Textbook of Pathology, 6th Edition

135











CHAPTER 6





Figure 6.6 Stages in phagocytosis of a foreign particle. A, Opsonisation of the particle. B, Pseudopod engulfing the opsonised particle.
C, Incorporation within the cell (phagocytic vacuole) and degranulation. D, Phagolysosome formation after fusion of lysosome of the cell.


1. Recognition and attachment Disposal of microorganisms can proceed by following Inflammation and Healing
2. Engulfment mechanisms:
3. Killing and degradation A. Intracellular mechanisms:
i) Oxidative bactericidal mechanism by oxygen free radicals
1. RECOGNITION AND ATTACHMENT
Phagocytosis is initiated by the expression of surface a) MPO-dependent
receptors on macrophages which recognise microorganisms: b) MPO-independent
mannose receptor and scavenger receptor. The process of ii) Oxidative bactericidal mechanism by lysosomal granules
phagocytosis is further enhanced when the microorganisms iii) Non-oxidative bactericidal mechanism
are coated with specific proteins, opsonins, from the serum B. Extracellular mechanisms:
or they get opsonised. Opsonins establish a bond between These mechanisms are discussed below.
bacteria and the cell membrane of phagocytic cell. The main A. INTRACELLULAR MECHANISMS. There are
opsonins present in the serum and their corresponding intracellular metabolic pathways which more commonly kill
receptors on the surface of phagocytic cells (PMNs or microbes by oxidative mechanism and less often non-
macrophages) are as under:
oxidative pathways.
i) IgG opsonin is the Fc fragment of immunoglobulin G; it is i) Oxidative bactericidal mechanism by oxygen free
the naturally occurring antibody in the serum that coats the radicals. An important mechanism of microbicidal killing is
bacteria while the PMNs possess receptors for the same. by oxidative damage by the production of reactive oxygen
ii) C3b opsonin is the fragment generated by activation of metabolites (O’ H O , OH’, HOCl, HOI, HOBr).
2
2
2
complement pathway. It is strongly chemotactic for attracting A phase of increased oxygen consumption (‘respiratory
PMNs to bacteria. burst’) by activated phagocytic leucocytes requires the
iii) Lectins are carbohydrate-binding proteins in the plasma essential presence of NADPH oxidase.
which bind to bacterial cell wall. NADPH-oxidase present in the cell membrane of
phagosome reduces oxygen to superoxide ion (O’ ):
2. ENGULFMENT 2
The opsonised particle bound to the surface of phagocyte is 2O 2O’
ready to be engulfed. This is accomplished by formation of 2 2
cytoplasmic pseudopods around the particle due to NADPH (Superoxide
activation of actin filaments beneath cell wall, enveloping it oxidase anion)
in a phagocytic vacuole. Eventually, the plasma membrane
enclosing the particle breaks from the cell surface so that NADPH NADP + H +
membrane lined phagocytic vacuole or phagosome lies
internalised and free in the cell cytoplasm. The phagosome Superoxide is subsequently converted into H O which
2
2
fuses with one or more lysosomes of the cell and form bigger has bactericidal properties:
vacuole called phagolysosome. 2O’ + 2H + H O 2
2
2
(Hydrogen peroxide)
3. KILLING AND DEGRADATION
Next comes the stage of killing and degradation of micro- This type of bactericidal activity is carried out either via
organism to dispose it off justifying the function of enzyme myeloperoxidase (MPO) present in the azurophilic
phagocytes as scavanger cells. The microorganisms after granules of neutrophils and monocytes, or independent of
being killed by antibacterial substances are degraded by enzyme MPO, as under:
hydrolytic enzymes. However, this mechanism fails to kill a) MPO-dependent killing. In this mechanism, the enzyme
and degrade some bacteria like tubercle bacilli. MPO acts on H O in the presence of halides (chloride, iodide
2
2

136 or bromide) to form hypohalous acid (HOCl, HOI, HOBr). CHEMICAL MEDIATORS OF INFLAMMATION
This is called H O -MPO-halide system and is more potent Also called as permeability factors or endogenous mediators
2
2
antibacterial system in polymorphs than H O alone: of increased vascular permeability, these are a large and
2
2
MPO increasing number of endogenous compounds which can
H O 2 HOCl + H O enhance vascular permeability. However, currently many
2
2
Cl’, Br’, I’ (Hypochlorous acid) chemical mediators have been identified which partake in
other processes of acute inflammation as well e.g.
b) MPO-independent killing. Mature macrophages lack the vasodilatation, chemotaxis, fever, pain and cause tissue
enzyme MPO and they carry out bactericidal activity by damage.
SECTION I
–
producing OH ions and superoxide singlet oxygen (O’) from The substances acting as chemical mediators of
H O in the presence of O’ (Haber-Weiss reaction) or in the inflammation may be released from the cells, the plasma, or
2
2
2
++
presence of Fe (Fenton reaction): damaged tissue itself. They are broadly classified into 2 groups:
i) mediators released by cells; and
O’ 2 OH’ ii) mediators originating from plasma.
Haber-Weiss reaction Table 6.2 presents a list of chemical mediators of acute
H O 2
2
Fe ++ inflammation.
Chemical mediators derived from various sources and
Fenton reaction
OH’ their contribution in acute inflammation are shown in
(Hydroxyl radical) Fig. 6.7.
Reactive oxygen metabolites are particularly useful in I. Cell-derived Mediators
eliminating microbial organisms that grow within
phagocytes e.g. M. tuberculosis, Histoplasma capsulatum. 1. VASOACTIVE AMINES. Two important pharmaco-
logically active amines that have role in the early
ii) Oxidative bactericidal mechanism by lysosomal inflammatory response (first one hour) are histamine and 5-
granules. In this mechanism, the preformed granule-stored hydroxytryptamine (5-HT) or serotonin; another recently
products of neutrophils and macrophages are discharged or added group is of neuropeptides.
secreted into the phagosome and the extracellular
environment. While the role of MPO is already highlighted i) Histamine. It is stored in the granules of mast cells,
above, others liberated by degranulation of macrophages and basophils and platelets. Histamine is released from these cells
neutrophils are protease, trypsinase, phospholipase, and by various agents as under:
General Pathology and Basic Techniques
alkaline phosphatase. Progressive degranulation of a) Stimuli or substances inducing acute inflammation e.g.
neutrophils and macrophages along with oxygen free radicals heat, cold, irradiation, trauma, irritant chemicals,
degrades proteins i.e. induces proteolysis. immunologic reactions etc.
b) Anaphylatoxins like fragments of complement C3a, and
iii) Non-oxidative bactericidal mechanism. Some agents C5a, which increase vascular permeability and cause
released from the granules of phagocytic cells do not require oedema in tissues.
oxygen for bactericidal activity. These include the following:
c) Histamine-releasing factors from neutrophils, monocytes
a) Granules. Some of liberated lysosomal granules do not kill and platelets.
by oxidative damage but cause lysis of within phagosome. d) Interleukins.
These are lysosomal hydrolases, permeability increasing
factors, cationic proteins (defensins), lipases, ptoteases,
DNAases.   TABLE 6.2: Chemical Mediators of Acute Inflammation.

b) Nitric oxide. Nitric oxide reactive free radicals similar to I. CELL-DERIVED MEDIATORS
oxygen free radicals are formed by nitric oxide synthase and 1. Vasoactive amines (Histamine, 5-hydroxytryptamine,
is a potent mechanism of microbial killing. Nitric oxide is neuropeptides)
produced by endothelial cells as well as by activated 2. Arachidonic acid metabolites (Eicosanoids)
macrophages. i. Metabolites via cyclo-oxygenase pathway (prostaglandins,
thromboxane A 2 , prostacyclin, resolvins)
B. EXTRACELLULAR MECHANISMS. Following ii. Metabolites via lipo-oxygenase pathway (5-HETE,
leukotrienes, lipoxins)
mechanisms explain the bactericidal activity at extracellular 3. Lysosomal components (from PMNs, macrophages)
level: 4. Platelet activating factor
5. Cytokines (IL-1, TNF-α, TNF-β, IFN-γ, chemokines)
i) Granules. Degranulation of macrophages and neutrophils 6. Free radicals (Oxygen metabolites, nitric oxide)
explained above continues to exert its effects of proteolysis
outside the cells as well. II. PLASMA-DERIVED MEDIATORS (PLASMA PROTEASES)
Products of:
ii) Immune mechanisms. As already discussed in Chapter 1. The kinin system
4, immune-mediated lysis of microbes takes place outside 2. The clotting system
the cells by mechanisms of cytolysis, antibody-mediated lysis 3. The fibrinolytic system
and by cell-mediated cytotoxicity. 4. The complement system

137











CHAPTER 6















Figure 6.7 Chemical mediators of inflammation. Inflammation and Healing

The main actions of histamine are: vasodilatation, i) Metabolites via cyclo-oxygenase pathway: Prostaglan-
increased vascular (venular) permeability, itching and pain. dins, thromboxane A , prostacyclin. The name ‘prosta-
2
Stimulation of mast cells and basophils also releases products glandin’ was first given to a substance found in human
of arachidonic acid metabolism including the release of slow- seminal fluid but now the same substance has been isolated
reacting substances of anaphylaxis (SRS-As). The SRS-As consist from a number of other body cells. Prostaglandins and related
of various leukotrienes (LTC , LTD and LTE ). compounds are also called autocoids because these substances
4
4
4
ii) 5-Hydroxytryptamine (5-HT or serotonin). It is present are mainly auto- and paracrine agents. The terminology used
in tissues like chromaffin cells of GIT, spleen, nervous tissue, for prostaglandins is abbreviation as PG followed by suffix
mast cells and platelets. The actions of 5-HT are similar to of an alphabet and a serial number e.g. PGG , PGE etc.
2
2
histamine but it is a less potent mediator of increased vascular Cyclo-oxygenase (COX), a fatty acid enzyme present as
permeability and vasodilatation than histamine. It may be COX-1 and COX-2, acts on activated arachidonic acid to form
mentioned here that carcinoid tumour is a serotonin-secreting prostaglandin endoperoxide (PGG ). PGG is enzymatically
2
2
tumour (Chapter 20). transformed into PGH with generation of free radical of
2
oxygen. PGH is further acted upon by enzymes and results
2
iii) Neuropeptides. Another class of vasoactive amines is in formation of the following 3 metabolites (Fig. 6.8):
tachykinin neuropeptides, such as substance P, neurokinin a) Prostaglandins (PGD , PGE and PGF -α). PGD and PGE
2
A, vasoactive intestinal polypeptide (VIP) and somatostatin. act on blood vessels to cause increased venular permeability, 2
2
2
2
These small peptides are produced in the central and vasodilatation and bronchodilatation and inhibit
peripheral nervous systems. inflammatory cell function. PGF -α induces vasodilatation
The major proinflammatory actions of these neuropeptides 2
is as follows: and bronchoconstriction.
b) Thromboxane A (TXA ). Platelets contain the enzyme
a) Increased vascular permeability. thromboxane synthetase and hence the metabolite,
2
2
b) Transmission of pain stimuli. thromboxane A , formed is active in platelet aggregation,
c) Mast cell degranulation. 2
besides its role as a vasoconstrictor and broncho-constrictor.
2. ARACHIDONIC ACID METABOLITES (EICO- c) Prostacyclin (PGI ). PGI induces vasodilatation, broncho-
2
2
SANOIDS). Arachidonic acid metabolites or eicosanoids are dilatation and inhibits platelet aggregation.
the most potent mediators of inflammation, much more than d) Resolvins are a newly described derivative of COX
oxygen free radicals. pathway. These mediators act by inhibiting production of
Arachidonic acid is a fatty acid, eicosatetraenoic acid; pro-inflammatory cytokines. Thus, resolvins are actually
Greek word ‘eikosa’ means ‘twenty’ because of 20 carbon atom helpful—drugs such as aspirin act by inhibiting COX activity
composition of this fatty acid. Arachidonic acid is a and stimulating production of resolvins.
constituent of the phospholipid cell membrane, besides its It may be mentioned here that some of the major anti-
presence in some constituents of diet. Arachidonic acid is inflammatory drugs act by inhibiting activity of the enzyme
released from the cell membrane by phospholipases. It is then COX; e.g. non-steroidal anti-inflammatory drugs (NSAIDs),
activated to form arachidonic acid metabolites or eicosanoids COX-2 inhibitors.
by one of the following 2 pathways: via cyclo-oxygenase ii) Metabolites via lipo-oxygenase pathway: 5-HETE,
pathway and via lipo-oxygenase pathway: leukotrienes, lipoxins. The enzyme, lipo-oxygenase, a

138











SECTION I





Figure 6.8 Arachidonic acid metabolites via cyclooxygenase pathway.

predominant enzyme in neutrophils, acts on activated i) Granules of neutrophils. Neutrophils have 3 types of
arachidonic acid to form hydroperoxy eicosatetraenoic acid granules: primary or azurophil, secondary or specific, and
(5-HPETE) which on further peroxidation forms following 2 tertiary.
metabolites (Fig. 6.9): a) Primary or azurophil granules are large azurophil granules
a) 5-HETE (hydroxy compound), an intermediate product, which contain functionally active enzymes. These are
is a potent chemotactic agent for neutrophils. myeloperoxidase, acid hydrolases, acid phosphatase,
b) Leukotrienes (LT) are so named as they were first isolated lysozyme, defensin (cationic protein), phospholipase,
from leucocytes. Firstly, unstable leukotriene A (LTA ) is cathepsin G, elastase, and protease.
4
4
formed which is acted upon by enzymes to form LTB 4 b) Secondary or specific granules contain alkaline phosphatase,
(chemotactic for phagocytic cells and stimulates phagocytic lactoferrin, gelatinase, collagenase, lysozyme, vitamin-B 12
cell adherence) while LTC , LTD and LTE have common binding proteins, plasminogen activator.
4
4
4
actions by causing smooth muscle contraction and thereby c) Tertiary granules or C particles contain gelatinase and acid
induce vasoconstriction, bronchoconstriction and increased hydrolases.
vascular permeability; hence they are also called as slow- Myeloperoxidase causes oxidative lysis by generation of
reacting substances of anaphylaxis (SRS-As). oxygen free radicals, acid hydrolases act within the cell to
General Pathology and Basic Techniques
c) Lipoxins (LX) are a recently described product of cause destruction of bacteria in phagolysosome while prote-
lipooxygenase pathway. Lipooxygenase-12 present in ases attack on the extracellular constituents such as basement
platelets acts on LTA derived from neutrophils and forms membrane, collagen, elastin, cartilage etc.
4
LXA and LXB . Lipoxins act to regulate and counterbalance However, degradation of extracellular components like
4
4
actions of leukotrienes. collagen, basement membrane, fibrin and cartilage by
proteases results in harmful tissue destruction which is kept
3. LYSOSOMAL COMPONENTS. The inflammatory in check by presence of antiproteases like α -antitrypsin and
cells—neutrophils and monocytes, contain lysosomal α -macroglobulin. 1
granules which on release elaborate a variety of mediators 2
of inflammation. These are as under: ii) Granules of monocytes and tissue macrophages. These
cells on degranulation also release mediators of inflammation
like acid proteases, collagenase, elastase and plasminogen
activator. However, they are more active in chronic
inflammation than acting as mediators of acute inflammation.

