SGD 02

Section 2Y
Case Study
A 25 year old male with productive cough for 3 months with whitish
sputum underwent sputum AFB for two times which both yielded 3+ result.

The patient experienced difficulty of breathing which lead to his admission

to hospital X where it was documented through chest radiographs that the
patient has bilateral pleural effusion, multiple bilateral opacities and apical
cavitations.

The patient stayed in the hospital for 3 weeks then succumbed to death.
The family consented for an autopsy with cardiac findings of tan-white
areas of discoloration in the left ventricular myocardium which
microscopically appeared as areas with cardiac myocytes with pyknotic
nuclei and with areas with loss of nuclei and striations. Areas with
neutrophilic infiltrates are also seen.
Etiology
Pulmonary Tuberculosis

● Caused by Mycobacterium tuberculosis

○ a slow-growing obligate aerobe and a facultative intracellular bacilli.
○ aerobic, non–spore-forming, nonmotile, facultative, curved intracellular rods
measuring 0.2-0.5 μm by 2-4 μm.
○ their cell walls contain mycolic, acid-rich, long-chain glycolipids and
phospholipoglycans (mycocides) that protect mycobacteria from cell lysosomal
attack and also retain red basic fuchsin dye after acid rinsing (acid-fast stain).
Mycobacterium tuberculosis

● Humans are the only known reservoir for M tuberculosis. The organism is spread
primarily as an airborne aerosol from an individual who is in the infectious stage of TB
● M. tuberculosis have the ability to survive and proliferate within mononuclear
phagocytes, which ingest the bacterium
○ It is able to invade local lymph nodes and spread to extrapulmonary sites, such as
the bone marrow, liver, spleen, kidneys, bones, and brain, usually via
hematogenous routes
■ primary extrapulmonary disease is rare except in immunocompromised
hosts
Genetic Factors
The genes that follow have polymorphisms that are associated with susceptibility to
tuberculosis:
● NRAMP1
○ 4 different polymorphisms of the NRAMP1 gene were associated with an increased
risk for TB
● SP110
○ A study of 27 different polymorphisms in this gene found 3 that were associated
with increased risk of TB
● CISH
○ The product of this gene functions to suppress cytokine signaling, which is
important for inflammatory signaling. One study found that a single-nucleotide
polymorphism upstream from CISH was associated with susceptibility to TB,
malaria, and invasive bacterial disease
● CD209
○ An association was found between susceptibility to TB and a polymorphism
upstream from the CD209 gene in a multiracial South African population.
Incidence and Epidemiology
● In immunocompetent individuals, exposure to M tuberculosis usually results in a
latent/dormant infection.
○ Only about 5% of these individuals later show evidence of clinical disease.

● According to the World Health Organization (WHO) global TB report in 2020, the
Philippines has the highest TB incidence rate in Asia, with 554 cases for every 100,000
Filipinos.
○ According to the data presented by DOH, over 100,000 Filipinos may die of
tuberculosis (TB) in the next five years or 20,000 TB deaths per year if TB services
continue to be disrupted because of mobility restrictions brought about by
COVID-19.
Pathogenesis
 Pathogenesis

Exposure to
Entry into Replication in
Mycobacterium
macrophages macrophages
tuberculosis

Th1-mediated
macrophage activation Th1 response
and killing of bacteria
Innate Immunity

Granulomatous
inflammation and
tissue damage
 Pathogenesis

Exposure to
Entry into Replication in
Mycobacterium
macrophages macrophages
tuberculosis

Th1-mediated
macrophage activation Th1 response
and killing of bacteria
Innate Immunity

Granulomatous
inflammation and
tissue damage
Morphological and
Gross Feature
Histopathology
Morphological Feature

Mycobacterium tuberculosis
- Fairly large nonmotile rod-shaped
bacterium
- Distant relative to Actinomycetes
- Rods are 2-4 micrometrs in length
and 0.2-0.5 um in width’
- Facultative intracellular parasite,
usually in macrophages and has a
slow generation time (15-20 hrs)
- MTB complexes are found in the
well-aerated upper lobes of the lungs
MICROSCOPIC
MORPHOLOGY
(+) CASEOUS NECROSIS

(+) GRANULOMA (EPITHELIOID

CELLS)
MICROSCOPIC
MORPHOLOGY
(+) LANGHAN GIANT CELL

(+) LYMPHOCYTES
Gross Feature
● Scattered tan granulomas are
present
● Irregularly sized rounded
nodules that are firm and tan
● Central necrosis - ceseation
Gross Feature
● Very extensive granulomatous
disease
● Secondary tuberculosis
○ Pattern of multiple caseating
granulomas
● Histoplasmosis, cryptococcosis,
coccidioidomycosis
○ can mimic this pattern
Gross Feature
● Cavitation is typical for large
granulomas with tuberculosis.
○ more common in the upper LARGER BRONCHUS
lobes.
Gross Feature
● Ghon complex
○ Characteristic gross
appearance with primary GRANULOMA SUBPLEURAL
tuberculosis GRANULOMA
● Granulomas decrease in size
and can calcify
 GRANULOMA SUBPLEURAL
GRANULOMA

