Tuberculosis
Etiology
1- Mycobacterium tuberculosis for which humans are the main reservoir.
2- non-TB mycobacterium as M. bovis, M. africanum, and M. microti.
Patients with active pulmonary TB :
1- Smear +ve
2- pulmonary cavitary lesions are especially infectious because of the
high number of bacteria contained within a lesion.
3- Laryngeal & endo-bronchial TB
TB spread by respiratory droplets inhalation (particles < 5 μ in diameter)
containing tubercle bacilli may remain suspended in room air for several
hours. However, once these droplets land on a surface, it is difficult to
resuspend again by sweeping the floor, shaking out bed linens. Contact
with fomites (eg, contaminated surfaces, food, and personal respirators)
do not appear to facilitate spread.
Contagiousness factors:
I-
Organism related : Certain strains of M. tuberculosis are more
contagious
II-
patients related as with positive sputum smears are more
contagious than those with positive results only on culture, as
Patients with cavitary disease.
III-
Environment related :Transmission is enhanced by frequent or
prolonged exposure to untreated patients who are dispersing
large numbers of tubercle bacilli in overcrowded, poorly
ventilated enclosed spaces; consequently, people living in
poverty or in institutions are at particular risk. Health care
practitioners who have close contact with active cases have
increased risk.
However, most of those who are infected do not develop active disease.
Contagiousness decreases rapidly with treatment for within 2 weeks.
Much less commonly, contagion results from aerosolization of organisms
after irrigation of infected wounds, in mycobacteriology laboratories, or
in autopsy rooms or by ingestion of milk or milk products (eg, cheese)
contaminated with M. bovis, but this transmission route has been largely
eradicated in developed countries.
Pathophysiology
The balance between the host’s resistance and microbial virulence
determines whether the infection ultimately resolves without treatment,
remains dormant, or becomes active. The disease has 2 stages :
1- Inactive dis. : include Primary dis. & Latent phase
2- Active disease
Inactive dis. :
When the bacilli enter the body with no previous infection to contact the
LN, lung, skin or GIT then the cell wall will initiate active immune
reaction leading to controlling of the bacilli by granuloma & outer fibrous
tissue with the bacilli inside either dead or inactive. The disease is
asymptomatic in the majority but can cause flue like illness, fever & LAP
with erythema nodosa in the shin, on the chest there may be normal
exam., LAP or pleural effusion which is self-resolving, the tuberculin
skin test and interferon-gamma release blood assays (IGRA) became +ve
& the patient is not infective, In 95% of cases, after about 3 wk of
uninhibited growth, the immune system suppresses bacillary replication,
usually before symptoms or signs develop. Foci of bacilli in the lung or
other sites resolve into epithelioid cell granulomas, which may have
caseous and necrotic centers. Tubercle bacilli can survive in this material
for years; Infectious foci may leave fibronodular scars in the apices of
one or both lungs (Simon foci) or small areas of consolidation (Ghon
foci). A Ghon focus with lymph node involvement is a Ghon complex,
which, if calcified, is called a Ranke complex.
Less often, the primary focus progresses immediately, causing acute
illness with pneumonia (sometimes cavitary), pleural effusion, and
marked mediastinal or hilar lymph node enlargement (which, in children,
may compress bronchi) & can spread by blood to extra-pulmonary sites
as LN ,pleura or any organ & this sequence is more common among
young children however, meningitis is the most feared because of its high
mortality in the very young and very old.
Active disease
Person with inactive dis. Have a 5 to 10% lifetime risk of developing
active disease mostly in the next 2 years , but it can also occur decades
later. Any organ initially seeded may become a site of reactivation, but
reactivation occurs most often in the lung apices, presumably because of
favorable local conditions such as high O
2
tension causing what is called
post-primary pulmonary TB.
Conditions that impair cellular immunity (which is essential for defense
against TB) significantly facilitate reactivation as HIV infection, diabetes,
head and neck cancer, gastrectomy, jejunoileal bypass surgery, dialysis-
dependent chronic kidney disease, and significant weight loss, drugs that
suppress the immune system also facilitate development of active TB as
corticosteroids and TNF inhibitors , Tobacco use also is a risk factor.
In some patients, active disease develops when they are reinfected rather
than when latent disease reactivates.
TB damages tissues through delayed-type hypersensitivity, typically
producing granulomatous necrosis with a caseous histologic appearance.
Lung lesions are characteristically but not invariably cavitary, Pleural
effusion is less common than in progressive primary TB but may result
from direct extension or hematogenous spread. Rupture of a large
tuberculous lesion into the pleural space may cause empyema with or
without bronchopleural fistula and sometimes causes pneumothorax.