4. PLATELET ACTIVATING FACTOR (PAF). It is
released from IgE-sensitised basophils or mast cells, other
leucocytes, endothelium and platelets. Apart from its action
on platelet aggregation and release reaction, the actions of
PAF as mediator of inflammation are:
increased vascular permeability;
vasodilatation in low concentration and vasoconstriction
otherwise;
bronchoconstriction;
adhesion of leucocytes to endothelium; and
chemotaxis.
5. CYTOKINES. Cytokines are polypeptide substances pro-
duced by activated lymphocytes (lymphokines) and activated
Figure 6.9 Arachidonic acid metabolites via lipooxygenase pathway. monocytes (monokines). These agents may act on ‘self’ cells

producing them or on other cells. Although over 200 Hageman factor (factor XII) of clotting system plays a key role 139
cytokines have been described, major cytokines acting as in interactions of the four systems. Activation of factor XII in
mediators of inflammation are: interleukin-1 (IL-1), tumour vivo by contact with basement membrane and bacterial
necrosis factor (TNF)-α and β, interferon (IFN)-γ, and endotoxins, and in vitro with glass or kaolin, leads to
chemokines (IL-8, PF-4). activation of clotting, fibrinolytic and kinin systems. In
IL-1 and TNF-α are formed by activated macrophages inflammation, activation of factor XII is brought about by
while TNF-β and IFN-γ are produced by activated T cells. contact of the factor leaking through the endothelial gaps. CHAPTER 6
The chemokines include interleukin 8 (released from The end-products of the activated clotting, fibrinolytic and
activated macrophages) and platelet factor-4 from activated kinin systems activate the complement system that generate
platelets, both of which are potent chemoattractant for permeability factors. These permeability factors, in turn,
inflammatory cells and hence their name. further activate clotting system.
The actions of various cytokines as mediator of The inter-relationship among 4 systems is summarised
inflammation are as under: in Fig. 6.10.
i) IL-1 and TNF-αα αα α, TNF-ββ ββ β induce endothelial effects in the 1. THE KININ SYSTEM. This system on activation by
form of increased leucocyte adherence, thrombogenicity, factor Xlla generates bradykinin, so named because of the
elaboration of other cytokines, fibroblastic proliferation and slow contraction of smooth muscle induced by it. First,
acute phase reactions. kallikrein is formed from plasma prekallikrein by the action Inflammation and Healing
ii) IFN-γγ γγ γ causes activation of macrophages and neutrophils of prekallikrein activator which is a fragment of factor Xlla.
and is associated with synthesis of nitric acid synthase. Kallikrein then acts on high molecular weight kininogen to
iii) Chemokines are a family of chemoattractants for form bradykinin (Fig. 6.11).
inflammatory cells (as discussed above) and include: Bradykinin acts in the early stage of inflammation and
IL-8 chemotactic for neutrophils; its effects include:
platelet factor-4 chemotactic for neutrophils, monocytes smooth muscle contraction;
and eosinophils; vasodilatation;
MCP-1 chemotactic for monocytes; and increased vascular permeability; and
eotaxin chemotactic for eosinophils. pain.

6. FREE RADICALS: OXYGEN METABOLITES AND 2. THE CLOTTING SYSTEM. Factor Xlla initiates the
NITRIC OXIDE. Free radicals act as potent mediator of cascade of the clotting system resulting in formation of
inflammation: fibrinogen which is acted upon by thrombin to form fibrin
i) Oxygen-derived metabolites are released from activated and fibrinopeptides (Fig. 6.12).
neutrophils and macrophages and include superoxide The actions of fibrinopeptides in inflammation are:
oxygen (O’ ), H O , OH’ and toxic NO products. These increased vascular permeability;
2
2
2
oxygen-derived free radicals have the following action in chemotaxis for leucocyte; and
inflammation: anticoagulant activity.
Endothelial cell damage and thereby increased vascular 3. THE FIBRINOLYTIC SYSTEM. This system is activated
permeability. by plasminogen activator, the sources of which include
Activation of protease and inactivation of antiprotease kallikrein of the kinin system, endothelial cells and
causing tissue matrix damage. leucocytes. Plasminogen activator acts on plasminogen
Damage to other cells. present as component of plasma proteins to form plasmin.
The actions of free radicals are counteracted by Further breakdown of fibrin by plasmin forms fibrino-
antioxidants present in tissues and serum which play a peptides or fibrin split products (Fig. 6.13).
protective role (page 33). The actions of plasmin in inflammation are as follows:
ii) Nitric oxide (NO) was originally described as vascular activation of factor XII to form prekallikrein activator that
relaxation factor produced by endothelial cells. Now it is stimulates the kinin system to generate bradykinin;
known that NO is formed by activated macrophages during splits off complement C to form C which is a
the oxidation of arginine by the action of enzyme, NO permeability factor; and 3 3a
synthase. NO plays the following role in mediating degrades fibrin to form fibrin split products which
inflammation: increase vascular permeability and are chemotactic to
Vasodilatation leucocytes.
Anti-platelet activating agent
Possibly microbicidal action. 4. THE COMPLEMENT SYSTEM. The activation of
complement system can occur either:
II. Plasma-derived Mediators (Plasma Proteases) i) by classic pathway through antigen-antibody complexes;

These include the various products derived from activation or
and interaction of 4 interlinked systems: kinin, clotting, ii) by alternate pathway via non-immunologic agents such as
fibrinolytic and complement. Each of these systems has its bacterial toxins, cobra venoms and IgA.
inhibitors and accelerators in plasma with negative and Complement system on activation by either of these two
positive feedback mechanisms respectively. pathways yields activated products which include

140











SECTION I






















Figure 6.10 Inter-relationship among clotting, fibrinolytic, kinin and complement systems.


anaphylatoxins (C3a, C4a and C5a), and membrane attack evident in hypersensitivity conditions. Such self-damaging


complex (MAC) i.e. C5b,C6,7,8,9. effects are kept in check by the host mechanisms in order to
The actions of activated complement system in resolve inflammation. These mechanisms are as follows:
General Pathology and Basic Techniques
inflammation are as under: i) Acute phase reactants. A variety of acute phase reactant
C3a, C5a, C4a (anaphylatoxins) activate mast cells and
basophils to release of histamine, cause increased vascular (APR) proteins are released in plasma in response to tissue
trauma and infection. Their major role is to protect the normal
permeability causing oedema in tissues, augments cells from harmful effects of toxic molecules generated in
phagocytosis. inflammation and to clear away the waste material. APRs
C3b is an opsonin. include the following:
C5a is chemotactic for leucocytes.
Membrane attack complex (MAC) (C5b-C9) is a lipid i) Certain cellular protection factors (e.g. α -antitrypsin, α -
1
1
dissolving agent and causes holes in the phospholipid chymotrypsin, α -antiplasmin, plasminogen activator
2
membrane of the cell. inhibitor): They protect the tissues from cytotoxic and
proteolytic damage.
REGULATION OF INFLAMMATION ii) Some coagulation proteins (e.g. fibrinogen, plasminogen, von
Willebrand factor, factor VIII): They generate factors to
The onset of inflammatory responses outlined above may replace those consumed in coagulation.
have potentially damaging influence on the host tissues as
iii) Transport proteins (e.g. ceruloplasmin, haptoglobin): They
carry generated factors.
iv) Immune agents (e.g. serum amyloid A and P component,
C-reactive protein): CRP is an opsonising agent for
phagocytosis and its levels are a useful indictor of
inflammation in the body.
v) Stress proteins (e.g. heat shock proteins—HSP, ubiquitin):
They are molecular chaperons who carry the toxic waste
within the cell to the lysosomes.
vi) Antioxidants (e.g. ceruloplasmin are active in elimination
of excess of oxygen free radicals.
The APR are synthesised mainly in the liver, and to some
extent in macrophages. APR along with systemic features of

Figure 6.11 Pathway of kinin system. fever and leucocytosis is termed ‘acute phase response’.

1. Polymorphonuclear Neutrophils (PMNs) 141
Commonly called as neutrophils or polymorphs, these cells
along with basophils and eosinophils are known as
granulocytes due to the presence of granules in the
cytoplasm. These granules contain many substances like
proteases, myeloperoxidase, lysozyme, esterase, aryl CHAPTER 6
sulfatase, acid and alkaline phosphatase, and cationic
proteins. The diameter of neutrophils ranges from 10 to
15 μm and are actively motile (Table 6.3,A). These cells
comprise 40-75% of circulating leucocytes and their number
is increased in blood (neutrophilia) and tissues in acute
bacterial infections. These cells arise in the bone marrow from
stem cells (Chapter 12).
The functions of neutrophils in inflammation are as
follows:
i) Initial phagocytosis of microorganisms as they form the
first line of body defense in bacterial infection. The steps Inflammation and Healing
involved are adhesion of neutrophils to vascular endo-
thelium, emigration through the vessel wall, chemotaxis,
engulfment, degranulation, killing and degradation of the
foreign material.
ii) Engulfment of antigen-antibody complexes and non-
Figure 6.12 Pathway of the clotting system. microbial material.
iii) Harmful effect of neutrophils in causing basement
Deficient synthesis of APR leads to severe form of disease in membrane destruction of the glomeruli and small blood
the form of chronic and repeated inflammatory responses. vessels.
ii) Glucosteroids. The endogenous glucocorticoids act as
anti-inflammatory agents. Their levels are raised in infection 2. Eosinophils
and trauma by self-regulating mechanism. These are larger than neutrophils but are fewer in number,

iii) Free cytokine receptors. The presence of freely circulating comprising 1 to 6% of total blood leucocytes (Table 6.3,E).
soluble receptors for cytokines in the serum correlates directly Eosinophils share many structural and functional similarities
with disease activity. with neutrophils like their production in the bone marrow,
locomotion, phagocytosis, lobed nucleus and presence of
iv) Anti-inflammatory chemical mediators. As already granules in the cytoplasm containing a variety of enzymes,
described, PGE or prostacyclin have both pro-inflammatory of which major basic protein and eosinophil cationic protein
2
as well as anti-inflammatory actions.
are the most important which have bactericidal and toxic
action against helminthic parasites. However, granules of
THE INFLAMMATORY CELLS
eosinophils are richer in myeloperoxidase than neutrophils
The cells participating in acute and chronic inflammation are and lack lysozyme. High level of steroid hormones leads to
circulating leucocytes, plasma cells and tissue macrophages. fall in number of eosinophils and even disappearance from
The structure, function and production of these cells are dealt blood.
with in detail in Chapter 14. Here, it is pertinent to describe The absolute number of eosinophils is increased in the
the role of these cells in inflammation. Summary of their following conditions and, thus, they partake in inflammatory
morphology, characteristics and functions is given in responses associated with these conditions:
Table 6.3. i) allergic conditions;
ii) parasitic infestations;
iii) skin diseases; and
iv) certain malignant lymphomas.

3. Basophils (Mast Cells)
The basophils comprise about 1% of circulating leucocytes
and are morphologically and pharmacologically similar to
mast cells of tissue. These cells contain coarse basophilic
granules in the cytoplasm and a polymorphonuclear nucleus
(Table 6.3,F). These granules are laden with heparin and
histamine. Basophils and mast cells have receptors for IgE
Figure 6.13 The activation of fibrinolytic system. and degranulate when cross-linked with antigen.

142
  TABLE 6.3: Morphology and Functions of Inflammatory Cells.
Morphology Features Mediators
i. Initial phagocytosis of bacteria i. Primary granules (MPO, lysozyme,
and foreign body cationic proteins, acid hydrolases,
ii. Acute inflammatory cell elastase)
ii. Secondary granules (lysozyme, alk.
phosph, collagenase, lactoferrin)
iii. Tertiary granules (gelatinase,
cathepsin)
SECTION I
A, POLYMORPH iv. Reactive oxygen metabolites
i. Bacterial phagocytosis i. Acid and neutral hydrolases
ii. Chronic inflammatory cell (lysosomal)
iii. Regulates lymphocyte response ii. Cationic protein
iii. Phospholipase
iv. Prostaglandins, leukotrienes
B, MONOCYTE/MACROPHAGE v. IL-1

i. Humoral and cell-mediated i. B cells: antibody production
immune responses ii. T cells: delayed hypersensitivity,
ii. Chronic inflammatory cell cytotoxicity
iii. Regulates macrophage response
C, LYMPHOCYTE
i. Derived from B cells i. Antibody synthesis
ii. Chronic inflammatory cell ii. Antibody secretion



D, PLASMA CELL
i. Allergic states i. Reactive oxygen metabolites
ii. Parasitic infestations ii. Lysosomal (major basic protein,
General Pathology and Basic Techniques
iii. Chronic inflammatory cell cationic protein, eosinophil
peroxidase, neurotoxin)
iii. PGE 2 synthesis
E, EOSINOPHIL

i. Receptor for IgE molecules i. Histamine
ii. Electron-dense granules ii. Leukotrienes
iii. Platelet activating factor


F, BASOPHIL/MAST CELL



The role of these cells in inflammation are: i) In tissues, they are dominant cells in chronic inflammation
i) in immediate and delayed type of hypersensitivity and late stage of acute inflammation.
reactions; and ii) In blood, their number is increased (lymphocytosis) in
ii) release of histamine by IgE-sensitised basophils. chronic infections like tuberculosis.
5. Plasma Cells
4. Lymphocytes
These cells are larger than lymphocytes with more abundant
Next to neutrophils, these cells are the most numerous of cytoplasm and an eccentric nucleus which has cart-wheel
the circulating leucocytes (20-45%). Apart from blood, pattern of chromatin (Table 6.3,D). Plasma cells are normally
lymphocytes are present in large numbers in spleen, thymus, not seen in peripheral blood. They develop from B
lymph nodes and mucosa-associated lymphoid tissue lymphocytes and are rich in RNA and γ-globulin in their
(MALT). They have scanty cytoplasm and consist almost cytoplasm. There is an interrelationship between
entirely of nucleus (Table 6.3,C). plasmacytosis and hyperglobulinaemia. These cells are most
Their role in antibody formation (B lymphocytes) and in active in antibody synthesis.
cell-mediated immunity (T lymphocytes) has been discussed Their number is increased in the following conditions:
in Chapter 4; in addition these cells participate in the i) prolonged infection with immunological responses e.g.
following types of inflammatory responses: in syphilis, rheumatoid arthritis, tuberculosis;

