Lecture 9

GENERAL FEATURES OF CHRONIC INFLAMMATION

Though there may be differences in chronic inflammatory response depending upon the tissue involved
and causative organisms, there are some basic similarities amongst various types of chronic inflammation.
These general features characterise any chronic inflammation.
1. MONONUCLEAR CELL INFILTRATION.
Role of macrophages in inflammation. The functions of mononuclear-phagocyte cells are as under:
(i) Phagocytosis (cell eating) and pinocytosis (cell drinking).
(ii) Macrophages on activation by lymphokines released by T lymphocytes or by non-immunologic
stimuli elaborate a variety of biologically active substances such as:
(a) Proteases like collagenase and elastase which degrade collagen and elastic tissue.
(b) Plasminogen activator which activates the fibrinolytic system.
(c) Products of complement.
(d) Some coagulation factors (factor V and thromboplastin) which convert fibrinogen to fibrin.
(e) Chemotactic agents for other leucocytes.
(f) Metabolites of arachidonic acid.
(g) Growth promoting factors for fibroblasts, blood vessels and granulocytes.
(h) cytokines like interleukin-1 and tumor necrosis factor.
Chronic inflammatory lesions are infiltrated by mononuclear inflammatory cells like phagocytes and
lymphoid cells. Phagocytes are represented by circulating monocytes, tissue macrophages, epithelioid
cells and sometimes, multinucleated giant cells. The macrophages comprise the most important cells in
chronic inflammation. These may appear at the site of chronic inflammation from: (i) chemotactic factors
for macrophages as already described;
(ii) local proliferation of macrophages; and
(iii) longer survival of macrophages at the site of inflammation.
2. TISSUE DESTRUCTION OR NECROSIS.
Tissue destruction and necrosis are common in many chronic inflammatory lesions and
are brought about by activated macrophages by release of a variety of biologically-active
substances.
3. PROLIFERATIVE CHANGES. As a result of necrosis, proliferation of small blood vessels and
fibroblasts is stimulated resulting in formation of inflammatory granulation tissue. Eventually, heal-
ing by fibrosis and collagen laying takes place.
TYPES OF CHRONIC INFLAMMATION
Conventionally, chronic inflammation is subdivided into 2 types:
1. Non-specific, when the irritant substance produces a non-specific chronic inflammatory reaction with
formation of granulation tissue and healing by fibrosis e.g. chronic osteomyelitis, chronic ulcer.
2. Specific, When the injurious agent causes a characteristic histological tissue response e.g. tuberculosis,
leprosy, syphilis.
However, for a more descriptive classification, histological features are used for classifying chronic
inflammation into 2 corresponding types:
1. Chronic non-specific inflammation. It is characterised by non-specific inflammatory cell infiltration
e.g. chronic osteomyelitis, lung abscess. A variant of this type of chronic inflammatory response is
chronic suppurative inflammation in which infiltration by polymorphs and abscess formation are
additional features e.g. actinomycosis.
2. Chronic granulematous inflammation. It is characterised by formation of granulomas e.g. tu-
berculosis, leprosy, syphilis, sarcoidosis etc.
CHRONIC GRANULOMATOUS INFLAMMATION
Granuloma is defined as a circumscribed, tiny lesion, about 1 mm in diameter, composed predominantly
of collection of modified macrophages called epithelioid cells, and rimmed at the periphery by lymphoid
cells. The word 'granuloma` is composed of granule meaning circumscribed granule-like lesion, and
-oma which is a suffix commonly used for true tumours but here indicates inflammatory mass or
collection of macrophages.

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 The epithelioid cells, so called because of their epithelial cell-like appearance, are modified
macrophages which are somewhat elongated, having pale-staining abundant cytoplasm, lightly-staining
nucleus and the cell membrane of adjacent epithelioid cells is closely apposed.
Besides the presence of epithelioid cells and lymphoid cells, granulomas may have giant cells,
necrosis and fibrosis.