Symptoms and Signs
In active pulmonary TB, even moderate or severe disease, patients may
have no symptoms, except “not feeling well,”
Systemic feature: anorexia, fatigue, weight loss & Low-grade fever is
common but not invariable. Drenching night sweats are a classic
symptom., which develop gradually over several weeks
Chest symptoms: Cough is most common. At first, it may be minimally
productive of yellow or green sputum but cough may become more
productive as the disease progresses. Hemoptysis due to cavitary TB or
sometimes due to fungal growth in a cavity. Dyspnea may result from
lung parenchymal damage, spontaneous pneumothorax, or pleural TB
with effusion.
With HIV coinfection, the clinical presentation is often atypical & more
likely to have symptoms of extrapulmonary or disseminated disease.
Extrapulmonary TB causes various systemic and localized manifestations
depending on the affected organs
Diagnosis
Pulmonary TB work up is indicated for:
1- Abnormal CXR taken while evaluating respiratory symptoms
(cough > 3 wk, hemoptysis, chest pain, dyspnea)
2- an unexplained illness as FUO
3- positive tuberculin skin test or IGRA done as a screening test or
during contact investigation.
4- patients with possible TB exposure (eg, via infected family
members, friends, or other contacts; institutional exposure; travel
to TB-endemic areas).
Initial tests are chest x-ray and organisms isolation from sputum or
lavage.
Once TB is diagnosed, patients should be tested for HIV infection, and
those with risk factors for hepatitis B or C should be tested for those
viruses. Baseline tests of hepatic and renal function should typically be
done.
CXR
In adults, a multinodular infiltrate as consolidation or cavity above or
behind the clavicle is most characteristic of active TB; it suggests
reactivation of disease. It is best visualized in an apical-lordotic view or
with chest CT. Middle and lower lung infiltrates are nonspecific but
should prompt suspicion of primary TB in patients (usually young) whose
symptoms or exposure history suggests recent infection, particularly if
there is pleural effusion. Calcified hilar nodes may be present; they may
result from primary TB infection.
Organisms isolation:
Sputum testing is the mainstay for diagnosis of pulmonary TB. If patients
cannot produce sputum spontaneously, aerosolized hypertonic saline can
be used to induce it. If induction is unsuccessful, bronchial washings,
which are particularly sensitive, can be obtained by fiberoptic
bronchoscopy. Because induction of sputum and bronchoscopy entail
some risk of infection for medical staff, these procedures should be done
as a last resort in selected cases.
The first step is typically microscopic examination to check for acid-fast
bacilli (AFB) by Ziehl-Neelsen stains for conventional light microscopy
or fluorochrome stains for fluorescent microscopy. Smear microscopy
can detect about 10,000 bacilli/mL of sputum, making it insensitive when
fewer bacilli are present, as occurs in early reactivation or in patients with
HIV coinfection.
Culture is also required to isolate bacteria for drug-susceptibility testing
and genotyping beside diagnosis. Culture can detect as few as 10
bacilli/mL of sputum and can be done using solid or liquid media.
However, it can take up to 3 months for final confirmation of culture
results. Solid is called Löwenstein–Jensen medium.
Liquid media are more sensitive and faster that solid media, with results
available in 2 to 3 wk but cannot do drugs sensitivity.
Nucleic acid amplification test for TB can shorten the time to diagnosis
from 1 to 2 wk to 1 to 2 days ,some NAATs are more sensitive than
sputum smear and about as sensitive as culture for diagnosing TB.
Drug susceptibility tests (DSTs) should be done for:
1- patients with culture-positive sputum after 3 mo of treatment
2- if cultures become positive after a period of negative cultures.
Tests of other specimens
Transbronchial biopsies can be done on infiltrative lesions, and samples
are submitted for culture, histologic evaluation, and molecular (NNAT)
testing with a very good results reaching 90% but the sample should be
stored in normal saline not formalin .
Skin testing
The Tuberculin skin test (TST or Mantoux or PPD—purified protein
derivative) is usually done, although it is +ve in primary infection, latent
or active, and is not diagnostic of active disease. The standard dose in the
US of 5 tuberculin units (TU) of PPD in 0.1 mL of solution is injected on
the volar forearm. It is critical to give the injection intradermally, not
subcutaneously. A well-demarcated bleb or wheal should result
immediately. The diameter of induration (not erythema) transverse to the
long axis of the arm is measured 48 to 72 h after injection. Recommended
cutoff points for a positive reaction depend on the clinical setting:
•
>5 mm: Patients at high risk of developing active TB if infected,
such as those who have chest x-ray evidence of past TB, who are
immunosuppressed because of HIV infection or drugs (eg, TNF-
α inhibitors, corticosteroid use equivalent to prednisone 15 mg/day
for > 1 mo), or who are close contacts of patients with infectious
TB
•
>10 mm: Patients with some risk factors, such as injection drug
users, recent immigrants from high-prevalence areas, residents of
high-risk settings (eg, prisons, homeless shelters), patients with
certain disorders (eg, silicosis, renal insufficiency, diabetes, head
or neck cancer), and those who have had gastrectomy or jejunoileal
bypass surgery
•
>15 mm: Patients with no risk factors (who typically should not be
tested)
Results can be falsely negative, most often in patients who are febrile,
elderly, HIV-infected (especially if CD4 count is < 200 cells/μL), or very
ill, many of whom show no reaction to any skin test (anergy). False-
positive results may occur if patients have nontuberculous mycobacterial
infections or have received the BCG vaccine. However, the effect of
BCG vaccination on TST wanes after several years; after this time, a
positive test is likely to be due to TB infection.