143











CHAPTER 6








Figure 6.14 Giant cells of various types. A, Foreign body giant cell with uniform nuclei dispersed throughout the cytoplasm. B, Langhans’ giant
cells with uniform nuclei arranged peripherally or clustered at the two poles. C, Touton giant cell with circular pattern of nuclei and vacuolated
cytoplasm. D, Anaplastic tumour giant cell with nuclei of variable size and shape. E, Reed-Sternberg cell. F, Osteoclastic tumour giant cell. Inflammation and Healing


ii) hypersensitivity states; and c) Products of complement.
iii) multiple myeloma. d) Some coagulation factors (factor V and thromboplastin)
which convert fibrinogen to fibrin.
6. Mononuclear-Phagocyte System e) Chemotactic agents for other leucocytes.
(Reticuloendothelial System) f) Metabolites of arachidonic acid.
This cell system includes cells derived from 2 sources with g) Growth promoting factors for fibroblasts, blood vessels
common morphology, function and origin (Table 6.3,B). and granulocytes.
These are as under: h) Cytokines like interleukin-1 and TNF-α.
Blood monocytes. These comprise 4-8% of circulating i) Oxygen-derived free radicals.
leucocytes. 7. Giant Cells
Tissue macrophages. These include the following cells in
different tissues: A few examples of multinucleate giant cells exist in normal
i) Macrophages in inflammation. tissues (e.g. osteoclasts in the bones, trophoblasts in placenta,
ii) Histiocytes which are macrophages present in megakaryocytes in the bone marrow). However, in chronic
connective tissues. inflammation when the macrophages fail to deal with
iii) Kupffer cells are macrophages of liver cells. particles to be removed, they fuse together and form
iv) Alveolar macrophages (type II pneumocytes) in lungs. multinucleated giant cells. Besides, morphologically distinct
v) Macrophages/histiocytes of the bone marrow. giant cells appear in some tumours also. Some of the common
vi) Tingible body cells of germinal centres of lymph nodes. types of giant cells are described below (Fig. 6.14):
vii) Littoral cells of splenic sinusoids. A. Giant cells in inflammation:
viii) Osteoclasts in the bones. i) Foreign body giant cells. These contain numerous nuclei (up
ix) Microglial cells of the brain. to 100) which are uniform in size and shape and resemble
x) Langerhans’ cells/dendritic histiocytes of the skin. the nuclei of macrophages. These nuclei are scattered
xi) Hoffbauer cells of the placenta. throughout the cytoplasm. These are seen in chronic infective
xii) Mesangial cells of glomerulus. granulomas, leprosy and tuberculosis.
The mononuclear phagocytes are the scavenger cells of
the body as well as participate in immune system of the body ii) Langhans’ giant cells. These are seen in tuberculosis and
sarcoidosis. Their nuclei are like the nuclei of macrophages
(Chapter 4); their functions in inflammation are as under:
and epithelioid cells. These nuclei are arranged either around
Role of macrophages in inflammation. The functions of the periphery in the form of horseshoe or ring, or are clustered
mononuclear-phagocyte cells are as under: at the two poles of the giant cell.
i) Phagocytosis (cell eating) and pinocytosis (cell drinking). iii) Touton giant cells. These multinucleated cells have
ii) Macrophages on activation by lymphokines released by T vacuolated cytoplasm due to lipid content e.g. in xanthoma.
lymphocytes or by non-immunologic stimuli elaborate a iv) Aschoff giant cells. These multinucleate giant cells are
variety of biologically active substances as under: derived from cardiac histiocytes and are seen in rheumatic
a) Proteases like collagenase and elastase which degrade nodule (Chapter 16).
collagen and elastic tissue. B. Giant cells in tumours:
b) Plasminogen activator which activates the fibrinolytic i) Anaplastic cancer giant cells. These are larger, have
system. numerous nuclei which are hyperchromatic and vary in size

144 and shape. These giant cells are not derived from ii) Immune status of host. Patients who are immuno-
macrophages but are formed from dividing nuclei of the suppressed from congenital or acquired immunodeficiency
neoplastic cells e.g. carcinoma of the liver, various soft tissue have lowered inflammatory response and spread of
sarcomas etc. infections occurs rapidly e.g. in AIDS, congenital immuno-
ii) Reed-Sternberg cells. These are also malignant tumour deficiency diseases, protein calorie malnutrition, starvation.
giant cells which are generally binucleate and are seen in iii) Congenital neutrophil defects. Congenital defects in
various histologic types of Hodgkin’s lymphomas. neutrophil structure and functions result in reduced
iii) Giant cell tumour of bone. This tumour of the bones has inflammatory response.
uniform distribution of osteoclastic giant cells spread in the iv) Leukopenia. Patients with low WBC count with
SECTION I
stroma. neutropenia or agranulocytosis develop spreading infection.
v) Site or type of tissue involved. For example, the lung
FACTORS DETERMINING VARIATION IN has loose texture as compared to bone and, thus, both tissues
INFLAMMATORY RESPONSE react differently to acute inflammation.
Although acute inflammation is typically characterised by vi) Local host factors. For instance, ischaemia, presence of
vascular and cellular events with emigration of neutrophilic foreign bodies and chemicals cause necrosis and are thus
leucocytes, not all examples of acute inflammation show cause more harm.
infiltration by neutrophils. On the other hand, some chronic
inflammatory conditions are characterised by neutrophilic 3. Type of Exudation
infiltration. For example, typhoid fever is an example of acute The appearance of escaped plasma determines the morpho-
inflammatory process but the cellular response in it is logic type of inflammation as under:
lymphocytic; osteomyelitis is an example of chronic
inflammation but the cellular response in this condition is i) Serous, when the fluid exudate resembles serum or is
mainly neutrophilic. watery e.g. pleural effusion in tuberculosis, blister formation
The variation in inflammatory response depends upon a in burns.
number of factors and processes. These are discussed below: ii) Fibrinous, when the fibrin content of the fluid exudate is
high e.g. in pneumococcal and rheumatic pericarditis.
1. Factors Involving the Organisms
iii) Purulent or suppurative exudate is formation of creamy
i) Type of injury and infection. For example, skin reacts pus as seen in infection with pyogenic bacteria e.g. abscess,
to herpes simplex infection by formation of vesicle and to acute appendicitis.
General Pathology and Basic Techniques
streptococcal infection by formation of boil; lung reacts to iv) Haemorrhagic, when there is vascular damage e.g. acute
pneumococci by occurrence of lobar pneumonia while to haemorrhagic pneumonia in influenza.
tubercle bacilli it reacts by granulomatous inflammation.
v) Catarrhal, when the surface inflammation of epithelium
ii) Virulence. Many species and strains of organisms may produces increased secretion of mucous e.g. common cold.
have varying virulence e.g. the three strains of C. diphtheriae
(gravis, intermedius and mitis) produce the same diphtherial MORPHOLOGY OF ACUTE INFLAMMATION
exotoxin but in different amount.
Inflammation of an organ is usually named by adding the
iii) Dose. The concentration of organism in small doses suffix-itis to its Latin name e.g. appendicitis, hepatitis,
produces usually local lesions while larger dose results in cholecystitis, meningitis etc. A few morphologic varieties of
more severe spreading infections.
acute inflammation are described below:
iv) Portal of entry. Some organisms are infective only if 1. PSEUDOMEMBRANOUS INFLAMMATION. It is
administered by particular route e.g. Vibrio cholerae is not inflammatory response of mucous surface (oral, respiratory,
pathogenic if injected subcutaneously but causes cholera if bowel) to toxins of diphtheria or irritant gases. As a result of
swallowed.
denudation of epithelium, plasma exudes on the surface
v) Product of organisms. Some organisms produce enzymes where it coagulates, and together with necrosed epithelium,
that help in spread of infections e.g. hyaluronidase by forms false membrane that gives this type of inflammation
Clostridium welchii, streptokinase by streptococci, its name.
staphylokinase and coagulase by staphylococci.
2. ULCER. Ulcers are local defects on the surface of an organ
produced by inflammation. Common sites for ulcerations are
2. Factors Involving the Host
the stomach, duodenum, intestinal ulcers in typhoid fever,
i) Systemic diseases. Certain acquired systemic diseases intestinal tuberculosis, bacillary and amoebic dysentery,
in the host are associated with impaired inflammatory ulcers of legs due to varicose veins etc. In the acute stage,
response e.g. diabetes mellitus, chronic renal failure, cirrhosis there is infiltration by polymorphs with vasodilatation while
of the liver, chronic alcoholism, bone marrow suppression long-standing ulcers develop infiltration by lymphocytes,
from various causes (drugs, radiation, idiopathic). These plasma cells and macrophages with associated fibroblastic
conditions render the host more susceptible to infections. proliferation and scarring.

3. SUPPURATION (ABSCESS FORMATION). When bacilli of plague etc. Septicaemia is generally accompanied 145
acute bacterial infection is accompanied by intense by systemic effects like toxaemia, multiple small
neutrophilic infiltrate in the inflamed tissue, it results in tissue haemorrhages, neutrophilic leucocytosis and disseminated
necrosis. A cavity is formed which is called an abscess and intravascular coagulation (DIC).
contains purulent exudate or pus and the process of abscess iii) Pyaemia is the dissemination of small septic thrombi in
formation is known as suppuration. The bacteria which cause the blood which cause their effects at the site where they are
suppuration are called pyogenic. CHAPTER 6
lodged. This can result in pyaemic abscesses or septic infarcts.
Microscopically, pus is creamy or opaque in appearance a) Pyaemic abscesses are multiple small abscesses in various
and is composed of numerous dead as well as living organs such as in cerebral cortex, myocardium, lungs and
neutrophils, some red cells, fragments of tissue debris and renal cortex, resulting from very small emboli fragmented
fibrin. In old pus, macrophages and cholesterol crystals from septic thrombus. Microscopy of pyaemic abscess
are also present (Fig. 6.15). shows a central zone of necrosis containing numerous
bacteria, surrounded by a zone of suppuration and an
An abscess may be discharged to the surface due to outer zone of acute inflammatory cells (Fig. 6.16,A).
increased pressure inside or may require drainage by the b) Septic infarcts result from lodgement of larger fragments
surgeon. Due to tissue destruction, resolution does not occur of septic thrombi in the arteries with relatively larger foci
but instead healing by fibrous scarring takes place. of necrosis, suppuration and acute inflammation e.g. Inflammation and Healing
Some of the common examples of abscess formation are
as under: septic infarcts of the lungs, liver, brain, and kidneys from
septic thrombi of leg veins or from acute bacterial
i) Boil or furruncle which is an acute inflammation via hair endocarditis (Fig. 6.16,B).
follicles in the dermal tissues.
ii) Carbuncle is seen in untreated diabetics and occurs as a SYSTEMIC EFFECTS OF ACUTE INFLAMMATION
loculated abscess in the dermis and soft tissues of the neck.
The account of acute inflammation given up to now above is
4. CELLULITIS. It is a diffuse inflammation of soft tissues based on local tissue responses. However, acute
resulting from spreading effects of substances like inflammation is associated with systemic effects as well.
hyaluronidase released by some bacteria. These include fever, leucocytosis and lymphangitis-
5. BACTERIAL INFECTION OF THE BLOOD. This lymphadenitis.
includes the following 3 conditions: 1. Fever occurs due to bacteraemia. It is thought to be
i) Bacteraemia is defined as presence of small number of mediated through release of factors like prostaglandins,
bacteria in the blood which do not multiply significantly. interleukin-1 and TNF-α in response to infection.
They are commonly not detected by direct microscopy. Blood 2. Leucocytosis commonly accompanies the acute
culture is done for their detection e.g. infection with inflammatory reactions, usually in the range of 15,000-
Salmonella typhi, Escherichia coli, Streptococcus viridans. 20,000/μl. When the counts are higher than this with ‘shift
ii) Septicaemia means presence of rapidly multiplying, to left’ of myeloid cells, the blood picture is described as
highly pathogenic bacteria in the blood e.g. pyogenic cocci, leukaemoid reaction. Usually, in bacterial infections there is






























Figure 6.15 An abscess in the skin. It contains pus composed of necrotic tissue, debris, fibrin, RBCs and dead and living neutrophils. Some
macrophages are seen at the periphery.

146











SECTION I






























General Pathology and Basic Techniques
Figure 6.16 Sequelae of pyaemia.


neutrophilia; in viral infections lymphocytosis; and in FATE OF ACUTE INFLAMMATION
parasitic infestations, eosinophilia. Typhoid fever, an The acute inflammatory process can culminate in one of the
example of acute inflammation, however, induces leucopenia
with relative lymphocytosis. following outcomes (Fig. 6.17):
1. Resolution. It means complete return to normal tissue
3. Lymphangitis-lymphadenitis is one of the important following acute inflammation. This occurs when tissue
manifestations of localised inflammatory injury. The changes are slight and the cellular changes are reversible e.g.
lymphatics and lymph nodes that drain the inflamed resolution in lobar pneumonia.
tissue show reactive inflammatory changes in the form
of lymphangitis and lymphadenitis. This response 2. Healing. Healing by fibrosis takes place when the tissue
represents either a nonspecific reaction to mediators destruction in acute inflammation is extensive so that there
released from inflamed tissue or is an immunologic is no tissue regeneration. But when tissue loss is superficial,
response to a foreign antigen. The affected lymph nodes it is restored by regeneration.
may show hyperplasia of lymphoid follicles (follicular
hyperplasia) and proliferation of mononuclear phago- 3. Suppuration. When the pyogenic bacteria causing acute
cytic cells in the sinuses of lymph node (sinus histio- inflammation result in severe tissue necrosis, the process
cytosis) (Chapter 14). progresses to suppuration. Initially, there is intense neutro-
philic infiltration. Subsequently, mixture of neutrophils,
4. Shock may occur in severe cases. Massive release of bacteria, fragments of necrotic tissue, cell debris and fibrin
cytokine TNF-α, a mediator of inflammation, in response comprise pus which is contained in a cavity to form an
to severe tissue injury or infection results in profuse abscess. The abscess, if not drained, may get organised by
systemic vasodilatation, increased vascular permeability dense fibrous tissue, and in time, get calcified.
and intravascular volume loss. The net effect of these
changes is hypotension and shock. Systemic activation of 4. Chronic inflammation. Persisting or recurrent acute
coagulation pathway may occur leading to microthrombi inflammation may progress to chronic inflammation in which
throughout the body and result in disseminated the processes of inflammation and healing proceed side by
intravascular coagulation (DIC), bleeding and death. side.

147













Figure 6.17 Fate of acute inflammation. CHAPTER 6


CHRONIC INFLAMMATION response to stimuli such as cytokines (lymphokines) and
bacterial endotoxins. On activation, macrophages release
DEFINITION AND CAUSES. Chronic inflammation is several biologically active substances e.g. acid and neutral
defined as prolonged process in which tissue destruction and proteases, oxygen-derived reactive metabolites and
inflammation occur at the same time. cytokines. These products bring about tissue destruction, Inflammation and Healing
Chronic inflammation can be caused by one of the neovascularisation and fibrosis.
following 3 ways: Other chronic inflammatory cells include lymphocytes,
1. Chronic inflammation following acute inflammation. plasma cells, eosinophils and mast cells. In chronic inflam-
When the tissue destruction is extensive, or the bacteria mation, lymphocytes and macrophages influence each other
survive and persist in small numbers at the site of acute and release mediators of inflammation.
inflammation e.g. in osteomyelitis, pneumonia terminating 2. TISSUE DESTRUCTION OR NECROSIS. Tissue
in lung abscess.
destruction and necrosis are central features of most forms
2. Recurrent attacks of acute inflammation. When of chronic inflammatory lesions. This is brought about by
repeated bouts of acute inflammation culminate in activated macrophages which release a variety of biologi-
chronicity of the process e.g. in recurrent urinary tract cally active substances e.g. protease, elastase, collagenase,
infection leading to chronic pyelonephritis, repeated acute lipase, reactive oxygen radicals, cytokines (IL-1, IL-8,
infection of gallbladder leading to chronic cholecystitis. TNF-α), nitric oxide, angiogenesis growth factor etc.
3. Chronic inflammation starting de novo. When the infec- 3. PROLIFERATIVE CHANGES. As a result of necrosis,
tion with organisms of low pathogenicity is chronic from the proliferation of small blood vessels and fibroblasts is
beginning e.g. infection with Mycobacterium tuberculosis. stimulated resulting in formation of inflammatory
granulation tissue. Eventually, healing by fibrosis and
GENERAL FEATURES OF CHRONIC INFLAMMATION collagen laying takes place.

