Infectious Disease and Microbiology - Tuberculosis

Basics

Description

Tuberculosis (TB) is an infectious disease caused primarily by Mycobacterium tuberculosis. The organism most commonly affects the lungs, but virtually any organ can be involved. Infection may remain clinically silent as latent tuberculosis infection (LTBI) or progress to active tuberculosis disease.

After inhalation, the organism may be eliminated by the immune system, contained within granulomas as latent infection, or progress directly to active disease. Latent organisms can reactivate years later when host immunity declines.

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Special Populations

Older Adults

Older adults have an increased risk of reactivation TB and may present atypically. Classic symptoms such as fever, productive cough, or marked constitutional symptoms may be absent, so a high index of suspicion is important.

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Children

Tuberculosis remains an important cause of morbidity and mortality among children worldwide.

Children, particularly very young children, are more likely than adults to progress rapidly from initial infection to active disease. They also have a higher risk of severe forms such as:

• Miliary tuberculosis
• Tuberculous meningitis

Microbiologic confirmation is often difficult because children frequently have paucibacillary disease and may not produce sputum.

Specimens may therefore be obtained by:

• Induced sputum
• Early-morning gastric aspirate or lavage
• Nasopharyngeal aspirate in selected settings

Clinical findings, exposure history, imaging, and immunologic testing therefore play an important role.

Treatment principles are similar to those used in adults, although drug doses must be calculated carefully according to body weight.

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Pregnancy

Pregnancy itself does not necessarily increase progression of tuberculosis, but active TB poses significant risks to both mother and fetus.

When treatment of latent infection is necessary during pregnancy, careful consideration of hepatotoxicity is important.

For active drug-susceptible TB, commonly used agents during pregnancy include:

• Isoniazid
• Rifampin
• Ethambutol

Management should follow current specialist and public-health recommendations.

Congenital tuberculosis is rare and results from transplacental or perinatal transmission. Neonatal infection may also occur after birth through close exposure to an infectious mother.

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Epidemiology

Tuberculosis remains one of the most important infectious diseases worldwide.

The global disease burden is substantially greater in:

• South and Southeast Asia
• Sub-Saharan Africa
• Parts of the Western Pacific
• Regions with high HIV prevalence
• Areas with limited access to healthcare

In countries with lower incidence, cases occur disproportionately among:

• Persons born in high-prevalence countries
• Immunocompromised patients
• Individuals living in congregate settings
• Patients with socioeconomic barriers to healthcare

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Risk Factors

Factors that increase the likelihood of acquiring infection or progressing from latent infection to active TB include:

• Close exposure to an infectious patient
• Overcrowded living conditions
• Homelessness
• Poverty
• Incarceration
• Residence in shelters or institutional settings
• HIV infection
• Diabetes mellitus
• Chronic kidney disease
• Silicosis
• Malnutrition
• Use of tumor necrosis factor inhibitors
• Organ transplantation
• Other immunosuppressive therapy
• Alcohol misuse
• Injection drug use
• Recent immigration from a high-prevalence region

The strongest risk factor for progression from latent infection to active disease is impaired cell-mediated immunity, especially advanced HIV infection.

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General Prevention

Prevention depends on rapid recognition of infectious cases, appropriate isolation, effective therapy, and identification of exposed contacts.

Patients with suspected infectious pulmonary TB should be placed in airborne isolation, ideally in a negative-pressure room.

Healthcare workers entering the room should use appropriate respiratory protection such as an N95 respirator or equivalent.

Other important preventive measures include:

• Prompt treatment of active TB
• Contact investigation
• Screening of high-risk populations
• Treatment of latent tuberculosis infection
• Reporting cases to public-health authorities
• Appropriate infection-control procedures in healthcare facilities

Patients with contagious pulmonary TB should avoid close contact with vulnerable individuals, particularly:

• Young children
• Immunocompromised persons

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Transmission and Pathophysiology

Tuberculosis is transmitted mainly by airborne droplet nuclei generated when a person with infectious pulmonary or laryngeal TB:

• Coughs
• Sneezes
• Speaks
• Sings

The small particles remain suspended in the air and may be inhaled into the alveoli.

Once inhaled, M. tuberculosis is engulfed by alveolar macrophages.

Several outcomes are possible:

1. The organism is eliminated.
2. Primary disease develops.
3. The immune system contains the organism, producing latent infection.
4. Latent infection later reactivates.

The host response involves formation of granulomas, which limit bacterial spread but may contain viable organisms for many years.