1. The giant cells are formed by fusion of adjacent epithelioid cells or by internal nuclear division
without cytoplasmic division and may have 50-100 nuclei. These nuclei may be arranged at the
periphery like horse-shoe or ring or clustered at the two poles (Langhans' giant cells), or they may be
present centrally (foreign body giant cells). The former are commonly seen in tuberculosis while the
latter are common in foreign body tissue reactions.

2. Necrosis may be a feature of some granulomatous conditions e.g. central caseation necrosis of
tuberculosis, so called because of cheese-like appearance and consistency of necrosis.
3. Fibrosis is due to proliferation of fibroblasts at the periphery of granuloma.
The following two factors favour the formation of granulomas:
(i) Presence of poorly digestible irritant which may be organisms like Mycobacterium tuberculosis, par-
ticles of talc etc.
(ii) Presence of cell-mediated immunity to the irritant, implying thereby the role of hypersensitivity in
granulomatous inflammation.
The classical example of granulomatous inflammation is the tissue response to tubercle bacilli which is
called as tubercle. The evolution of tubercle is described below under Tuberculosis:
1. Fibroblastic proliferation, 2. Epithelioid cells, 3. Langhans' giant cell,
4. Caseation necrosis
A fully-developed tubercle is about 1 mm in diameter with central area of caseation necrosis, surrounded
by epithelioid cells and one to several multinucleated giant cells (commonly Langhans's type), surrounded
at the periphery by lymphocytes and bounded by fibroblasts and fibrous tissue.
EXAMPLES OF GRANULOMATOUS INFLAMMATION
Granulomatous inflammation is typical of reaction to poorly digestible agents elicited by tuberculosis,
leprosy, fungal infections, schistosomiasis, foreign particles etc.
TUBERCULOSIS
Tissue response in tuberculosis represents classical example of chronic granulomatous inflammation in
humans.
CAUSATIVE ORGANISM. Tubercle bacillus or Koch's bacillus (named after discovery of the organism
by Robert Koch in 1882) called Mycobacterium tuberculosis causes tuberculosis in the lungs and other
tissues of the human body. The organism is a strict aerobe and thrives best in tissues with high oxygen
tension like in the apex of the lung.
The organism has 5 distinct pathogenic strains:
hominis, bovis, avium, murine, and cold-blooded vertebrate strain.
M tuberculosis hominis is a slender rod-like bacillus, 4 (4 in length, and can be demonstrated by the
following methods:
1. Acid-fast (Ziehl-Neelsen) staining. The acid fastness of the tubercle bacilli is due to waxy content in the
cell wall of the organism making it impermeable to the usual stains. It takes up stain by heated carbol
fuchsin and resists decolourisation by acids and alcohols (acid fast and alcohol fast) and can be
decolorised by 20% sulfuric acid.
2. Fluorescent dye methods.
3. Culture of the organism in Lowenstein-Jensen (L.J.) medium for 6 weeks.
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4. Guinea pig inoculation method by subcutaneous injection of the organisms.
LEPROSY
Leprosy or Hansen's disease (after discovery of the causative organism by Hansen in 1874) is a chronic
infectious disease affecting mainly the cooler parts of the body such as skin, mouth, respiratory tract,
eyes, peripheral nerves, superficial lymph nodes and testis.
CAUSATIVE ORGANISM. The disease is caused by Mycobacterium leprae, which closely resembles
Mycobacterium tuberculosis but is less acid-fast. The organisms in tissues appear as compact rounded
masses (globi) or are arranged in parallel fashion like cigarettes in pack.
M. leprae can be demonstrated in tissue sections, in skin smears by splitting the skin, scrapings from
cut edges of dermis and, in nasal smears by the following techniques:
1. Acid-fast (Ziehl-Neelsen) staining. The staining procedure is similar as for demonstration of M.
tuberculosis but can be decolorized by 5% sulphuric acid (less acid fast).
