Mycobacterium

Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. While lungs are the most common site of infection, mycobacteria can colonize and infect other organ systems including the lymph nodes, skin, sinuses, eyes, ears, bones, CNS, and urinary tract.

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General Characteristics

Basic features

Morphology and properties:

  • Straight or slightly curved bacilli
  • Growth:
    • Slow-growing bacilli
    • Most species can be cultured on simple substrates using amino acids and glycerol.
    • Most species grow on blood agar.
  • Nonmotile, non-spore-forming bacilli
  • Obligate aerobes (some are microaerophilic)
  • Catalase positive
  • Facultative intracellular bacilli
  • Have a characteristic cell wall (envelope) that confers several unique properties:
    • Presence of a hydrophobic waxy layer composed of mycolic acids
    • Linked to a peptidoglycan layer by a polysaccharide arabinogalactan
    • ↓ Permeability to many drugs and efflux pumps
    • Mycobacteria can invade host cells without presenting with any clinical signs.

Staining properties:

  • Acid-fast bacilli:
    • Property conferred by mycolic acid
    • Do not destain by acid alcohol after being stained with aniline dyes
  • Gram stain:
    • Usually cannot penetrate the waxy cell wall of the Mycobacterium tuberculosis complex (MTBC)
    • Most commonly produce no stain or variable results

Classification

  • Phylum: Actinobacteria
  • Family: Mycobacteriaceae
  • Genus: Mycobacterium (consists of > 150 species)

Mycobacteria:

  • Typical mycobacteria: MTBC species:
    • M. tuberculosis (most important)
    • M. bovis
    • M. africanum
    • M. microti
    • M. canetti
  • Atypical, non-tuberculous mycobacteria (NTM): 
    • Classified according to the Runyon system
    • Classification is based on growth rate and pigment production.
    • Groups Ⅰ–Ⅲ are slow growing (> 7 days), and group Ⅳ is considered fast growing (< 7 days):
      • Group I: Photochromogens produce pigment in the presence of light.
      • Group II: Scotochromogens produce pigment in the absence of light.
      • Group III: Non-photochromogens lack pigment (includes Mycobacterium avium complex (MAC) bacteria).
      • Group IV: produce mature colonies in culture media in < 7 days
  • Noncultivable: M. leprae complex (M. leprae and M. lepromatosis)
  • Saprophytic
  • Skin-ulcer types
Classification of mycobacteria flowchart

Classification of mycobacteria

Image by Lecturio. License: CC BY-NC-SA 4.0

Most important pathogenic species:

  • MTBC causes tuberculosis (TB).
  • M. leprae complex causes leprosy.
  • M. avium and M. intracellulare (known together as M. avium complex (MAC)) cause: 
    • Pulmonary infections similar to TB
    • Disseminated infections in immunocompromised individuals

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Pathogenesis

Reservoirs

  • M. tuberculosis: humans are the only natural reservoir.
  • M. leprae natural reservoir: armadillos
  • M. avium and M. intracellulare are found in water and soil.

Transmission

  • M. tuberculosis transmission: respiratory droplets from patients with active disease
  • M. leprae transmission: 
    • Direct contact with lesions
    • Inhalation of infectious droplets
  • MAC transmission: 
    • Inhalation into the respiratory tract
    • Ingestion into the GI tract

Virulence

  • Cell envelope:
    • Major constituent: mycolic acid
    • Mycolic acid is attached to glycolipids.
    • Glycolipids are responsible for “cord formation” on microscopy (grossly corresponds to granuloma formation).
  • Catalase-peroxidase: resists host-cell oxidative response
  • Sulfatides and trehalose dimycolate: triggers toxicity
  • Lipoarabinomannan (LAM): induces cytokines

Host risk factors

  • Elderly
  • Children
  • Immunocompromised patients
  • Institutionalized patients
  • IV drug use
  • HIV or other immunodeficiencies
  • Travel to high-risk regions

General mycobacterial pathophysiology

  • In humans, mycobacterial infections can affect multiple anatomical sites.
  • Bacteria enter through the skin and mucosal barriers.
  • Pulmonary and cutaneous infections are the most common.
  • Infections with NTM occur most commonly in immunocompromised hosts as opportunistic infections.
  • Mycobacteria can colonize their hosts and cause latent infections without any obvious clinical signs.