Though there may be differences in chronic inflammatory SYSTEMIC EFFECTS OF CHRONIC INFLAMMATION
response depending upon the tissue involved and causative
organisms, there are some basic similarities amongst various Chronic inflammation is associated with following systemic
types of chronic inflammation. Following general features features:
characterise any chronic inflammation:
1. Fever. Invariably there is mild fever, often with loss of
1. MONONUCLEAR CELL INFILTRATION. Chronic weight and weakness.
inflammatory lesions are infiltrated by mononuclear
inflammatory cells like phagocytes and lymphoid cells. 2. Anaemia. As discussed in Chapter 12, chronic inflam-
Phagocytes are represented by circulating monocytes, tissue mation is accompanied by anaemia of varying degree.
macrophages, epithelioid cells and sometimes, 3. Leucocytosis. As in acute inflammation, chronic
multinucleated giant cells. The macrophages comprise the inflammation also has leucocytosis but generally there is
most important cells in chronic inflammation. These may relative lymphocytosis in these cases.
appear at the site of chronic inflammation from:
i) chemotactic factors and adhesion molecules for continued 4. ESR. ESR is elevated in all cases of chronic inflammation.
infiltration of macrophages; 5. Amyloidosis. Long-term cases of chronic suppurative
ii) local proliferation of macrophages; and inflammation may develop secondary systemic (AA)
iii) longer survival of macrophages at the site of inflam- amyloidosis.
mation.
TYPES OF CHRONIC INFLAMMATION
The blood monocytes on reaching the extravascular space
transform into tissue macrophages. Besides the role of Conventionally, chronic inflammation is subdivided into 2
macrophages in phagocytosis, they may get activated in types:

148 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 characteri-
stic histologic tissue response e.g. tuberculosis, leprosy,
syphilis.
However, for a more descriptive classification, histo-
logical features are used for classifying chronic inflammation
SECTION I
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 granulomatous inflammation. It is characterised
by formation of granulomas e.g. tuberculosis, leprosy,
syphilis, actinomycosis, sarcoidosis etc.

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
derived from granule meaning circumscribed granule-like
lesion, and -oma which is a suffix commonly used for true
tumours but here it indicates a localised inflammatory mass
General Pathology and Basic Techniques
or collection of macrophages.
PATHOGENESIS OF GRANULOMA. Formation of
granuloma is a type IV granulomatous hypersensitivity
reaction (page 77). It is a protective defense reaction by the
host but eventually causes tissue destruction because of
persistence of the poorly digestible antigen e.g. Mycobacterium
tuberculosis, M. leprae, suture material, particles of talc etc.
The sequence in evolution of granuloma is schematically
shown in Fig. 6.18 and is briefly outlined below:
1. Engulfment by macrophages. Macrophages and
monocytes engulf the antigen and try to destroy it. But since Figure 6.18 Mechanism of evolution of a granuloma (IL=interleukin;
the antigen is poorly degradable, these cells fail to digest IFN= interferon; TNF = tumour necrosis factor).
and degrade the antigen, and instead undergo morphologic
changes to epithelioid cells. iv) Growth factors (transforming growth factor-β, platelet-
derived growth factor) elaborated by activated macrophages
2. CD4+ T cells. Macrophages, being antigen-presenting stimulate fibroblast growth.
cells, having failed to deal with the antigen, present it to CD4+ Thus, a granuloma is formed of macrophages modified
T lymphocytes. These lymphocytes get activated and as epithelioid cells in the centre, with some interspersed
elaborate lymphokines (IL-1, IL-2, interferon-γ, TNF-α). multinucleate giant cells, surrounded peripherally by
3. Cytokines. Various cytokines formed by activated CD4+ lymphocytes (mainly T cells), and healing by fibroblasts or
T cells and also by activated macrophages perform the collagen depending upon the age of granuloma.
following roles: COMPOSITION OF GRANULOMA. In general, a
i) IL-1 and IL-2 stimulate proliferation of more T cells. granuloma has the following structural composition:
ii) Interferon-γ activates macrophages. 1. Epithelioid cells. These are so called because of their
iii) TNF-α promotes fibroblast proliferation and activates epithelial cell-like appearance, are modified macrophages/
endothelium to secrete prostaglandins which have role in histiocytes which are somewhat elongated, having vesicular
vascular response in inflammation. and lightly-staining slipper-shaped nucleus, and pale-

staining abundant cytoplasm with hazy outlines so that the EXAMPLES OF GRANULOMATOUS 149
cell membrane of adjacent epithelioid cells is closely apposed.
Epithelioid cells are weakly phagocytic. INFLAMMATION
2. Multinucleate giant cells. Multinucleate giant cells are Granulomatous inflammation is typical of reaction to poorly
formed by fusion of adjacent epithelioid cells and may have digestible agents elicited by tuberculosis, leprosy, fungal
20 or more nuclei. These nuclei may be arranged at the infections, schistosomiasis, foreign particles etc. A CHAPTER 6
periphery like horseshoe or ring, or are clustered at the two comprehensive list of important examples of granulomatous
poles (Langhans’ giant cells), or they may be present centrally conditions, their etiologic agents and salient features is given
(foreign body giant cells). The former are commonly seen in in Table 6.4. The principal examples (marked with asterisk
tuberculosis while the latter are common in foreign body in the table) are discussed below while a few others appear
tissue reactions. Like epithelioid cells, these giant cells are in relevant Chapters later.
weakly phagocytic but produce secretory products which
help in removing the invading agents. TUBERCULOSIS
3. Lymphoid cells. As a cell mediated immune reaction to Tissue response in tuberculosis represents classical example
antigen, the host response by lymphocytes is integral to of chronic granulomatous inflammation in humans.
composition of a granuloma. Plasma cells indicative of
accelerated humoral immune response are present in some CAUSATIVE ORGANISM. Tubercle bacillus or Koch’s Inflammation and Healing
types of granulomas. bacillus (named after discovery of the organism by Robert
4. Necrosis. Necrosis may be a feature of some granulo- Koch in 1882) called Mycobacterium tuberculosis causes
matous conditions e.g. central caseation necrosis of tuberculosis in the lungs and other tissues of the human body.
tuberculosis, so called because of cheese-like appearance and The organism is a strict aerobe and thrives best in tissues with
consistency of necrosis. high oxygen tension such as in the apex of the lung.
Out of various pathogenic strains for human disease
5. Fibrosis. Fibrosis is a feature of healing by proliferating included in Mycobacterium tuberculosis complex, currently
fibroblasts at the periphery of granuloma. most common is M. tuberculosis hominis (human strain), while
The classical example of granulomatous inflammation is M. tuberculosis bovis (bovine strain) used to be common
the tissue response to tubercle bacilli which is called tubercle pathogen to human beings during the era of consumption of
seen in tuberculosis (described below). A fully-developed unpasteurised milk but presently constitutes a small number
tubercle is about 1 mm in diameter with central area of of human cases. Other less common strains included in the
caseation necrosis, surrounded by epithelioid cells and one complex are M. africanum (isolated from patients from parts
to several multinucleated giant cells (commonly Langhans’ of Africa), M. microti, M. pinnipedii and M. canettii. A non-
type), surrounded at the periphery by lymphocytes and pathogenic strain, M. smegmatis, is found in the smegma and
bounded by fibroblasts and fibrous tissue (Fig. 6.19).
as contaminant in the urine of both men and women.
M. tuberculosis hominis is a slender rod-like bacillus,
0.5 μm by 3 μm, is neutral on Gram staining, and can be
demonstrated by the following methods:
1. Acid fast (Ziehl-Neelsen) staining. The acid fastness of the
tubercle bacilli is due to mycolic acids, cross-linked fatty acids
and other lipids 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 decolourised
by 20% sulphuric acid (compared to 5% sulphuric acid for
declourisation for M. leprae which are less acid fast) (Fig. 6.20).
False positive AFB staining is seen due to Nocardia,
Rhodococcus, Legionella, and some protozoa such as Isospora
and Cryptosporidium.
2. Fluorescent dye methods.
3. Culture of the organism from sputum in Lowenstein-
Jensen (L.J.) medium for 6 weeks.
4. Guinea pig inoculation method by subcutaneous injection
of the organisms.
5. Molecular methods such as PCR are the most recent
methods.
Figure 6.19 Morphology of a tubercle. There is central caseation ATYPICAL MYCOBACTERIA (NON-TUBERCULOUS
necrosis, surrounded by elongated epithelioid cells having characteristic
slipper-shaped nuclei, with interspersed Langhans’ giant cells. Periphery MYCOBACTERIA). The term atypical mycobacteria or non-
shows lymphocytes. tuberculous mycobacteria is used for mycobacterial species

150
  TABLE 6.4: Principal Granulomatous Conditions.
Conditions Etiologic Agent Special Characteristics
I. BACTERIAL
1. Tuberculosis* Mycobacterium tuberculosis Tuberculous granulomas with central caseation necrosis; acid-fast bacilli.
2. Leprosy* Mycobacterium leprae Foamy histiocytes with acid-fast bacilli (lepromatous);
epithelioid cell granulomas (tuberculoid).
3. Syphilis* Treponema pallidum Gummas composed of histiocytes; plasma cell infiltration; central necrosis.
SECTION I
4. Granuloma inguinale C. donovani Anal and genital lesions; macrophages and neutrophils show Donovan
(Donovanosis) (Donovan body) bodies.
5. Brucellosis Brucella abortus Dairy infection to humans; enlarged reticuloendothelial organs
(Mediterranean fever) (lymph nodes, spleen, bone marrow); non-specific granulomas.
6. Cat scratch disease Coccobacillus Lymphadenitis; reticuloendothelial hyperplasia; granulomas with
central necrosis and neutrophils.
7. Tularaemia Francisella (Pasteurella) Necrosis and suppuration (acute); tubercles hard or with minute
(Rabbit fever) tularensis central necrosis (chronic).
8. Glanders Actinobacillus mallei Infection from horses and mules; subcutaneous lesions and lymphadenitis;
infective granulomas.

II. FUNGAL
1. Actinomycosis* Actinomycetes israelii Cervicofacial, abdominal and thoracic lesions; granulomas and abscesses
(bacterial) with draining sinuses; sulphur granules.

2. Blastomycosis Blastomyces dermatitidis Cutaneous, systemic and lung lesions; suppuration; ulceration
and granulomas.
3. Cryptococcosis Cryptococcus neoformans Meninges, lungs and systemic distribution; organism yeast-like
with clear capsule.
General Pathology and Basic Techniques
4. Coccidioidomycosis Coccidioides immitis Meninges, lungs and systemic distribution; granulomas
and abscesses; organism cyst containing endospores.

III. PARASITIC
Schistosomiasis Schistosoma mansoni, Eggs and granulomas in gut, liver, lung; schistosome pigment;
(Bilharziasis) haematobium, japonicum eosinophils in blood and tissue.

IV. MISCELLANEOUS
1. Sarcoidosis* Unknown Non-caseating granulomas (hard tubercles); asteroid and Schaumann
bodies in giant cells.
2. Crohn’s disease Unknown Transmural chronic inflammatory infiltrates; non-caseating
(Regional enteritis) ? Bacteria, ?? Viruses sarcoid-like granulomas.
3. Silicosis Silica dust Lung lesions, fibrocollagenous nodules.
4. Berylliosis Metallic beryllium Sarcoid-like granulomas in lungs; fibrosis; inclusions in giant cells
(asteroids, Schaumann bodies, crystals).
5. Foreign body Talc, suture, oils, wood Non-caseating granulomas with foreign body giant cells; demonstration
granulomas splinter etc. of foreign body.
*Diseases discussed in this chapter.

other than M. tuberculosis complex and M. leprae. Non- Conventionally, atypical mycobacteria are classified on
tuberculous mycobacteria are widely distributed in the the basis of colour of colony produced in culture and the
environment and are, therefore, also called as environmental speed of growth in media:
mycobacteria. They too are acid fast. Occasionally, human Rapid growers. These organisms grow fast on solid media
tuberculosis may be caused by atypical mycobacteria which (within 7 days) but are less pathogenic than others. Examples
are non-pathogenic to guinea pigs and resistant to usual anti-
tubercular drugs. include M. abscessus, M.fortuitum, M. chelonae.

alcoholism and immunocompromised states like AIDS. 151
However, the exact incidence of disease cannot be
determined as all patients infected with M. tuberculosis may
not develop the clinical disease and many cases remain
reactive to tuberculin without developing symptomatic
disease. CHAPTER 6
HIV-ASSOCIATED TUBERCULOSIS. HIV-infected
individuals have very high incidence of tuberculosis all over
the world. Vice-versa, rate of HIV infection in patients of
tuberculosis is very high. Moreover, HIV-infected individual
on acquiring infection with tubercle bacilli develops active
disease rapidly (within few weeks) rather than after months
or years. Pulmonary tuberculosis in HIV presents in typical
manner. However, it is more often sputum smear negative
but often culture positive. Extra-pulmonary tuberculosis is
more common in HIV disease and manifests commonly by
involving lymph nodes, pleura, pericardium, and Inflammation and Healing
tuberculous meningitis. Infection with M. avium-intracellulare
Figure 6.20 Tuberculosis of the lymph nodes showing presence of (avian or bird strain) is common in patients with HIV/AIDS.
acid-fast bacilli in Ziehl-Neelsen staining.
MODE OF TRANSMISSION. Human beings acquire
infection with tubercle bacilli by one of the following routes:
Slow growers. These species grow mycobacteria on solid
media (in 2-3 weeks). Based on the colour of colony formed, 1. Inhalation of organisms present in fresh cough droplets
they are further divided into following: or in dried sputum from an open case of pulmonary
tuberculosis.
Photochromogens: These organisms produce yellow pigment 2. Ingestion of the organisms leads to development of tonsi-
in the culture grown in light.
llar or intestinal tuberculosis. This mode of infection of
Scotochromogens: Pigment is produced, whether the growth human tubercle bacilli is from self-swallowing of infected
is in light or in dark. sputum of an open case of pulmonary tuberculosis, or
Non-chromogens: No pigment is produced by the bacilli and ingestion of bovine tubercle bacilli from milk of diseased
the organism is closely related to avium bacillus. cows.
The examples of slow growers are M. avium-intracellulare, 3. Inoculation of the organisms into the skin may rarely occur
M. kansasii, M. ulcerans and M. fortuitum. from infected postmortem tissue.
The infection by atypical mycobacteria is acquired 4. Transplacental route results in development of congenital
directly from the environment, unlike person-to-person tuberculosis in foetus from infected mother and is a rare mode
transmission of classical tuberculosis. They produce human of transmission.
disease, atypical mycobacteriosis, similar to tuberculosis but
are much less virulent. The lesions produced may be SPREAD OF TUBERCULOSIS. The disease spreads in the
granulomas, nodular collection of foamy cells, or acute body by various routes:
inflammation. 1. Local spread. This takes place by macrophages carrying
Five patterns of the disease are recognised: the bacilli into the surrounding tissues.
i) Pulmonary disease produced by M. kansasii or M. avium- 2. Lymphatic spread. Tuberculosis is primarily an infection
intracellulare. of lymphoid tissues. The bacilli may pass into lymphoid
ii) Lymphadenitis caused by M. avium-intracellulare or M. follicles of pharynx, bronchi, intestines or regional lymph
scrofulaceum. nodes resulting in regional tuberculous lymphadenitis which
iii) Ulcerated skin lesions produced by M. ulcerans or M. is typical of childhood infections. Primary complex is primary
marinum. focus with lymphangitis and lymphadenitis.
iv) Abscesses caused by M.fortuitum or M. chelonae. 3. Haematogenous spread. This occurs either as a result of
v) Bacteraemias by M. avium-intracellulare as seen in tuberculous bacillaemia because of the drainage of
immunosuppressed patients of AIDS. lymphatics into the venous system or due to caseous mate-
rial escaping through ulcerated wall of a vein. This produces
INCIDENCE. In spite of great advances in chemotherapy millet seed-sized lesions in different organs of the body like
and immunology, tuberculosis still continues to be lungs, liver, kidneys, bones and other tissues and is known
worldwide in distribution, more common in developing as miliary tuberculosis.
countries of Africa, Latin America and Asia. Other factors
contributing to higher incidence of tuberculosis are 4. By the natural passages. Infection may spread from:
malnutrition, inadequate medical care, poverty, crowding, i) lung lesions into pleura (tuberculous pleurisy);
chronic debilitating conditions like uncontrolled diabetes, ii) transbronchial spread into the adjacent lung segments;

