Pathology of Infections Objectives: ©bharti B-Pathologyof infections-SGUSOM 2

Pathology of infections
Bharti Bhusnurmath, MD
Department of Pathology
St. Georges University
Bharti B-Pathologyof infections-SGUSOM 2
Objectives
The student should be able to:
Explain the difference between
infection and disease
Describe the sequential responses of
the host to microorganisms once they
have entered the body (neutrophils,
lymphocytes, macrophages,
inflammatory exudates, antibodies,
fever).
Describe the routes through which
organisms can spread within the body
once they have set up a focus of
infection and determine the clinical
features of the same.
Distinguish bacteremia from septicemia
and elucidate the clinical features of
septicemia.
Explain the role played by exotoxins
and endotoxins in producing tissue
damage and shock
Differentiate the usual tissue responses
to different groups of organisms - acute
inflammation, necrosis,
lymphomononuclear cells, eosinophils,
granulomas, mixed inflammation,
fibrosis, necrosis, pseudomembrane
Based on a given tissue response they
should be able to suspect the likely
group of organisms.
Conceptualize the steps involved in
making a clinical diagnosis of
infectious disease.
Some specific infections will be
discussed in the lectures to illustrate
classical pathological responses to the
broad categories of organisms. For the
specific organisms discussed, the
student should be able to -
Identify the diseases produced by the
organism
Explain the pathogenetic mechanisms
of the organism (direct contact, toxins,
enzymes, induction of cell mediated or
humoral immune responses)
Identify the type of host response to
the organism and histological changes
in the lesions.
List the mode of infection, route of
entry, primary site of infection,
sequence of changes (if any), areas of
spread and complications.
Derive important clinical features of the
diseases caused by the organism
based on the knowledge of pathology.
Select the important investigations for
diagnosis.
Recognize any special relevant data on
epidemiology (age, sex, geography) for
the organism and explain the same.
Importance of infectious
diseases
Major problem in spite of improved
living conditions, vaccinations,
antibiotics
More than 10 million deaths per year in
developing countries
New and fatal infections are still being
recognized
Special features of infectious
diseases
Caused by organisms- the etiology is
identifiable
Potentially curable
Communicability - potential for
outbreaks of epidemics
Preventable
Reading assignments
Refer to the objectives and limit
yourself to satisfying them. It would not
be possible to read everything there is
to know about infections
Chapter 9 on the general pathology of
Infectious diseases- Pg 319-338
Read from systemic pathology for the
specific infections that would be
discussed in detail during the lectures
Preamble
Basic concepts of micro organisms will
be learnt through the microbiology
course
My lectures deal with - how does the
body respond to infections
Some responses are specific, others
nonspecific
The number of infections is too large
Only some selected examples of
different categories of microorganisms
will be discussed
Exam questions will be limited to the
material covered in lectures and labs
only
Infective agents
Wide range prions , viruses, bacteria,
fungi to helminths ( several meters)
There is a constant battle between the
agents and the host defenses
The outcomes of this battle could be
variable
Infection vs. Disease
Some organisms enter the body but get
cleared - not an infection
Others enter, multiply but do not cause
tissue damage It is called infection
but there is no disease
The ability of the organism to produce
the infection is called infectivity
Still others multiply and produce tissue
damage. This is called infectious
disease
The ability of the organism to do this is
called pathogenecity
Clinical case-1
A fifty year old male felt itching and pain in
his forearm. He noticed a reddish patch on
the skin there. It was swollen and painful. A
day later it turned yellowish and soft. It
started leaking pus the next day.
What do these features suggest?
The lesions showed plenty of gram positive
bacteria, necrosis, PMNs and hyperemia
(acute inflammation)
How did the bacteria reach this site?
What are the other routes of entry of
microorganisms in to the body?
Sequence of events once the bacteria
entered the skin?
The surrounding skin started becoming
tender, hard and reddish. The axillary region
became painful. A hard nodule could be
palpated there. He developed fever.
What do these features indicate?
What is the cause of fever?