M. tuberculosis complex

Epidemiology

  • MTBC bacteria cause TB.
  • TB is an airborne disease that affects the lungs and, sometimes, other organs.
  • Causes 1.4 million deaths per year worldwide
  • 30% of the global population is infected.
  • 10% of infected people will develop active disease.
  • Leading cause of deaths in patients with HIV

Pathophysiology

  • 1st step is inhalation of aerosol droplets.
  • Deposition into the lungs leads to 3 possible outcomes:
    • Clearance of bacteria
    • Primary active disease:
      • Proliferation of bacteria within alveolar macrophages
      • Cytokines produced by macrophages (IL-12 and Il-18) attract other phagocytic cells.
      • A tubercle (granulomatous structure) forms (promoted by TNF-ɑ)
      • Tubercle expands into lung parenchyma → Ghon complex
      • Bacteria can then spread to draining lymph nodes → lymphadenopathy
      • Ghon complex + lymphadenopathy/calcification → Ranke complex
      • If spread is not controlled by immune cells, bacteremia with seeding of other organs may occur → miliary TB
      • When bacteria erode into airways (caseating granulomas), the patient becomes contagious.
      • Infection may progress to a chronic stage with episodes of healing and subsequent scarring of lesions.
      • Spontaneous eradication is rare.
  • Latent infection (clinical (secondary) disease may occur many years later):
    • Lifetime risk of reactivation: 5%–10%
    • Immunosuppression is a factor in reactivation.

Clinical presentation

  • Pulmonary manifestations associated with systemic symptoms are most common in primary and secondary TB.
  • Miliary (disseminated) TB occurs in 15%–20% of cases (usually in children or immunocompromised individuals).
Table: Manifestations of MTBC infection
Primary TB Secondary TB Extrapulmonary (miliary) TB
Presentation Within 2 years of infection in 5%–10% of cases Reactivation of infection in immunocompromised patients Immunocompromised individuals
Location
  • Mid and lower lobes
  • Subpleural necrosis
    • Cavitary lesions in upper lobes of lung
    • Miliary spread in lungs may occur.
      • Lymph node
      • Pleura
      • GU tract
      • CNS
      • Kidney
        Symptoms
        • Malaise
        • Weight loss
        • Cough
        • Night sweats
        • Hemoptysis
          Recurrence of symptoms
          • Non-specific signs
          • Enlarged viscera
          • Cutaneous lesions
          • Multiple organ dysfunction
            GU: genitourinary
            CNS: central nervous system
            TB: tuberculosis

            Identification

            Sputum:

            • 3 specimens, at least 1 early morning
            • Acid-fast bacillus (AFB) smear
            • Mycobacterial culture
            • Nuclear acid amplification test

            Blood or urine mycobacterial culture: in patients with HIV or immunocompromised individuals

            Tuberculin skin test (TST; PPD (purified protein derivative) or Mantoux test): 

            • Intradermal injection of tuberculin antigen
            • Can detect active or latent infection
            • Measure induration area after 48–72 hours; positive if: 
              • > 5 mm in patients with HIV or immunosuppression, or recent contact with an individual with TB
              • > 10 mm in patients from high-risk countries, IV drug users, medical and lab workers
              • > 15 mm in patients with no known risk factors for TB

            lnterferon-γ release assay (IGRA): no distinction between active and inactive TB

            M. leprae complex

            Epidemiology

            • M. leprae complex bacteria cause leprosy.
            • Prevalence is < 1 in 10,000.
            • Highest incidence in India, Brazil, Indonesia, Bangladesh, and Nigeria
            • Risk factors for acquisition:
              • Close contact with patients with leprosy
              • Armadillo exposure (natural reservoir of M. leprae)
              • Elderly
              • Genetic factors
              • Immunosuppression

            Pathophysiology

            • Bacteria are inhaled or transmitted through direct skin contact.
            • Bacteria are taken up by alveolar macrophages and disseminated by blood.
            • M. leprae spreads to the nerves and skin, where it proliferates (especially in Schwann cells).
            • Leprosy can manifest in different forms and reflects the spectrum of the host immune response.
            • Ridley-Jopling classification of leprosy:
              • Tuberculoid (TT)
              • Borderline tuberculoid (BT)
              • Mid-borderline (BB)
              • Borderline lepromatous (BL)
              • Lepromatous (LL)
              • Indeterminate (I)
            • Tuberculoid and lepromatous forms are at the 2 ends of the spectrum:
              • Tuberculoid leprosy:
                • Good cellular immune response (TH1 response)
                • Delayed-type hypersensitivity with interferon-γ and macrophage activation
                • Involves the skin (localized) and peripheral nerves
              • Lepromatous leprosy:
                • Minimal cellular immune response
                • Humoral (antibody) response (activated by TH2 cells)
                • Extensive skin involvement
                • Nerve involvement tends to be symmetric
            Immune response to leprosy