152 iii) tuberculous salpingitis into peritoneal cavity (tuberculous hours. However, patients having disseminated tuberculosis
peritonitis); may show negative test due to release of large amount of
iv) infected sputum into larynx (tuberculous laryngitis); tuberculoproteins from the endogenous lesions masking the
v) swallowing of infected sputum (ileocaecal tuberculosis); hypersensitivity test. A positive test is indicative of cell-
and mediated hypersensitivity to tubercular antigens but does
vi) renal lesions into ureter and down to trigone of bladder. not distinguish between infection and disease. The test may
be false positive in atypical mycobacterial infection and false
HYPERSENSITIVITY AND IMMUNITY IN TUBER- negative in sarcoidosis, some viral infections, Hodgkin’s
CULOSIS. Hypersensitivity or allergy, and immunity or disease and fulminant tuberculosis.
SECTION I
resistance, play a major role in the development of lesions in Immunisation against tuberculosis. Protective immuni-
tuberculosis. Tubercle bacilli as such do not produce any sation against tuberculosis is induced by injection of
toxins. Tissue changes seen in tuberculosis are not the result attenuated strains of bovine type of tubercle bacilli, Bacille
of any exotoxin or endotoxin but are instead the result of Calmette-Guérin (BCG). Cell-mediated immunity with
host response to the organism which is in the form of consequent delayed hypersensitivity reaction develops with
development of cell-mediated hypersensitivity (or type IV healing of the lesion, but the cell-mediated immunity persists,
hypersensitivity) and immunity. Both these host responses rendering the host tuberculin-positive and hence immune.
develop as a consequence of several lipids present in the
microorganism which include the following: EVOLUTION OF TUBERCLE. The sequence of events which
1. mycosides such as ‘cord factor’ which are essential for take place when tubercle bacilli are introduced into the tissue
growth and virulence of the organism in the animals; and are as under (Fig. 6.21):
2. glycolipids present in the mycobacterial cell wall like 1. When the tubercle bacilli are injected intravenously
‘Wax-D’ which acts as an adjuvant acting along with into the guinea pig, the bacilli are lodged in pulmonary
tuberculoprotein.
It has been known since the time of Robert Koch that the
tissue reaction to tubercle bacilli is different in healthy animal
not previously infected (primary infection) from an animal
who is previously infected (secondary infection).
1. In the primary infection, intradermal injection of tubercle
bacilli into the skin of a healthy guinea pig evokes no visible
General Pathology and Basic Techniques
reaction for 10-14 days. After this period, a nodule develops
at the inoculation site which subsequently ulcerates and heals
poorly as the guinea pig, unlike human beings, does not
possess any natural resistance. The regional lymph nodes
also develop tubercles. This process is a manifestation of
delayed type of hypersensitivity (type IV reaction) and is
comparable to primary tuberculosis in children although
healing invariably occurs in children.
2. In the secondary infection, the sequence of changes is
different. The tubercle bacilli are injected into the skin of the
guinea pig who has been infected with tuberculosis 4-6 weeks
earlier. In 1-2 days, the site of inoculation is indurated and
dark, attaining a diameter of about 1 cm. The skin lesion
ulcerates which heals quickly and the regional lymph nodes
are not affected. This is called Koch’s phenomenon and is
indicative of hypersensitivity and immunity in the host.
Similar type of changes can be produced if injection of
live tubercle bacilli is replaced with old tuberculin (OT).
Hypersensitivity and immunity are closely related and
are initiated through CD4+ T lymphocytes sensitised against
specific antigens in tuberculin. As a result of this sensitisation,
lymphokines are released from T cells which induce
increased microbicidal activity of the macrophages.

Tuberculin (Mantoux) skin test. This test is done by
intradermal injection of 0.1 ml of tuberculoprotein, purified
protein derivative (PPD). Delayed type of hypersensitivity
develops in individuals who are having or have been Figure 6.21 Schematic evolution of tubercle. In fully formed
granuloma, the centre is composed of granular caseation necrosis,
previously infected with tuberculous infection which is surrounded by epithelioid cells and Langhans’ giant cells and peripheral
identified as an indurated area of more than 15 mm in 72 rim of lymphocytes bounded by fibroblasts.

capillaries where an initial response of neutrophils is evoked on the surface. This is called cold abscess although there are 153
which are rapidly destroyed by the organisms. no pus cells in it.
2. After about 12 hours, there is progressive infiltration by ii) In tuberculosis of tissues like bones, joints, lymph nodes
macrophages. This is due to coating of tubercle bacilli with and epididymis, sinuses are formed and the sinus tracts are
serum complement factors C2a and C3b which act as lined by tuberculous granulation tissue.
opsonins and attract the macrophages. Macrophages iii) The adjacent granulomas may coalesce together enlarging CHAPTER 6
dominate the picture throughout the remaining life of the the lesion which is surrounded by progressive fibrosis.
lesions. If the tubercle bacilli are, however, inhaled into the iv) In the granuloma enclosed by fibrous tissue, calcium salts
lung alveoli, macrophages predominate the picture from the may get deposited in the caseous material (dystrophic
beginning. calcification) and sometimes the lesion may even get ossified
3. The macrophages start phagocytosing the tubercle bacilli over the years.
and either kill the bacteria or die away themselves. In the
latter case, they further proliferate locally as well as there is TYPES OF TUBERCULOSIS
increased recruitment of macrophages from blood
monocytes. Lung is the main organ affected in tuberculosis. Depending
upon the type of tissue response and age, the infection with
4. As a part of body’s immune response, T and B cells are tubercle bacilli is of 2 main types:
activated. Activated CD4+T cells develop the cell-mediated A. Primary tuberculosis; and Inflammation and Healing
delayed type hypersensitivity reaction, while B cells result in B. Secondary tuberculosis.
formation of antibodies which play no role in body’s defence
against tubercle bacilli. A. Primary Tuberculosis
5. In 2-3 days, the macrophages undergo structural changes
as a result of immune mechanisms—the cytoplasm becomes The infection of an individual who has not been previously
pale and eosinophilic and their nuclei become elongated and infected or immunised is called primary tuberculosis or Ghon’s
vesicular. These modified macrophages resemble epithelial complex or childhood tuberculosis.
cells and are called epithelioid cells. Primary complex or Ghon’s complex is the lesion
6. The epithelioid cells in time aggregate into tight clusters produced in the tissue of portal of entry with foci in the
draining lymphatic vessels and lymph nodes. The most
or granulomas. Release of cytokines in response to sensitised commonly involved tissues for primary complex are lungs
CD4+T cells and some constituents of mycobacterial cell wall and hilar lymph nodes. Other tissues which may show
play a role in formation of granuloma.
primary complex are tonsils and cervical lymph nodes, and
7. Some of the macrophages form multinucleated giant cells in the case of ingested bacilli the lesions may be found in
by fusion of adjacent cells. The giant cells may be Langhans’ small intestine and mesenteric lymph nodes.
type having peripherally arranged nuclei in the form of The incidence of disseminated form of progressive
horseshoe or ring, or clustered at the two poles of the giant primary tuberculosis is particularly high in immunocompro-
cell; or they may be foreign body type having centrally-placed mised host e.g. in patients of AIDS.
nuclei. Primary complex or Ghon’s complex in lungs consists of 3
8. Around the mass of epithelioid cells and giant cells is a components (Fig. 6.22):
zone of lymphocytes, plasma cells and fibroblasts. The lesion
at this stage is called hard tubercle due to absence of central 1. Pulmonary component. Lesion in the lung is the primary
necrosis. focus or Ghon’s focus. It is 1-2 cm solitary area of tuberculous
9. Within 10-14 days, the centre of the cellular mass begins
to undergo caseation necrosis, characterised by cheesy
appearance and high lipid content. This stage is called soft
tubercle which is the hallmark of tuberculous lesions. The
development of caseation necrosis is possibly due to
interaction of mycobacteria with activated T cells (CD4+
helper T cells via IFN-γ and CD8+ suppressor T cells directly)
as well as by direct toxicity of mycobacteria on macrophages.
Microscopically, caseation necrosis is structureless,
eosinophilic and granular material with nuclear debris.
10. The soft tubercle which is a fully-developed granuloma
with caseous centre does not favour rapid proliferation of
tubercle bacilli. Acid-fast bacilli are difficult to find in these
lesions and may be demonstrated at the margins of recent
necrotic foci and in the walls of the cavities.
The fate of a granuloma is variable:
i) The caseous material may undergo liquefaction and Figure 6.22 The primary complex composed of 3 components:
extend into surrounding soft tissues, discharging the contents Ghon’s focus, draining lymphatics, and hilar lymph nodes.

154











SECTION I












Figure 6.23 Caseating granulomatous lymphadenitis. A, Cut section of matted mass of lymph nodes shows merging capsules and large areas
of caseation necrosis (arrow). B, Caseating epithelioid cell granulomas with some Langhans’ giant cells in the cortex of lymph node.

pneumonia located peripherally under a patch of pleurisy, Nodal lesions are potential source of re-infection later
in any part of the lung but more often in subpleural focus in (Fig. 6.23, B).
the upper part of lower lobe.
In the case of primary tuberculosis of the alimentary tract
Microscopically, the lung lesion consists of tuberculous due to ingestion of tubercle bacilli, a small primary focus is
granulomas with caseation necrosis. seen in the intestine with enlarged mesenteric lymph nodes

2. Lymphatic vessel component. The lymphatics draining producing tabes mesenterica. The enlarged and caseous
the lung lesion contain phagocytes containing bacilli and may mesenteric lymph nodes may rupture into peritoneal cavity
develop beaded, miliary tubercles along the path of hilar and cause tuberculous peritonitis.
General Pathology and Basic Techniques
lymph nodes. FATE OF PRIMARY TUBERCULOSIS. Primary complex
3. Lymph node component. This consists of enlarged hilar may have one of the following sequelae (Fig. 6.24):
and tracheo-bronchial lymph nodes in the area drained. The
affected lymph nodes are matted and show caseation necrosis 1. The lesions of primary tuberculosis of lung commonly
(Fig. 6.23, A). do not progress but instead heal by fibrosis, and in time
undergo calcification and even ossification.
Microscopically, the lesions are characterised by extensive 2. In some cases, the primary focus in the lung continues to
caseation, tuberculous granulomas and fibrosis. grow and the caseous material is disseminated through




























Figure 6.24 Sequelae of primary complex. A, Healing by fibrosis and calcification. B, Progressive primary tuberculosis spreading to the other
areas of the same lung or opposite lung. C, Miliary spread to lungs, liver, spleen, kidneys and brain. D, Progressive secondary pulmonary tuberculosis
from reactivation of dormant primary complex.

bronchi to the other parts of the same lung or the opposite ance is typical of tuberculous granulomas with caseation 155
lung. This is called progressive primary tuberculosis. necrosis.
3. At times, bacilli may enter the circulation through erosion Patients with HIV infection previously exposed to
in a blood vessel and spread to various tissues and organs. tuberculous infection have particularly high incidence of
This is called primary miliary tuberculosis and the lesions are reactivation of primary tuberculosis and the pattern of lesions
seen in organs like the liver, spleen, kidney, brain and bone in such cases is similar to that of primary tuberculosis i.e. CHAPTER 6
marrow. with involvement of hilar lymph nodes rather than cavitary
and apical lesions in the lung. In addition, infection with M.
4. In certain circumstances like in lowered resistance and avium-intracellulare occurs more frequently in cases of AIDS.
increased hypersensitivity of the host, the healed lesions of
primary tuberculosis may get reactivated. The bacilli lying FATE OF SECONDARY PULMONARY TUBERCULOSIS.
dormant in acellular caseous material are activated and cause The subapical lesions in lungs can have the following courses:
progressive secondary tuberculosis. It affects children more 1. The lesions may heal with fibrous scarring and
commonly but adults may also develop this kind of calcification.
progression. 2. The lesions may coalesce together to form larger area of
tuberculous pneumonia and produce progressive secondary
B. Secondary Tuberculosis pulmonary tuberculosis with the following pulmonary and
extrapulmonary involvements: Inflammation and Healing
The infection of an individual who has been previously i) Fibrocaseous tuberculosis
infected or sensitised is called secondary, or post-primary or ii) Tuberculous caseous pneumonia
reinfection, or chronic tuberculosis. iii) Miliary tuberculosis.
The infection may be acquired from (Fig. 6.25):
endogenous source such as reactivation of dormant primary I. FIBROCASEOUS TUBERCULOSIS. The original area
complex; or of tuberculous pneumonia undergoes massive central
exogenous source such as fresh dose of reinfection by the caseation necrosis which may:
tubercle bacilli. either break into a bronchus from a cavity (cavitary or open
Secondary tuberculosis occurs most commonly in lungs fibrocaseous tuberculosis); or
in the region of apex. Other sites and tissues which can be remain, as a soft caseous lesion without drainage into a
involved are tonsils, pharynx, larynx, small intestine and bronchus or bronchiole to produce a non-cavitary lesion
skin. Secondary tuberculosis of other organs and tissues is (chronic fibrocaseous tuberculosis).
described in relevant chapters later while that of lungs is The cavity provides favourable environment for
discussed here. proliferation of tubercle bacilli due to high oxygen tension.
The cavity may communicate with bronchial tree and
Secondary Pulmonary Tuberculosis becomes the source of spread of infection (‘open tuberculosis’).
The open case of secondary tuberculosis may implant
The lesions in secondary pulmonary tuberculosis usually tuberculous lesion on the mucosal lining of air passages
begin as 1-2 cm apical area of consolidation of the lung, which producing endobronchial and endotracheal tuberculosis.
may in time develop a small area of central caseation necrosis Ingestion of sputum containing tubercle bacilli from
and peripheral fibrosis. It occurs by haematogenous spread
of infection from primary complex to the apex of the affected endogenous pulmonary lesions may produce laryngeal and
intestinal tuberculosis.
lung where the oxygen tension is high and favourable for
growth of aerobic tubercle bacilli. Microscopically, the appear-
Grossly, tuberculous cavity is spherical with thick fibrous
wall, lined by yellowish, caseous, necrotic material and
the lumen is traversed by thrombosed blood vessels.
Around the wall of cavity are seen foci of consolidation.
The overlying pleura may also be thickened (Fig. 6.26).
Microscopically, the wall of cavity shows eosinophilic,
granular, caseous material which may show foci of
dystrophic calcification. Widespread coalesced
tuberculous granulomas composed of epithelioid cells,
Langhans’ giant cells and peripheral mantle of
lymphocytes and having central caseation necrosis are
seen. The outer wall of cavity shows fibrosis (Fig. 6.27).

