Pathphysiology of TB

Macrophages are the primary cells infected by M. tuberculosis.

Once inside the macrophage, M. tuberculosis organisms replicate within the phagosome by blocking fusion of the
phagosome & lysosome. It blocks phagolysosome formation by :
1- inhbiting Ca2+ signals and the recruitment
2- assembly of the proteins that mediate phagosome-lysosome fusion.

Thus, during the earliest stage of primary tuberculosis (<3 weeks) in the nonsensitized individual, bacteria proliferate in the
pulmonary alveolar macrophages & airspaces, resulting in bacteremia & seeding of multiple sites.

Despite the bacteremia, most people at this stage are asymptomatic or have a mild flulike illness.

About 3 weeks after infection,

The development of cell-mediated immunity occurs approximately 3 weeks after exposure.

Processed mycobacterial antigens reach the draining lymph nodes and are presented in a major MHC II context by dendritic cell macrophages
to CD4+ T cells.

Under the influence of macrophage-secreted IL-12, CD4+ T cells of the TH1 subset are generated, capable of secreting IFN-γ.IFN-γ
released by the CD4+ T cells of the TH1 subset is crucial in activating macrophages.
IFN-γ stimulates formation of the phagolysosome in infected macrophages, exposing the bacteria to an acidic environment.
IFN-γ also stimulates expression of nitric oxide synthase, which produces nitric oxide, capable of destroying several mycobacterial constituents .

Activated macrophages, in turn, release a variety of mediators with important effects, including :

(a) secretion of TNF, which is responsible for recruitment of monocytes, which in turn undergo activation and differentiation into the
"epithelioid histiocytes" that characterize the granulomatous response;

(b) expression of the inducible nitric oxide synthase (iNOS) gene, which results in elevated nitric oxide levels at the site of infection.
Nitric oxide is a powerful oxidizing agent and results in generation of reactive nitrogen intermediates and other free radicals
capable of oxidative destruction of several mycobacterial constituents, from cell wall to DNA;

(c) generation of reactive oxygen species that can have antibacterial activity.

Defects in any of the steps of a TH1 response (including IL-12, IFN-γ, TNF, or nitric oxide production) result in poorly formed granulomas,
absence of resistance, and disease progression.

Clinical Course:
Localized secondary tuberculosis may be asymptomatic.

When manifestations appear, they are usually insidious in onset; there is gradual development of both systemic and localizing symptoms.

Systemic symptoms, probably related to cytokines released by activated macrophages (e.g., TNF and IL-1), often appear early in the
course and include:
- malaise,
- anorexia,
- weight loss,
- fever. Commonly, the fever is low grade and remittent (appearing late each afternoon and then subsiding), and night sweats occur.

With progressive pulmonary involvement, increasing amounts of sputum, at first mucoid and later purulent, appear.
When cavitation is present, the sputum contains tubercle bacilli. Some degree of hemoptysis is present in about half of all cases of pulmonary
tuberculosis due to erosion of a vessel in the wall of the cavity.

Pleuritic pain may result from extension of the infection to the pleural surfaces pleurisy.

Extrapulmonary manifestations of tuberculosis are legion and depend on the organ system involved (for example, tuberculous salpingitis may
present as infertility, tuberculous meningitis with headache and neurologic deficits, Pott disease with paraplegia).
Tuberculosis
Tuberculosis (TB) is caused by infection with Mycobacterium tuberculosis (MTB), which is part of a complex of organisms including: M. bovis (reservoir cattle) & M. africanum (reservoir human).

Pathology and pathogenesis

M. bovis infection arises from drinking non-sterilised milk from infected cows. Factors increasing the risk of TB
- M. tuberculosis is spread by the inhalation of aerosolised droplet nuclei from other infected patients the organisms lodge in the alveoli & The estimated lifetime risk of developing disease after primary infection is 10%, with
initiate the recruitment of macrophages and lymphocytes. roughly half of this risk occurring in the first 2 years after infection.