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Etiology

Mycobacterium tuberculosis is a:

• Slender bacillus
• Obligate aerobe
• Slow-growing organism
• Acid-fast bacterium

Its acid-fast property results from the lipid-rich mycolic acid content of the bacterial cell wall.

On Ziehl-Neelsen staining, acid-fast bacilli appear as red rods against a contrasting background.

Humans are the major reservoir for M. tuberculosis.

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Clinical Presentation

The clinical presentation depends on:

• Whether disease is primary or reactivated
• Organ involvement
• Host immune status
• Age
• Bacterial burden

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Primary Pulmonary Tuberculosis

Primary infection may be asymptomatic.

When symptoms occur, they can include:

• Cough
• Fever
• Malaise
• Fatigue
• Pleuritic discomfort

Primary disease more commonly involves the lower or middle lung zones and may be associated with hilar or mediastinal lymphadenopathy.

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Reactivation Pulmonary Tuberculosis

Reactivation or postprimary TB typically presents more gradually.

Classic manifestations include:

• Persistent cough
• Fever
• Night sweats
• Weight loss
• Fatigue
• Loss of appetite
• Hemoptysis
• Pleuritic chest pain

Upper-lobe or apical involvement is characteristic.

Cavitation may develop because of tissue necrosis.

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Extrapulmonary Tuberculosis

TB can involve almost any organ.

Common extrapulmonary forms include:

• Lymph-node TB
• Pleural TB
• Tuberculous meningitis
• Bone and joint TB
• Genitourinary TB
• Abdominal TB
• Pericardial TB

Extrapulmonary disease is more common among immunocompromised patients.

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Tuberculous Lymphadenitis

Tuberculous lymphadenitis commonly affects cervical lymph nodes and is sometimes termed scrofula.

Nodes may be:

• Enlarged
• Firm
• Relatively painless
• Matted together

Advanced disease may produce fluctuation, sinus formation, or drainage.

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Tuberculous Meningitis

Tuberculous meningitis generally develops gradually.

Symptoms may include:

• Persistent headache
• Fever
• Malaise
• Vomiting
• Altered mental status

Neurologic findings can include:

• Meningismus
• Cranial nerve palsies
• Focal neurologic deficits
• Seizures

This is a medical emergency because delayed therapy can result in severe neurologic disability or death.

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Skeletal Tuberculosis

Spinal tuberculosis is classically referred to as Pott disease.

It may cause:

• Back pain
• Vertebral destruction
• Kyphotic deformity
• Paravertebral abscess
• Spinal cord compression

Other bones and joints may also be affected.

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Gastrointestinal Tuberculosis

Gastrointestinal TB may cause:

• Abdominal pain
• Diarrhea
• Weight loss
• Intestinal obstruction
• Ascites

The terminal ileum and ileocecal region are commonly involved.

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Genitourinary Tuberculosis

Genitourinary TB may remain asymptomatic for prolonged periods.

Possible manifestations include:

• Dysuria
• Hematuria
• Flank discomfort
• Infertility

Persistent sterile pyuria should raise suspicion for genitourinary TB in an appropriate epidemiologic setting.

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Miliary and Disseminated Tuberculosis

Miliary TB results from hematogenous dissemination of M. tuberculosis.

It can involve multiple organs, including:

• Lungs
• Liver
• Spleen
• Bone marrow
• Brain
• Kidneys

Patients may present with:

• Prolonged fever
• Night sweats
• Weight loss
• Weakness
• Hepatosplenomegaly

Severe disease may resemble sepsis or multiorgan failure.

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Physical Examination

Physical findings may be minimal, even in significant disease.

Possible findings include:

Pulmonary disease

• Crackles
• Dullness to percussion
• Increased tactile fremitus
• Reduced breath sounds over an effusion

Lymph-node disease

• Enlarged cervical nodes
• Firm or matted lymphadenopathy

CNS disease

• Meningismus
• Cranial nerve deficits
• Altered mental status

Abdominal disease

• Tenderness
• Ascites
• Signs of obstruction

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Diagnosis

Diagnosis requires distinction between:

• Latent tuberculosis infection
• Active tuberculosis disease

Neither the tuberculin skin test nor an interferon-gamma release assay can by itself prove active disease.

Active disease requires microbiologic, molecular, radiographic, and clinical evaluation.

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Tuberculin Skin Test

The tuberculin skin test, or TST, measures delayed-type hypersensitivity to purified protein derivative.