He developed palpitations. The spleen and
liver became enlarged. Small spots of
hemorrhage appeared on his skin and
mucous membranes (petechiae). He lapsed
in to coma and died.
How can we explain these features?
Steps
Enter the body - ingestion, inhalation,
inoculation
Multiply locally
Spread
Tissue planes, basement membranes,
pleura, pericardium, peritoneum,
meninges
Lymphatics
Blood stream (plasma, RBC, leucocytes)
Nerves
Spread of infection
- Example: Staphylococci
Skin infection - folliculitis, furuncle,
carbuncle, cellulitis, impetigo
Multiple abscesses
Lymphatics - lymphadenitis (local,
distant)
Venous o(regional veins, thoracic
duct) oreach the major vena cava and
right side of heart right sided valve
(tricuspid, pulmonary) endocarditis
Reach the lung through pulmonary
artery and produce lung abscess
Through the pulmonary veins oleft
side of the heart (mitral, aortic valve)
endocarditis
Septicemia (blood spread)
Distant abscess - brain, kidney, spleen,
brain
Bharti B-Pathologyof infections-SGUSOM 27 Bharti B-Pathologyof infections-SGUSOM 28
Bacteremia
Spread of bacteria in the blood
bacteremia
Occurs in disease as well as
physiological activities like chewing
but is transient in the latter. The
bacteria are destroyed by immune
system
Septicemia
If the bacteria in the blood multiply- it is
called septicemia
Usually accompanied by high grade
fever, chills and is a serious condition
Can set up distant foci of spread in
other tissues- lead to septicemic
abscesses
Mechanisms of damage
Direct injury to tissue
Induce cell death by contact, entry
Exotoxins, endotoxins, enzymes
Tissue destruction, vascular damage,
ischemic injury
Indirect through the host immune
responses
Types of tissue responses
Acute inflammation - bacteria
Lymph mononuclear - virus
(intracellular organisms)
Granulomatous - tuberculosis,
leprosy
Mixed acute, chronic - fungus
Eosinophils - parasites
Fibrosis - Schistosoma
chronic
Necrosis - Clostridia (gas
gangrene)
Pseudomembrane - Diphtheria,
Clostridium
difficile
Body response to infection
Local inflammation at the site of
infection
Systemic
Local response (inflammation)
Bacteria - polymorphonuclear
leucocytes (PMNs), exudate
Virus - macrophage, lymphocytes
Fungus - mixed PMN + lympho + macro
giant cells
Systemic responses
mediated through cytokines
Fever, headache, leucocytosis
Increase in metabolic rate
The experience is then stored in the
memory cells [T, B] for the future
Steps in the diagnosis of
Infectious disease
Clinical features classical history,
physical examination
Knowledge of epidemiology - common
infections in the geographic area
Isolate the organism - pus, blood,
tissue, fluids
Antibody response demonstrate
rising titers
Biopsy - type of tissue response,
demonstrate organism by special
stains, immunological techniques, PCR
Therapeutic response - e.g. malaria,
tuberculosis
Microorganisms
Gram positive and gram negative
bacteria, virus, fungi, rickettsia,
parasites
Learn the classification and properties
of the organisms from the microbiology
course, revise parasitic lesions from
parasitology course
My lectures tissue responses to
selected organisms to understand the
disease processes
Gram negative bacteria
Clinical case 2
A ten year old school student developed
fever, headache and neck stiffness. He
rapidly became drowsy and went in to coma.
Death occurred within 48 hours. The CSF
showed Nisseria meningitides - gram
negative diplococci)
What term would you use to indicate
infection of the meninges?
How did the organisms reach the
meninges?
What type of tissue response would you
see in the meninges?
What changes would you expect in the
CSF?