- Macrophages undergo transformation into epithelioid & Langhans cells which aggregate with lymphocytes to form classical
1) Patient-related
tuberculous granuloma: "The normal lung tissue is lost and replaced by a mass of fibrous tissue with granulomatous inflammation characterised by the 1- Age (children > young adults < elderly).
presence of large numbers of macrophages and multinucleate giant cells. The central area of this focus of granulomatous inflammation shows caseous 2- First-generation immigrants from high-prevalence countries
degeneration . 3- Close contacts of patients with smear-positive pulmonary TB
- Numerous granulomas aggregate to form a primary lesion or 'Ghon focus' ( a pale yellow, caseous nodule, usually a few mm to 1-2 cm in 4- Overcrowding (prisons, collective dormitories); homelessness (doss
houses and hostels)
diameter), characteristically situated in the periphery of the lung.
5- Chest radiographic evidence of self-healed TB
- Spread of organisms to the hilar lymph nodes is followed by a similar pathological reaction; the combination of a primary lesion & 6- Primary infection < 1 year previously
regional lymph nodes is referred to as the 'primary complex of Ranke'. 7- Smoking: cigarettes and bidis (Indian cigarettes made of tobacco
wrapped in temburini leaves).
• Reparative processes : 2) Associated diseases
- Encase the primary complex in a fibrous capsule limiting the spread of bacilli: so-called latent TB. If no further complications, this lesion
1- Immunosuppression: HIV, anti-TNF therapy, high-dose corticosteroids,
eventually calcifies & is clearly seen on a chest X-ray.
cytotoxic agents.
- Lymphatic or haematogenous spread may occur before immunity is established, seeding secondary foci in other organs including lymph nodes, 2- Malignancy (especially lymphoma and leukaemia)
serous membranes, meninges, bones, liver, kidneys and lungs, which may lie dormant for years. 3- Type 1 diabetes mellitus
- The only clue that infection has occurred may be the appearance of a cell-mediated, delayed-type hypersensitivity reaction to 4- Chronic renal failure
tuberculin, demonstrated by tuberculin skin testing. 5- Silicosis
• If these reparative processes fail: primary progressive disease ensues ( Figure ) 6- Gastrointestinal disease associated with malnutrition (gastrectomy,
(1) Spread from the primary focus to hilar & mediastinal lymph glands to form the 'primary complex', which in most cases heals spontaneously. jejuno-ileal bypass, cancer of the pancreas, malabsorption)
(2) Direct extension of the primary focus progressive pulmonary TB. 7- Deficiency of vitamin D or A
(3) Spread to the pleura tuberculous pleurisy & pleural effusion. 8- Recent measles: increases risk of child contracting TB
(4) Blood-borne spread: few bacilli pulmonary, skeletal, renal, genitourinary infection often months or years later;
massive spread miliary TB & meningitis
Clinical Features of Pulmonary Disease
Primary pulmonary TB Post-primary pulmonary TB
- Primary TB refers to the infection of a previously uninfected (tuberculin-negative) individual. Post-primary disease refers to :
- few patients develop a self-limiting febrile illness 1- exogenous ('new' infection) or
- but clinical disease only occurs if there is a hypersensitivity reaction or progressive 2- endogenous (reactivation of a dormant primary lesion) infection in a person who has been
infection
sensitised by earlier exposure.
Features of primary TB - It is most frequently pulmonary and characteristically occurs in the apex of an upper lobe where the
Disease Infection (4-8 weeks) oxygen tension favours survival of the strictly aerobic organism.
- Lymphadenopathy: hilar (often unilateral), paratracheal or
- Influenza-like illness
mediastinal - The onset is usually insidious, developing slowly over several weeks.
- Collapse (especially right middle lobe)
- Skin test conversion
- Consolidation (especially right middle lobe) - Primary complex Systemic symptoms include: Clinical presentations of pulmonary TB
- Obstructive emphysema - fever,
- Cavitation (rare) Hypersensitivity - night sweats, - Chronic cough, often with haemoptysis.
- Pleural effusion - malaise, - Pyrexia of unknown origin
- Erythema nodosum - Unresolved pneumonia
- Endobronchial - loss of appetite & weight,
- Miliary
- Phlyctenular conjunctivitis - Exudative pleural effusion
- Dactylitis - accompanied by progressive pulmonary
- Meningitis
symptoms (Box ). - Asymptomatic (diagnosis on chest X-ray)
- Pericarditis - Weight loss, general debility
- Spontaneous pneumothorax
Progressive primary disease may appear during the course of the initial illness or after a latent period of weeks or months. This form of TB may present with one of these complications :
Miliary TB Pulmonary Non-pulmonary
Blood-borne dissemination gives rise to miliary TB: Cryptic TB Massive haemoptysis.
-
- Empyema necessitans
- May present acutely BUT Cor pulmonale
-
- Laryngitis
- More frequently is characterised by 2-3 weeks of fever, Fibrosis/emphysema
-
- Age over 60 years - Enteritis
night sweats, anorexia, weight loss and a dry cough. Atypical mycobacterial infection
-
- Intermittent low-grade pyrexia of Aspergilloma
-
( from swallowed sputum )
- Hepatosplenomegaly may develop - Anorectal disease*
unknown origin Lung/pleural calcification
-
- presence of a headache may indicate coexistent - Unexplained weight loss, general - Amyloidosis
Obstructive airways disease
-
tuberculous meningitis. - Poncet's polyarthritis
debility (hepatosplenomegaly in 25-50%) Bronchiectasis
-
- Anaemia & leucopenia reflect bone marrow involvement. - Normal chest X-ray Bronchopleural fistula
-
- 'Cryptic' miliary TB is an unusual presentation sometimes - Blood dyscrasias; leukaemoid Radiological changes include:
seen in old age reaction, pancytopenia - ill-defined opacification in one or both of upper lobes
- Negative tuberculin skin test - as progression occurs:
- Auscultation of the chest is frequently normal, with consolidation, collapse & cavitation develop to varying degrees ( Figure )
advanced disease widespread crackles are evident. - Confirmation by biopsy
(granulomas and/or acid-fast - It is often difficult to distinguish active from quiescent disease on radiological criteria
- Fundoscopy may show choroidal tubercles. alone, but the presence of a miliary pattern or cavitation favours active disease.
bacilli demonstrated) of liver or
- Chest X-ray,The classical appearances are of fine 1-2 mm - In extensive disease, collapse may be marked and result in significant displacement
bone marrow of the trachea and mediastinum.
lesions ('millet seed') distributed throughout the lung
fields, although the appearances are coarser. - a caseous lymph node may drain into an adjoining bronchus resulting in
tuberculous pneumonia.
Clinical Features of Extra-Pulmonary Disease
Lymphadenitis Gastrointestinal disease
- Frequently Cervical & mediastinal glands are affected - TB can affect any part of the bowel
- Followed axillary & inguinal; more than one region may involved. - Patients may present with a symptoms & signs ( ).
- may represent 1ry infection,spread from contiguous sites or reactivation - Upper gastrointestinal tract involvement is rare
- Ileocaecal disease accounts for about half of abdominal TB cases.
- The nodes are usually painless and initially mobile but become matted
together with time. Fever, night sweats, anorexia & weight loss are usually prominent
right iliac fossa mass may be palpable & acute abdomen (30% cases)
- When caseation and liquefaction occur :
1- the swelling becomes fluctuant Tuberculous peritonitis is characterised by:
2- may discharge through the skin with the formation of : 1- abdominal distension,
a- a 'collar-stud' abscess 2- pain
b- sinus formation. 3- constitutional symptoms.
4- The ascitic fluid is exudative & cellular with a predominance
- During or after treatment : of lymphocytes.
paradoxical enlargement, development of new nodes & suppuration 5- Laparoscopy reveals multiple white 'tubercles' over the
may all occur but without evidence of continued infection . peritoneal & omental surfaces.
N.B Supraclavicular lymphadenopathy is often the result of spread from mediastinal disease.
Low-grade hepatic dysfunction is common in miliary disease patients
Genitourinary disease may be frankly icteric with a mixed hepatic/cholestatic picture.
- Usually Haematuria, frequency and dysuria. - Ultrasound or CT may reveal :
- Rarely Fever & night sweats . 1-thickened bowel wall, 2- abdominal lymphadenopathy,
- In women : infertility from endometritis, pelvic pain swelling from 3-mesenteric thickening or ascites.
salpingitis, tubo-ovarian abscess occur. - Barium enema & small bowel enema reveal narrowing, shortening &
distortion of the bowel with caecal involvement .
- In men, epididymitis or prostatitis. Diagnosis rests on obtaining histology by either colonoscopy or mini laparotomy.
- sterile pyuria found on urine microscopy and culture. (The main differential diagnosis is Crohn's disease).
Pericardial disease Bone and joint disease Central nervous system disease
- Two forms: 1- pericardial effusion & 2- constrictive pericarditis Pott's disease (spine is the most common site for bony TB) :
- Usually insidious with breathlessness & abdominal swelling.
Meningeal disease:
- The infection starts as a discitis then spreads along the spinal ligaments to involve the adjacent
represents the most important form of
- Rarley - Fever & night sweats . anterior vertebral bodies, causing: 1) angulation of the vertebrae
- Coexistent pulmonary disease, except pleural effusion. 2) with subsequent kyphosis.
central nervous system TB (see Fig. ).
Hepatomegaly, Raised JVP, prominent Ascites, Pulsus paradoxus & Peripheral - Paravertebral & psoas abscess formation & large (cold) abscess in the inguinal region.
- Unrecognised & untreated, it is rapidly fatal.
Oedema are common to both types. - CT and/or MRI are valuable in 1) gauging the extent of disease, 2) the amount of cord compression,
- Pericardial effusion : frequently blood-stained 3) the site for needle biopsy or open exploration if required. - Even when appropriate treatment is
- pericardial calcification occurs in around 25% of cases. - The major differential diagnosis is malignancy, ( affect the vertebral body and leave the disc intact) prescribed - mortality rates of 30%
- Iis associated with: 1- increased pericardial dullness - Important complications : spinal instability or cord compression. - survivors may be left with
2- globular enlarged heart on chest X-ray.
- Constriction is associated with Early third heart sound, Atrial fibrillation, neurological sequelae. .
Joints :
Raised JVP . - TB can affect any joint, but most frequently the hip or knee.
Diagnosis is on clinical, radiological & echocardiographic grounds. - Presentation is usually insidious with pain & swelling; ( fever and night sweats are uncommon )
Open pericardial biopsy can be performed - Radiological changes are often non-specific, but as disease progresses, reduction in joint space& erosions.
- The addition of corticosteroids to antituberculosis treatment - Poncet's arthropathy refers to an immunologically mediated polyarthritis.
Diagnosis & treatment of Tuberculosis (TB)
Treatment Diagnosis
The presence of: 1- unexplained cough for more than 2–3
2 3 weeks, in regions where TB is prevalent or
Treatment of new TB patients (World Health Organization recommendations) 2- typical chest X-ray
ray changes, should prompt further investigation
Intensive phase Continuation phase Comments
Standard regimen Specimens required
2 mths of HRZE 4 mths of HR Pulmonary
Applies only in countries: 1- Sputum preferable 3 samples,, including an early morning sample
1- With High levels of isoniazid resistance in new TB patients, (induced with nebulised hypertonic saline if not expectorating)
2 mths of HRZE 4 mths of HRE 2- Where isoniazid drug susceptibility testing in new patients is not 2- Bronchoscopy with : washings or bronchoalveolar lavage.
lavage
done (or results are unavailable) before continuation phase begins.
3- Gastric washing (mainly used for children).
children)
Dosing frequency
Extrapulmonary
Daily* Daily Optimal
Acceptable alternative for any new patient receiving directly observed 1- Fluid examination (cerebrospinal, ascitic, pleural, pericardial, joint): yield classically very low.
low
Daily* 3 mes/wk 2- Tissue biopsy (from affected site): bone marrow/liver may be diagnostic in disseminated disease.disease
therapy (DOT).
Acceptable alternative, provided that the patient is receiving directly • The diagnosis of extrapulmonary TB is more challenging as there here are generally fewer organisms
3 mes/wk 3 mes/wk observed therapy (DOT) and is NOT living with HIV or living in an HIV-
HIV (particularly in meningeal or pleural fluid), so culture or histopathology of tissue is more important.
prevalent setting. Diagnostic tests
*Daily (rather than 3 $mes weekly) intensive-phase
phase dosing may help to prevent acquired drug resistance in TB patients starting treatment with isoniazid resistance.

1- Tuberculin skin test: low sensitivity/specificity; useful only in primary or deep-seated