The result is interpreted according to the diameter of induration, not erythema.

Traditionally:

≥5 mm is considered positive in high-risk patients such as:

• HIV-positive individuals
• Recent close contacts of infectious TB cases
• Certain severely immunocompromised patients

≥10 mm may be considered positive in patients with significant epidemiologic or medical risk factors.

≥15 mm is considered positive in persons without known risk factors.

Interpretation should follow current public-health guidance.

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Interferon-Gamma Release Assays

Interferon-gamma release assays, or IGRAs, detect a T-cell response to M. tuberculosis-specific antigens.

Advantages include:

• Single patient visit
• No booster phenomenon
• Less interference from prior BCG vaccination

IGRAs are particularly useful in:

• BCG-vaccinated patients
• Patients unlikely to return for TST reading

Neither TST nor IGRA reliably differentiates latent infection from active disease.

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BCG Vaccination

The Bacille Calmette-Guérin (BCG) vaccine is used routinely in many countries with high TB prevalence.

It provides its greatest benefit in children by reducing the risk of severe forms such as:

• Miliary TB
• Tuberculous meningitis

Prior BCG vaccination can cause false-positive TST results, although the effect decreases with time.

IGRAs are generally not affected by BCG vaccination.

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Laboratory Diagnosis of Active Tuberculosis

Acid-Fast Bacillus Smear

Respiratory specimens are examined for acid-fast bacilli.

A positive smear supports mycobacterial infection but is not fully specific for M. tuberculosis because nontuberculous mycobacteria may also stain acid-fast.

Smear positivity generally indicates a higher bacterial burden and greater infectiousness.

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Mycobacterial Culture

Culture remains an important reference method because it:

• Confirms viable organisms
• Allows species identification
• Permits drug-susceptibility testing

The major disadvantage is that M. tuberculosis grows slowly, so conventional culture can require several weeks.

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Molecular Testing

Nucleic-acid amplification tests can rapidly identify M. tuberculosis directly from clinical samples and may simultaneously detect important drug-resistance mutations.

They are particularly valuable because results are available much faster than conventional culture.

Culture should still be obtained for complete susceptibility testing.

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Sputum Collection

For suspected pulmonary TB, respiratory specimens should be obtained for:

• AFB smear
• Molecular testing
• Mycobacterial culture

Multiple specimens improve diagnostic sensitivity.

Induced sputum may be used when a patient cannot produce an adequate spontaneous sample.

If sputum studies remain nondiagnostic despite strong suspicion, bronchoscopy with bronchoalveolar lavage may be considered.

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Extrapulmonary Diagnosis

Smears and cultures from extrapulmonary specimens are often less sensitive because disease may be paucibacillary.

Diagnosis may therefore rely heavily on:

• Tissue biopsy
• Histopathology
• Molecular testing
• Culture

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Pathology

The classic histopathologic finding is a caseating granuloma.

Granulomas contain:

• Activated macrophages
• Epithelioid histiocytes
• Multinucleated giant cells
• Lymphocytes

Central caseous necrosis may develop.

However, granulomas are not specific for tuberculosis and may be seen in fungal infections and other diseases.

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Imaging

Chest X-ray

Primary TB

Typical findings can include:

• Lower- or middle-lobe infiltrates
• Hilar or mediastinal lymphadenopathy
• Pleural effusion

Reactivation TB

More commonly demonstrates:

• Upper-lobe infiltrates
• Apical disease
• Cavitation
• Fibrotic changes
• Nodules

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Chest CT

CT may reveal abnormalities not easily visible on plain radiographs.

Important findings include:

• Cavities
• Nodules
• Bronchial wall abnormalities
• Tree-in-bud opacities

The tree-in-bud pattern suggests endobronchial spread of infection but is not specific for tuberculosis.

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Differential Diagnosis

Pulmonary tuberculosis can resemble many other diseases.

Important alternatives include:

• Nontuberculous mycobacterial infection
• Histoplasmosis
• Other endemic fungal infections
• Lung abscess
• Necrotizing bacterial pneumonia
• Sarcoidosis
• Lung cancer
• Lymphoma

The differential diagnosis depends on the patient’s epidemiology, immune status, radiographic pattern, and microbiologic findings.

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Treatment of Latent Tuberculosis Infection

Treatment of LTBI significantly reduces the risk of future active disease.

Modern practice favors shorter rifamycin-based regimens in many patients because adherence is generally better than with prolonged isoniazid monotherapy.