Neisseria meningitides
gram negative diplococci
Transmitted by respiratory droplets
(nasopharynx)
Most patients develop no symptoms
except mild flu ocarrier
Less commonly invade blood stream-
septicemia -- meningococcemia
In some patients localize in the
meninges meningitis
Meningitis
Pyogenic inflammation of meninges
and subarachnoid space
Gross: meninges - dull, congested,
purulent exudate
Micro: PMN, fibrin, vascular
congestion (acute inflammation)
Clinical: Fever, headache, cloudy
consciousness, neck stiffness
Diagnosis - Spinal tap (CSF) - PMN, n
protein,
p Glucose, demonstrate organisms
Other causes of meningitis -
tuberculosis, viral, fungal
Clinical case 2-a
A classmate of this student contracted the
infection. He developed high fever,
tachycardia, purpura and died of shock.
Autopsy revealed bilateral adrenal
hemorrhages.
How did the pathogenetic mechanism differ in this
student compared to the first boy?
Why was the cause of adrenal hemorrhage
(Waterhouse Friderichsen syndrome)?
What other organisms can produce meningitis?
Fulminant meningococcemia
Fever, tachycardia,
hypotension, shock, toxemia,
purpura
Disseminated intravascular
coagulation (DIC)
Waterhouse Friderichsen
Syndrome when there are
bilateral adrenal hemorrhages
Organisms in meningitis
Neonates up to 2 months- Strep. agalactiae,
E. coli and Listeria monocytogenes
Infancy and childhood- Strep. pneumoniae,
N.meningitidis, H. Influenzae
Adoloscence- N. menigitidis
20-60 years- Strep. pneumoniae, N.
meningitidis, Listeria monocytogenes, gram
negative bacilli
Hemophilus influenza used to be a
common cause of meningitis in
children and young adults but is now
rare because of vaccinations
50
Clinical case 3
An 18 year old sexually active male
developed dysuria and penile discharge. The
discharge revealed Nisseria gonorrhea (gram
negative diplococci)
What would be the tissue response here?
How does the infection spread?
What are the lesions in females with this
infection?
What are the complications related to spread to
the fallopian tubes?
What are the features of systemic spread?
If this person had the infection at the time of
delivering a baby, what lesions can you expect
the baby to develop?
Neisseria gonorrhoeae
(gram - ve diplococci)
Sexually transmitted
disease
Males urethritis,
epididymitis
Urethral discharge and
dysuria
Oropharyngitis and
proctitis in homosexual
males
Females - cervicitis,
salpingitis, peritonitis
Dysuria, vaginal discharge,
inter menstrual bleeding
Pelvic inflammatory disease
[PID]
If chronic oscarring of the
fallopian tubes leading to
infertility
Gonorrhea - dissemination
Rare [0.5 - 3% cases] -
hematogenous
Tenosynovitis, arthritis
Hemorrhagic skin lesions
Endocarditis
Rarely meningitis
Gonorrhea in the newborn
Infection acquired during
passage of the fetus
through cervix during
labor
Purulent conjunctivitis
[ophthalmia neonatorum]
Use of erythromycin /
Silver nitrate eye drops
after birth can prevent it
Diagnosis - gonorrhea
Males - microscopy of exudate- pmn
and gram negative diplococci
Females - culture of exudate- essential
because gram negative diplococci are a
normal part of the vaginal flora
Could yield false negative result if there
are fewer organisms
Chlamydial infection can also produce
similar symptoms and is more common
Clinical case 4
A 20 year female developed high grade fever
and weakness. The liver and spleen were
enlarged and soft .A week later she
developed diarrhea and blood in the stools.
The abdomen was tender. There was
evidence of leucopenia. The blood sample
drawn on the fourth day of illness showed
growth of Salmonella typhi. In the third week
she developed severe anemia and heart
failure.
How do these organisms enter the body?
What is the route of spread in the body?
What are the tissue responses over the
course of the illness?
How do you explain anemia and leucopenia?
Why did she develop heart failure later in the
course of illness?
Can she become a carrier of the infection?
How do you treat this situation?