deep infection
2- Stain :
• Direct microscopy of sputum is the most important first step.
• The probability of detecting acid-fast
fast bacilli is proportional to the bacillary burden in the sputum
(typically posi ve when 5000–1010 000 organisms are present).
a- Ziehl–Neelsen.
H= isoniazid R= rifampicin Z= pyrazinamide E= ethambutol b- Auramine fluorescence:
- It's more sensitive (though less specific) than Ziehl–Neelsen;
Ziehl (as result it's more widely used).
First line drugs - By fluorescence microscopy bacilli appear as yellow-orange
orange on a green background.
Drugs Dose Mechanism of action Side effects 3- Culture :
The activated drug 1- polyneuropathy
Pyridoxine(vitamin
Pyridoxine B6) 10mg/d is given to prevent
a- Solid media (Lowenstein
wenstein–Jensen , Middlebrook):
200 – 300 mg/day covalently binds to
Isoniazid and inhibits (InhA) & polyneuropathy. - MTB grows slowly taking between 4 -6 weeks to appear on solid medium.
(INH) ( 5 mg/kg/day ) (KasA) enzymes, which 2- Hepatitis & Hepatotoxicity b- Liquid media (e.g. BACTEC or mycobacteria growth indicator tube "MGIT")
are essential for the 3- others: - MTB grows Faster growth between 1–3 weeks in liquid media.
synthesis of mycolic Convulsions - Optic neuritis - Radioactive BACTEC method is the most widely accepted detects mycobacterial growth
acid. Hypersensitivity - Drugs interactions by measuring the libera on of 14CO2, following metabolism of 14Clabelled substrate
- Nausea, vomiting, and rash. present in the medium.
450 – 600 mg/day Bactericidal - Hepatitis - The use of microscopic-observation
observation drug-sensitivity
drug (MODS) assay allows :
Rifampicin It inhibits DNA- - Hypersensitivity nephritis . • detection of bacteria & susceptibility rapidly
(10 mg/kg/day) dependent RNA - Flu-like symptoms : by comparing growth in multiple
multi wells with antimycobacteria within liquid media.
polymerase. fever, chills & myalgias 4- Nucleic acid amplification "PCR" ( such as: Xpert/ RIF test ) :
Hypersensitivity ( rash ) • PCR is only useful at the initial stage of diagnosis as it frequently remains positive despite treatment
20 – 30 mg/kg/day Bactericidal. Nausea, Vomiting & diarrhea. due to the detection of dead organisms.
Pyrazinamide Hepatitis • Uses :
Hyperuricemia & Gout is rare. 1- Rapid identification of MTB.
Bacteriostatic inhibits : Hypersensitivity ( rash ) 2- Useful
seful in differentiating between MTB & non-tuberculosis mycobacteria (NTM) M) .
10 – 25 mg/kg/day arabinosyl transferase Nausea, Vomiting & diarrhea. 3- Identifying TB in smear-negative
negative sputum specimens.
Ethambutol Optic neuritis 4- Detect the presence of rifampicin resistance.
resistance
Hyperuricemia . - Genetic mutations in bacterial DNA conferring rifampicin resistance are highly predictive
pred of
Nephrotoxic (MDR). test of first choice in those with MDR.
multi-drug resistance(MDR).
Streptomycin 1 gm I.M daily Bactericidal Ototoxic irreversible. - Molecular testing for drug resistance has also become possible using PCR.
Nephrotoxic.
Nephrotoxic
5- Pleural fluid: adenosine deaminase
Regimen : • Adenosine deaminase in pleural fluid (to
to a lesser extent in CSF),, may assist in confirming suspected TB.
A) in patients with fully sensitive organisms: 12 months of therapy is recommended for CNS TB (ethambutol may replaced by streptomycin). 6- Response to empirical antituberculous drugs (usually seen aDer 5–10
10 days)
• Standard treatment involves 6 months’ therapy for all patients with new-onset
onset pulmonary TB & Non-CNS extrapulmonary TB:
1- Initial intensive phase: designed to kill actively growing bacteria , Baseline blood tests
Isoniazid, Rifampin, Pyrazinamide , Ethambutol for 2 months AND then followed by : • FBC, CRP, ESR, U&E and LFTs
2- Continuation phase: to destroy any remaining bacteria :
Isoniazid & Rifampin for the next 4 months Detection of latent TB
The diagnosis of latent TB infection (LTBI) involves demonstration of immune memory
me to mycobacterial
B) If drug sensi$vity is unavailable at 2 months : proteins Two tests are available :
• Con
on nue the 4 drug regime un l it is available (even if this is for more than 2 months).
months)
N.B. Where drug resistance is not anticipated, patients can be assumed to be non
non-infec#ous
infec#ous a$er 2 weeks of appropriate therapy. Tuberculin skin test (TST)
Other treatments : A positive result is indicated by a delayed hypersensitivity reaction evident 48–72 hours after the intradermal
1- Drugs : injection of purified protein derivative (PPD) resulting in:
a- Corticosteroids : reduce inflammation & limit tissue damage,,, currently recommended in : • A raised indurated lesion >6 mm diameter in nonvaccinated adults
- Treating CNS meningeal disease / pericardial effusion / pleural effusion / TB of the ureter. • A raised indurated lesion >15 mm in BCG-vaccinated
BCG adults.
- Children
hildren with endobronchial disease. False negative (anergic) TSTs in :
- Suppress
uppress hypersensitivity drug reactions. 1- Immunosuppression
mmunosuppression due to HIV infec on (CD4+ <200/mm3)
b- Pyridoxine : is not required, unless subjects are at higher risk of pyrazinamide-related
pyrazinamide peripheral neuropathy in 2- Sarcoidosis
diabetes, renal failure, HIV, and alcoholics. 3- Drugs (chemotherapy, anti-TNFTNF therapy, steroids)
4- Cross-reactivity with non-tuberculous
tuberculous mycobacteria (NTM) and BCG vaccination
2- Surgery : ( Usually only after a full course of antituberculosis treatment )
• Surgery should be considered in cases complicated by : These limitations may be overcome by employing (IGRAs)
massive haemoptysis, loculated empyema, constrictive pericarditis, lymph node suppuration, cord compression. Interferon-gamma
gamma release assays (IGRAs) :
• BUT usually only after a full course of antituberculosis treatment. - IGRAs detect T-cell
cell secretion of interferon-gamma
interferon
Response : (IFN-γ) following exposure to M tuberculosis-specific
tuberculosis
• The effectiveness of therapy for pulmonary TB is assessed by further sputum smear at 2 months & at 5 months. antigens (ESAT-6, CFP-10,).
• Treatment failure is defined as : - Where a person has been infected (previously or
currently) with TB, activated T cells within their
- a posi ve sputum smear or culture at 5 months or
extracted whole-blood
blood secrete quantifiable levels of
- any patient with a multidrug resistant strain, regardless of whether they are smear-positive
smear or negative.
interferon gamma in response to re-exposure
exposure to TB-
TB
Site of treatment : specific antigens.
• Most patients can be treated at home. - Disadvantages : Doesn't differentiate between active
• Admission to a hospital unit (with
with appropriate isolation
isolation) should be considered in : and latent infection.
1- Uncertainty about the diagnosis 2- Intolerance of medication 3- Adverse
dverse social conditions or - Advantages: it is highly specific compared with the
4- Significant risk of MDR-TB
TB (culture
(culture-posi ve aDer 2 months on treatment, or contact with known MDR-TB).
MDR TST /and has a similar or better sensitivity.
Fig. 19.43 The principles of interferon-gamma
gamma release assays.
Monitoring : Baseline liver function test and Renal function test, are important for patients treated with standard therapy.
• Rifampicin may cause asymptomatic hyperbilirubinaemia ( BUT, with isoniazid & pyrazinamide, may also cause hepatitis ). - A sample of either purified T cells (T-SPOT.TB®
SPOT.TB® test) or whole
- Mild asymptomatic increases in transaminases are common blood (QuantiFERON®–TB TB Gold test) is incubated in the presence
- Hepatotoxicity
epatotoxicity only occurs in 22–5%. of antigens specific to Mycobacterium tuberculosis (MTB).
Treatment : - Stop treatment allowing : 1- any symptoms to subside & 2- 2 liver function tests (LFTs) to recover.
- The release of interferongamma (IFN-γ)) by the cells is measured
- Less hepatotoxic regimens : streptomycin, ethambutol , fluoroquinolone.
fluoroquinolone
by enzyme-lined
lined immunosorbent assay (ELISA).
Directly observed therapy (DOT): Chemoprophylaxis :
• DOT is defined as : treatment supervised by a healthcare professional or family member where the person is observed • Indications of Chemoprophylaxis :
swallowing their medication to improve adherence (dosing
dosing frequency may reduced to threetimes /week to make DOT more convenient) 1- Asymptomatic
symptomatic contact with a positive tuberculin skin test but a normal chest X-ray
X .
Poor adherence to is a major factor in prolonged illness, risk of relapse, and the emergence of drug resistance. 2- Children aged < 16 years iden fied during contact tracing as having a strongly posi ve tuberculin test.
test
• Criteria for implementation of directly observed therapy for TB : 3- Children aged < 2 years in close contact with smearpositive
s pulmonary disease.
1- Patients thought unlikely to comply 4- Babies of mothers with pulmonary TB.
- History of serious mental illness .
- History of non-adherence
adherence to TB therapy in past or during current treatment course . • Regimen :
2- Homelessness people - Course of rifampicin & isoniazid for 3 months or
3- Multi-drug resistant TB - Course of isoniazid for 6 months

Drug-resistant TB:
- Drug-resistant TB : is defined by : the presence of resistance to any first
first-line
line agent.
resistance.
- Multidrug-resistant TB (MDR-TB) : is defined by : resistance to at least rifampicin & isoniazid, with or without other drug resistance
- Extensively drug-resistant TB (XDR-TB): mpicin & isoniazid, in addition to any quinolone and at least one injectable secondline agent (as: amikacin).
TB): is defined as resistance to at least rifampicin amika

• it requires prolonged treatmentt with less effective, more toxic and more expensive
ensive therapies.
th
• The mortality rate from MDR-TB B is high and that from XDR-TB higher still.
 Anti-Tuberculosis
Tuberculosis
Chemotherapy for Tuberculosis
- The organism grows slowly; thus, the disease may have to be treated for 6 months to 2 years.
- Resistant organisms readily emerge, particularly in patients who have had prior therapy or who fail to adhere to the treatmen
treatmentt protocol.

Strategies for addressing drug resistance

Strains of M. tuberculosis that are resistant to a particular agent emerge during treatment with a single drug. Therefore, multidrug therapy is employe
employed
when treating tuberculosis to delay or prevent the emergence of resistant strains.
- The combination of drugs should prevent tthe emergence of resistant strains.
- The multidrug regimen is continued beyond the disappearance of clinical disease to eradicate any persistent organisms.
- The
he drug regimen can be individually tailored to the patient.
- Patient compliance is often low w
when
hen multidrug schedules last for 6 months or longer
The initial short-course
course chemotherapy for tuberculosis includes:
Isoniazid, R
Rifampin, Ethambutol, and Pyrazinamide
yrazinamide for 2 months AND then Isoniazid and Rifampin
ifampin for the next 4 months
More drugs may be added to the firstfirst-line
ones for patients who have previously had tuberculosis or those in whom multidrug-resistant
multidrug resistant tuberculosis is suspected. The added drugs normally include
include:

aminoglycoside
noglycoside or capreomycin - fluoroquinolone - perhaps a second-line
second line antituberculosis agent
(streptomycin,
streptomycin, kanamycin, amikacin) (cycloserine, aminosalicylic acid)
cycloserine, ethionamide, para-aminosalicylic
One successful strategy for achieving better ttreatment
reatment completion rates is directly observed therapy, also known as DOT, in which patients take their medication while being
supervised and observed.
DOT have been shown to: 1-- decrease drug resistance 2- relapse and mortality rates 3- improve cure rates.