2. Fite-Faraco staining procedure is considered better for more adequate staining of tissue sections.
3. Gomory methenamine silver (GMS) staining can also be employed.
Definite laboratory cultivation of M. leprae has not been possible yet. However, nine-banded
armadillo, a rodent, acts as an experimental animal model as it develops leprosy which is
histopathologically and immunologically similar to human leprosy.
INCIDENCE. The disease is endemic in areas with hot and moist climates and in poor tropical countries.
According to the WHO, five countriesIndia, Brazil, Indonesia, Mayanmar (Burma) and Nigeria,
together constitute vast majority of leprosy cases, of which India accounts for 64% of all registered
leprosy cases globally. In India, the disease is seen more commonly in regions like Tamil Nadu,
Pondicherry, Andhra Pradesh, Orissa, West Bengal and Assam. Very few cases are now seen in Europe
and the United States.
MODE OF TRANSMISSION. Leprosy is a slow communicable disease and the incubation period
between first exposure and appearance of signs of disease varies from 2 to 20 years (average about 3
years). The infectivity may be from the following
sources:
1. Direct contact with untreated leprosy patients who shed numerous bacilli from damaged skin, nasal
secretions, mucous membrane of mouth and hair follicles.
2. Materno-foetal transmission across the placenta.
3. Transmission from milk of leprosy patient to infant.
CLASSIFICATION. Leprosy is broadly classified-into 2 main types:
Lepromatous type representing low resistance; and
Tuberculoid type representing high resistance.
REACTIONS IN LEPROSY. The polar forms of leprosy do not undergo any change in clinical and
histopathological picture. The borderline groups are unstable and may move across the spectrum in either
direction with upgrading or downgrading of patient's immune state. Accordingly, there may be two types
of lepra reaction:
CLINICAL FEATURES. These show variation in the two main forms of leprosy
1 Lepromatous leprosy.
The skin lesions are generally symmetrical, multiple, slightly hypopigmented and erythematous macules,
papules, nodules or diffuse infiltrates The nodular lesions may coalesce to give leonine facies appearance.
The lesions are hypoaesthetic or anaesthetic but the sensory disturbance is not as distinct.
2 Tuberculoid leprosy.
The skin lesions are either single, or a few asymmetncal lesions are seen which are hypo pigmented and
erythematous macules. There is a distinct sensory impairment
HISTOPATHOLOGY OF LEPROSY. Usually, skin biopsy from the margin of lesions is submitted to
diagnosis and for classification of leprosy The main features in various groups are given below
1 Lepromatous leprosy. The following features characterise lepromatous polar leprosy
(i) In the dermis, there is proliferation. Polar forms of leprosy. Lepromatous leprqsy (LL) (A, B, C). A,
Patient with nodular symmetrical lesions with leonine facies. B, Proliferation of lepra cells around blood

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vessels and dermal adnexal structures with subepidermal clear zone. C, 'Globi' and 'cigarettes in pack'
appearance of bacilli in AFB staining.
Tuberculoid leprosy (TT) (D,E,F). D, Patient with flat, macular and asymmetrical lesions. E,
Granulomatous lesion in the vicinity of dermal nerve without clear subepidermal zone. F, Scanty and
granular forms of bacilli in a destroyed nerve in AFB staining. Macrophages with foamy change,
particularly around the blood vessels, nerves and dermal appendages. The foamy macrophages are called
'lepra cells' or Virchow cells.
(ii) The lepra cells are heavily laden with acid-fast bacilli demonstrated with AFB staining. The AFB may
be seen as compact globular masses (globi) or arranged in parallel fashion like 'cigarettes in a pack'.
(iii) The dermal infiltrate of lepra cells characteristically doesnot encroach upon the basal layer of
epidermis and is separated from epidermis by a subepidermal uninvolved clear zone.