Common contemporary approaches may include:

• Isoniazid plus rifapentine
• Rifampin alone
• Isoniazid plus rifampin
• Isoniazid monotherapy when other regimens are unsuitable

The regimen should be chosen based on:

• Age
• Pregnancy
• HIV status
• Drug interactions
• Potential source-case resistance
• Liver disease
• Adherence considerations

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Pyridoxine

Pyridoxine, or vitamin B6, is often administered with isoniazid to reduce the risk of peripheral neuropathy.

It is particularly important in patients at higher risk, including:

• Pregnancy
• Diabetes
• HIV infection
• Malnutrition
• Alcohol use disorder
• Chronic kidney disease
• Pre-existing neuropathy

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Treatment of Active Drug-Susceptible Pulmonary TB

The classic initial regimen consists of four drugs:

• Isoniazid
• Rifampin
• Pyrazinamide
• Ethambutol

This combination is often abbreviated as:

RIPE

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Intensive Phase

During the first 2 months, treatment generally consists of:

Rifampin + isoniazid + pyrazinamide + ethambutol

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Continuation Phase

For drug-susceptible pulmonary disease that responds appropriately, treatment then usually continues with:

Isoniazid + rifampin

for an additional 4 months, giving a typical total treatment duration of 6 months.

Longer treatment may be necessary in selected circumstances.

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Extrapulmonary Tuberculosis Treatment

Many forms of extrapulmonary TB are treated using the same basic regimen as pulmonary TB.

Some forms may require prolonged therapy or additional interventions, particularly:

• CNS tuberculosis
• Bone and joint disease
• Complicated disease

Treatment duration should be individualized according to the site and response.

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Tuberculous Meningitis

Tuberculous meningitis requires prompt multidrug therapy.

Adjunctive corticosteroids reduce mortality and are commonly recommended.

Treatment courses are generally longer than those used for uncomplicated pulmonary disease.

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HIV and Tuberculosis

TB is a major opportunistic infection in patients with HIV.

HIV alters the clinical picture.

Patients with advanced immunosuppression may have:

• Less cavitation
• Lower-lobe disease
• Diffuse infiltrates
• Normal chest radiographs
• More extrapulmonary or disseminated disease

Treatment of drug-susceptible TB generally uses the same major drugs, but management must consider:

• Timing of antiretroviral therapy
• Drug-drug interactions
• Immune reconstitution inflammatory syndrome
• Rifamycin interactions

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Drug-Resistant Tuberculosis

Drug-Resistant TB

This refers to infection resistant to one or more antituberculous drugs.

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Multidrug-Resistant TB

MDR-TB traditionally means resistance to at least:

• Isoniazid
• Rifampin

Treatment requires specialist management and susceptibility-directed multidrug therapy.

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Rifampin-Resistant TB

Resistance to rifampin is particularly important because it often predicts broader resistance and requires an MDR-type treatment approach.

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Extensively Drug-Resistant TB

Definitions of XDR-TB have evolved over time.

Current classifications emphasize resistance beyond rifampin and isoniazid to important second-line agents, particularly fluoroquinolones and key newer drugs.

Older definitions based primarily on injectable agents should not be used automatically for contemporary classification.

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Second-Line and Drug-Resistant TB Agents

Depending on susceptibility and current guidelines, treatment may include agents such as:

• Levofloxacin
• Moxifloxacin
• Linezolid
• Bedaquiline
• Pretomanid
• Clofazimine
• Cycloserine
• Other specialist-selected agents

Modern treatment of resistant TB increasingly uses all-oral regimens, reducing reliance on older toxic injectable drugs.

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Drug Toxicities

Antituberculous drugs require careful monitoring because adverse effects may be significant.

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Isoniazid

Important adverse effects include:

• Hepatitis
• Peripheral neuropathy

The risk of neuropathy is reduced with pyridoxine.

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Rifampin

Important effects include:

• Hepatotoxicity
• Orange-red discoloration of urine, sweat, tears, and other body fluids
• Numerous drug-drug interactions

Rifampin strongly induces hepatic drug-metabolizing enzymes.

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Pyrazinamide

Important adverse effects include:

• Hepatotoxicity
• Hyperuricemia
• Arthralgia

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Ethambutol

The major toxicity is optic neuritis.

Patients should be monitored for:

• Reduced visual acuity
• Impaired red-green color discrimination

Visual symptoms require prompt evaluation.

