Mycobacterium Infection– Tuberculosis and Leprosy
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
drjonahp@yahoo.com
Introduction
Mycobacteria are the causative organisms for diseases such as Tuberculosis (TB), Leprosy, Buruli ulcer, and Pulmonary nontuberculous mycobacterial disease, to name the most important ones.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Introduction
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Microbiology
Mycobacterium are
1. Very thin
2. Rod shaped in appearance
3. About 0.2-0.4 X 2-10 µm in size
4. Non motile
5. Sometimes showing filamentous branching like fungus.
6. Forms mould-like pellicle in liquid culture.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Classification
Typical Mycobacteria or (Mycobacterium Tuberculosis complex):
M tuberculosis, M bovis, M bovis BCG and M africanum
Atypical Mycobacteria:
Photo-chromogens, Scoto-chromogens, Non Photo-chromogens, Rapid growers
Non-Cultivable Mycobacteria: M leprae
Saprophytic Mycobacteria: M butyricum, M pheli, M smegmatis
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Tuberculosis
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Introduction
Tuberculosis is a chronic infectious disease which can affect all organs of the human body, but more often the lungs.
Robert Koch in 1882 isolated the mammalian tubercle bacillus on heat coagulated Bovine serum and proved its causative role in Tuberculosis by satisfying the Koch’s postulate.
Mycobacterium tuberculosis complex includes:
M tuberculosis, M bovis, M bovis BCG, M africanum, and M microti (Vole)
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Epidemiology
Infection source is ill people and animals (mainly cattle).
Ways of infection contamination:
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Morphology
Straight or slightly curved rod in shape, of about 3 µm X 3 µm in size. Occurring slightly in pairs or small clumps which are ‘ACID and ALCOHOL FAST’. They resist decolourization by 20% sulphuric acid and absolute alcohol for 10 minutes.
Classification:
Primary tuberculosis;
Hematogenous tuberculosis;
Secondary tuberculosis.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Tuberculosis infection
Pulmonary (respiratory) Tuberculosis or Extrapulmonary (non-respiratory) Tuberculosis.
Pulmonary TB may arise from exogenous re-infection or endogenous re-activation of a latent focus remaining from an initial infection.
Sites of xtrapulmonary disease include the pleura, lymph nodes, pericardium, kidneys, meninges, bones and joints, larynx, skin, intestines, peritoneum and eyes.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Transmission
Tubercle bacilli are transmitted through the air by aerosolized droplet nuclei that are produced when a person with pulmonary or laryngeal TB coughs, sneezes, speaks, or sings.
Droplet nuclei may also be produced by other methods such as bronchoscopy, endotracheal intubation, processing of secretions in laboratory and hospitals.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Transmission
The nuclei, which contains 1-3 µm of tuberculosis organisms, are small enough to remain airborne for long periods of time and to reach the alveoli within the lungs when inhaled.
Tubercle bacilli are not transmitted on inanimate objects such as dishes, clothing, or beddings, and organisms deposited on skin or intact mucosa do not invade tissues.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Persons at risk to infection
Contacts of sputum positive TB cases.
Persons with HIV infections.
Immigrants from countries with high prevalence.
Persons in institutions such as prison or drug rehabilitation centers.
Persons with other risk factors (DM, silicosis, prolonged corticosteroids and immunosuppressive therapies).
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Pathophysiology of TB (natural hx)
1. Upon inhalation of tubercle bacilli droplet, nuclei settle into the alveoli of the lungs and are ingested by macrophages but some often survive in the tissue. Infection is present but shows no symptom of disease.
2.The tubercle bacilli multiplying in macrophages cause a chemotactic response that brings additional macrophages and other defensive cells to the area. These form a surrounding layer and in turn a Primary tubercle (Ghon focus). Most of the surrounding macrophages are not successful in destroying the bacteria, but release enzymes and cytokines that cause a lung damaging inflammation. Development of infection in the lungs will depend on virulence and host’s immune status.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Pathophysiology of TB (natural hx)
3. After a few weeks, disease symptoms appear as many of the macrophages die, releasing viable tubercle bacilli and forming a caseous center in the tubercle. The aerobic tubercle bacilli do not grow well in this confined location. However many remain dormant (latent TB) and serve as basis for later reactivation of the disease. The disease may be arrested at this stage, and lesions become calcified. Individuals with latent TB infections are not infectious and cannot transmit the organisms.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Pathophysiology of TB (natural hx)
If the patient is immunocompromised at the time of initial infection, the disease will more likely progress into bacterial pneumonia at the site of implantation, known as primary progressive disease.