Typhoid fever enteric fever
Salmonella typhi ( gm-ve bacilli)
Acquired through ingestion
(contaminated food and water)
Enter the ileal wall (no lesions at this
time) enter blood stream
bacteremia ( 1st week)
Liver enlarged - typhoid nodules
composed of Kupffer cell hyperplasia,
minute foci of hemorrhagic necrosis,
collections of macrophages (II week)
Spleen- enlarged soft spleen with
splenitis, typhoid nodules
Organisms now excreted through the
gall bladder in the bile in to the lumen
of the gut ore enter gut wall through
ileum
Sensitization has occurred during this
period contact with organisms
produces lymphoid hypertrophy and
necrosis in the mucosa (III week)
Lesions of enteric fever
Ileum - lymphoid hypertrophy (Peyers
patches), necrosis, ulceration,
No PMN
Only macrophages, erythrophagocytosis
Mesenteric LN enlarged, hemorrhagic
necrosis
Clinical features of enteric
fever
Fever, toxic appearance, leucopenia,
bradycardia
Endotoxin produces depression of
heart and bone marrow
Ulcers heal without scarring
Complications perforation peritonitis,
bleed (3
rd
and 4
th
weeks)
Diagnosis: - blood culture 1st week
Later - demonstrate antibodies (Widal
test)
In some persons chronic colonization
of gall bladder takes place symptom
less carriers
Carriers need to undergo
cholecystectomy
Clinical case 5
A 50 year old diabetic complained of dysuria.
Urinary tract infection was suspected. E. coli
(gram negative) were isolated from the urine.
He went on to develop high grade fever,
chills, and petechiae over the skin. The blood
pressure dropped and he went in to shock.
Sepsis was the basis of the shock.
Why do such harmless commensals
become pathogenic?
What is the role played by endotoxins in
gram negative shock?
What are the other gram negative
infections that can lead to endotoxic
shock?
Gram negative septicemia
Common clinical situation
Fever, septicemia, DIC, shock
Organisms - normally commensals but
become pathogenic in some situations
Immune deficiency, break in mucus
membrane
E.coli, H. influenza, Pseudomonas
aeruginosa, Klebsiella, Proteus, Serratia
Mechanism of septic shock
Gram negative organisms possess a
Lipopolysaccharide (LPS) wall
Bacterial lysis releases large amounts
of LPS in to blood
Formation of LPS - LBP
(lipopolysaccharide binder protein)
complex
LPS-LBP picked up by macrophages
Macrophages release TNF (tumor
necrosis factor)
TNF damages endothelial cells
PMNs adhere to endothelium, release
of IL-1, procoagulant factorDIC
Gram positive bacteria
Staphylococci
Gram positive
Can produce two types of lesions
1. Inflammatory
2. Toxin mediated
Inflammatory lesions of
Staphylococci
Skin - folliculitis, furuncle, carbuncle,
cellulitis, impetigo, paronychia,
surgical wound infection,
postpartum mastitis
Bacteremia
Endocarditis - right sided valves
Osteomyelitis, arthritis
Pneumonia - bronchopneumonia,
abscess with watery pus, empyema
Bacteremic abscesses - lung, kidney,
brain
80% Penicillin resistant (MRSA)
Toxin mediated lesions of
Staphylococci
Food poisoning - enterotoxin
Toxic shock syndrome - (TSS)
Intra vaginal tampon if left longer leads to
growth of Staph release of exotoxin in to
circulation rash, conjunctivitis,
vomiting, diarrhea
Scalded Skin Syndrome- (exfoliatintoxin)
Streptococci
Direct damage- suppurative
cellulitis, abscess, pneumonia
Exotoxin mediated- Scarlet fever
Indirect damage by immune
responses
75
Clinical case 6
A 20 year old apparently healthy young man
got drenched in rain in cold weather. He felt
weak and exhausted. The next day he
developed fever, chest pain, cough and
blood tinged sputum. Strep. pneumoniae
(gram positive) was demonstrated in the
PMNs in the sputum and by blood culture.
The chest X- ray showed uniform
consolidation of the right lower lobe. He
recovered completely in ten days and the
chest X- ray had returned to normal.
What was the tissue response in alveoli?
How does the infection spread in the
lungs?
Why was complete recovery possible?
What complications can arise in
pneumonia?
