2. Plan:
Definition
Risk factors and Etiology
Pathogenesis
Clinical presentation
Diagnosis
Differential diagnosis
Complications
Management
prevention
Take home message.
3.
4. Definition(1):
Tuberculosis, one of the oldest diseases known to affect
humans, is the second leading cause of death from an
infectious agent after HIV. It is caused by bacteria
belonging to the Mycobacterium tuberculosis complex.
The disease usually affects the lungs, although in up to
one-third of cases other organs are involved.
Of the pathogenic species belonging to the M.
tuberculosis complex, the most frequent and important
agent of human disease is M. tuberculosis. The complex
includes M. bovis (the bovine tubercle bacillus, once an important
cause of tuberculosis transmitted by unpasteurized milk and
currently the cause of a small percentage of cases in developing
countries), M. africanum (isolated from cases in West, Central,
and East Africa), M. microti (the “vole” bacillus, a less virulent
and rarely encountered organism), and M. canettii (a very rare
isolate in African cases).
5. Definition(2):
M. tuberculosis is a rod-shaped, non-spore-forming,
thin aerobic bacterium measuring 0.5 m by 3 m.
Mycobacteria, including M.tuberculosis (M. tb), are
often neutral on Gram’s staining. However, once
stained, the bacilli cannot be decolorized by acid
alcohol, a characteristic justifying their classification as
acid-fast bacilli (AFB).
Transmission usually takes place through the airborne
spread of droplet nuclei produced by patients with
infectious pulmonary tuberculosis.
6. Risk factors & Etiology(1):
Risk factors for acquisition of Tuberculosis (TB) are
usually exogenous to the patient. Thus likehood of being
infected depends on the environment and the features of
index case. However, the development of TB disease
depends on inherent immunologic status of the host.
Defects in Cell-mediated immunity (CMI) and level of
immunocompetence are major determinants for
development of disease: In fact, Infection with HIV is
one of the most significant risk factors for TB
infection.
TB has been reported in patients treated for arthritis,
inflammatory bowel disease, and other conditions
with TNF –alpha blockers/antagonists.
7. Risk factors & Etiology(2):
Steroids therapy, cancer chemotherapy, and hematologic
malignancies increase the risk of TB. In addition malnutrition
interferes with Cell-mediated immunity (CMI) response and
therefore accounts for much the increased frequency of TB in
impoverished patients.
Non-TB infections, such as measles, varicella and pertussis, may
activate quiescent TB.
Etiology: Infection with Mycobacterium tuberculosis.
Mycobacterium tuberculosis are pleomorphic, weakly gram-
positive curved rods. Mycobacteria are acid fast, which is the
capacity to form stable mycolate complexes with arylmethane dyes.
Mycobacteria grow slowly;
9. Pathogenesis (1):
M. tb is transmitted by airborne particles when a person with pulmonary TB
(PTB) coughs,
The organism is slow growing and tolerates the intracellular environment, where
may remain metabolically inert for years before reactivation and disease.
•Infection thought to occur in distal alveoli where the bacteria are ingested by
by alveolar macrophages
•Macrophages role: phagocytosis, growth arrest and intracellular killing of M. tb
10. Pathogenesis (2):
A cell-mediated immune (CMI) reponse terminates the unimpeded growth of
the M. tb 2-3wks after initial infection.
•Macrophages need activation by TNF and IFN-γ, derived from antigen-specific
T cells.
CD4 helper T cells activate the macrophages to kill the intracellular bacteria with
resultant epitheloid granuloma formation,
CD8 suppressor T cells lyse the macrophages infected with M. tb, resulting in
formation of caseating granulomas.
M. tb can’t continue to grow in acidic extracellular environment, so most
infections are controlled.
The main determinant of pathogenesis of TB is the ability to escape host
mechanisms, including macrophages and delayed hypersensitivity responses.
11. Pathogenesis (3):
Progression of the primary complex may lead to enlargement of hilar and
mediastinal nodes with resultant bronchial collapse.
Progressive primary TB may develop when the primary focus cavitates and
organisms spread through contiguous bronchi.