Complications of cavitary secondary tuberculosis are as
follows:
a) Aneurysms of patent arteries crossing the cavity
Figure 6.25 Progressive secondary tuberculosis. A, Endogenous producing haemoptysis.
infection from reactivation of dormant primary complex. B, Exogenous
infection from fresh dose of tubercle bacilli. b) Extension to pleura producing bronchopleural fistula.

156











SECTION I






Figure 6.26 Fibrocaseous tuberculosis. A, Non-cavitary (chronic) fibrocaseous tuberculosis (left) and cavitary/open fibrocaseous tuberculosis
(right). B, Chronic fibrocaseous tuberculosis lung. Sectioned surface shows a cavity in the apex of the lung (arrow). There is consolidation of lung
parenchyma surrounding the cavity.

c) Tuberculous empyema from deposition of caseous into pulmonary artery restricting the development of miliary
material on the pleural surface. lesions within the lung (Fig. 6.29). The miliary lesions are
d) Thickened pleura from adhesions of parietal pleura. millet seed-sized (1 mm diameter), yellowish, firm areas
II. TUBERCULOUS CASEOUS PNEUMONIA. The without grossly visible caseation necrosis.
caseous material from a case of secondary tuberculosis in an Microscopically, the lesions show the structure of tuber-
individual with high degree of hypersensitivity may spread cles with minute areas of caseation necrosis (Fig. 6.30).
to rest of the lung producing caseous pneumonia
(Fig. 6.28, A).
Clinical Features and Diagnosis of Tuberculosis

Microscopically, the lesions show exudative reaction with The clinical manifestations in tuberculosis may be variable
oedema, fibrin, polymorphs and monocytes but numerous depending upon the location, extent and type of lesions.
tubercle bacilli can be demonstrated in the exudates However, in secondary pulmonary tuberculosis which is the
General Pathology and Basic Techniques
(Fig. 6.28,B). common type, the usual clinical features are as under:
III. MILIARY TUBERCULOSIS. This is lymphohaemato- 1. Referable to lungs—such as productive cough, may be
genous spread of tuberculous infection from primary focus with haemoptysis, pleural effusion, dyspnoea, orthopnoea
or later stages of tuberculosis. The spread may occur to etc. Chest X-ray may show typical apical changes like pleural
systemic organs or isolated organ. The spread is either by effusion, nodularity, and miliary or diffuse infiltrates in the
entry of infection into pulmonary vein producing dissemi- lung parenchyma.
nated or isolated organ lesion in different extra-pulmonary 2. Systemic features—such as fever, night sweats, fatigue,
sites (e.g. liver, spleen, kidney, brain and bone marrow) or loss of weight and appetite. Long-standing and untreated




























Figure 6.27 Microscopic appearance of lesions of secondary fibrocaseous tuberculosis of the lung showing wall of the cavity.

157











CHAPTER 6













Figure 6.28 A, Bilateral tuberculous caseous pneumonia. B, Tuberculous caseous pneumonia showing exudative reaction. In AFB staining, Inflammation and Healing
these cases have numerous acid-fast bacilli (not shown here).

cases of tuberculosis may develop systemic secondary LEPROSY
amyloidosis. Leprosy or Hansen’s disease (after discovery of the causa-
The diagnosis is made by the following tests: tive organism by Hansen in 1874), was first described in
i) Positive Mantoux skin test. ancient Indian text going back to 6th Century BC, is a
ii) Positive sputum for AFB (on smear or culture). chronic non-fatal infectious disease affecting mainly the
iii) Complete haemogram (lymphocytosis and raised ERR). cooler parts of the body such as the skin, mouth, respiratory
iv) Chest X-ray (characteristic hilar nodules and other tract, eyes, peripheral nerves, superficial lymph nodes and
parenchymal changes). testis. Though the earliest and main involvement in leprosy
v) Fine needle aspiration cytology of an enlarged peripheral is of the skin and nerves but in bacteraemia from endothelial
colonisation or by bacilli filtered from blood by reticulo-
lymph node is quite helpful for confirmation of diagnosis endothelial system, other organs such as the liver, spleen,
(page 282). bone marrow and regional lymph nodes are also involved.
Causes of death in pulmonary tuberculosis are usually Advanced cases may develop secondary amyloidosis and
pulmonary insufficiency, pulmonary haemorrhage, sepsis renal disease, both of which are of immunologic origin.
due to disseminated miliary tuberculosis, cor pulmonale or
secondary amyloidosis. 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 split
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
decolourised by lower concentration (5%) of sulphuric acid
(less acid-fast) (Fig. 6.31).
2. Fite-Faraco staining procedure is a modification of Z.N.
procedure and is considered better for more adequate
staining of tissue sections.
3. Gomori methenamine silver (GMS) staining can also be
employed.
4. Molecular methods by PCR.
5. IgM antibodies to PGL-1 antigen seen in 95% cases of
Figure 6.29 Miliary tuberculosis lung. The sectioned surface of the lepromatous leprosy but only in 60% cases of tuberculoid
lung parenchyma shows presence of minute millet-seed sized tubercles. leprosy.

158











SECTION I











Figure 6.30 Miliary tubercles in lung having minute central caseation necrosis.


The slit smear technique gives a reasonable quantitative Myanmar (Burma), Madagascar and Nigeria, together
measure of M. leprae when stained with Ziehl-Neelsen constitute about 80% of leprosy cases, of which India
method and examined under 100x oil objective for accounts for one-third of all registered leprosy cases globally.
determining the density of bacteria in the lesion (bacterial In India, the disease is seen more commonly in regions like
index, BI). B.I. is scored from 1+ to 6+ (range from 1 to 10 Tamil Nadu, Bihar, Pondicherry, Andhra Pradesh, Orissa,
bacilli per 100 fields to > 1000 per field) as multibacillary West Bengal and Assam. Very few cases are now seen in
leprosy while B.I. of 0+ is termed paucibacillary. Europe and the United States.
Although lepra bacilli were the first bacteria identified
for causing human disease, M. leprae remains one of the few Mode of Transmission
bacterial species which is yet to be cultured on artificial Leprosy is a slow communicable disease and the incubation
General Pathology and Basic Techniques
medium. Nine-banded armadillo, a rodent, acts as an experi- period between first exposure and appearance of signs of
mental animal model as it develops leprosy which is disease varies from 2 to 20 years (average about 3 years).
histopathologically and immunologically similar to human The infectivity may be from the following sources:
leprosy. 1. Direct contact with untreated leprosy patients who shed
numerous bacilli from damaged skin, nasal secretions,
Incidence
mucous membrane of mouth and hair follicles.
The disease is endemic in areas with hot and moist climates 2. Materno-foetal transmission across the placenta.
and in poor tropical countries. According to the WHO, 3. Transmission from milk of leprosy patient to infant.
8 countries—India, China, Nepal, Brazil, Indonesia,
Immunology of Leprosy
Like in tuberculosis, the immune response in leprosy is also
T cell-mediated delayed hypersensitivity (type IV reaction)
but the two diseases are quite dissimilar as regards immune
reactions and lesions. M. leprae do not produce any toxins
but instead the damage to tissues is immune-mediated. This
is due to following peculiar aspects in immunology of
leprosy:
1. Antigens of leprosy bacilli. Lepra bacilli have several
antigens. The bacterial cell wall contains large amount of M.
leprae-specific phenolic glycolipid (PGL-1) and another
surface antigen, lipo-arabinomannan (LAMN). These
antigens of the bacilli determine the immune reaction of host
lymphocytes and macrophages. Another unique feature of
leprosy bacilli is invasion in peripheral nerves which is due
to binding of trisaccharide of M. leprae to basal lamina of
Schwann cells.

Figure 6.31 Lepra bacilli in LL seen in Fite-Faraco stain as globi 2. Genotype of the host. Genetic composition of the host as
and cigarettes-in-a-pack appearance inside the foam macrophages. known by MHC class (or HLA type) determines which

antigen of leprosy bacilli shall interact with host immune The test indicates that cell-mediated immunity is greatly 159
cells. Accordingly, the host response to the leprosy bacilli in suppressed in lepromatous leprosy while patients of
different individuals is variable. tuberculoid leprosy show good immune response. Delayed
type of hypersensitivity is conferred by T helper cells. The
3. T cell response. There is variation in T cell response in granulomas of tuberculoid leprosy have sufficient T helper
different individuals infected with leprosy bacilli: cells and fewer T suppressor cells at the periphery while the
i) Unlike tubercle bacilli, there is not only activation of CD4+ cellular infiltrates of lepromatous leprosy lack T helper cells. CHAPTER 6
T cells but also of CD8+ T cells.
ii) CD4+ T cells in lepra bacilli infected persons act not only
as helper and promoter cells but also assume the role of Classification
cytotoxicity. Leprosy is broadly classified into 2 main types:
iii) The two subpopulations of CD4+ T cells (or T helper Lepromatous type representing low resistance; and
cells)—T 1 cells and T 2 cells, elaborate different types of Tuberculoid type representing high resistance.
H
H
cytokines in response to stimuli from the lepra bacilli and
macrophages. Salient differences between the two main forms of lep-
iv) In tuberculoid leprosy, the response is largely by CD4+ T rosy are summarised in Table 6.5.
cells, while in lepromatous leprosy although there is excess Since both these types of leprosy represent two opposite
of CD8+ T cells (suppressor T) but the macrophages and poles of host immune response, these are also called polar Inflammation and Healing
suppressor T cells fail to destroy the bacilli due to CD8+ T forms of leprosy. Cases not falling into either of the two poles
cell defect. are classified as borderline and indeterminate types.
Leprosy is classified into 5 clinico-pathologic groups
4. Humoral response. Though the patients of lepromatous (modified Ridley and Jopling’s classification) as under:
leprosy have humoral components like high levels of TT—Tuberculoid Polar (High resistance)
immunoglobulins (IgG, IgA, IgM) and antibodies to BT—Borderline Tuberculoid
mycobacterial antigens but these antibodies do not have any BB—Mid Borderline (dimorphic)
protective role against lepra bacilli. BL—Borderline Lepromatous
Based on above unique immunologic features in leprosy, LL—Lepromatous Polar (Low resistance)
lesions in leprosy are classified into 5 distinct clinico- In addition, not included in Ridley-Jopling’s classifica-
pathologic types and three forms of reactional leprosy which tion are cases of indeterminate leprosy, pure neural leprosy,
are described below), and an intradermal immunologic test, and histoid leprosy resembling a nodule of dermatofibroma
lepromin test. and positive for lepra bacilli.
LEPROMIN TEST. It is not a diagnostic test but is used for
classifying leprosy on the basis of immune response. Intra- Reactional Leprosy
dermal injection of lepromin, an antigenic extract of M. leprae, There may be two types of lepra reactions: type I (reversal
reveals delayed hypersensitivity reaction in patients of reactions), and type II (erythema nodosum leprosum).
tuberculoid leprosy:
An early positive reaction appearing as an indurated area TYPE I: REVERSAL REACTIONS. The polar forms of
in 24-48 hours is called Fernandez reaction. leprosy do not undergo any change in clinical and histo-
A delayed granulomatous lesion appearing after 3-4 pathological picture. The borderline groups are unstable and
weeks is called Mitsuda reaction. may move across the spectrum in either direction with
Patients of lepromatous leprosy are negative by the upgrading or downgrading of patient’s immune state.
lepromin test. Accordingly, there may be two types of borderline reaction:


 TABLE 6.5: Differences between Lepromatous and Tuberculoid Leprosy.
Feature Lepromatous Leprosy Tuberculoid Leprosy
1. Skin lesions Symmetrical, multiple, hypopigmented, Asymmetrical, single or a few lesions,
erythematous, maculopapular or hypopigmented and erythematous macular.
nodular (leonine facies).
2. Nerve involvement Present but sensory disturbance is less severe. Present with distinct sensory disturbance.
3. Histopathology Collection of foamy macrophages or Hard tubercle similar to granulomatous lesion,
lepra cells in the dermis separated from eroding the basal layer of epidermis; no clear
epidermis by a ‘clear zone’. zone.
4. Bacteriology Lepra cells highly positive for lepra bacilli Lepra bacilli few, seen in destroyed nerves as
seen as ‘globi’ or ‘cigarettes-in-pack’ granular or beaded forms.
appearance.
5. Immunity Suppressed (low resistance). Good immune response (high resistance).
6. Lepromin test Negative Positive

160 1. Upgrading reaction is characterised by increased cell- The main features in various groups are given below.
mediated immunity and occurs in patients of borderline 1. Lepromatous leprosy:
lepromatous (BL) type on treatment who upgrade or shift The following features characterise lepromatous polar
towards tuberculoid type.
leprosy (Fig. 6.32):
Histologically, the upgrading reaction shows an increase i) In the dermis, there is proliferation of macrophages
of lymphocytes, oedema of the lesions, necrosis in the with foamy change, particularly around the blood vessels,
centre and reduced B.I. nerves and dermal appendages. The foamy macrophages
are called ‘lepra cells’ or Virchow cells.
2. Downgrading reaction is characterised by lowering of ii) The lepra cells are heavily laden with acid-fast bacilli
SECTION I
cellular immunity and is seen in borderline tuberculoid (BT) demonstrated with AFB staining. The AFB may be seen
type who downgrade or shift towards lepromatous type. as compact globular masses (globi) or arranged in parallel
Histologically, the lesions show dispersal and spread of fashion like ‘cigarettes-in-pack’ (see Fig. 6.31).
the granulomas and increased presence of lepra bacilli. iii) The dermal infiltrate of lepra cells characteristically
does not encroach upon the basal layer of epidermis and
TYPE II: ERYTHEMA NODOSUM LEPROSUM (ENL). is separated from epidermis by a subepidermal
ENL occurs in lepromatous patients after treatment. It is uninvolved clear zone.
characterised by tender cutaneous nodules, fever,
iridocyclitis, synovitis and lymph node involvement. iv) The epidermis overlying the lesions is thinned out, flat
and may even ulcerate.
Histologically, the lesions in ENL show infiltration by 2. Tuberculoid leprosy:
neutrophils and eosinophils and prominence of vasculitis. The polar tuberculoid form presents the following
Inflammation often extends deep into the subcutaneous histological features (Fig. 6.33):
fat causing panniculitis. Bacillary load is increased.
Secondary amyloidosis may follow repeated attacks of i) The dermal lesions show granulomas resembling hard
ENL in leprosy. tubercles composed of epithelioid cells, Langhans’ giant
cells and peripheral mantle of lymphocytes.
Histopathology of Leprosy ii) Lesions of tuberculoid leprosy have predilection for
Usually, skin biopsy from the margin of lesions is submitted dermal nerves which may be destroyed and infiltrated by
for diagnosis and for classification of leprosy. The epithelioid cells and lymphocytes.
histopathologic diagnosis of multibacillary leprosy like LL iii) The granulomatous infiltrate erodes the basal layer of
General Pathology and Basic Techniques
and BL offers no problem while the indeterminate leprosy epidermis i.e. there is no clear zone.
and tuberculoid lesions are paucibacillary and their diagnosis iv) The lepra bacilli are few and seen in destroyed nerves.
is made together with clinical evidence.
3. Borderline leprosy:
In general, for histopathologic evaluation in all suspected The histopathologic features of the three forms of
cases of leprosy the following broad guidelines should be borderline leprosy are as under:
followed: i) Borderline tuberculoid (BT) form shows epithelioid cells
cell type of granuloma; and plentiful lymphocytes. There is a narrow clear
nerve involvement; and subepidermal zone. Lepra bacilli are scanty and found in
bacterial load. nerves.



