First line drugs

There are four recommended first
first-line
line agents utilized for antituberculosis therapy because of their efficacy and acceptable degree of toxicity.

Mechanism of Action Side Effecs

1- Peripheral neuritis
- Isoniazid is a prodrug that is activated by : - manifesting as: paresthesias of the hands and feet,
mycobacterial catalase--peroxidase (KatG). - which is the most common adverse effect, appears to be due to a relative
..pyridoxine deficiency.
-Genetic
Genetic and biochemical evidence has implicated
Isoniazid at least two different target enzymes for isoniazid within the unique Type II Most of the toxic reactions are corrected by supplementation of 25 to 50 mg per
day of pyridoxine (vitamin B6).
(INH) fatty acid synthase system involved in the production of mycolic acids.
2- Hepatitis and idiosyncratic hepatotoxicity:
[Note:: Mycolic acid is found in mycobacterial cell walls.]
- Potentially fatal hepatitis is the most severe side effect.
is a synthetic analog - It is caused by a toxic metabolite of monoacetylhydrazine,
monoacetylhydrazine, formed during …
of pyridoxine. The targeted enzymes areare: …the metabolism of isoniazid.
1- E Enoyl acyl carrier protein reductase (InhA)
It is the most potent 2- -ketoacyl-ACP synthase (KasA). 3- Drug interactions:
drugs BUT is never Because isoniazid inhibits metabolism of phenytoin, isoniazid can potentiate the
given as a single adverse effects of that drug (e.g., nystagmus and ataxia).
agent in the ttt of The activated drug covalently binds to and inhibits these enzymes, which are
4- Other adverse effects:
active tuberculosis essential for the synthesis of mycolic acid.
Mental abnormalities - convulsions - optic neuritis - Hypersensitivity
………………………………………………………………………………… (rashes and fever)
- Nausea, vomiting, and rash.
Rifampin blocks transcription by interacting with the -subunit of - Hepatitis and death due to liver failure is rare :
bacterial but not human DNA-dependent
DNA RNA polymerase. the drug should be used carefully in patients who are alcoholic, elderly, or have
Rifampin chronic liver disease due to the increased incidence of severe hepatic dysfunction.
dysfunction
Rifamycins: Rifampin inhibits mRNA synthesis by suppressing the initiation step.
- Often, when rifampin is dosed intermittently:
intermittently:
a flu-like
like syndrome is associated with fever, chills, and myalgias
Any of these
rifamycins must
sometimes is associated with acute renal failure, hemolytic anemia, and shock.
always be used in It is the preferred drug for use in tuberculosis-infected
tuberculosis with the
conjunction with at Rifabutin human immunodeficiency virus (HIV) patients who are treated with: th: - Adverse
verse effects similar to those of rifampin but can also cause:
least one other protease inhibitors or nonnucleoside reverse
reverse transcriptase inhibitors
antituberculosis drug. a derivative of
rifampin because it is a less potent inducer of cytochrome P450 enzymes. Uveitis - skin hyperpigmentation
hy - neutropenia.
- Activity
tivity comparable to that of rifampin but has a longer half-life
than rifampin and rifabutin,
rifabutin which permits weekly dosing.
Rifapentine Similar to previous side effects
- for the intensive phase (initial 2 months) of the short-course
therapy for tuberculosis, rifapentine is given twice weekly.
- In the subsequent phase,
phase rifapentine is dosed once per week
for 4 months.
Pyrazinamide is bactericidal to actively dividing organisms, but the mechanism of its
- Hypersensitivity ( rash )
action is unknown.
- Nausea, Vomiting & diarrhea.
Pyrazinamide Pyrazinamide must be enzymatically hydrolyzed to pyrazinoic acid, which is the active - Hepatitis
form of the drug. - Hyperuricemia & Gout is rare.
It is used
sed in combination with : isoniazid, rifampin, and ethambutol.

Ethambutol is bacteriostatic inhibits

nhibits arabinosyl transferase .. an enzyme that is - optic neuritis, which results in diminished visual acuity and loss of ability
Ethambutol important for the synthesis of the mycobacterial arabinogalactan cell wall. to discriminate between red and green.
- urate excretion is decreased.
decrease
It is used in combination with pyrazinamide, isoniazid,
isoniazid and rifampin

Second line drugs

- The consider 2nd line because they are no more effective than the first
first-line
line agents and their toxicities are often more serious or because they are particularly active against atypical strains of m
mycobacteria.
- They are useful in : 1- patients who cannot tolerate the first
first-line drugs or 2- who are infected with myobacteria that are resistant to the first
first-line agents.

Streptomycin Capreomycin Cycloserine Ethionamide Fluoroquinolones Macrolides

This is the first antibiotic effective
in the treatment of tuberculosis
This is a peptide that inhibits
The antibiotic binds to the 30S
ribosomal.
Polysomes become depleted, because
the aminoglycosides interrupt the
process of polysome disaggregation
and assembly.
protein synthesis.
It appears to antagonize the steps
in bacterial cell wall synthesis
involving D-alanine.
D Ethionamide can inhibit
This is a structural analog of
isoniazid,, but it is not believed to
act by the same mechanism.
acetylation of isoniazid
moxifloxacin - levofloxacin
have an important place in the
treatment of multidrug-resistant
multidrug
tuberculosis.
Azithromycin
Clarithromycin
Azithromycin is preferred for HIV-
HIV
infected patients because it is
least likely to interfere with the
metabolism of antiretroviral drugs.

-CNS
CNS disturbances, - gastric
astric irritation - hepatotoxicity
- Ototoxicity - Nephrotoxicity nephrotoxicity and ototoxicity. - seizure
seizu - peripheral
eripheral neuropathies
- Paralysis - skin rash - Peripheral
Perip neuropathies - optic
ptic neur
neuritis.
Anti-Tuberculosis drugs
First line drugs
Drugs Dose Mechanism of action Side effects
1- polyneuropathy
200 – 300 The activated drug covalently binds to Pyridoxine(vitamin B6) 10mg/d is given to
Isoniazid mg/day and inhibits (InhA) & (KasA) enzymes, prevent polyneuropathy.
(INH) which are essential for the synthesis of 2- Hepatitis & Hepatotoxicity
( 5 mg/kg/day ) mycolic acid.. 3- others:
Convulsions - Optic neuritis
Hypersensitivity - Drugs interactions
450 – 600 - Nausea, vomiting, and rash.
Bactericidal - Hepatitis
Rifampicin mg/day It inhibits DNA-dependent RNA polymerase. - Hypersensitivity nephritis .
- Flu-like symptoms :
(10 mg/kg/day) fever, chills & myalgias
- Hypersensitivity ( rash )
20 – 30 Bactericidal. - Nausea, Vomiting & diarrhea.
Pyrazinamide
mg/kg/day - Hepatitis
- Hyperuricemia & Gout is rare.
10 – 25 - Hypersensitivity ( rash )
Bacteriostatic inhibits : - Nausea, Vomiting & diarrhea.
Ethambutol mg/kg/day arabinosyl transferase - Optic neuritis
- Hyperuricemia .
Streptomycin 1 gm I.M daily Bactericidal - Ototoxic irreversible.
- Nephrotoxic.
Second line drugs
- The consider 2nd line because they are no more effective than the first-line agents and their toxicities are often more serious or because they are
particularly active against atypical strains of mycobacteria.
- They are useful in :
1- patients who cannot tolerate the first-line drugs or
2- who are infected with myobacteria that are resistant to the first-line agents.

Para-amino Salicylic acid Cycloserine Ethionamide

8 – 12 gm/day 15 – 30 gm/kg/day .5 – 1 g /day

It appears to antagonize the steps in bacterial cell This is a structural analog of isoniazid, but it is not
Compete with PABA wall synthesis involving D-alanine. believed to act by the same mechanism.
Ethionamide can inhibit acetylation of isoniazid

- GIT upsets -CNS disturbances, - gastric irritation - hepatotoxicity

- Hepatotoxic - seizure - peripheral neuropathies
- Nephrotoxic - Peripheral neuropathies - optic neuritis.
- thyroid function.

Fluoroquinolones Aminoglycosides Capreomycin

Streptomycin & Amikacin & Kanamycin This is a peptide that inhibits protein synthesis.
moxifloxacin - levofloxacin
have an important place in the treatment of - Ototoxic
multidrug-resistant tuberculosis. - Nephrotoxic - Ototoxic
- N-M block - Nephrotoxic

- The combination of drugs should prevent the emergence of resistant strains.

- The multidrug regimen is continued beyond the disappearance of clinical disease to eradicate any persistent organisms.
- The drug regimen can be individually tailored to the patient.
- Patient compliance is often low when multidrug schedules last for 6 months or longer

The initial short-course chemotherapy for tuberculosis includes:

Isoniazid, Rifampin, Ethambutol, and Pyrazinamide for 2 months AND then
Isoniazid and Rifampin for the next 4 months
More drugs may be added to the first-line
ones for patients who have previously had tuberculosis or those in whom multidrug-resistant tuberculosis is suspected.
The added drugs normally include:
aminoglycoside or capreomycin - fluoroquinolone - perhaps a second-line antituberculosis agent
(cycloserine, ethionamide, para-aminosalicylic acid)
 Pathyophysiology of Pneumonia

Pulmonary defense mechanisms.