Strep pneumonia
Lobar pneumonia
Healthy young adults; exposed to cold,
strain, exhaustion
Cough, fever, chest pain, bloody
sputum
Exudate rich in fibrin, RBC, PMN (acute
inflammation) seen in lumen of alveoli
Bronchioles and alveolar walls not
damaged
Spreads rapidly through the pores of
Khn to involve the entire lobe
Macrophages clear up the debris a few
days later
Antibiotics accelerate the process
Most patients show a total resolution in
10 days
Complications are rare - abscess,
fibrosis (organization), empyema
Other type of pneumonia-
bronchopneumonia
Patchy involvement of lung
Klebsiella, E.coli, Pseudomonas, Staph
Destruction of bronchioles, alveoli
Can coalesce to involve the entire lobe
mimicking lobar pneumonia
Children, elderly, bed ridden
May lead to abscesses, empyema
Streptococci
damage by immune response
Cross reacting antibodies get
deposited on normal tissue antigens
e.g. Rheumatic fever
Immune complex deposition in organs
e.g. glomerulonephritis
Clinical case 7
A 12 year old girl developed pharyngitis. The
throat swab revealed pathogenic
streptococci. Two weeks later she developed
fever, arthritis, skin nodules and carditis. The
ASO titers were elevated.
Why did the heart and other connective tissues
get damaged?
Why was there a gap of two weeks?
What chronic sequela can you expect in the
heart?
Rheumatic fever
(Cross reacting antibodies)
Initial Streptococcal sore throat, skin
infection [specific strains]
Lag period of 2-3 weeks after the initial
infection
Then develop fever, arthritis, carditis,
skin nodules, erythema
Antibodies generated to M protein of
the bacteria cross react with tissue
glycoprotein in joints, heart, skin, etc.
Get deposited in the tissues and elicit
inflammatory reaction at the site of
deposition
Not a result of bacteremia or direct
damage by the bacteria
Carditis- Aschoff bodies in the heart
Rheumatic carditis can become chronic
omitral stenosis
Clinical case 8
A 17 year old male had developed pustules on
the skin due to streptococcal infection. 3
weeks later he developed acute onset fever,
weakness, oliguria, hematuria and
hypertension. The glomeruli were acutely
inflamed although the organisms could not
be demonstrated there.
What was the mechanism of
glomerulonephritis?
What is the usual outcome?
Post streptococcal glomerulonephritis
(Immune complex mediated)
Initial Streptococcal sore throat, skin
infection [specific strains]
Lag period of 1- 4 weeks after the initial
infection
Then develop acute malaise, fever,
oliguria, hematuria, hypertension
Antibodies to Strep produced and
circulate in the blood
Strep antigens and the antibodies
combine to form immune complexes
that circulate in the blood
Immune complexes get deposited in
the basement membrane of the
glomeruli
Activate complement and induce acute
inflammation glomerulonephritis
Resolves spontaneously in most patients as
the immune complexes are cleared up
89
Clinical case 9
An eight year old school boy developed severe
sore throat (pharyngitis and laryngitis). There
was severe hyperemia, necrosis and a
whitish membrane on the surface.
Corynebacterium diphtheria (gram positive)
was isolated from the throat swab. The
cervical lymph nodes were massively
enlarged (bull neck). A tracheotomy was
performed to relieve the respiratory distress.
Three weeks later he developed paralysis of
lower limbs and died of cardiac failure.
What was the tissue response in the
throat?
What is a pseudo membrane?
Why was there respiratory distress?
What was the mechanism of paralysis and
cardiac failure?
Diphtheria
Corynebacterium diphtheria - gram +ve
bacillus
Severe throat infection in children - can
be fatal
Pharynx, tonsil - severe necrosis of
mucosa
Necrotic cells, PMN, exudate (pseudo
membrane)
92
Edema, lymph nodes in neck (Bull
neck)
May need tracheotomy (laryngeal
edema)
Powerful exotoxin - heart failure (3
wks), spinal nerve (paralysis)
Immunization can prevent the
disease
93
Clinical case 10
A 40 year male was receiving broad spectrum
antibiotics for lung abscess. He developed
severe bloody diarrhea. Colonoscopy
revealed multiple small ulcers and pseudo
membrane covering the mucosa. Clostridium
difficile (gram positive) was isolated from the
mucosa.
