTB)
- TH1 produce IFNy → activation of macrophages
- Granulomatous inflammation and tissue damage
- TH1 → IFN-y → Macrophage activation (M1) → differentiation into epitheloid histiocytes → aggregation and formation of granulomas → TNF and chemokines which recruit more monocytes to the scene → infection halts or caseous necrosis and progression ensues in immunosuppressed
- Entry into macrophages
Pulmonary Tuberculosis
- Signs and symptoms of active pulmonary TB
- Triad of respiratory infection
- Fever or night sweats for ≥ 3 weeks
- Sputum (blood-stained
- Cough for ≥ 3 weeks
- Accompanied by signs of chronic disease
- Weight loss
- Loss of appetite
- Fatigue
- Malaise
- Bone pain (a sign of disseminated TB)
- Triad of respiratory infection
Diagnosis
TB is diagnosed based on clinical symptoms, sputum smear microscopy, chest X-ray, culture, and tuberculin skin test
Diagnosis
| Diagnosis | Description |
|---|---|
| Clinical diagnosis of TB | Two or more of the following: persistent cough, fever, weight loss, failure to thrive or lethargy AND two or more of the following: positive contact, abnormal respiratory signs, abnormal CXR, positive mantouX |
| Bacteriologically confirmed TB | Specimen is positive for MTB |
- Samples
- Expectorated sputum (> 5 years of age)
- Induced sputum
- Nasopharyngel aspirate
- Gastric aspirate
- Stool
- Biopsy
- Aspirates (pleural, pericardial or peritoneal)
- CSF
- Urine
- Investigations
- Sputum smear microscopy (SSM) for acid-fast bacilli: for definitive diagnosis. 98% of patients with 2 positive sputum smears will have TB. Should be performed within 2 days on all 3 sputum samples. Some countries follow a two-sputa sample protocol. 100 microscopic fields must be examined (for 6 – 10 minutes) before a slide is reported negative.
- “On-the-spot”: collected on the spot when a patient is identified as a pulmonary TB suspect
- Early morning: collected early the following day at home
- Second “on-the-spot”: collected when the patient returns to the hospital with the second specimen
- Chest X-ray: less sensitive. 50% of patients with a chest-Xray will be false positive. Cannot distinguish between old and new cases.
- May show apical cavitations and/or infiltrates
- Laboratory culture: used when SSM is negative but symptoms strongly suggest TB.
- Mycobacterial Growth Indicator Tube (MGIT): liquid culture with an average time of detection is 10 – 14 days. Used to diagnose multidrug resistant TB (MGIT-DST)
- Microscopic Observation Drugs Susceptibility: an alternative liquid culturefor case detection and drug susceptibility testing
- Xpert MTB/RIF: rapid molecular test that detects Mycobacterium tuberculosis and resistance to rifampicin. Useful for diagnosis in sputum samples, even in cases of low bacterial load or HIV co-infection. Also allows for the early detection of MDR-TB
- Tuberuclin skin test (Mantoux test): used to detect latent TB.
- Quantiferon
- HIV testing
- Sputum smear microscopy (SSM) for acid-fast bacilli: for definitive diagnosis. 98% of patients with 2 positive sputum smears will have TB. Should be performed within 2 days on all 3 sputum samples. Some countries follow a two-sputa sample protocol. 100 microscopic fields must be examined (for 6 – 10 minutes) before a slide is reported negative.
Standard Treatment for Active Pulmonary TB
Active TB is defined as sputum positive, positive chest X-ray + symptoms of TB. The treatment mnemonic for standard active TB is RIPE. The duration of treatment is 6 months. DOTS (Directly Observed Therapy) is the most important intervention when treating TB, in order to prevent MDR TB. All TB drugs are hepatotoxic. Repeat chest X-ray and sputum acid-fast bacilli to confirm eradication.
Duration of treatment of active pulmonary TB
| Phase | Duration |
|---|---|
| Intensive phase | First 2 months. With RHZE |
| Continuation phase | 4 months. With RH |
Side-effect of standard anti-TB drugs
| Drug | Side effects |
|---|---|
| Rifampin (R) | Red/orange secretions in tears and urine (this is harmless). Can also cause hepatitis, isolated hyperbilirubinaemia and drug-drug interaction (cytochrome P45 inducer), false-positive urine opiate screening |
| Isoniazid (H) | B6 deficiency resulting in peripheral neuropathy (numbness and tingling). Supplement with pyridoxine (B6). Can also cause hepatitis. |
| Pyrazinamide (Z) | Hyperuricemia. Contraindicated in pregnancy (fetotoxic) |
| Ethambutol (E) | Optic neuritis. Should not be given to children too young to be monitored for changes in vision |
| Streptomycin (S) | First-line injectable. May cause hearing problems. Should not be given to pregnant women |
- First-line TB drugs
- Isoniazide (H)
- Rifampicin (R)
- Pyrazinamide (Z)
- Ethambutol (E)
- Streptomycin (S)
Treatment of Latent TB
Latent TB is in persons with a positve skin test reaction who are in one of the high risk groups. It is treated with Isoniazid daily for 9 months to prevent the latent infection from developing into active TB. It is important to exclude active TB since using only one drug may create drug resistance.