Abrupt changes in direction of air flow in the nasal
passages can trap potential pathogens.

The epiglottis and cough reflex prevent introduction

of particulate matter in the lower airway.
- The ciliated respiratory epithelium propels the
overlying mucus layer (right) upward toward
the mouth.
- In the alveoli, cell-mediated immunity, humoral
factors, and the inflammatory response defend
against lower respiratory tract infections. (C,
complement.).

Although pneumonia is a relatively common disease, it occurs infrequently in immunocompetent individuals due to effectiveness of host
defenses, including :
1- anatomic barriers and
2- cleansing mechanisms in the nasopharynx and upper airways
3- local humoral & cellular factors in the alveoli.

Pulmonary pathogens reach the lungs by one of four routes:

(1) direct inhalation of infectious respiratory droplets,
(2) aspiration of oropharyngeal contents,
(3) direct spread along the mucosal membrane surface from the upper to the lower respiratory system, and
(4) hematogenous spread.

The pulmonary antimicrobial defense mechanisms :

Incoming air with suspended particulate matter is subjected to turbulence in the nasal passages and then to abrupt changes in direction as
the airstream is diverted through the pharynx and along the branches of the tracheobronchial tree.
- Particles larger than 10 mm are trapped in the nose or pharynx;
- those with diameters of 2-9 mm are deposited on the mucociliary blanket;
- only smaller particles reach the alveoli.

N.B. M tuberculosis and Legionella pneumophila are examples of bacteria that are deposited directly in the lower airways through inhalation.

A) Bacteria trapped in the upper airways :

can colonize the oropharynx & subsequently be aspirated into the lungs either by microaspiration or by overt aspiration through an
open epiglottis (eg, in patients who lose consciousness after excessive alcohol intake).

B) Bacteria deposited on the mucociliary blanket :

The respiratory epithelium has special properties for fighting off infection :
• Epithelial cells are covered with beating cilia blanketed by a layer of mucus.
• Each cell has about 200 cilia that beat up to 500 times/min, moving the mucus layer upward toward the larynx.
• The mucus itself contains antimicrobial compounds such as lysozyme and secretory IgA antibodies.

Chronic cigarette smokers have decreased mucociliary clearance secondary to damage of cilia & are often unable to clear respiratory
secretions adequately and must, therefore, rely more heavily on the cough reflex to clear pathogens.
Cough reflex is an important physiologic mechanism by which aspirated
material, excess secretions, and foreign bodies are removed from the airway.

C) Bacteria that reach the terminal bronchioles, alveolar ducts, and alveoli :
- are inactivated primarily by alveolar macrophages and neutrophils.
- Opsonization of the microorganism by complement and antibodies enhances phagocytosis by these cells.

Impairment at any level of host defenses increases the risk of developing pneumonia.
 1- Children with cystic fibrosis have defective ciliary activity and are prone to develop recurrent sinopulmonary infections, particularly with S aureus.
2- Patients with granulocytopenia, whether acquired or congenital, are also susceptible to lung infections with gram-negative bacteria and fungi.
3- Antigenic stimulation of T cells leads to the production of lymphokines that activate macrophages with enhanced bactericidal activity. HIV-infected
patients have depleted CD4 T lymphocyte counts and are predisposed to a variety of bacterial (including mycobacterial) and fungal infections.

Clinical Manifestations
Most patients with pneumonia have fever, cough, tachypnea, tachycardia, and an infiltrate on chest x-ray film.
Extrapulmonary manifestations that may provide clues to the etiologic agents include the presence of serum cold agglutinins (Mycoplasma
pneumoniae), pharyngitis (Chlamydia pneumoniae), erythema nodosum rash (fungal and mycobacterial infections), hyponatremia
(Legionella), and diarrhea (Legionella).

The following questions should be answered to guide empiric therapy for a patient who presents with symptoms consistent with
pneumonia:
(1) Is this pneumonia community acquired or institution acquired (eg, hospital, jail, nursing home)?
(2) Is this patient immunocompromised (HIV infected, a transplant recipient)?
(3) Is this patient an injection drug user?
(4) Has this patient had a recent alteration in consciousness (suggestive of aspiration)?
(5) Are the symptoms acute (days) or chronic (weeks to months)?
(6) Has this patient lived in or traveled through geographic areas associated with specific endemic infections (histoplasmosis, coccidioidomycosis)?
(7) Has this patient had recent zoonotic exposures associated with pulmonary infections (psittacosis, Q fever)?
(8) Could this patient have a contagious infection of public health importance (tuberculosis)?
(9) Could this patient's pulmonary infection be associated with a common source exposure (Legionella or influenza outbreak)?
Pneumonia
Management Pathophysiology
General measures Pneumonia results from :
1- Oxygen : should be administered to all patients with : 1- Proliferation of microbial pathogens at the alveolar level :
- Indication : Tachypnoea, Hypoxaemia, Hypotension, Acidosis • Microorganisms gain access to the lower respiratory tract in several ways, BY :
- Aim : To maintain SaO2 between 94% and 98% / PaO2 at or above 60 mmHg . A
A) Aspiration from the oropharynx (most common)
common , occurs frequently :
Provided
rovided the patient is not at risk of carbon dioxide retention, due to loss of hypoxic drive in COPD . - During sleep
eep (especially in the elderly).
(In COPD, keep it between 88% and 92%). - In
n patients with decreased levels of consciousness.
- Continuous positive airway pressure (CPAP) should be considered in those who remain hypoxic despite this, and
B
B) Inhalation as contaminated droplets.
these patients should be managed in (ICU),, where mechanical ventilation can be rapidly employed.
C
C) Hematogenous spread "rare" (e.g., from tricuspid endocarditis).
2- IV fluids :
- Required in hypotensive patients showing evidence of volume depletion. D
D) Contiguous
ontiguous extension from an infected pleural or mediastinal space.
- Otherwise, an adequate oral intake of fluid should be encouraged. • Mechanical factors are critically important in host defense :
- Inotropic support may be required in patients with shock
shock. A)) Hairs & turbinates of nares capture larger inhaled particles before they reach lower respiratory tract.
3- Antibiotics : B)) Branching architecture
re of the tracheobronchial tree traps particles on the airway lining, where
The first dose of antibiotic should be administered within 4 hours of presentation in hospital and treatment should mucociliary clearance and local antibacterial factors either clear or kill the potential pathogen.
not be delayed while investigations are awaited. C)) Gag reflex & Cough mechanism protects from aspiration.
- Parenteral antibiotics should be switched to oral once temperature has se?led for a period of 24 hours.
hours D)) Normal flora adhering to mucosal
ucosal cells of the oropharynx prevents pathogenic bacteria from binding
- If patients fail to respond to initial treatment microbiological advice should be sought and alternative
a and thereby decreases the risk of pneumonia caused by these more virulent bacteria.
diagnoses considered : (e.g. S. aureus
aureus, which requires
es addition of flucloxacillin/fusidic acid).
acid)
E)) When
- The antibiotic should be adjusted after culture & sensitivity results . - These barriers are overcome or
- Current regimens : - The
he microorganisms are small enough to be inhaled to the alveolar level
Antibiotic treatment for CAP Alveolar
lveolar macrophages are extremely efficient at clearing and killing pathogens.
Macrophages are assisted by local proteins (e.g., surfactant proteins A and D) that have:
have
Uncomplicated CAP intrinsic opsonizing properties or antibacterial or antiviral
an activity.
Amoxicillin 500 mg 3 times daily orally Once engulfed by the macrophage, the pathogens—even
pathogens if not killed—are
are eliminated via either :
a- Mucociliary elevator or
If patient is allergic to penicillin b- Lymphatics
larithromycin 500 mg twice daily orally or Erythromycin
• Clarithromycin rythromycin 500 mg 4 times daily orally
• Only when capacity of the alveolar macrophages to ingest or kill the microorganisms is exceeded
If Staphylococcus is cultured or suspected clinical
linical pneumonia become manifest.
larithromycin 500 mg twice daily IV plus Flucloxacillin 1–2
• Clarithromycin 2 g 4 times daily IV.
In that situation, alveolar macrophages initiate the inflammatory response to bolster lower respiratory tract defenses.
If Mycoplasma or Legionella is suspected
larithromycin 500 mg twice daily orally or IV or Erythromycin
• Clarithromycin rythromycin 500 mg 4 times daily orally or IV 2- Host's response to those pathogens.
plus The host inflammatory response, triggers the clinical syndrome of pneumonia.
• Rifampicin 600 mg twice daily IV in severe cases • The release of :
- IInflammatory mediators, such as : (IL)-1
1 & (TNF) results in fever.
Severe CAP - Inflammatory mediators released by macrophages and the newly recruited neutrophils create an alveolar
larithromycin 500 mg twice daily IV or Erythromycin 500 mg 4 times daily IV
• Clarithromycin capillary leak equivalent to that seen in the acute respiratory distress syndrome (ARDS), although in
plus pneumonia this leak is localized (at least initially) ,, resulting in :
amoxiclav 1.2 g 3 times daily IV or
• Co-amoxiclav 1- Radiographic infiltrate
Ceftriaxone 1–22 g daily IV or 2- Rales
ales detectable on auscultation,
Amoxicillin 1 g 4 times daily IV plus flucloxacillin 2 g 4 times daily IV 3- Hypoxemia
ypoxemia results from alveolar filling.
filli
4- Analgesia : 4- Erythrocytes can cross the he alveolar-capillary
alveolar membrane resulting in hemoptysis.
- Simple analgesia such as paracetamol or NSAID helps treat pleuritic pain, thereby reducing the risk of further - Chemokines, such as IL-8 & granulocyte colony-stimulating
colony factor stimulate the release of neutrophils and
complications due to restricted breathing because of pain (e.g. sputum retention/atelectasis
retention/ / infection). their attraction to the lung, producing both :
1- Peripheral leukocytosis
5- Thromboprophylaxis : 2- Increased purulent secretions
- If admitted for >12
12 hours subcutaneous low molecular weight heparin should be prescribed unless • Some
ome bacterial pathogens appear to interfere with the hypoxemic vasoconstriction that would normally occur with
contraindications exist and TED (thromboembolus deterrent) stockings fitted. fluid-filled
filled alveoli, resulting in severe hypoxemia.
• Increased respiratory drive in the systemic inflammatory responsere syndrome (SIRS) leads to respiratory alkalosis.
6- Nutritional supplementation
supplementation.
• Decreased compliance due to :
7- Physiotherapy: help expectoration in those who suppress cough because of pleural pain.
pai 1- capillary leak 2- hypoxemia 3- increased respiratory drive 4-
4 increased secreLons 5- infection-related
related bronchospasm
all lead to dyspnea.