Why did the usually harmless organism
become pathogenic?
What was the mechanism of tissue
damage? Bharti B-Pathologyof infections-SGUSOM 94
Pseudo membranous colitis
Clostridium difficile (gram +ve bacillus)
Antibiotic associated colitis (after
antibiotics are administered for some
other illness)
Broad spectrum antibiotics eliminate
normal flora of the gut that normally
afford protection
Severe mucosal suppurative
inflammation - multiple ulcers
Small vascular thrombosis
Necrotic mucosa forms a pseudo
membrane that can be seen on
colonoscopy
Viral infections
97
Viral infections
Effects on cells
Cytopathic destroy cells- e.g.
Hepatitis B
Perinuclear vacuolation - e.g. HPV -
cervix
Nuclear and cytoplasmic inclusions
e.g. CMV, herpes, rabies
Multinucleate giant cells - herpes,
measles
Cell proliferation - wart, neoplasm
Inflammatory response to
viruses
No pmn
Predominantly lymph mononuclear
cells (lymphocytes, monocytes),
plasma cells
Antibody response may be protective
(used for diagnosis)
Rickettsial infections
Clinical case 11
A 25 year old homeless male developed painful
hemorrhagic nodules in the skin. He had
evidence of body lice. He later developed
pneumonia, went in to stupor and died. Weil
Felix test (antibodies cross reacting with
Proteus antigen) was positive, confirming the
diagnosis of epidemic typhus. Immuno
fluoroscence demonstrated Rickettsiae
Prowazeki in the lesions.
How do the Rickettsial lesions spread?
What is the genesis of hemorrhagic
nodules in the skin?
What are the other lesions seen in
epidemic typhus?
What are the features of other main
Rickettsial infections (Rocky Mountain
spotted fever, Q fever)?
Rickettsial infections
Epidemic typhus - R. prowazeki
Spread by head and body lice
Painful hemorrhagic nodules in skin
Endothelial proliferation ovasculitis,
thrombosis, hemorrhage
Sparse lymph mononuclear cell response
Can cause pneumonia, hepatitis, CNS
involvement [ typhus nodule]
Apathy, stupor, coma, death
If severe - necrosis of earlobes, scrotum,
nose, finger
Diagnosis
Epidemic typhus
Immunofluorescence - demonstrate
organism
Weil Felix test - antibodies cross react
with Proteus antigen
Rocky Mountain spotted fever
Rickettsia rickettsii
Oklahoma, Tennessee, Arkansas,
Georgia
Fever, headache, myalgia followed by
skin rash
Vascular necrosis, hemorrhage,
vasculitis, thrombosis
Severe oCNS and lung involvement
Immunofluorescence on skin biopsy
for diagnosis
Q fever (Cloxiella burnetti)
Droplet infection (air borne) from sheep,
cattle
No skin rash
Pneumonia, liver, spleen, bone marrow
Ring granuloma in liver biopsy
= central fat, fibrinoid material,
surrounded by epithelioid cells
Diagnosis: immunofluorescence,
serology
Fungal infections
Fungal infections
Tissue inflammation
Mixture of acute and chronic
PMN + lymphocytes + monocytes + giant cells
Gives a clue to look for fungi
Tendency to invade blood vessels o
hemorrhage, thrombosis, infarction
Exception- Cryptococcus sometimes elicits no
inflammatory response
Candida (moniliasis)
Usually superficial - oral thrush, vagina,
muco cutaneous
Can become invasive and disseminated in
immune compromised persons
Abscesses - kidney, lung, liver, heart
PAS stain - pink slender hyphae
110
Cryptococcus - Torulosis
Lungs most commonly involved
If disseminated omeningitis
Usually granulomas with giant cells
Sometimes inflammatory reaction absent
(clue to search for Cryptococcus)
111
PAS, silver stain, mucicarmine
Cystic spaces containing soap bubble
like organisms
CSF add a drop of India ink organisms
appear as clear halo negative staining