● Primary Tuberculosis ● Secondary/Reactive

○ Seen in children Tuberculosis
○ Seen in adults
 Clinical
Manifestations
● Productive cough for 3 months with whitish sputum
● Difficulty of breathing
● Bilateral pleural effusion
● Chest radiographs revealed - bilateral pleural effusion,
multiple bilateral opacities and apical cavitation
● Cardiac findings of tan-white areas of discoloration in the left
ventricular myocardium whichmicroscopically appeared
as areas with cardiac myocyteswith pyknotic nuclei and
with areas with loss of nuclei and striations.
Chest Radiograph

Bilateral pleural effusion Apical cavitation

Diagnostic
Methods
Mantoux Tuberculin Skin Test (TST)

- Intradermal injection of small

amount of tuberculin into skin
- Read within 48-72 hours
 TB Blood Test
- measures how your immune system reacts to the germs that cause
TB.
- used to more precisely confirm or rule out latent or active TB.
- Positive TB blood test: infected with TB bacteria.
- Negative TB blood test: person’s blood did not react to the test;
latent TB infection or TB disease is not likely.
- Preferred TB test for:
● People who have received the TB vaccine bacille
Calmette–Guérin (BCG).
● People who have a difficult time returning for a second
appointment to look for a reaction to the TST.
Chest Radiograph

- PA radiograph is the standard view

- In PTB, abnormalities are often seen in the apical
and posterior segments of the upper lobe or in the
superior segments of the lower lobe.
- Lesions may differ in size, shape, density and
cavitation
- May suggest TB but cannot be used to definitively
diagnose
- May be used to rule out possibility of pulmonary TB
in person who has had + reaction to TST or TB
blood test and no symptoms of disease
Diagnostic Microbiology

- Detection of AFB may provide the initial bacteriologic evidence of

the presence of mycobacteria in a clinical specimen.
- Smear microscopy: quickest and easiest procedure
- AFB in smear are counted. The smears are classified as: 4+, 3+, 2+, or
1+
- The greater the number, the more infectious the patient
GeneXpert Mtb/Rif
Gene-Xpert, a CBNAAT (cartridge based nucleic acid amplification test)
is a widely accepted diagnostic test for Tuberculosis. This test is a rapid
diagnostic test for Tuberculosis detection as well as Rifampicin
resistance in direct smear negative cases.
Advantages
● One step process – automated
● Quick (results < 2 hours)
● Requires fewer biosafety measures than culture/LPA, so can be used in
lower-level laboratories
● High sensitivity
● High specificity
● Can detect rifampicin resistance
● Same machine can also be used for HIV, hepatitis C diagnoses / viral
load monitoring
● Can work on many extrapulmonary TB samples
Disadvantages
● The shelf life of the cartridges is only 18 months;
● A very stable electricity supply is required;
● The instrument needs to be recalibrated annually;
● The cost of the test;
● The temperature ceiling is critical.
Treatment /
Management
Isoniazid (INH)
Pyrazinamide (PZA)
Rifampin (RIF)
Ethambutol (EMB)
 ● Antibiotic

Isoniazid
● Treats latent or active TB
● First-line treatment alongside with pyrazinamide,
ethambutol and rifampin
● Available only in Tablets

Side effects:
- Tingling feeling, muscle weakness
- Dizziness
- Nausea / vomitting
- Dry mouth
- Dark urine, clay-coloured stools, jaundice
- Vision changes
- A seizure
- Pale skin, bleeding (nosebleeds, bleeding gums)
Contraindications

● History of hypersensitivity to the drug ● severe renal impairment

● caloric undernutrition ● severe nausea and vomiting
● gout that has lasted a long time

● alcoholism ● high blood sugar

● peripheral neuropathy ● abnormal liver function tests

● acute liver failure ● anemia from pyruvate kinase

and G6PD deficiencies
● recurring liver problems
● diabetic complications
● liver problems
● severe liver disease

Pyrazinamide
● Antimicrobial agent
● Initial treatment of Active TB
● Co-administered with other
effective anti-TB drugs
● Administered orally
Side Effects:
● Fever
Porphyria
●
● Dysuria
● Hepatic reaction
● Nausea/Vomiting
● Thrombocytopenia and
sideroblastic anemia with
erythroid hyperplasia
● Mild arthralgia
● Myalgia
● Hypersensitivity reactions
 Contraindications

● Diabetes Use cautiously in patients with:

● Pregnancy
● Gout
● Lactation
● Porphyria ● Hepatic and renal impairment
● HIV
● Alcoholism ● Diabetes Mellitus

● Severe liver disease

Interaction:
With allopurinol, colchicine and probenecid - its effectiveness decreases
Ethambutol (Myambutol)
● Used with other medications to
treat tuberculosis (TB)
● Antibiotic
● Inhibits mycobacterial
arabinosyl transferase (MOA)
● Inhibits polymerization reaction
of arabinoglycans (essential
component of mycobacterial
cell wall)
● Inhibits growth of mycobacteria
 Ethambutol