Site of Care Investigations

Certain patients clearly can be managed at home, and
Others require
uire treatment in the hospital. Is this pneumonia ? typically answered by : clinical & radiographic methods
CURB-65 criteria : A) Clinical Diagnosis
Diagnosis: History & Examination
• Differential Diagnosis : includes both infectious and noninfectious entities such as : careful history is important
1- AAcute bronchitis.
2- AAcute exacerbations of chronic bronchitis.
3- HHeart failure known cardiac disease may suggest worsening pulmonary edema
4- PPulmonary embolism History of source of emboli as AF.
5- Pulmonary or Plural TB.
6- Malignancy: bronchoalveolar cell carcinoma
7- RRadiation pneumonitis underlying carcinoma may suggest lung injury secondary to irradiation.
irradiation
TThe sensitivity & specificity of the findings on physical examination are less than ideal ( 58% -67%)
67%) .
Therefore, chest radiography is often necessary to differentiate CAP from other conditions
conditions.
B) Radiographic findings : may include :
a- Risk
isk factors for increased severity (e.g., cavitation or multilobar involvement).
• Score of 0, the 30-day
day mortality rate is 1.5%, b- Radiographic results suggest an etiologic diagnosis , e.g. :
can be treated outside the hospital. - Pneumatoceles suggest infection with S. aureus.
• Score of 2, the 30-day
day mortality rate is 9.2%, - Upper-lobe cavitating lesion suggests tuberculosis.
Patients
atients should be admitted to the hospital. 1- Chest X
X-ray :
• Scores of >=3,, mortality rates are 22% overall; - This must be repeated 6 weeks aDer discharge (unless
unless complications occur ) to rule out an underlying bronchial
these patients may require admission to an ICU. malignancy predisposing to pneumonia by causing obstruction.
Follow-Up
Up • Strep. pneumonia : (Radiological abnormalities can lag behind clinical signs)
- Consolidation with air bronchograms// effusions / collapse due to retention of secretions …..can
can all be seen.
• Fever & leukocytosis usually resolve within 22–4 days - A normal chest X-ray
ray on presentaLon should be repeated aAer 2–3
2 days where CAP is suspected
BUT physical findings may persist longer. • Mycoplasma
Mycoplasma.. Usually one lobe is involved but infection can be bilateral and extensive.
• Chest radiographic abnormalities are slowest to resolve and may • Legionella lobar shadowing, with the occasional small pleural effusion.
Legionella. There is lobar and then multi-lobar
require 4–12
12 weeks to clear, with the speed of clearance
depending on : a- patient's age & b b- underlying lung disease. 2- CT scan :
• Patients may be discharged from the hospital once their clinical • CT of value in a patient with suspected postobstructive pneumonia caused by a tumor or foreign body.
conditions are stable. For outpatients, the clinical & radiologic assessments are usually all that is done before treatment for
• Follow-up radiograph can be done 44–6 weeks later. CAP is started since most laboratory results are not available soon enough .
• If relapse
pse or recurrence is documented ( particularly in the same
lung segment) , the possibilityy of an underlying neoplasm . if so, what is the likely etiology? requires the aid of laboratory techniques.
Prognosis see prognosis of CURB
CURB-65 score 1- Blood tests : Full blood count / urea and electrolytes / biochemistry / C-reactive
C protein …are
are helpful.
• The prognosis of CAP depends on : • Strep. pneumonia :
1- Patient's age - White cell count is >15 × 109/L (90% polymorphonuclear leucocytosis);
2- Comorbidities - inflammatory markers significantly elevated: ESR >100
100 mm/hour / CRP >100 mg/L.
ite of treatment (inpatient or outpatient).
3- Site • Mycoplasma :
• Young patients without comorbidity recover fully aAer ~2 w. - White cell count is usually normal.
• Older patients and those with comorbid conditions can take - In presence of anaemia, haemolysis should be ruled out (direct Coombs’ test & measurement of cold agglutinins).
several weeks longer to recover fully. • Legionella :
- Lymphopenia
ymphopenia without marked leucocytosis,
Prevention - Hyponatraemia,
yponatraemia, hypoalbuminaemia
- High
igh serum levels of liver aminotransferases.
The main preventive
ventive measure is vaccination for :
1- Influenza vaccines : 2- Other tests : The causative organism must be identified:
• Unprotected
nprotected patients at risk from complications should be • Sputum culture and Gram
Gram-stain are required for all patients:
vaccinated immediately and given chemoprophylaxis with - S. pneumoniae
pneumoniae: Gram-positive diplococcic
either oseltamivir or zanamivir for 2 weeks. - S. aureus
aureus: Gram-positive
positive organisms commonly in clusters like a bunch of grapes
- Also diagnostic in infections caused by S. aureus, H. influenzae,
influenzae M. catarrhalis, Gram-negative
negative organisms.
organisms
2- Pneumococcal vaccines.:
• Blood culture :
• An available 7-valent pneumococca
mococcal conjugate vaccine - Should
hould be done for all patients who have moderate
erate to severe CAP, ideally before antibiotics are admi
administered.
produces T cell–dependent antigens
ntigens tthat result in long-term - In S. pneu
pneumoniae infection, positive blood culture
ture indic
indicates more severe disease with greaterr mortality.
mortalit
immunologic memory.
Chronic Obstructive Pulmonary Disease (COPD)
Pathogenesis of COPD : (IHLL)
1- Inflammation & fibrosis of the bronchial wall, Both lead to obstruction of airflow & cause :
Chronic Bronchitis
2- Hypertrophy of the submucosal glands and hypersecretion of mucus mismatching of ventilation & perfusion. Definition :
Chronic
hronic producCve cough of more than 3 months’ duraCon for more than 2
3- Loss of alveolar tissue decreases the surface area for gas exchange. consecutive years .
4- Loss of elastic fibers leads to airway collapse. Typically,the cough has been present for many years, with a gradual
Normally the elas c fibers have 2 func ons: increase in acute exacerbations that produce frankly purulent sputum.
1- Recoil of elastic fibers that were stretched during inspiration provides the force needed to move air out Types :
of the lung during expiration. 1- Simple bronchitis Chronic bronchitis
tis without airflow obstruction.
2- Elastic fibers are attached to the airways,providing radial traction to hold airways open during expiration 2- Chronic
hronic obstructive bronchitis chronic bronchitis with airflow obstruction.
In persons with COPD : the loss of elastic fibers causes: (Top) Normal bronchial airway with elastic Causes :
1- Predisposes
edisposes to airway collapse.
2- Increases air trapping.
fibers that provide traction and hold the • It's associated with chronic irritation from smoking & recurrent infections.
infection
airway open.
3- Impairs the expiratory flow rate. (Bottom)) Obstruction of the airway caused by : In chronic bronchitis, airway obstruction is caused by :
The term COPD encompasses two types of obstructive airway disease: (A)) hypertrophy of the bronchial wall, 1- Inflammation
nflammation of the major and small airways.
• Emphysema, with enlargement of air spaces and destruction of lung tissue. (B)) inflammation and hypersecretion of mucus 2- There is edema and hyperplasia of submucosal glands and excess mucus
(C) loss of elastic fibers
ibers that hold the airway open excretion into the bronchial tree.
• Chronic obstructive bronchitis, with obstruction of airways.