Latex agglutination test using antibodies-
most specific
112
Aspergillus
Opportunistic - in immune suppressed,
leukemia
Allergic - asthma, alveolitis, chronic
obstructive pulmonary disease
Colonizing - fungal balls in lung cavities
[Tb, old abscesses]
Invasive - necrotizing pneumonia, vascular
invasion
Dissemination to heart, brain, kidney
Demonstrate by PAS, silver stains
Mucormycosis
Opportunistic infection - e.g. diabetes
Enter through the nose (n brain),
lungs, gut
Marked vascular invasion onecrosis,
infarction
Diagnosis: silver stain, PAS
Tuberculosis
Tuberculosis
1/3 of the worlds population is infected
> 2 million deaths each year
Approx. 1 billion new infections will occur
between 2000 - 2020, 200 million will develop
the disease and 35 million will die
HIV/AIDS and multi drug resistant (MDR)-TB
will aggravate the problem
Clinical case 12
A 7 year old boy from Asia developed fever,
cough and chest pain with weight loss. The
sputum was bloody. Chest X-ray revealed a
sub pleural lesion (2 cm) on the right side.
The hilar lymph nodes were enlarged.
Sputum showed Mycobacterium
tuberculosis. A diagnosis of primary
tuberculosis was made.
What outcomes can occur when tubercle
bacilli enter the lungs?
How does the tissue respond to tubercle
bacilli?
What is a tubercle?
How are epithelioid cells formed? What is
their function?
How does caseation occur?
What is Ghons focus?
How do the lesions progress?
Tuberculosis
Many are exposed by in inhalation
Only in some persons the bacteria
multiply in the lungs (infection)
In most persons the body gets rid of
them no clinical disease
Only 5% newly infected persons
develop disease
Recent resurgence due to HIV
Tubercle
Classical histological response takes
three weeks to develop because it
needs cell mediated hypersensitivity
Central caseation surrounded by
epithelioid cells
Giant cells Langhans (peripheral ring
of nuclei) and foreign body type
(irregularly placed nuclei)
Macrophages, lymphocytes
Surrounded by fibrosis
Tubercle
Granuloma : tumor like compact
nodule composed of epithelioid cells
giant cells (granuloma)
Effect of cell mediated hypersensitivity
Epithelioid cells
? Response to ingested fraction of
tubercle bacilli (mycolic acid)
Large eosinophilic cells resembling
epithelial cells
No phagocytic activity
Have secretory function
May be responsible for inducing
necrosis
Caseation necrosis
Gross: chalk like or cheesy
Micro: pink to red with eosin stain
Tissue structure destroyed, no outlines
can be made out (unlike coagulation
necrosis where the individual cells are
dead but the tissue architecture is
preserved)
Result of type IV hypersensitivity [CMH]
Induced by bacilli products, epithelioid
cell secretion, T cell cytokines
The cell mediated hypersensitivity also
results in tubercle formation
Clinical features
Fever
Cough with sputum (bloody)
Chest pain
Weight loss
125
Primary lesion
Primary lesion is always in the lung
parenchyma and is called Ghons lesion
Located in the lower part of upper lobe or upper
part of lower lobe
Infection spreads by lymphatics to hilar LN
The triad of Ghons + lymphatics + LN is
called Primary complex
Heals in most people fibrosis,
calcification
Some bacteria may remain dormant for life
time and can get reactivated at a later date
Clinical case 12 contd.
4 weeks later his condition worsened. The liver
and spleen got enlarged. Chest X-ray showed
millet sized nodules all over the lung fields.
He became comatose and died. Autopsy
revealed military tubercles all over the body.
A diagnosis of progressive primary complex
with military tuberculosis was made.