Figure 6.32 Lepromatous leprosy (LL). There is collection of proliferating foam macrophages (lepra cells) in the dermis with a clear subepidermal
zone.

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Figure 6.33 Tuberculoid leprosy (TT). Granuloma eroding the basal layer of the epidermis. The granuloma is composed of epithelioid cells with Inflammation and Healing
sparse Langhans’ giant cells and lymphocytes.

ii) Borderline lepromatous (BL) form shows predominance Anti-leprosy vaccines have been developed and are
of histiocytes, a few epithelioid cells and some irregularly undergoing human trials but since the incubation period of
dispersed lymphocytes. Numerous lepra bacilli are seen. leprosy is quite long, the efficacy of such vaccines will be
iii) Mid-borderline (BB) or dimorphic form shows sheets known after a number of years.
of epithelioid cells with no giant cells. Some lymphocytes
are seen in the peri-neurium. Lepra bacilli are present, SYPHILIS
mostly in nerves. Syphilis is a venereal (sexually-transmitted) disease caused

4. Indeterminate leprosy: by spirochaetes, Treponema pallidum. Other treponemal
The histopathologic features are non-specific so that the diseases are yaws, pinta and bejel. The word ‘syphilis’ is
diagnosis of non-specific chronic dermatitis may be made. derived from the name of the mythological handsome boy,
However, a few features help in suspecting leprosy as Syphilus, who was cursed by Greek god Apollo with the
under: disease.
i) Lymphocytic or mononuclear cell infiltrate, focalised
particularly around skin adnexal structures like hair Causative Organism
follicles and sweat glands or around blood vessels. T. pallidum is a coiled spiral filament 10 μm long that moves
ii) Nerve involvement, if present, is strongly supportive actively in fresh preparations. The organism cannot be
of diagnosis. stained by the usual methods and can be demonstrated in
iii) Confirmation of diagnosis is made by finding of lepra the exudates and tissues by:
bacilli. 1. dark ground illumination (DGI) in fresh preparation;
2. fluorescent antibody technique;
Clinical Features 3. silver impregnation techniques; and
4. PCR as a research method.
The two main forms of leprosy show distinctive clinical The organism has not been cultivated in any culture
features: media but experimental infection can be produced in rabbits
1. Lepromatous leprosy: and chimpanzees. The organism is rapidly destroyed by cold,
i) The skin lesions in LL are generally symmetrical, heat, and antiseptics.
multiple, slightly hypopigmented and erythematous
macules, papules, nodules or diffuse infiltrates. The nodular Immunology
lesions may coalesce to give leonine facies appearance. T. pallidum does not produce any endotoxin or exotoxin. The
ii) The lesions are hypoaesthetic or anaesthetic but the pathogenesis of the lesions appears to be due to host immune
sensory disturbance is not as distinct as in TT. response.
2. Tuberculoid leprosy: There are two types of serological tests for syphilis:
i) The skin lesions in TT occur as either single or as a few treponemal and non-treponemal.
asymmetrical lesions which are hypopigmented and A. Treponemal serological tests: These tests measure
erythematous macules. antibody to T. pallidum antigen and are as under:
ii) There is a distinct sensory impairment. i) Fluorescent treponemal antibody-absorbed (FTA-ABS) test.

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Figure 6.34 Organ involvement in various stages of acquired syphilis.
A, Primary syphilis: Primary lesion is ‘chancre’ on glans penis. B, Secondary syphilis: Mucocutaneous lesions—mucous patches on oral and vaginal
mucosa and generalised skin eruptions. C,Tertiary syphilis: Localised lesion as gumma of liver with scarring (hepar lobatum); diffuse lesions (right)
in aorta (aneurysm, narrowing of mouths of coronary ostia and incompetence of aortic valve ring) and nervous system.


ii) Agglutinin assays e.g. microhaemagglutination assay for 1. PRIMARY SYPHILIS. Typical lesion of primary syphilis
T. pallidum (MHA-TP), and Serodia TP-PA which is more is chancre which appears on genitals or at extra-genital sites
sensitive. in 2-4 weeks after exposure to infection (Fig. 6.34,A). Initially,
iii) T. pallidum passive haemagglutination (TPHA) test. the lesion is a painless papule which ulcerates in the centre
so that the fully-developed chancre is an indurated lesion
B. Non-treponemal serological tests. These tests measure with central ulceration accompanied by regional
General Pathology and Basic Techniques
non-specific reaginic antibodies IgM and IgG immuno- lymphadenitis. The chancre heals without scarring, even in
globulins directed against cardiolipin-lecithin-cholesterol the absence of treatment.
complex and are more commonly used. These tests are as
under: Histologically, the chancre has following features:
i) Reiter protein complement fixation (RPCF) test: test of choice i) Dense infiltrate of mainly plasma cells, some
for rapid diagnosis. lymphocytes and a few macrophages.
ii) Venereal Disease Research Laboratory (VDRL) test: ii) Perivascular aggregation of mononuclear cells, parti-
Wassermann described a complement fixing antibody cularly plasma cells (periarteritis and endarteritis).
against antigen of human syphilitic tissue. This antigen is iii) Proliferation of vascular endothelium.
used in the Standard Test for Syphilis (STS) in Wassermann Antibody tests are positive in 1-3 weeks after the appear-
complement fixing test and Venereal Disease Research ance of chancre. Spirochaetes can be demonstrated in the
Laboratory (VDRL) test.
exudates by DGI.
Mode of Transmission 2. SECONDARY SYPHILIS. Inadequately treated patients
Syphilitic infection can be transmitted by the following of primary syphilis develop mucocutaneous lesions and
routes: painless lymphadenopathy in 2-3 months after the exposure
1. Sexual intercourse resulting in lesions on glans penis, (Fig. 6.34,B). Mucocutaneous lesions may be in the form of
the mucous patches on mouth, pharynx and vagina; and
vulva, vagina and cervix. generalised skin eruptions and condyloma lata in anogenital
2. Intimate person-to-person contact with lesions on lips, region.
tongue or fingers. Antibody tests are always positive at this stage.
3. Transfusion of infected blood. Secondary syphilis is highly infective stage and spirochaetes
4. Materno-foetal transmission in congenital syphilis if the can be easily demonstrated in the mucocutaneous lesions.
mother is infected. 3. TERTIARY SYPHILIS. After a latent period of appear-
ance of secondary lesions and about 2-3 years following first
Stages of Acquired Syphilis
exposure, tertiary lesions of syphilis appear. Lesions of
Acquired syphilis is divided into 3 stages depending upon tertiary syphilis are much less infective than the other two
the period after which the lesions appear and the type of stages and spirochaetes can be demonstrated with great
lesions. These are: primary, secondary and tertiary syphilis. difficulty. These lesions are of 2 main types (Fig. 6.34,C):

ii) The characteristic ‘Hutchinson’s teeth’ which are small, 163
widely spaced, peg-shaped permanent teeth.
iii) Mucocutaneous lesions of acquired secondary syphilis.
iv) Bony lesions like epiphysitis and periostitis.
v) Interstitial keratitis with corneal opacity.
vi) Diffuse fibrosis in the liver.
vii)Interstitial fibrosis of lungs. CHAPTER 6
viii) If the foetus with congenital syphilis is born dead, it is
premature, with macerated skin, enlarged spleen and liver,
and with syphilitic epiphysitis.
Histologically, the basic morphology of lesions in syphilis
is seen in all the affected organs: perivascular plasma cell
rich inflammatory infiltrate and endothelial cell
proliferation. Many spirochaetes can be demonstrated in
involved tissues.

ACTINOMYCOSIS Inflammation and Healing
Actinomycosis is a chronic suppurative disease caused by
Figure 6.35 Typical microscopic appearance in the case of syphilitic
gumma of the liver. Central coagulative necrosis is surrounded by anaerobic bacteria, Actinomycetes israelii. The disease is
palisades of macrophages and plasma cells marginated peripherally by conventionally included in mycology though the causative
fibroblasts. organism is filamentous bacteria and not true fungus. The
disease is worldwide in distribution. The organisms are
i) Syphilitic gumma. It is a solitary, localised, rubbery commensals in the oral cavity, alimentary tract and vagina.
lesion with central necrosis, seen in organs like liver, testis, The infection is always endogeneous in origin and not by
bone and brain. In liver, the gumma is associated with person-to-person contact. The organisms invade, proliferate
scarring of hepatic parenchyma (hepar lobatum). and disseminate in favourable conditions like break in
mucocutaneous continuity, some underlying disease etc.
Histologically, the structure of gumma shows the
following features (Fig. 6.35): MORPHOLOGIC FEATURES. Depending upon the
a) Central coagulative necrosis resembling caseation but anatomic location of lesions, actinomycosis is of 4 types:
is less destructive so that outlines of necrosed cells can cervicofacial, thoracic, abdominal, and pelvic (Fig. 6.36).
still be faintly seen. 1. Cervicofacial actinomycosis. This is the commonest
b) Surrounding zone of palisaded macrophages with form (60%) and has the best prognosis. The infection enters
many plasma cells, some lymphocytes, giant cells and from tonsils, carious teeth, periodontal disease or trauma
fibroblasts. following tooth extraction. Initially, a firm swelling
develops in the lower jaw (‘lumpy jaw’). In time, the mass
ii) Diffuse lesions of tertiary syphilis. The lesions appear breaks down and abscesses and sinuses are formed. The
following widespread dissemination of spirochaetes in the discharging pus contains typical tiny yellow sulphur
body. The diffuse lesions are predominantly seen in
cardiovascular and nervous systems which are described in
detail later in the relevant chapters. Briefly, these lesions are
as under:
a) 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 (Chapter 15).
b) Neurosyphilis may manifest as:
meningovascular syphilis affecting chiefly the meninges;
tabes dorsalis affecting the spinal cord; and
general paresis affecting the brain.

CONGENITAL SYPHILIS. Congenital syphilis may develop
in a foetus of more than 16 weeks gestation who is exposed
to maternal spirochaetaemia. The major morphologic features
as under:
i) Saddle-shaped nose deformity due to destruction of bridge
of the nose. Figure 6.36 Actinomycosis, sites and routes of infection.

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Figure 6.37 Actinomycosis. Microscopic appearance of sulphur granule lying inside an abscess. The margin of the colony shows hyaline
filaments highlighted by Masson’s trichrome stain (right photomicrograph).

granules. The infection may extend into adjoining soft ETIOLOGY AND PATHOGENESIS. The cause of
tissues as well as may destroy the bone. sarcoidosis remains unknown. Currently, possible etiology
2. Thoracic actinomycosis. The infection in the lungs is is an infectious or noninfectious environmental agent in a
due to aspiration of the organism from oral cavity or genetically susceptible individual. Likely infectious agents
extension of infection from abdominal or hepatic lesions. include Propionibacter acnes, atypical mycobacteria and
Initially, the disease resembles pneumonia but mycobacterial protein of M. tuberculosis. Since the disease is
subsequently the infection spreads to the whole of lung, characterised by granulomatous tissue reaction, possibility
pleura, ribs and vertebrae. of cell-mediated immune mechanisms has been suggested.
3. Abdominal actinomycosis. This type is common in The following observations point towards a possible immune
appendix, caecum and liver. The abdominal infection origin of sarcoidosis:
General Pathology and Basic Techniques
results from swallowing of organisms from oral cavity or 1. Just as in tuberculosis, sarcoidosis is characterised by
extension from thoracic cavity. distinctive granulomatous response against poorly degradable
4. Pelvic actinomycosis. Infection in the pelvis occurs antigen, but quite unlike tuberculosis, the antigen in
as a complication of intrauterine contraceptive devices sarcoidosis has eluded workers so far. PCR studies on
(IUCD’s). affected pulmonary tissue have given equivocal result as
regards presence of mycobacterial antigen.
Microscopically, irrespective of the location of actino- 2. There are immunologic abnormalities in sarcoidosis is
mycosis, the following features are seen (Fig. 6.37): substantiated by high levels of CD4+T cells lavaged from lung
i) The inflammatory reaction is a granuloma with central lesions. There is also elevation in levels of IL-2 receptors in
suppuration. There is formation of abscesses in the centre serum and in lavaged fluid from lungs.
of lesions and at the periphery chronic inflammatory cells,
giant cells and fibroblasts are seen. 3. There is presence of activated alveolar macrophages which
ii) The centre of each abscess contains the bacterial elaborate cytokines that initiate the formation of non-
colony, ‘sulphur granule’, characterised by radiating caseating granulomas.
filaments (hence previously known as ray fungus) with MORPHOLOGIC FEATURES. The lesions in sarcoidosis
hyaline, eosinophilic, club-like ends representative of are generalised and may affect various organs and tissues
secreted immunoglobulins. at sometime in the course of disease, but brunt of the
iii) Bacterial stains reveal the organisms as gram-positive disease is borne by the lungs and lymph nodes (Fig. 6.38).
filaments, nonacid-fast, which stain positively with Microscopically, the following features are present
Gomori’s methenamine silver (GMS) staining. (Fig. 6.39):
1. The diagnostic feature in sarcoidosis of any organ or
SARCOIDOSIS (BOECK’S SARCOID)
tissue is the non-caseating sarcoid granuloma, composed of
Sarcoidosis is a systemic disease of unknown etiology. It is epithelioid cells, Langhans’ and foreign body giant cells
worldwide in distribution and affects adults from 20-40 years and surrounded peripherally by fibroblasts.
of age. The disease is characterised by the presence of non- 2. Typically, granulomas of sarcoidosis are ‘naked’ i.e.
caseating epithelioid cell granulomas (‘sarcoid granuloma’) either devoid of peripheral rim of lymphocytes or there is
in the affected tissues and organs, notably lymph nodes and paucity of lymphocytes.
lungs. Other sites are the skin, spleen, uvea of the eyes, 3. In late stage, the granuloma is either enclosed by
salivary glands, liver and bones of hands and feet. The hyalinised fibrous tissue or is replaced by hyalinised fibrous
histologic diagnosis is generally made by exclusion. mass.

HEALING 165
Healing is the body response to injury in an attempt to restore
normal structure and function. Healing involves 2 distinct
processes:
Regeneration when healing takes place by proliferation of CHAPTER 6
parenchymal cells and usually results in complete restoration
of the original tissues.
Repair when healing takes place by proliferation of
connective tissue elements resulting in fibrosis and scarring.
At times, both the processes take place simultaneously.

REGENERATION
Some parenchymal cells are short-lived while others have a
longer lifespan. In order to maintain proper structure of
tissues, these cells are under the constant regulatory control
of their cell cycle. These include growth factors such as: Inflammation and Healing
epidermal growth factor, fibroblast growth factor, platelet-
Figure 6.38 Common location of lesions in sarcoidosis. The lesions derived growth factor, endothelial growth factor,
are predominantly seen in lymph nodes and throughout lung parenchyma.
transforming growth factor-β.
Cell cycle (page 26) is defined as the period between two
4. The giant cells in sarcoid granulomas contain certain successive cell divisions and is divided into 4 unequal phases
cytoplasmic inclusions as follows: (Fig. 6.40):
i) Asteroid bodies which are eosinophilic and stellate- M (mitosis) phase: Phase of mitosis.
shaped structures. G (gap 1) phase: The daughter cell enters G phase after
1
ii) Schaumann’s bodies or conchoid (conch like) bodies which mitosis. 1
are concentric laminations of calcium and of iron salts, S (synthesis) phase: During this phase, the synthesis of
complexed with proteins. nuclear DNA takes place.
iii) Birefringent cytoplasmic crystals which are colourless. G (gap 2) phase: After completion of nuclear DNA
2
Similar types of inclusions are also observed in chronic duplication, the cell enters G phase.
berylliosis (Chapter 17). 2
G (gap 0) phase: This is the quiescent or resting phase of
0
the cell after an M phase.
KVIEM’S TEST. It is a useful intradermal diagnostic test.
The antigen prepared from involved lymph node or spleen Not all cells of the body divide at the same pace. Some
is injected intradermally. In a positive test, nodular lesion mature cells do not divide at all while others complete a cell
appears in 3-6 weeks at the inoculation site which on cycle every 16-24 hours. The main difference between slowly-
microscopic examination shows presence of non-caseating dividing and rapidly-dividing cells is the duration of G 1
granulomas. phase.




























