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
Acid-fast stain of Mycobacterium tuberculosis
Image: “Mycobacterium tuberculosis bacteria” by CDC/Dr. George P. Kubica. License: Public Domain
Electron micrograph of Mycobacterium tuberculosis
Image: “Mycobacterium tuberculosis 01” by Elizabeth White. License: Public Domain
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
Image by Lecturio. License: CC BY-NC-SA 4.0Most 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
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.
Tuberculosis infection step 1: M. tuberculosis inhalation and phagocytosis by alveolar macrophages
Image by Lecturio. License: CC BY-NC-SA 4.0
Tuberculosis infection step 2: Inflammatory cell recruitment
Image by Lecturio. License: CC BY-NC-SA 4.0
AM: alveolar macrophages
Tuberculosis infection step 3: Granuloma formation
Image by Lecturio. License: CC BY-NC-SA 4.0
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).
| 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 |
|
|
|
| Symptoms |
|
Recurrence of symptoms |
|
CNS: central nervous system
TB: tuberculosis
Pulmonary tuberculosis (TB): primary and secondary disease manifestations
Image by BioDigital, edited by Lecturio
X-ray of a patient with tuberculosis:
Image: “Tuberculosis-X-ray-1” by CDC. License: Public Domain
Chest X-ray of bilateral reticular infiltrates (white triangles) and cavitary lesion (black arrows) in the right upper lobe
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
- Tuberculoid leprosy:
Immune response to leprosy
Image by Lecturio. License: CC BY-NC-SA 4.0Clinical 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.
| Tuberculoid | Lepromatous | |
|---|---|---|
| Presentation | Immunocompetent individuals | Immunocompromised individuals |
| Location | Skin and nerves | Skin and nerves |
| Symptoms |
|
|
Lagophthalmos in a patient with lepromatous leprosy:
Image: “ Lagophthalmos” by Department of Neurology, Chhatrapati Shahuji Maharaj Medical University, Uttar Pradesh, Lucknow, India. License: CC BY 2.5
Patient is attempting to close his eyelids but is unable to do so.
Leprosy:
Image: “Erythematous rash in trunk” by Infectious Diseases, Hattiesburg Clinic, Hattiesburg, Mississippi; Dermatology, Hattiesburg Clinic, Hattiesburg, Mississippi. License: CC BY 4.0
Erythematous skin patches
Widespread skin lesions consistent with lepromatous leprosy:
Image: “Leonine facies in leprosy” by Cieron Roe and Lucy Sarah May. License: CC BY 4.0
The patient is beginning to develop leonine facies, with a large number of papules and nodules afflicting the face, chest, back, legs, and groin. Large well-circumscribed plaques appear on the triceps aspect of the right arm and over his left shoulder and right flank.
Clawed fingers:
Image: “Typical Deformity in a Patient with Leprosy” by Andrea Rinaldi. License: CC BY 4.0
Typical deformity in a patient with advanced leprosy
Identification
The organism is identified by skin biopsy:
- Histopathological examination
- PCR
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)
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 2.0Clinical 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
- Older males with chronic obstructive pulmonary disease:
- Individuals with AIDS:
- Disseminated infection:
- Fever, night sweats
- Abdominal pain
- Diarrhea
- Lymphadenitis:
- Localized lymph node enlargement (abdominal, mediastinal, cervical)
- Fever
- Disseminated infection:
Identification
- Mycobacterial blood culture
- Histopathology and culture of the involved sites (bone marrow, lymph nodes)
References
- Alia, E. (2019). Atypical Mycobacterial Diseases. Emedicine. Retrieved February 21, 2021, from https://emedicine.medscape.com/article/220455-overview#a4
- 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
- Griffith, D.E. (2020). Overview of nontuberculous mycobacterial infections. Retrieved March 1, 2021, from https://www.uptodate.com/contents/overview-of-nontuberculous-mycobacterial-infections
- 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
- 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
- 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
- Smith, D. (2020). Leprosy. Emedicine. Retrieved February 22, 2021, from https://emedicine.medscape.com/article/220455-overview#a4
- 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
- Centers for Disease Control and Prevention. Tuberculosis (TB). https://www.cdc.gov/tb/default.htm. Accessed January 13, 2021.