128
Progressive primary complex
Rarely the primary lesion fails
to heal
Progressive involvement of
surrounding lung
Invades blood vessels and
spreads all over the body -
miliary tuberculosis, may end
fatally
Lungs, liver, spleen, kidney,
brain, gut
Millet sized granulomas all
over
Primary tuberculosis -
nomenclature
Earlier called childhood tuberculosis
because almost always the first
exposure took place during childhood
Now adults can be exposed for the first
time similar response
Primary tuberculosis is a better term
130
Secondary tuberculosis
The patient would have had an earlier
exposure to tubercle bacilli without
developing disease
Or recovered from primary Tb
Subsequently
Gets a new (second) time infection
(reinfection)
Or the bacteria from an earlier lesion that
had become dormant get activated
(reactivation)
The tissue response will be different
because the person already had
developed the hypersensitivity
The lesions of secondary
tuberculosis are usually located at
the apex
Secondary tuberculosis -
histology
Rapid development of caseation within
a few days
Cavity formation
Fibrosis, quick healing, calcification
Why? already equipped with cell
mediated Hypersensitivity/ cell
mediated immunity
133
This was earlier called adult
tuberculosis because almost every one
was already exposed to tuberculosis in
childhood
It is not a suitable term since these
days many adults get exposed to
tuberculosis for the first time and may
develop primary tuberculosis
It is better termed secondary
tuberculosis and could occur by
reinfection or reactivation
How do the cavities develop?
Caseous mass located near bronchial
passages erodes through the wall of bronchi
Necrotic contents spills out into the
bronchial tree
Coughed out in sputum
The lesion is now empty and becomes a
cavity
Not a feature of primary tuberculosis
because there is no caseation there
Progressive secondary
tuberculosis
Less than 5% of secondary tuberculosis no
healing
Direct spread to rest of lung, pleura, LN
Pneumonia, caseation, cavity, fibrosis,
calcification
Bronchiectasis (destruction, dilatation of
bronchi)
Pleural effusion, thickening
Blood spread - miliary - all over the body
136
Secondary tuberculosis
Other organ involvement in
tuberculosis
GIT - ileocecal ulcers, intestinal obstruction,
peritonitis
Bones, joints (cold abscess of the spine -
rupture in to paravertebral soft tissue)
LN - axillary, cervical, mesenteric
Kidney - hematuria, pyuria
Other organs Tb - Contd
Heart constrictive pericarditis
CNS chronic meningitis, tuberculoma
(behaves like a brain tumor)
Liver, spleen - organomegaly
Endometrium - infertility
Adrenals - Addisons disease
(insufficiency)
Tuberculin (PPD)test
Inject tubercle protein in to the skin
Study the response
Measure the extent of hyperemia
If beyond a particular diameter, assume
active tuberculous infection and treat
The exact cut off point varies with the
geographic area, previous vaccination
with BCG and presence of HIV infection
PPD criteria to treat
>5mm - in HIV+, history of recent
contact, chest X-ray with old TB scar
>10mm - in I/V drug abusers, homeless,
born in countries with high incidence, health
care workers, residents of nursing homes,
underlying disease with high risk of TB-
silicosis, diabetes, chemotherapy, leukemia,
gastrectomy, steroid therapy etc.
>15mm - Everybody
Lab diagnosis- Tb
Mimics lung cancer clinically and
radiologically and hence accurate
diagnosis is important
Sputum: demonstrate tubercle bacilli
by acid fast stain, PCR, culture
Fine needle aspiration cytology from
LN or lung
Lymph node biopsy
Bronchoscopic biopsy
Pleural tap - AFB, epithelioid cells,
giant cells
If all of these fail therapeutic trial
Tb in the immune
compromised
HIV, steroid therapy, lymphomas
Re-emergence of Tb in developed
countries due to HIV
Severe widespread infection
144
Poor cell reaction - no granulomas
Extensive necrosis (not caseation)
Abundant AFB
No cavitation, fibrosis
Other organisms Mycobacterium avium
intracellulare
145
Histoplasmosis
Clinically and histologically similar to Tb
except that the primary lesions are
multiple unlike Tb where the primary
lesion is single

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