In the remaining group whose immune system is competent, the infection will usually be halted after a brief period of bacillary dissemination.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Pathophysiology of TB (natural hx)
In immunocompetent individuals, the Primary tubercle (or Ghon focus) is held in check due to the development of T cell mediated hypersensitivity that usually occurs 4-8 weeks after initial infection.
At this time, the patient will demonstrate a positive reaction to a Mantoux Tuberculin (PPD test) or Skin Test (TST), and any remaining viable organisms within the body will be walled off in caseating granulomas.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Pathophysiology of TB (natural hx)
4. In some individuals, disease symptoms appear as a mature tubercle is formed. The disease progresses as the caseous center enlarges in a process termed liquefaction. The caseous center now enlarges and forms an air-filled tuberculous cavity in which the aerobic bacilli multiplies outside macrophages.
5. Liquefaction continues until the tubercle ruptures, allowing bacilli to spill into a bronchiole and so be distributed throughout the lungs and then to the circulatory and lymphatic systems.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Pathophysiology of TB (natural hx)
Ten percent (10%) of persons with symptomatic primary infection will at some later date develop active TB (reactivation disease) because the immune system fails to contain the organism.
This most often presents as pulmonary tuberculosis (PTB), although extrapulmonary tuberculosis (CNS, renal, hepatic, GI, skeletal) is not uncommon.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Diagnosis of Tuberculosis
The most common form of TB in adults is post-primary pulmonary tuberculosis (PTB). This has a great epidemiological significance.
Diagnosis is based on
Clinical,
Radiological and/or
Bacteriological evidence.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Signs and Symptoms of PTB
Persistent cough (of more than 2 weeks).
Cough with blood-stained sputum (hemoptysis).
Dyspnea, chest pain, hoarseness of voice.
Fever with night sweats.
Loss of weight and loss of appetite.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Laboratory Investigations
Sputum direct smear for AFB (3 specimens).
Culture and Sensitivity using egg-based media.
Chest X-ray often reveals lesions in the apical and posterior segments of the upper lobes (soft, usually little or no fibrosis).
Mantoux Tuberculin (PPD) or Skin Test has some role in diagnosis.
NAA technology example GeneXpert assay.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Goals of Treatment
Cure the individual to prevent morbidity and mortality.
Prevent relapse of the disease.
Minimize transmission of M tuberculosis.
Prevent emergence of MDR -TB.
Multi-drug-resistant tuberculosis (MDR-TB) is a form of tuberculosis (TB) infection caused by bacteria that are resistant to treatment with at least two of the most powerful first-line anti-TB medications (drugs), isoniazid and rifampin.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Treatment of Active TB
Essential First Line Drugs
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Extensively drug resistant TB
Extensively drug-resistant tuberculosis (XDR-TB) is a form of tuberculosis caused by mycobacterium that are resistant to some of the most effective anti-TB drugs. The XDR-TB strains have arisen after the mismanagement of individuals with multidrug-resistant TB (MDR-TB).
The World Health Organization (WHO) defines XDR-TB as MDR-TB that is resistant to at least one fluoroquinolone and a second-line injectable drug (amikacin, capreomycin, or kanamycin).
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Treatment of Active TB
DOTS Regimen
Directly observed treatment means that an observer supervises a patient as he/she swallows the antiTB tablets, in a way that is sensitive and supportive to the patient's needs.
This ensures that a TB patient takes the right anti-tuberculosis drugs, in the right doses, at the right intervals.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Treatment of Active TB
Treatment Regimens
The course of treatment is divided into an Initial (Intensive) phase and the Continuation (Maintenance) Phase.
The 2-month Intensive Phase with 3 or 4 drugs is to rapidly convert the sputum and improve clinical symptoms.
The 4-month Continuation Phase with 2 or 3 drugs has a sterilizing effect to eliminate the remaining bacilli and prevent relapse.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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TB blood tests
Interferon-Gamma Release Assays, (IGRAs)
Measures how strong a person’s immune system reacts to TB bacteria. There are two types of IGRAs
a) QuantiFERON®–TB Gold In-Tube test (QFT-GIT)
b) T-SPOT®.TB test (T-Spot)
IGRAs are the preferred method of TB infection testing for people who have received Bacille Calmette–Guérin (BCG) vaccine. BCG is a vaccine to prevent contracting TB infection.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Leprosy
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Introduction
Leprosy is a chronic infectious disease caused by the bacteria Mycobacterium leprae, an acid fast, rod shaped bacillus. Mainly involves the peripheral nerves and skin.