IGRAs
The IGRA is a blood test based on the release of interferon-γ by
lymphocytes exposed in vitro to TB-specific antigens. Although results of
IGRAs are not always concordant with TST, these tests appear to be as
sensitive as and more specific than TST in contact investigations.
Importantly, they are often negative in patients with remote TB infection.
Long-term studies are being done to see whether TST-positive, IGRA-
negative patients (particularly those with immunosuppression) are at low
risk of reactivation.
A positive TST or IGRA test result suggests LTBI or active TB so need
work up to exclude active TB including CXR & sputum examination by
microscopy and culture.
Prognosis
In immunocompetent patients with drug-susceptible pulmonary TB, even
severe disease with large cavities, appropriate therapy is usually curative
if it is instituted and completed. Still, TB causes or contributes to death in
about 10% of cases, often in patients who are debilitated for other
reasons. Disseminated TB and TB meningitis may be fatal in up to 25%
of cases despite optimal treatment.
TB is much more aggressive in immunocompromised patients and, if not
appropriately and aggressively treated, may be fatal in as little as 2 mo
from a patient's initial presentation, especially with MDR-TB.
Treatment
Hospitalization
The main indications for hospitalization are
•
Serious concomitant illness
•
Need for diagnostic procedures
•
Social issues (eg, homelessness)
•
Need for respiratory isolation, as for people living in congregate
settings as elderly home especially if effective treatment cannot be
ensured
Initially, all hospitalized patients should be in respiratory isolation,
release from respiratory isolation usually requires 3 negative sputum
smears over 2 days, including at least one early-morning negative
specimen.
Most patients with TB can be treated as outpatients, with instructions on
how to prevent transmission .
Pattern of treatment
- directly observed therapy (DOT). it increases the likelihood that
the full treatment course will be completed it is particularly
important in:
•
For children and adolescents
•
For patients with HIV infection, psychiatric illness, or substance
abuse
•
After treatment failure & relapse
•
development of drug resistance or infection with MDR or XDR TB
- self-administered treatment (SAT) is an option for patients who
are committed to treatment; ideally, fixed-dose combination drug
preparations are used to avoid the possibility of monotherapy,
which can lead to drug resistance. Mechanical drug monitoring
devices have been advocated to improve adherence with SAT.
Drug resistance
Multi-drug resistance (MDR-TB) is resistant to INH and RIF, with or
without resistance to other drugs.
XDR-TB extends the resistance profile of MDR-TB to include
fluoroquinolones and at least one injectable drug (eg, streptomycin,
amikacin, kanamycin, capreomycin). drug resistance has major negative
implications for TB control; alternative treatments require a longer
treatment course with less effective, more toxic, and more expensive 2nd-
line drugs with mortality is higher .
Resistant strains can be transmitted from person to person.
Treatment regimens
Treatment of all patients with new, previously untreated TB should
consist of a
- 2 months initial intensive phase
- 4 months continuation phase
Initial intensive–phase therapy is with 4 antibiotics: INH, RIF, PZA, and
EMB These drugs can be given daily throughout this phase in order to
kill as much as we could of the bacteria with no drug resistance
development.
after 2 months of intensive 4-drug treatment, PZA and usually EMB are
stopped & INH and RIF are continued for 4 more mo (6 mo total).
Causes of non-responding
1- MDR-TB
2- Nonadherence
3- extensive cavitary disease
4- malabsorption of drugs .
Management of drug-resistant TB
Generally, MDR-TB requires treatment for 18 to 24 months using a
regimen that contains 4 or 5 active drugs. DOT is essential to avoid
development of additional drug resistance through non-adherence.
Other treatments
1- Surgical resection of a persistent TB cavity or a region of
necrotic lung tissue is occasionally necessary. The main
indication for resection is persistent, culture-positive MDR-
TB or XDR-TB in patients with a region of necrotic lung
tissue into which antibiotics cannot penetrate. Other
indications include uncontrollable hemoptysis and bronchial
stenosis .
2- Corticosteroids are sometimes used to treat TB when
inflammation is a major cause of morbidity for a duration 2-
3weeks and are indicated for:
A- patients with acute respiratory distress syndrome
B- closed-space infections, such as meningitis and pericarditis.
C- Critical patients to bridge time till the anti-TB action started
D- Urogenital , joints or GIT TB to prevent stricture &
adhesion .