Emphysema
protected by antiprotease enzymes as : α1-antitrypsin
Normally, the lung is p
In smokers in whom COPD develops :
Two recognized causes of emphysema : - Inadequate antiprotease production and release to neutralize
1- Increased elastase production: - Excess protease production
• Cigarette smoke stimulate movement of inflammatory cells into the lungslungs,, resulting in increased release of
proteinases as: elastase ( seserine elastase from neutrophils / metalloelastase from alveolar macrophages )
that digests elastin resulting in breakdown of elastin and other alveolar wall components.
components
2- Inherited deficiency of α1--proteinase inhibitor (α
α1 – antitrypsin):
antitrypsin)
• Accounts for 1% of all cases of COPD.
• More
ore common in young persons before age of 40 years .
• Smoking & repeated respiratory tract infections, decrease α1-antitrypsin
antitrypsin levels risk for emphysema .
• Human α1-antitrypsin is available
ailable for replacement therapy.
Emphysema is characterized by :
1- Loss of lung elasticity
2- Destruction
estruction of the alveolar walls and capillary beds.
3- Abnormal
bnormal enlargement of the air spaces distal to the terminal bronchioles,
Enlargement of the air spaces leads to hyperinflation of the lungs produces an increase in (TLC).
There are two commonly recognized types of emphysema:
1- Centriacinar :
• Affects the bronchioles in the central part of the
respiratory lobule ( terminal bronchioles (TB) &
respiratory bronchioles (RB) ), with initial
preservation of the alveolar ducts and sacs.
• Most
ost common type of emphysema
emphysema.
Seen
een predominantly in male smokers
smokers.
• Centriacinar
entriacinar changes in upper parts of the lung.
2- Panacinar
• Produces
roduces initial involvement of the peripheral alveoli Later extends to involve the more central bronchioles.
• More
ore common in persons with α1-antitrypsin deficiency.
Also
lso found in smokers in association with centrilobular emphysema.
• Panacinar changes are seen in lower parts of the lung
Clinical Manifestations
1. Dyspnea : In Emphysemaa & chronic bronch
bronchitis
- Persons with emphysema have marked dyspnea and struggle to maintain normal blood gas levels with increased ventilatory effort
(overventilate) , including prominent use of the accessory muscles.
- The seated position,which stabilizes chest structures and allows for maximum chest expansion and use of accessory muscles, is preferred. 1- Reduced elastic recoil: leads to
2. Productive chough : In Chronic Bronchitis The lung’s reduced ability to retract ((flaccid lung)) can lead to obstructive lung disease, because :
- Cough is productive of thick, purulent sputum owing to ongoing local inflammation & infection.
reduced elastic recoil (increased compliance) of the lung requires an increase in intrathoracic pressure for
- Sputum viscosity is increased largely as a result of presence of free DNA (of high molecular weight and highly viscous) from lysed cells.
- Hemoptysis with increased inflammation ation and mucosal injury.
expiration, resulting in compression of the intrathoracic airways massive increase in flow resistance.
- Cough is much less effective owing to 1- narrow airway caliber & 2- greater volume and viscosity of secretions. • Positive pressure in alveoli :
3. Breath sounds :
In Emphysema :
1-- Reduced lung’s elastic recoil generates the positive pressure in the alveoli :
- Decreased in intensity of breathing sound reflecting decreased airflow. - With loss of lung elasticity and hyperinflation of the lungs greater
reater intrathoracic pressure is necessary
- Wheezes, when present , are of diminished intensity - Crackles & rhonchi,, in superimposed processes as infection for expiration because compliance and resistance are increased This causes compression of the
In Chronic Bronchitis : Persistent airway narrowing & mucus obstruction : bronchioles so, airway pressure increases further.
further
- Produce localized or diffuse wheezing ( responsive to bronchodilators). - The
he airways often collapse during expiration because pressure in surrounding lung tissues exceeds
- Prolonged expiratory time .
airway pressure Air becomes trapped in lungs, producing an increase in the anteroposterior
anteropos
- Inspiratory & expiratory coarse crackles : mucus production + defective mucociliary clearance excessive secretions in the airways.
dimensions of the chest, the so-called barrel chest.
4. Cardiac examination :
- Elastic recoil can be raised by increasing the inspiratory volume leading to a shift in the resting
- Tachycardia as in chronic bronchitis, especially with exacerbations of bronchitis or hypoxemia.
- Pulmonary hypertension If hypoxemia mia is significant and chronic,,, Cardiac examination may reveal : position toward inspiration (barrel
barrel chest).
chest
• Prominent pulmonary valve closure (increased P2, pulmonary component of the 2nd heart sound) or - Pursed-lip breathing, increases the resistance to the outflow of air, preventing airway collapse by
• Elevated jugular venous pressure AND peripheral edema resulting from Rt heart failure. increasing airway pressure.
5. Imaging :
- Hyperinflation with 1- fla8ened hemidiaphragms 22- anteroposterior chest diameter. 2-- External compression produces positive pressure in the alveoli by contraction of expiratory muscles,
- Parenchymal destruction produces : attenuated peripheral vascular markings. BUT this will also compress the bronchioles thus bring a massive increase in flow resistance.
resistance
- Pulmonary hypertension produces : proximal pulmonary artery dilation . THUS :
- Cardiac size may be increased, suggesting right heart volume overload
overload. Maximal expiratory flow rate (V max) is a function of the ratio between elastic recoil (K) and resistance (RL) .
- Cystic or bullous changes.
6. Pulmonary function tests : • Respiratory function :
In Emphysema : - If tidal volume(TV) remains constant :
• The loss of elastic recoil in lung tissue supporting the airways results in increased 1- functional residual capacity (FRC) 2
2- residual volume (RV) 3- dead space.
dynamic compression of airways, (especially during forced expiration) all flow rates
With premature airway collapse, FEV1, FVC, FEV1/FVC (FEV1% ratio) .
are reduced:With - V
Vital capacity (VC) is because of the reduced expiratory volume.
• "Expiratory flow-volume
volume curve" shows substantial limitation in flow
flow.
In Chronic Bronchitis : 2- Bronchial obstruction : leads to
• Diffuse airway obstruction is demonstrated as a global reduction in expiratory flows & volumes. FEV1, FVC, FEV1/FVC (FEV1%) . 1- maximum breathing capacity (V˙ max)
• expiratory flow-volume
volume curve" shows substantial limitation in flow
flow. 2- FEV1 .
- Increased RV and FRC, reflecting air trapped in the lung as a result of : 3- differing ventilation of various alveoli results in abnormal distribution resulting in : Hypoxemia.
Hypoxemia
a- Diffuse
iffuse airway obstruction (chronic bronchitis)
b- Early airway closure caused by loss of elastic recoil (emphysema) 3- Loss of alveolar wall : leads to
- TLC is increased substantial amount of this increase comes from gas trapped in poorly lung units, including bullae. 1- diminished diffusion area abnormal diffusion of gases resulting in : Hypoxemia .
7. Arterial blood gases :
In Emphysema : (Emphysema is a disease of alveolar wall destruction)
The hypoxia of underventilated alveoli leads to vasoconstriction, increased pulmonary vascular resistance,
- The loss of the alveolar capillaries creates: areas of high ventilation relative to perfusion.
- They may able to maintain nearly normal PO2 and PCO2 levels despite advanced disease pulmonary hypertension, an increased right ventricular load (cor pulmonale).
pulmonale)
- Hypercapnia, respiratory acidosis, and a compensatory metabolic alkalosis are common in severe disease.
In Chronic Bronchitis : 4- Loss of pulmonary capillaries : leads to
- In contrast to persons with emphysema, those with chronic obstructive bronchitis are unable to maintain normal blood gases by 1- increase in functional dead space
increasing their breathing effort " Ventilation
Ventilation-perfusion mismatching " is common in chronic bronchitis. 2- increased pulmonary artery pressure and vascular resistance with development of " cor pulmonale"
- Hypoxemia (arterial
arterial PO2 levels fall below 55 mm Hg) at rest tends to be more profound than in emphysema causes reflex
• The fluid retention and peripheral oedema is due to failure of excretion of sodium and water by the hypoxic kidney
vasoconstriction of the pulmonary vessels persons with chronic obstructive bronchitis develop pulmonary hypertension and,
eventually, right-sided
sided heart failure with peripheral edema ((i.e., cor pulmonale). rather than Rt. heart failure.
- Hypercapnia, Cyanosis, respiratory acidosis, and a compensatory metabolic alkalosis
alkalosis. • With severe fluid overload, tricuspid incompetence may develop with :
8. Polycythemia : Chronic hypoxemia (especially in chronic bronchitis) is associated with erythropoietin-mediated
erythropoietin increase in hematocrit. elevated jugular venous pressure (JVP) / ascites / upper abdominal discomfort due to liver swelling.
The mnemonics “pink puffer” and “blue bloater” used to differentiate the clinical manifestations of :
Emphysema & Chronic obstructive bronchitis ( In practice, differentiation between the t two types is often difficult )
A major difference between the pink puffers & the blue bloaters is the respiratory responsiveness to the hypoxic stimuli.
stimuli
• Chronic obstructive bronchitis is characterized by excessive bronchial secretions and airway obstruction that Centrilobular emphysema :
causes mismatching of ventilation & perfusion Thus, persons with chronic bronchitis are unable to compensate by • In centrilobular emphysema a distribution abnormality also develops,, because of differing resistances
resist in
different bronchioles resulting in hypoxemia..
increasing their ventilation; instead, hypoxemia & cyanosis develop. (These are blue bloaters, or nonfighters ).
• Patients with centrilobular emphysema are called “blue bloaters” .
• Pulmonary emphysema : there iis a proportionate loss of ventilation & perfusion
perfusi area in the lung. Panlobu
Panlobular emphysema :
- These persons are pink puffers,
ffers, or fighters able to overventilate and thus maintain
mai relatively normal blood gas • In pa
panlobular emphysema , an enlargementt of the ffunctional dead space forces them to breathe more
m deeply.
levels until late in the disease. • Patie alled are called “pink puffers”.
Patients with panlobular emphysema are called
 Investigations
1- Lung function tests:
- Show evidence of airflow limitation : FEV1: FVC ratio is reduced /and
and PEFR is low.
In many patients the airflow limitation is partly reversible (usually a change in FEV1 of <15%), and it can be difficult to
distinguish between COPD and asthma.
- Lung volumes : be normal or increased;
- Carbon monoxide gas transfer factor: is low when significant emphysema is present.
2- Chest X-ray : see above in clinical manifestations
3- High-resolution CT scans : when the plain chest XX-ray is normal.
4- Haemoglobin level and PCV : can be elevated as a result of persistent hypoxaemia (2ry
( polycythaemia).
5- Blood gases :
- At rest normal - On exercise patients desaturate .
- In more advanced cases 1- resting hypoxaemia and 2- hypercapnia.
6- Sputum examination :
- Strep. pneumoniae and H. influenzae are the only common organisms to produce acute exacerbations.
- Occasionally, Moraxella catarrhalis may cause infective exacerbations.