Lymphohematogenous dissemination, especially in young patients, may lead to
Miliary TB when caseous material reaches the bloodstream from primary focus
or a caseating metastatic focus in the wall of pulmonary vein (Weigert focus).
TB meningitis may also result from hematogenous dissemination.
Bacilli may remain dormant in the apical posterior areas of the lung for
months or years, with later progression of disease resulting in the development of
reactivation-type TB (ie, endogenous reinfection TB)
16. Clinical presentation(1):
Latent tuberculosis describes the asymptomatic stage of infection with M.
tuberculosis. The tuberculin skin test (TST) is positive, but the chest
radiograph is normal, and there are no signs or symptoms of illness.
Tuberculosis disease occurs when there are clinical signs and symptoms or an
abnormal chest radiograph.
The term tuberculosis usually refers to the disease. The interval between latent
tuberculosis and the onset of disease may be several weeks or many decades in
adults.
In young children, tuberculosis usually develops as an immediate complication of
the primary infection, and the distinction between infection and disease may be less
obvious.
17. Clinical presentation(2):
Primary pulmonary tuberculosis in older infants and children is usually an
asymptomatic infection.
Often the disease is manifested by a positive TST with minimal abnormalities on the
chest radiograph, such as an infiltrate with hilar lymphadenopathy or Ghon
complex.
Hilar lymphadenopathy may compress the bronchi or trachea malaise, low-grade
fever, erythema nodosum, or symptoms resulting from lymph node enlargement
may occur after the development of delayed hypersensitivity.
Lymphadenopathy is common in primary pulmonary disease. The most common
extrathoracic sites of lymphadenitis are the cervical, supraclavicular, and
submandibular areas (scrofula).
18. Clinical presentation(3):
Progressive primary disease is characterized by a primary pneumonia that develops
shortly after initial infection.
Progression to pulmonary disease, disseminated miliary disease, or progression
of central nervous system (CNS) granulomas to meningitis occurs most commonly
in the first year of life.
Tuberculous pleural effusion, which may accompany primary infection, generally
represents the immune response to the organisms and most commonly occurs in older
children or adolescents. (Pleurocentesis reveals lymphocytes and an increased
protein level, but the pleural fluid usually does not contain bacilli.)
Reactivation pulmonary tuberculosis, common in adolescents and typical in adults,
usually is confined to apical segments of upper lobes or superior segments of lower
lobes. There is usually little lymphadenopathy and no extrathoracic infection
because of established hypersensitivity.
19. Clinical presentation(4):
Advanced disease is associated with cavitation and endobronchial spread of bacilli.
Symptoms include fever, night sweats, malaise, and weight loss. A productive
cough and hemoptysis often herald cavitation and bronchial erosion.
Miliary tuberculosis :The lesions are of roughly the same size as a millet seed, from
which the name miliary is derived.
Miliary tuberculosis is characterized by fever, general malaise, weight loss,
lymphadenopathy, night sweats, and hepatosplenomegaly. Diffuse bilateral
pneumonitis is common, and meningitis may be present.
The chest radiograph reveals bilateral miliary infiltrates, showing overwhelming
infection. TST may be nonreactive as a result of anergy. Liver orbone marrow
biopsy is useful for the diagnosis.
20. Clinical presentation(4):
Tuberculous meningitis most commonly occurs in children under 5 years old and
often within 6 months of primary infection.
This condition may have an insidious onset, initially characterized by low-grade fever,
headache, and subtle personality change.
Progression of the infection results in basilar meningitis with impingement of the
cranial nerves and is manifested by meningeal irritation and, eventually, increased
intracranial pressure, deterioration of mental status, and coma.
CT scans show hydrocephalus, edema, periventricular lucencies, and infarctions.
CSF analysis reveals pleocytosis (50 to 500 leukocytes/mm3), which early in the
course of disease may be either lymphocytes or polymorphonuclear leukocytes. Glucose
is low, and protein is significantly elevated.
Acid-fast bacilli are not detected frequently in the CSF by either routine or fluorescent
staining procedures. Although culture is the standard for diagnosis, PCR for M.
tuberculosis is useful to confirm meningitis.