Treatment of Drug Resistant TB
This requires second-line anti-TB drugs. Very expensive (cost may be up to 5,000 – 8,000 USD per patient). Some cases of MDR TB and XDR TB are not curable.
Definition of terms
| Term | Description |
|---|---|
| Multidrug-resistant tuberculosis (MDR TB) | Resistance to at least two or more anti-TB drugs (including isoniazid and rifampicin). |
| Extensively Drug-resistant Tuberculosis (XDR TB) | Fulfills the definition of MDR TB but is also resistant to any fluoroquinolone and at least one additional group A drug (most potent group of drugs in the ranking of second-line medications – levofloxacin, moxifloxacin, bedaquiline and linezolid) |
| Primary resistance | Occurs when a person is infected for the first time with a drug-resistant train of TB from someone who may not be receiving adequate treatment |
| Acquired drug resistace | Occurs when active TB is treated with a single drug. May be caused by poor adherence, inappropriate prescription or irregular drug supply |
Duration of treatment of MDR TB
| Phase | Duration |
|---|---|
| Intensive | 6 – 9 months |
| Continuation phase | 18 months |
- Second-Line TB drugs
- Amikacin
- Capreomycin
- Cycloserine
- Ethionamide
- Fluoroquinolones (ciprofloxacin, ofloxacin, levofloxaxin, moxifloxacin, gatifloxacin)
- Kanamycin
- Para-aminosalicylic acid (rarely used)
- These drugs are toxic and may have serious side effect
Treatment of Extrapulmonary TB
TB can infect any tissue in the body. Extrapulmonary TB is an indication for prolonged therapy (12 months or more). Add steroids (PO prednisone) to TB meningitis and TB pericarditis in addition to the RIPE regimen.
Some examples of extrapulmonary TB
| Extrapulmonary TB | Description |
|---|---|
| TB osteomyelitis (Pott’s disease) | Infection of the bone. Presents with bone pain |
| TB meningitis | Presents with meningeal symptoms. Add steroids in treatment. |
| TB pericarditis | Presents with symptoms of pericarditis. Add steroids in treatment |
| Miliary TB | Widespread dissemination of TB to the bones, meninges, pericardium, liver, spleen etc. |
HIV and TB Co-Infection
TB is the most common opportunistic infection in people living with HIV/AIDS. TB and HIV/AIDS co-infection form a lethal combination, with each accelerating the other’s progress. Without preventive TB treatment, as many as 1 in 3 people with HIV will develop TB. A HIV positive person infected with TB is up to 50 times more likely to become sick with TB.
- Why is co-infection a lethal combination?
- It is harder to diagnose TB in HIV-positive individuals
- TB progresses faster in HIV-infected individuals
- TB is almost certainly rapidly fatal if undiagnosed or left untreated in HIV-positive individuals
- TB can occur early in the course of HIV infection
- Preventing TB in HIV-infected patients
- Treat latent infection with isoniazid (after excluding active TB)
- Isoniazing preventive therapy (IPT) for people living with AIDS
Screening Tests
- Management of a positive screen
- Get a chest X-ray or sputum stain or GeneXpert
- Negative test: treat for latent tuberculosis
- Isoniazid/B6 and Rifapentine for 3 months (unless pregnant or children < 2 years) or
- Isoniazid/B6 for 9 months
- Positive test: treat for active tuberculosis
- RHZE therapy
Purified protein derivative (PPD) test (Mantoux)
Used for screening asymptomatic individuals who are in OR will be in an at-risk condition. Induration is read 2 days after tuberculin is injected. More induration = Greater immune response = More TB antibodies = Possible infection. A negative PPD should be repeated for 1-2 weeks for accuracy.
| Induration | Interpretation |
|---|---|
| > 15 mm | Positive reading |
| >10mm | Positive reading |
| > 5 mm | Positive in immunosuppressed patients (HIV/AIDS), History of abnormal X-ray, on steroids, close contact with TB |
- Who is screened?
- Healthcare workers
- Patients about to start an anti-TNF drug (to check for latent TB)
- Patients have had close contact with TB infected persons
- Positive PPD treatment
- Get a chest X-ray and sputum stain (as if they were symptomatic)
- Negative chest X-ray: Treat for latent TB
- 9 months of INH/B6
- Positive chest X-ray and/or sputum: Treat for Active TB
- RIPE (2 months); Rifampin and INH(6 months)
Interferon Gamma Release Assay (IGRA)
IGRA is used to screen for TB in patients who have received the Bacille-Calmette-Guerin (BCG) vaccine since it will not give false positives unlike the PPD.