(iv) The epidermis overlying the lesions is thinned out, flat and may even ulcerate.
2. Tuberculoid leprosy. The polar tuberculoid form presents the following histological features:
i) The dermal lesions show granulomas resembling hard tubercles composed of epithelioid cells,
Langhans' giant cells and peripheral mantle of lympohcytes.
ii) Lesions of tuberculoid leprosy have predilection for dermal nerves which may be destroyed and
infiltrated by epithelioid cells and lymphocytes.
iii) The granulomatous infiltrate erodes the basal layer of epidermis i.e. there is no clear zone.
iv) The AFB are few and seen in destroyed nerves.
3. Borderline leprosy. The histopathologic features of the three forms of borderline leprosy are as under:
i) Borderline tuberculoid (BT) form shows epithelioid cells and plentiful lymphocytes. There is a narrow
clear subepidermal zone. AFB are scanty and found in nerves.
ii) Borderline lepromatous (BL) form shows predominance of histiocytes, a few epithelioid cells and
some irregularly dispersed lymphocytes. Numerous AFB are seen.
iii) Midborderline (BB) form shows sheets of epithelioid cells with no giant cells. Some lymphocytes are
seen in the perineurium. AFB are present, mostly in nerves.
4. Indeterminate leprosy. The histopathologic features are nonspecific so that the diagnosis of non-
specific chronic dermatitis may be made. However, a few feature help in suspecting leprosy like:
(i) Lymphocytic or mononuclear cell infiltrate, focalised particularly around skin adnexal structures like
hair follicles and sweat glands or around blood vessels.
(ii) Nerve involvement, if present, is strongly supportive of diagnosis.
(iii) Confirmation of diagnosis is made by finding of AFB.
SYPHILIS
Syphilis is a venereal (sexually-transmitted) disease caused by spirochaetes, Treponema pallidum. Other
treponemal diseases are yaws, pinta and bej el.
CAUSATIVE ORGANISM. T. pallidum is a coiled spiral filament 10 m long that moves actively in
fresh preparations. The organism cannot be stained by the usual methods and can be demonstrated in the
exudates and tissues by:
1. dark ground illumination (DGI) in fresh preparation;
2. fluorescent antibody technique: and
3. silver impregnation techniques.
The organism has not been cultivated in any culture media but experimental infection can be
produced in rabbits and chimpanzees. The organism is rapidly destroyed by cold, heat, and antiseptics.
Develop mucocutaneous lesions and painless lymphadenopathy in 2-3 months after the exposure.
Mucocutaneous lesions may be in the form of the mucous patches on mouth, pharynx and
vagina; and generalised skin eruptions and condyloma lata in anogenital region.
The lesions are of 2 main types:
i) Syphilitic gumma. it is a solitary, localised, rubbery lesion with central necrosis, seen in organs like
liver, testis, bone and brain. In liver, the gumma is associated with scarring of hepatic parenchyma (hepar
lobatum).
Histologically, the structure of gumma shows:

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(a) central coagulate necrosis resembling caseation but is less destructive so that outlines of necrosed cells
can still be faintly seen; and
(b) surrounding zone of palisaded macrophages with lymphocytes, plasma cells, giant cells and
fibroblasts.
(ii) Diffuse lesions of tertiary syphilis. The lesions appear following widespread dissemination of
spirochetes in the body. The diffuse lesions are predominantly seen in cardiovascular and nervous
systems.
Cardiovascular syphilis mainly involves thoracic aorta. The wall of aorta is weakened and dilated due to
syphilitic aortitis and results in aortic aneurysm, incompetence of aortic valve and narrowing of mouths of
coronary ostia.
Actinomycosis
Actinomycosis is a chronic suppurative disease caused by anaerobic bacteria, Actinomycetes
israelii. The disease is conventionally included in the mycology though the causative organism is
filamentous bacteria and not true fungus. The disease is world wide in distribution. The organisms are
commensals in the oral cavity, alimentary tract and vagina. The infection is always endogenous in origin
and not person-to-person. The organisms invade, proliferate and disseminate in favourable conditions like
break in mucocutaneous continuity, some underlying disease etc.