21. Clinical presentation(5):
Skeletal tuberculosis results from either hematogenous seeding or direct extension
from a caseous lymph node. This is usually a chronic disease with an insidious onset
that may be mistaken for chronic osteomyelitis caused by Staphylococcus aureus.
Radiographs reveal cortical destruction.
Biopsy and culture are essential for proper diagnosis. Tuberculosis of the spine,
Pott’s disease, is the most common skeletal site followed by the hip as well as fingers
and toes (dactylitis).
Other forms of tuberculosis include abdominal tuberculosis that occurs from
swallowing infected material. This is a relatively uncommon complication in developed
nations where dairy herds are inspected for bovine tuberculosis.
Tuberculous peritonitis is associated with abdominal tuberculosis and presents as
fever, anorexia, ascites, and abdominal pain.
Urogenital tuberculosis is a late reactivation complication and is rare in children.
Symptomatic illness presents as dysuria, frequency, urgency, hematuria, and sterile
pyuria.
22. Clinical presentation(summary I):
In summary Signs and symptoms are variable:
History:
Prolonged fever
Malaise
Anorexia
Cough
Weigh loss
Hemoptysis
Back Pain
Fever and Rash
Lymphadenopathy
Fever of Unknown Origin
Contact in infected adult*
23. Clinical presentation(Summary II):
P/E : (Signs depend on focus of infection)
Primary in lung: signs of bronchial obstruction, pleural effusion,
etc
Primary in tonsils: cervical adenitis
Primary in small bowel: malabsorption, peritonitis
Miliary TB: meningitis, chest signs, hepatomegaly
…
24. Diagnosis(1):
Making the diagnostic of TB in children is extremely
challenging because of the difficulty in isolating M.tub.
Definitive TB diagnosis depends on isolationof organism
from secretions or biopsy specimens.
To make thne diagnosis of congenital TB, the infant
should have proven TB lesions and at least one of the
following:
1. Skin lesions during the first week of life, including papular
lesions or petechiae
2. Documentation of TB infection of thr placenta or the
maternal genital tract
3. Presence of primary complex in liver
4. Exclusion of the possibility of postnatal transmission.
25. Diagnosis(2):
Tuberculin Skin Test (TST): is a widely used diagnostic
test for evaluation of patients who have symptoms of
Tuberculosis or in whom infection of M.tub is suspected.
The TST response to tuberculin antigen is a
manifestation of a T-cell−mediated delayed
hypersensitivity.
The Mantoux test, an intradermal injection of 5 TU
(tuberculin units) of purified protein derivative
standard (PPD-S), usually on the volar surface of the
forearm, is the standard TST. It is usually positive 2 to 6
weeks after onset of infection (occasionally 3 months) and
at the time of symptomatic illness.
26. Diagnosis(3):
TST is neither 100% sensitive nor 100% specific.
Interferon gamma release assays (IGRA) are now
replacing the TST as the preferred test for screening
and testing for TB in children greater than (years old
who have been vaccinated with BCG.
Acid-fast baccilli Staining (Ziehl-neelsen staining)
Culture:
The ultimate diagnostic confirmation relies on culture
of the organism, a process that usually is more
successful with tissue, such as pleura or pericardial
membrane from biopsy, rather than pleural or
pericardial fluid. Sputum is an excellent source for
diagnosis in adults but is difficult to obtain in young
children.
27. Diagnosis(4):
Induced sputum or gastric fluid obtained via
an indwelling nasogastric tube with samples taken
before or immediately on waking contains
swallowed sputum and provides appropriate
samples in young children.
Large volumes of fluid (CSF, pericardial fluid)
yield a higher rate of recovery of organisms,
compared with the less significant size of the
initial parenchymal focus, together historically
referred to as the Ghon complex (with or
without calcification of the lymph nodes).
28. Diagnosis(5):
Radiographic studies aid greatly in the diagnosis
of extrapulmonary tuberculosis in children.
Plain radiographs, CT, and MRI of the
tuberculous spine usually show collapse and
destruction of the vertebral body with narrowing
of the involved disk spaces.
In tuberculosis of the CNS, CT or MRI of the
brains of patients with tuberculous meningitis
may be normal during early stages of the
infection. As disease progresses, basilar
enhancement and communicating hydrocephalus
with signs of cerebral edema or early focal
ischemia are the most common findings.