            Immune response to leprosy

            Image by Lecturio. License: CC BY-NC-SA 4.0

            Clinical presentation

            • Hypopigmented or reddish skin patches associated with loss of sensation
            • Paresthesia
            • Painless wounds in the extremities
            • Facial or ear lumps
            • Enlarged and tender peripheral nerves
            • Ophthalmic injury (corneal abrasions/ulcerations, lagophthalmos)
            • Late findings may include facial paralysis, collapsed nose, clawed fingers, foot drop, lack of eyelashes/eyebrows.
            • Immunological reactions (systemic inflammatory complications) may occur.
            Table: Clinical spectrum of leprosy
            Tuberculoid Lepromatous
            Presentation Immunocompetent individuals Immunocompromised individuals
            Location Skin and nerves Skin and nerves
            Symptoms
            • Early peripheral nerve damage
            • Complete sensory loss
            • Visible nerve enlargement
            • Autoamputation of the digits
            • Rash: few hypopigmented atrophic plaques with flat centers and raised demarcated borders
              • Late diffuse nerve damage, patchy sensory loss
              • No nerve enlargement
              • Rash: many macules, papules, or nodules with damage to nose cartilage, bone, testicles; “lion-like” facies

                Identification

                The organism is identified by skin biopsy:

                • Histopathological examination
                • PCR

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                M. avium complex

                Epidemiology

                • Most commonly acquired from environment (water sources)
                • No documented human-to-human transmission
                • Commonly affects people with pre-existing lung disease and immunocompromised patients (AIDS)

                Pathophysiology

                • Usually presents as pulmonary infection in immunocompetent individuals
                • Can present as disseminated disease or localized lymphadenitis in patients with AIDS:
                  • Risk increases as CD4 count falls below 50
                  • MAC infection is one of the AIDS-defining conditions.
                  • MAC bacteria enter through the GI mucosa and are phagocytosed by macrophages in the lamina propria.
                  • Lymphatic drainage transports mycobacteria to the abdominal lymph nodes from where they can enter the bloodstream.
                  • Spread can occur to many sites: spleen, bone marrow, and liver are most common
                  • Most signs and symptoms are due to the elaboration of cytokines.
                  • Rarely the direct cause of death but ↑ the risk of superinfection
                  • Localized lymphadenitis:
                    • Usually after the initiation of antiretroviral therapy
                    • Results from the immune reconstitution inflammatory syndrome (IRIS)
                Abdominal ct proving mac infection

                MAC infection: abdominal CT demonstrating multiple abscessed intra-abdominal lymph nodes

                Image: “Mycobacterium avium complex immune reconstitution inflammatory syndrome: long term outcomes” by Riddell J, Kaul DR, Karakousis PC, Gallant JE, Mitty J, Kazanjian PH. License: CC BY 2.0

                Clinical presentation

                • Immunocompetent patients:
                  • Older males with chronic obstructive pulmonary disease:
                    • Cough, fever, upper-lobe infiltrates/cavities
                    • Resembles TB, but less severe
                  • Women > 50 years of age with no preexisting history: often presents as bronchiectasis
                • Individuals with AIDS:
                  • Disseminated infection:
                    • Fever, night sweats
                    • Abdominal pain
                    • Diarrhea
                  • Lymphadenitis:
                    • Localized lymph node enlargement (abdominal, mediastinal, cervical)
                    • Fever

                Identification

                • Mycobacterial blood culture
                • Histopathology and culture of the involved sites (bone marrow, lymph nodes)

                References

                1. Alia, E. (2019). Atypical Mycobacterial Diseases. Emedicine. Retrieved February 21, 2021, from https://emedicine.medscape.com/article/220455-overview#a4
                2. Fordham von Reyn, C. (2020). Vaccines for prevention of tuberculosis. Retrieved January 14, 2021, from https://www.uptodate.com/contents/vaccines-for-prevention-of-tuberculosis
                3. Griffith, D.E. (2020). Overview of nontuberculous mycobacterial infections. Retrieved March 1, 2021, from https://www.uptodate.com/contents/overview-of-nontuberculous-mycobacterial-infections
                4. Pozniak, A. (2019). Clinical manifestations and complications of pulmonary tuberculosis. Retrieved January 13, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-complications-of-pulmonary-tuberculosis
                5. Riley, L.W. (2019). Tuberculosis: Natural history, microbiology, and pathogenesis. Retrieved January 13, 2021, from https://www.uptodate.com/contents/tuberculosis-natural-history-microbiology-and-pathogenesis
                6. Scollard, D., Stryjewska, B., Dacso, M. (2020). Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis. Retrieved March 1, 2021, from https://www.uptodate.com/contents/leprosy-epidemiology-microbiology-clinical-manifestations-and-diagnosis
                7. Smith, D. (2020). Leprosy. Emedicine. Retrieved February 22, 2021, from https://emedicine.medscape.com/article/220455-overview#a4
                8. Sterling, T. (2020). Treatment of drug-susceptible pulmonary tuberculosis in HIV-uninfected adults. Retrieved January 14, 2021, from https://www.uptodate.com/contents/treatment-of-drug-susceptible-pulmonary-tuberculosis-in-hiv-uninfected-adults
                9. Centers for Disease Control and Prevention. Tuberculosis (TB). https://www.cdc.gov/tb/default.htm. Accessed January 13, 2021.

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