● Orally
● Therapeutic
concentrations in the CSF
(Crosses BBB)
● Taken up by erythrocytes
and slowly released
● Partly metabolized & is
excreted in the urine &
feces
Side effects
● Optic neuritis / Retrobulbar
Neuritis
● Visual disturbances
● Red-Green color blindness
● Decreased visual acuity
● Joint pain
● Headache
● loss of appetite
● Nausea/vomiting
Contraindications
● Children
● Too young to permit assessment of
visual acuity and red-green color
discrimination.
● Diabetic retinopathy
● Gout
● Cataracts
● Sudden blindness and pain upon
moving the eye
● Decreased kidney function
Rifampin (Rifadin)
● Treatment for mycobacterium
tuberculosis
● Used for mycobacterium infections
like leprosy and staph infections
● Inhibits RNA polymerase (can’t make
RNA and can’t make CHONS)
● Can kill semi-dormant TB
● Allows short course treatment (6-9
months)
● Ok with pregnancy
● Can go to CSF
 Side effects
● Red fluids (red orange urine, tears,
sweat)
● Hepatotoxicity
● Rapid resistance if used alone.
● Interferes with certain drugs
Contraindications
● Alcoholism
● Liver problem
● Taking the following drugs:
○ warfarin, anticonvulsants,
HIV treatment (proteases
inhibitors), Methadone, oral
contraceptives,
glucocorticoids, digoxin,
verapamil, and
Cyclosporine
https://www.cdc.gov/tb/topic/treatment/tbdisease.htm
Complications
Massive hemoptysis

● Rare but serious complication of TB disease

Pulmonary circulation/ Formation of

Pseudoaneuryms (Rasmussen’s aneurysm)
→ Hemodynamic Collapse

● Treatment of choice:
○ selective embolization of the bleeding arteries

Reference: AAEM Resident and Student Association

a
Central nervous system tuberculosis
● Associated with high rates of early mortality
● Other major complications with long-term
morbidity:
○ Hydrocephalus
○ Stroke
○ Mass effect of tuberculomas
● TB meningitis → particularly poor outcomes
because of inflammation & thrombosis of cerebral
vasculature causing stroke, or from cerebral
vasospasm
● CNS tuberculomas→ silent & may develop or
enlarge during therapy
Complications associated with comorbidities
● TB patients often have co-morbidities
○ Organ transplantation
○ Rheumatologic disease
○ Diabetes
■ specific risk factor for slower
treatment response
■ increased morbidity
■ poor TB drug absorption
○ Hemodialysis
○ Malignancy
Tuberculosis pericarditis
● From contiguous spread from mediastinal nodes or hematogenous seeding
during dissemination with mycobacteremia
● Chronic pericardial inflammation → constrictive pericarditis
● Effusions
○ bloody & exudative
○ elevated leukocyte count (predominantly lymphocytes)
● Management:
○ Pericardiocentesis (effusions and tamponade)
○ Pericardectomy (constriction)
○ Aadjuvant corticosteroids
Complication at other Sites
Metabolic Complications

❖ Hypercalcemia- is a well known complication of granulomatous disease

❖ Symptoms include:
● Nephrolithiasis
● Acute Kidney Disease
● Osteoporosis
● Constipation
● Neuropsy chiatric manifestation
❖ Vit D Deficiency - has been associated with progression from latent infection to
active TB disease.
Complications of HIV associated TB

● Principles of TB treatment in HIV infected individuals are similar to those in HIV

uninfected patients
● evidence-base guidance recommends early initiation of (ART) together with TB
therapy
❖ 2 weeks in patients with CD4 count less than 50 cells/µl
❖ 8-12 weeks in patients with a higher CD4 counts
● Early (ART) initiation confers mortality benefit, but also increases Development of
(IRIS)
● TB-IRIS mortality is estimated 3%
● Rifabutin dosing in conjunction with protease inhibitors have recently changed
Infection Complication (Myecetoma)

❖ Residual TB cavity lesions may

become colonized by Aspergillus
and other fungi and termed as
fungal ball or Mycetomas
● Can cause chronic hemoptysis
● Occurs in 11-7%
❖ Definitive treatment Surgical Lobar PANEL (A) PANEL (B)
Resection
❖ Many patient with Myetoma have FIGURE 1. A 52 year old man with severe pulmonary
chronic pulmonary symptoms tuberculosis causing total fibrocavitary destruction of
the left lung.
References
● https://emedicine.medscape.com/article/230802-overview#a5
● https://doh.gov.ph/doh-press-release/DOH-PARTNERS-AIM-TO-GET-TB
-CARE-BACK-ON-TRACK#:~:text=According%20to%20the%20World%20H
ealth,cases%20for%20every%20100%2C000%20Filipinos.
● https://www.cdc.gov/tb/topic/treatment/tbdisease.htm
THANK YOU