PATHOLOGIC CHANGES. Depending upon the anatomic location of lesions, actinomycosis is of 4
types: cervicofacial, thoracic, abdominal and pelvic.
Microscopically, irrespective of the location of actinomycosis, the following features are seen:
(i) The inflammatory reaction is a granuloma with central suppuration. There is formation of abscesses in
the centre of lesions and at the periphery are seen chronic inflammatory cells, giant cells and fibroblasts.
(ii) The centre of each abscess contain the bacterial colony, 'sulfur granule', characterised by radiating
filaments (hence previously known as ray fungus) with hyaline, eosinophilic, club-like ends
representative of immunoglobulins.
(in) Bacterial stains reveal the organisms as gram-positive filaments, non-acid fast, and stain positively
with Gomory's methenamine silver (GMS) staining.
Schistosomiasis
Schistosomiasis is the most important helminth disease, most of the mortality comes from hepatic
granulomas and fibrosis.
In mild S. mansoni or S. japonicum infections, white, pinhead-sized granulomas are scattered
throughout the gut and liver. The center of the granuloma is the schistosome egg, which contains a
miracidium; this degenerates over time and calcifies. The granulomas are composed of macrophages,
lymphocytes, neutrophils, and eosinophils; the last-mentioned are distinctive for helminth infections.
In severe S. mansoni or S. japonlcum infections, inflammatory patches or pseudopolyps may form
in the colon. Schistosome eggs, diverted to the lung through portal collaterals, may produce
gronulomatous pulmonary arteritis with intimal hyperplasia, progressive arterial obstruction, and
ultimately heart failure (cor pulmonale), On histological examination, arteries in the lungs show
disruption of the elastica layer by granulomas and scars, luminal organizing thrombi, and angiomatoid
lesions similar to those of idiopathic pulmonary hypertension.
In S. haematoblum infection, bladder inflammatory patches due to massive egg deposition and
granulomas appear early and, when they erode, cause hematuria. The most frequent complication of S.
haematobium infection is inflammation and fibrosis of the urethral walls. This is also an association be-
tween urinary schistosomiasis and squamous carcinoma of the bladder.
HYDATID DISEASE (ECHINOCOCCOSIS)
Hydatid disease occurs as a result of infection by the larval cyst stage of the tapeworm,
Echinococcus granulosus. The uncomplicated hydatid cyst of the liver may be silent or may produce dull
ache in the liver area and some abdominal distension. Complications of hydatid cyst include its rupture
(e.g. into the peritoneal cavity, bile ducts and lungs), secondary infection and hydatid allergy due to
sensitisation of the host with cyst fluid. Hydatid cyst grows slowly and may eventually attain a size over
10 cm in diameter in about 5 years. E. granulosus generally causes unilocular hydarid cyst while E.
multilocularis results in multilocular or alveolar hydatid cyst in the liver.

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 The cyst wall is composed of 3 distinguishable zonesouter pericyst, intermediate characteristic
ectocyst and inner endocyst:
1. Pericyst is the outer host inflammatory reaction consisting of fibroblasts, mononuclear cells,
eosinophils and giant cells and eventually developing into dense fibrous capsule which may even calcify.
2. Ectocyst is the intermediate layer composed of characteristic acellular, chitinous, laminated
hyaline material.
3. Endocyst is the inner germinal layer bearing daughter cysts (brood-capsules) and scolices pro-
jecting into the lumen.
Hydatid sand is the grain-like material composed of numerous scolices present in the hydatid
fluid. Hydatid fluid, in addition, contains antigenic proteins so that its liberation into circulation gives rise
to pronounced eosinophilia or may cause anaphlaxis.