29. Differential diagnosis
The following conditions should be also be considered in
cases of suspected TB:
- Actinomycosis
- Aspergillosis
- Bronchiectasis
- Bronchopulmonary dysplasia
- Brucellosis
- Chronic granulomatous disease
- Coccidioidomycosis
- Failure to thrive
- Fever without a focus
- Histoplasmosis
- Meningitis, aseptic
- Meningitis, bacterial
- Nocardiosis
- Pleural effusion
- pneumonia
30. Complications:
The prognosis of tuberculosis in infants, children,
and adolescents is excellent with early recognition
and effective chemotherapy.
In most children with pulmonary tuberculosis, the
disease completely resolves, and ultimately
radiographic findings are normal. The prognosis
for children with bone and joint tuberculosis and
tuberculous meningitis depends directly on the
stage of disease at the time antituberculosis
medications are started.
Tuberculosis of the spine may result in angulation or
gibbus formation that requires surgical correction
after the infection is cured. Most childhood
tuberculous meningitis occurs in developing
countries, where the prognosis is poor.
31. Management(1):
Given the risk of drug-induced hepatotoxicity, WHO recommends the following dosages
of antituberculosis medicines for the treatment of tuberculosis in children:
isoniazid (H) – 10 mg/kg (range 10–15 mg/kg); maximum dose 300 mg/day
rifampicin (R) – 15 mg/kg (range 10–20 mg/kg); maximum dose 600 mg/day
pyrazinamide (Z) – 35 mg/kg (30–40 mg/kg)
ethambutol (E) – 20 mg/kg (15–25 mg/kg)
Recommendations for treatment of pulmonary TB:
1. 06 months course of Isoniazid(INH) and rifampin, supplemented during the first 02
months with Pyrazinamide and ethambutol (unless not indicated by culture) or
2. 02 month regimen of INH, rifampin, and pyrazinamide daily, followed by 04 months of
INH and rifampin twice a week (In country with low incidence of HIV)
32. Management(2):
Infants (aged 0–3 months) with suspected or confirmed pulmonary tuberculosis or
tuberculous peripheral lymphadenitis should be promptly treated with the standard
treatment regimens, as described above. Treatment may require dose adjustment to reconcile the
affect of age and possible toxicity in young infants.
The decision to adjust doses should be taken by a clinician experienced in managing
paediatric tuberculosis.
Recommendations for treatment of Extrapulmonary TB: same as Pulmonary
except for Osteoarticular TB &TB meningitis:
1. 12 months course of Isoniazid (INH) and rifampin, supplemented during the first 02
months with Pyrazinamide and ethambutol
34. Prevention:
Prevention of transmission in health care settings involves appropriate physical ventilation of
the air around the source case. Offices, clinics, and hospital rooms used by adults with possible
tuberculosis should have adequate ventilation, with air exhausted to the outside (negative-
pressure ventilation).
Health care providers should have annual TSTs.
The only available vaccine against tuberculosis is the bacilli Calmette-Guérin vaccine.
The original vaccine organism was a strain of Mycobacterium bovis attenuated by
subculture every 3 weeks for 13 years.
The preferred route of administration is intradermal injection with a syringe and needle because
this is the only method that permits accurate measurement of an individual dose.
The official recommendation of the World Health Organization is a single dose
administered during infancy.
Many infants who receive bacilli Calmette-Guérin vaccine never have a positive TST
reaction. When a reaction does occur, the induration size is usually less than 10 mm, and
the reaction wanes after several years.
36. Take home
message:
Tuberculosis is an important but underappreciated cause of morbidity and
mortality in young children, especially in high endemicity settings.
•Children are often ignored by programmes because they are thought not to
contribute to disease transmission due to the pauci-bacillary nature of their disease.
•Difficulties in establishing an accurate diagnosis lead to poor case ascertainment
and thus underestimate the true burden of disease.
•Clinicians need to understand the pathophysiology and natural course of disease,
and develop a high index of suspicion
•Early diagnosis and early initiation of therapy avoids debilitating complications
and death from tuberculosis, which is a largely curable and preventable disease.