Other organs involved are mucosa of mouth, upper respiratory tract, Eyes, bones and muscles, testes etc. Commonly involves every organ of the body except the CNS, Ovaries and Lungs.
Mycobacterium leprae was discovered by Gerhard Henrik Armauer Hansen in 1873 in Norway. Hence it is referred to as Hansen’s disease.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Epidemiology
It has a worldwide distribution but essentially a disease of developing countries. Transmission is by droplet inhalation but can occur by skin contact with infectious cases, soil or fomites. Other routes of infection are insect vectors e.g., Mosquitoes, Bedbugs and Tattooing needles.
Breast feeding and transplacental infection does not occur.
Humans and Armadillos are the only known natural hosts. It can affect all ages and both sexes, 95% of people who are exposed do not develop the disease.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Epidemiology
Leprosy has a long incubation period ranging from 2 to 40 years or more on an average 3-5 years. Generation time is 12 days.
Leprosy is a highly infectious disease with low pathogenicity.
Among household contacts of lepromatous cases about 5 to 12 percent are expected to show signs within 5 yrs.
About 80% of the worldwide cases are found in five countries, namely India, Myanmar, Indonesia, Brazil and Nigeria.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Microbiology
Gram positive obligate intracellular bacillus, optimal temperature for growth is 30-33°C, acid fast, stained with ZN stain, thick, pink rods of size 5µ x 0.5µ. Occurs characteristically in clumps or bundles (“globi”), has affinity for Schwann cells and cells of R-E system. Mycobacterium leprae grows best in cooler tissues (the skin, peripheral nerves, anterior chamber of the eye, upper respiratory tract, and testes), sparing warmer areas of the skin (the axilla, groin, scalp, and midline of the back).
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Pathogenesis
Mycobacterium Leprae bacteria targets Schwann cells. Causes anesthesia and muscle paralysis.
Repeated injuries to anesthesized areas leads to its gradual destruction.
Infiltration of skin, subcutaneous lesions leads to formation of visible lesions.
The first lesions are non specific indeterminate skin lesions.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Classifications of Leprosy
Indian Classification : Clinico-bacteriological
Madrid Classification : Clinico-bacteriological
Ridley Jopling classification (for research purposes) : Immuno-histological
WHO study group classification based on Chemotherapy of Leprosy : Clinico-bacteriological.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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WHO classification
There are two groups Paucibacillary and Multibacillary
The number of Mycobacterium leprae in the body is small (less than 1 million) and a skin smear test is negative.
The patient presents five or fewer skin lesions. Most cases of leprosy are PB.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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WHO classification
2. Multibacillary (MB):
Mycobacterium leprae can multiply in the body almost without any check and will thus present in high numbers.
The bacillus spreads to almost all areas of skin and peripheral nerves. A skin smear test is positive and the patient presents with more than five skin lesions.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Clinical presentation
Hyper-reactive or Tuberculoid leprosy has a small number of localized skin lesions and contain few bacilli with granulomatous response that often damages major nerve trunks.
Anergic or Lepromatous leprosy has numerous or confluent skin lesions, contain a high number of bacilli with clusters of “globi” within monocytes on microscopy.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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How to diagnose leprosy
1) Examine the skin
2) Check for skin patches
3) Test for skin sensation
4) Count the number of patches on the body
5) Look for damage to nerves
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Laboratory diagnoses of leprosy
Diagnosis may be made by doing a biopsy, in which a small piece of the skin (skin slit) is taken and a smear is made to examine histologically for “globi” and microscopically for the Mycobacterium leprae.
Early diagnosis is very important because it can prevent permanent deformities and disability.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Laboratory diagnoses of leprosy
Tuberculoid Leprosy (TT): Histologically TT resemble tuberculosis: Characterized by tuberculoid granuloma, made up of epithelioid cells in the center surrounded by abundant Langerhans giant cells, lymphocytes and foci of caseating necrosis. No acid-fast bacilli
Lepromatous Leprosy (LL): Characterized by diffuse infiltration of foamy macrophages in the dermis. Acid-fast bacilli are present inside these foamy cells either singly or in globi. There is a free subepidermal zone (‘grenz’ zone). Lymphocytes are scanty and giant cells are typically absent.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Treatment
1) Dapsone.
2) Rifampicin.
3) Clofazimine.
Leprosy treatment is simple, available and free.
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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Thank you
Dr. J. Y. Peter (BM BCh, MSc, FMCPath, MRCPath)
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