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Inpatient Considerations

Hospitalization may be required for:

• Respiratory isolation
• Severe pulmonary disease
• Disseminated TB
• CNS involvement
• Major complications
• Diagnostic uncertainty
• Inability to safely isolate at home

Discharge decisions should be coordinated with infection-control and public-health authorities rather than relying on a single fixed rule.

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Follow-up

Close follow-up during therapy is essential to assess:

• Symptom improvement
• Medication adherence
• Drug toxicity
• Microbiologic response
• Development of resistance

Patients with pulmonary TB typically undergo repeat sputum testing during therapy until culture conversion is documented.

Long-term follow-up may be appropriate in patients at increased risk of relapse.

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Patient Education

Patients should understand that successful treatment requires strict adherence to the full multidrug regimen.

Stopping therapy early or taking drugs inconsistently can result in:

• Relapse
• Persistent infectiousness
• Treatment failure
• Drug resistance

Patients should also be taught the warning signs of medication toxicity, including:

• Jaundice
• Persistent nausea or vomiting
• Severe abdominal pain
• Vision changes
• Numbness or tingling
• Severe rash

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Prognosis

Drug-susceptible tuberculosis is usually curable when:

• Diagnosis is timely
• The correct multidrug regimen is used
• The patient adheres to treatment
• Drug resistance is absent

Prognosis is less favorable with:

• Delayed diagnosis
• Advanced HIV
• CNS disease
• Disseminated TB
• Severe malnutrition
• Drug-resistant disease

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Complications

Pulmonary TB may lead to:

• Massive or recurrent hemoptysis
• Bronchiectasis
• Fibrotic lung disease
• Pulmonary cavitation
• Pneumothorax
• Pleural disease
• Secondary infection of residual cavities

Old cavities may occasionally become colonized by fungi, particularly Aspergillus, producing an aspergilloma.

Extrapulmonary complications depend on the affected organ and may include:

• Neurologic disability
• Spinal deformity
• Renal dysfunction
• Infertility
• Pericardial constriction

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High-Yield Clinical Approach

Persistent cough + fever + night sweats + weight loss

→ Think pulmonary tuberculosis

Upper-lobe cavitary lesion

→ Strongly consider reactivation TB

Primary infection + hilar lymphadenopathy

→ Think primary pulmonary TB

TB + cervical painless lymphadenopathy

→ Think tuberculous lymphadenitis / scrofula

TB + back pain + vertebral destruction

→ Think Pott disease

TB + subacute headache + cranial nerve palsy

→ Think tuberculous meningitis

Sterile pyuria + epidemiologic risk

→ Think genitourinary TB

Diffuse tiny pulmonary nodules + systemic illness

→ Think miliary TB

Acid-fast bacilli on sputum smear

→ Supports mycobacterial disease; confirm M. tuberculosis with molecular testing/culture

BCG vaccination + need for TB infection testing

→ IGRA is particularly useful

Active drug-susceptible TB

→ Think RIPE therapy

Isoniazid toxicity

→ Hepatitis + peripheral neuropathy

Ethambutol toxicity

→ Optic neuritis and red-green color impairment

Rifampin

→ Orange body fluids + numerous drug interactions

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Exam Essentials

Causative organism:

→ Mycobacterium tuberculosis

Transmission:

→ Airborne

Major reservoir:

→ Humans

Characteristic stain:

→ Acid-fast stain

Classic pathology:

→ Caseating granulomas

Latent infection:

→ Immune containment without active clinical disease

Tests for latent infection:

→ TST or IGRA

Does TST/IGRA prove active TB?

→ No

Best tests for active pulmonary TB:

→ Molecular testing + AFB smear + mycobacterial culture

Classic primary TB imaging:

→ Hilar lymphadenopathy with lower/middle lung involvement

Classic reactivation TB imaging:

→ Apical or upper-lobe disease with possible cavitation

Cervical TB lymphadenitis:

→ Scrofula

Spinal TB:

→ Pott disease

Disseminated hematogenous TB:

→ Miliary TB

Standard four-drug initial therapy:

→ Rifampin + isoniazid + pyrazinamide + ethambutol

Mnemonic:

→ RIPE

Isoniazid supplementation:

→ Pyridoxine

Major isoniazid toxicity:

→ Hepatitis and peripheral neuropathy

Major ethambutol toxicity:

→ Optic neuritis

Major rifampin clue:

→ Orange-red discoloration of body fluids

MDR-TB:

→ Resistance to at least isoniazid and rifampin

Major prevention strategy:

→ Early identification, airborne isolation, contact tracing, and treatment of latent infection