7- Electrocardiogram: is often normal

normal, BUT In advanced pulmonary hypertensio
tension :
- P wave is tall (P pulmonale) . - Right bundle branch block (RBBB) - Rt. ventricular hypertrophy.
8- Echocardiogram : is useful to assess cardiac function where there is disproportionate dyspnoea.
9- α1-Antitrypsin : levels & genotype are worth measuring in
in: 1- premature disease or 2- lifelong non-smokers.

Acute exacerbations of COPD Presence of hypercarbia (PCO2 >45 mmHg) has important implications for treatment (discussed below).
- Exacerbations are episodes of increased dyspnea and cough and change in the amount and character of sputum.
- They may or may not be accompanied by other signs of illness, including fever, myalgias, and sore throat.
throat
- Presence of cyanosis, peripheral oedema or alteration in consciousness indicates the need for referral to hospital.
1- Oxygen : ( Inn patients with an exacerbation of severe COPD, high concentrations of oxygen may cause respiratory depression & worsening acidosis)
• The aim is maintaining : PaO2 > 60 mmHg or SaO2 between 88% & 92% without worsening acidosis.
2- Bronchodilator s :
• Nebulised short-acting β2-agonists
agonists (salbutamol) combined with anticholinergic agent (ipratropium).
• These may be administered separately or together.
3- Glucocorticoids :
• 1- Reduce length of stay 2- hasten recovery 3- reduce chance of subsequent exacerbaCon or relapse for a period of up to 6 m. m
• The GOLD guidelines recommend : oral prednisolone (30 mg ) for a period of 2 weeks.
4- Antibiotics :
• Patients with COPD are frequently colonized with potential respiratory pathogenss (s. pneumoniae, H. influenzae, M. catarrhalis).
• Indications: Currently recommendedded for patients reporting increase in sputum purulence, sputum volume or breathlessness.
• Regimens : Aminopenicillin
minopenicillin or a macrolide
macrolide. / Co-amoxiclav if β-lactamase-producing
producing organisms susceptible.
5- Mechanical Ventilatory Support :
A) Noninvasive positive-pressure
pressure ventilation (NIPPV) :
• Indications: If, despite above measures, patient remains tachypnoeic, hypercapnic ,acidotic (PaCO2 > 45 mmHg / pH < 7.35)
• Its use is associated with reduced requirements for mechanical ventilation and reduced mortality
B) Invasive Mechanical Ventilation :
• Indications:
1- Severe
evere respiratory distress despite initial therapy, 2- life-threatening
threatening hypoxemia, 3- severe hypercarbia and/or acidosis,
4- markedly impaired mental status 55- respiratory arrest 6- hemodynamic instability

Pharmacotherapy
Reducing exposure • Complete cessation of smoking is accompanied by 1- improvement in lung function 2- deceleraCon in the rate of FEV1 decline .
• Pharmacologic approaches: 1- Bupropion 2- Nicotine replacement therapy as: gum, transdermal patch, inhaler 3- varenicline,, nicotinic acid receptor agonist/antagonist.
to noxious particles & gases
- Bronchodilator therapy is central to the management of breathlessness. - Compound bronchodilators, a selective β2
2 agonist and an anCmuscarinic agent, are used.
Bronchodilators - Oral bronchodilator therapy may be used in patients who cannot use inhaled devices efficiently.
- Significant improvements in breathlessness may be reported, despite
despite minimal changes in FEV1 reflecting improvements in lung emptying that reduce dynamic hyperinflation .
• In mild COPD : Short-acting β2-agonists
agonists Salbutamol or Terbutaline .
β-Adrenergic agonists • In moderate & severe COPD : long-acting
acting β2 agonists Formoterol or salmeterol .
• In mild COPD : Short-acting Ipratropium
pratropium bromide (improves symptoms and produces acute improvement in FEV1 ).
Antimuscarinic drugs • In moderate & severe COPD : long-acting
acting Tiotropium bromide (improve improve symptoms and reduce exacerbations BUT does not affect the decline in FEV1 ). )
Theophyllines • Theophylline preparations: improve breathlessness and quality of life, BUT their use is limited by : 1- side-effects 2- unpredictable metabolism 3- drug interactions.

Phosphodiesterase inhibitors • Roflumilast is an inhibitor with anti-inflammatory

inflammatory properties. It is used as an adjunct to bronchodilators for the maintenanc
maintenancee treatment of COPD patients.

Inhaled Corticosteroids (ICS)

• Indications :
Corticosteroids - Recommended in patients with severe disease (FEV1 < 50%) who report two or more exacerbaLons requiring anLbioLcs or oral steroids per year .
• Effects :
- Reduce
educe the frequency and severity of exacerbations.
exacerbations
Combination of :
- Regular use is associated with
th a small improvement in FEV1 (but ICS do not alter the natural history of the FEV1 declin
decline).
- Corticosteroid with
- Long-acting β2 agonist Oral Corticosteroids Prednisolone 30 mg daily should be given for 2 weeks
• Indications :
may protect against lung function decline - Useful during exacerbations ( BUT maintenance therapy contributes to osteoporosis "other side effects" should be avoided ) .
BUT does not improve overall mortality. • effects :
- If there is objective evidence of a substantial degree of improvement in airflow limitaLon (FEV1 increase >15%), prednisolone should be discontinued and replaced by :
inhaled corticosteroids (beclometasone 40 μgg twice daily adjusted according to response)
• long-term
term domiciliary oxygen therapy (LTOT) will benefit patients who have:
Arterial blood gases measured in clinically stable patients on optimal medical therapy on at least two occasions 3 weeks apart :
Oxygen therapy 1- PaO2 < 55 mmHg irrespecCve of PaCO2 and FEV1 < 1.5 L
2- PaO2 55–60 mmHg plus secondary polycythaemia, pulmonary hypertension, peripheral oedema or nocturnal hypoxaemia
Long-term
term oxygen therapy (LTOT)
3- Carboxyhaemoglobin of <3%
3% (i.e. paLents who have stopped smoking).
• A fall in pulmonary artery pressure : was achieved if oxygen was given for 15 hours daily,
Use : at least 15 hrs/day at 2–4
2 L/min
• Substantial improvement in mortality: was only achieve if oxygen was given for 19 hours daily.
Aim : to achieve O2 > 60 mmHg or
PaO2
SaO2 > 90 %

1- Vaccination: 1- Influenza vaccine (annually) 2- Polyvalent pneumococcal vaccin vaccine (single dose)
2- Mucolytic therapy : 4-week
week trial of Carbocysteine (Reduce
educe sputum viscosity + can reduce the number of acute exacerbations) .
3- Diuretic therapy: This is necessary for all oedematous patients.
Other measures 4- α1-Antitrypsin
Antitrypsin replacement:
replacement Weekly or monthly infusions of α1-antitrypsin
antitrypsin have been recommended for : 1-paLents
paLents with serum levels below 310 mg/L & 2-abnormal
2 abnormal lung function.
5- Heart failure : should be treated.
treate
6- Secondary polycythaemia : requires venesection if the PCV is >55%
7- Sensation
ensation of breathlessness:
breathlessness an be reduced by either promethazine or dihydrocodeine
Although opiates are the most effective treatment for intractable breathlessness they depress ventilation and carry the risk of respiratory failure.

Nonpharmacologic Therapies
• Exercise should be encouraged at all stages
Pulmonary rehabilitation • Multidisciplinary programmes that incorporate: 1- Physical training 2- Disease nutritional counselling reduce symptoms 3- Improve health status and enhance confidence.
isease education and nutrition

1- Bullectomy :
- Patients in whom large bullae compress surrounding normal lung tissue, who otherwise have minimal airflow limitation and a lack of generalised emphysema, considered for bullectomy.

Surgical intervention 2- Lung volume reduction surgery (LVRS) : Patients with :

- Predominantly
ominantly upper lobe emphysema - with preserved gas transfer - No
o evidence of pulmonary hypertension, benefit from lung volume reduction surgery (LVRS), in which:
peripheral emphysematous lung tissue is resected with the aim of reducing hyperinflation and decreasing the work of breathing.
• Candidates for lung transplantation: 1-
1 <65 years 2- have severe disability despite
espite m
maximal medical therapy 3- free of comorbid
orbid cconditions ( liver, renal diseases).
Lung Transplantation
tation • In contrast to LVRS, the anatomic
ic distribution
distrib pulmonary hypertension are not contraindications
of emphysema AND presence of pulmona ations to lu
lung transplantation.