Figure 6.39 Sarcoidosis in lymph node. Characteristically, there are non-caseating epithelioid cell granulomas which have paucity of lympho-
cytes. A giant cell with inclusions is also seen in the photomicrograph (arrow).

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Figure 6.40 Parenchymal cells in relation to cell cycle (G –Resting phase; G , G –Gaps; S–Synthesis phase; M–Mitosis phase). The inner
1
0
2
circle shown with green line represents cell cycle for labile cells; circle shown with yellow-orange line represents cell cycle for stable cells; and the
circle shown with red line represents cell cycle for permanent cells. Compare them with traffic signals—green stands for ‘go’ applies here to dividing
labile cells; yellow-orange signal for ‘ready to go’ applies here to stable cells which can be stimulated to enter cell cycle; and red signal for ‘stop’ here
means non-dividing permanent cells.
Depending upon their capacity to divide, the cells of the i) Proliferation of original cells from the margin of injury
body can be divided into 3 groups: labile cells, stable cells, with migration so as to cover the gap.
and permanent cells. ii) Proliferation of migrated cells with subsequent
General Pathology and Basic Techniques
1. Labile cells. These cells continue to multiply throughout differentiation and maturation so as to reconstitute the
life under normal physiologic conditions. These include: original tissue.
surface epithelial cells of the epidermis, alimentary tract, REPAIR
respiratory tract, urinary tract, vagina, cervix, uterine
endometrium, haematopoietic cells of bone marrow and cells Repair is the replacement of injured tissue by fibrous tissue.
of lymph nodes and spleen. Two processes are involved in repair:
2. Stable cells. These cells decrease or lose their ability to 1. Granulation tissue formation; and
proliferate after adolescence but retain the capacity to 2. Contraction of wounds.
multiply in response to stimuli throughout adult life. These Repair response takes place by participation of
include: parenchymal cells of organs like liver, pancreas, mesenchymal cells (consisting of connective tissue stem cells,
kidneys, adrenal and thyroid; mesenchymal cells like smooth fibrocytes and histiocytes), endothelial cells, macrophages,
muscle cells, fibroblasts, vascular endothelium, bone and platelets, and the parenchymal cells of the injured organ.
cartilage cells. Granulation Tissue Formation
3. Permanent cells. These cells lose their ability to proli- The term granulation tissue derives its name from slightly
ferate around the time of birth. These include: neurons of granular and pink appearance of the tissue. Each granule
nervous system, skeletal muscle and cardiac muscle cells. corresponds histologically to proliferation of new small blood
RELATIONSHIP OF PARENCHYMAL CELLS WITH vessels which are slightly lifted on the surface by thin
CELL CYCLE. If the three types of parenchymal cells des- covering of fibroblasts and young collagen.
cribed above are correlated with the phase of cell cycle, The following 3 phases are observed in the formation of
following inferences can be derived: granulation tissue (Fig. 6.41):
1. Labile cells which are continuously dividing cells remain 1. PHASE OF INFLAMMATION. Following trauma, blood
in the cell cycle from one mitosis to the next. clots at the site of injury. There is acute inflammatory
2. Stable cells are in the resting phase (G ) but can be stimu- response with exudation of plasma, neutrophils and some
0
lated to enter the cell cycle. monocytes within 24 hours.
3. Permanent cells are non-dividing cells which have left 2. PHASE OF CLEARANCE. Combination of proteolytic
the cell cycle and die after injury. enzymes liberated from neutrophils, autolytic enzymes from
Regeneration of any type of parenchymal cells involves dead tissues cells, and phagocytic activity of macrophages
the following 2 processes: clear off the necrotic tissue, debris and red blood cells.

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Figure 6.41 Active granulation tissue has inflammatory cell infiltrate, newly formed blood vessels and young fibrous tissue in loose matrix. Inflammation and Healing

3. PHASE OF INGROWTH OF GRANULATION In order to explain the mechanism of wound contraction,
TISSUE. This phase consists of 2 main processes: angio- a number of factors have been proposed. These are as under:
genesis or neovascularisation, and fibrogenesis. 1. Dehydration as a result of removal of fluid by drying of
i) Angiogenesis (neovascularisation). Formation of new wound was first suggested but without being substantiated.
blood vessels at the site of injury takes place by proliferation 2. Contraction of collagen was thought to be responsible for
of endothelial cells from the margins of severed blood vessels. contraction but wound contraction proceeds at a stage when
Initially, the proliferated endothelial cells are solid buds but the collagen content of granulation tissue is very small.
within a few hours develop a lumen and start carrying blood. 3. Discovery of myofibroblasts appearing in active
The newly formed blood vessels are more leaky, accounting granulation tissue has resolved the controversy surrounding
for the oedematous appearance of new granulation tissue. the mechanism of wound contraction. These cells have
Soon, these blood vessels differentiate into muscular features intermediate between those of fibroblasts and
arterioles, thin-walled venules and true capillaries. smooth muscle cells. Their migration into the wound area
The process of angiogenesis is stimulated with proteolytic and their active contraction decreases the size of the defect.
destruction of basement membrane. Angiogenesis takes place The evidences in support of this concept are both
under the influence of following factors:
morphological as well as functional characteristics of
a) Vascular endothelial growth factor (VEGF) elaborated by modified fibroblasts or myofibroblasts as under:
mesenchymal cells while its receptors are present in i) Fibrils present in the cytoplasm of these cells resemble
endothelial cells only. those seen in smooth muscle cells.
b) Platelet-derived growth factor (PDGF), transforming ii) These cells contain actin-myosin similar to that found in
growth factor-β (TGF-β), basic fibroblast growth factor non-striated muscle cells.
(bFGF) and surface integrins are all associated with iii) Cytoplasm of these modified cells demonstrates
cellular proliferation. immunofluorescent labelling with anti-smooth muscle
ii) Fibrogenesis. The newly formed blood vessels are antibodies.
present in an amorphous ground substance or matrix. The iv) Nuclei of these cells have infoldings of nuclear membrane
new fibroblasts originate from fibrocytes as well as by mitotic like in smooth muscle cells.
division of fibroblasts. Some of these fibroblasts have
combination of morphologic and functional characteristics v) These cells have basement membrane and desmosomes
of smooth muscle cells (myofibroblasts). Collagen fibrils begin which are not seen in ordinary fibroblasts.
to appear by about 6th day. As maturation proceeds, more vi) Drug response of granulation tissue is similar to that of
and more of collagen is formed while the number of active smooth muscle.
fibroblasts and new blood vessels decreases. This results in
formation of inactive looking scar known as cicatrisation. WOUND HEALING

Contraction of Wounds Healing of skin wounds provides a classical example of
combination of regeneration and repair described above.
The wound starts contracting after 2-3 days and the process
is completed by the 14th day. During this period, the wound Wound healing can be accomplished in one of the following
is reduced by approximately 80% of its original size. two ways:
Contracted wound results in rapid healing since lesser Healing by first intention (primary union)
surface area of the injured tissue has to be replaced. Healing by second intention (secondary union).

168











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Figure 6.42 Primary union of skin wounds. A, The incised wound as well as suture track on either side are filled with blood clot and there is
inflammatory response from the margins. B, Spurs of epidermal cells migrate along the incised margin on either side as well as around the suture
track. Formation of granulation tissue also begins from below. C, Removal of suture at around 7th day results in scar tissue at the sites of incision
and suture track.


Healing by First Intention (Primary Union) wound i.e. filling the space with haemorrhage, some
inflammatory cell reaction, epithelial cell proliferation along
This is defined as healing of a wound which has the following the suture track from both margins, fibroblastic proliferation
characteristics: and formation of young collagen. When sutures are removed
i) clean and uninfected; around 7th day, much of epithelialised suture track is avulsed
ii) surgically incised; and the remaining epithelial tissue in the track is absorbed.
iii) without much loss of cells and tissue; and
iv) edges of wound are approximated by surgical sutures. However, sometimes the suture track gets infected (stitch
General Pathology and Basic Techniques
The sequence of events in primary union is illustrated in abscess), or the epithelial cells may persist in the track (implan-
tation or epidermal cysts).
Fig. 6.42 and described below: Thus, the scar formed in a sutured wound is neat due to
1. Initial haemorrhage. Immediately after injury, the space close apposition of the margins of wound; the use of adhesive
between the approximated surfaces of incised wound is filled tapes avoids removal of stitches and its complications.
with blood which then clots and seals the wound against
dehydration and infection. Healing by Second Intention (Secondary Union)
2. Acute inflammatory response. This occurs within 24 This is defined as healing of a wound having the following
hours with appearance of polymorphs from the margins of characteristics:
incision. By 3rd day, polymorphs are replaced by i) open with a large tissue defect, at times infected;
macrophages. ii) having extensive loss of cells and tissues; and
iii) the wound is not approximated by surgical sutures but
3. Epithelial changes. The basal cells of epidermis from both is left open.
the cut margins start proliferating and migrating towards The basic events in secondary union are similar to
incisional space in the form of epithelial spurs. A well- primary union but differ in having a larger tissue defect
approximated wound is covered by a layer of epithelium in which has to be bridged. Hence healing takes place from the
48 hours. The migrated epidermal cells separate the base upwards as well as from the margins inwards. The
underlying viable dermis from the overlying necrotic healing by second intention is slow and results in a large, at
material and clot, forming scab which is cast off. The basal times ugly, scar as compared to rapid healing and neat scar
cells from the margins continue to divide. By 5th day, a of primary union.
multilayered new epidermis is formed which is differentiated The sequence of events in secondary union is illustrated
into superficial and deeper layers. in Fig. 6.43 and described below:

4. Organisation. By 3rd day, fibroblasts also invade the 1. Initial haemorrhage. As a result of injury, the wound
wound area. By 5th day, new collagen fibrils start forming space is filled with blood and fibrin clot which dries.
which dominate till healing is completed. In 4 weeks, the 2. Inflammatory phase. There is an initial acute inflam-
scar tissue with scanty cellular and vascular elements, a few matory response followed by appearance of macrophages
inflammatory cells and epithelialised surface is formed. which clear off the debris as in primary union.
5. Suture tracks. Each suture track is a separate wound and 3. Epithelial changes. As in primary healing, the epidermal
incites the same phenomena as in healing of the primary cells from both the margins of wound proliferate and migrate

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Figure 6.43 Secondary union of skin wounds. A, The open wound is filled with blood clot and there is inflammatory response at the junction of Inflammation and Healing
viable tissue. B, Epithelial spurs from the margins of wound meet in the middle to cover the gap and separate the underlying viable tissue from
necrotic tissue at the surface forming scab. C, After contraction of the wound, a scar smaller than the original wound is left.

into the wound in the form of epithelial spurs till they meet 6. Presence of infection. Bacterial contamination of an open
in the middle and re-epithelialise the gap completely. wound delays the process of healing due to release of
However, the proliferating epithelial cells do not cover the bacterial toxins that provoke necrosis, suppuration and
surface fully until granulation tissue from base has started thrombosis. Surgical removal of dead and necrosed tissue,
filling the wound space. In this way, pre-existing viable debridement, helps in preventing the bacterial infection of open
connective tissue is separated from necrotic material and clot wounds.
on the surface, forming scab which is cast off. In time, the Differences between primary and secondary union of
regenerated epidermis becomes stratified and keratinised. wounds are given in Table 6.6.
4. Granulation tissue. Main bulk of secondary healing is
by granulations. Granulation tissue is formed by proliferation Complications of Wound Healing
of fibroblasts and neovascularisation from the adjoining During the course of healing, following complications may
viable elements. The newly-formed granulation tissue is deep occur:
red, granular and very fragile. With time, the scar on
maturation becomes pale and white due to increase in 1. Infection of wound due to entry of bacteria delays the
collagen and decrease in vascularity. Specialised structures healing.
of the skin like hair follicles and sweat glands are not replaced 2. Implantation (epidermal) cyst formation may occur due to
unless their viable residues remain which may regenerate. persistence of epithelial cells in the wound after healing.
3. Pigmentation. Healed wounds may at times have rust-like
5. Wound contraction. Contraction of wound is an colour due to staining with haemosiderin. Some coloured
important feature of secondary healing, not seen in primary particulate material left in the wound may persist and impart
healing. Due to the action of myofibroblasts present in colour to the healed wound.
granulation tissue, the wound contracts to one-third to one-
fourth of its original size. Wound contraction occurs at a time 4. Deficient scar formation. This may occur due to inadequate
when active granulation tissue is being formed. formation of granulation tissue.


 TABLE 6.6: Differences between Primary and Secondary Union of Wounds.

Feature Primary Union Secondary Union
1. Cleanliness of wound Clean Unclean
2. Infection Generally uninfected May be infected
3. Margins Surgical clean Irregular
4. Sutures Used Not used
5. Healing Scanty granulation tissue at the incised Exuberant granulation tissue
gap and along suture tracks to fill the gap
6. Outcome Neat linear scar Contracted irregular wound
7. Complications Infrequent, epidermal inclusion cyst formation Suppuration, may require debridement

170 5. Incisional hernia. A weak scar, especially after a i) Fibronectin (nectere = to bind) is the best characterised
laparotomy, may be the site of bursting open of a wound glycoprotein in ECM and has binding properties to other cells
(wound dehiscence) or an incisional hernia. and ECM. It is of two types—plasma and tissue fibronectin.
6. Hypertrophied scars and keloid formation. At times the scar Plasma fibronectin is synthesised by the liver cells and is
formed is excessive, ugly and painful. Excessive formation trapped in basement membrane such as in filtration through
of collagen in healing may result in keloid (claw-like) the renal glomerulus.
formation, seen more commonly in Blacks. Hypertrophied Tissue fibronectin is formed by fibroblasts, endothelial
scars differ from keloid in that they are confined to the cells and other mesenchymal cells. It is responsible for the
borders of the initial wound while keloids have tumour-like primitive matrix such as in the foetus, and in wound healing.
SECTION I
projection of connective tissue.
ii) Tenascin or cytotactin is the glycoprotein associated with
7. Excessive contraction. An exaggeration of wound fibroblasts and appears in wound about 48 hours after injury.
contraction may result in formation of contractures or It disappears from mature scar tissue.
cicatrisation e.g. Dupuytren’s (palmar) contracture, plantar iii) Thrombospondin is mainly synthesised by granules of
contracture and Peyronie’s disease (contraction of the platelets. It functions as adhesive protein for keratinocytes
cavernous tissues of penis).
and platelets but is inhibitory to attachment of fibroblasts
8. Neoplasia. Rarely, scar may be the site for development and endothelial cells.
of carcinoma later e.g. squamous cell carcinoma in Marjolin’s
ulcer i.e. a scar following burns on the skin. 3. BASEMENT MEMBRANE. Basement membranes are
periodic acid-Schiff (PAS)-positive amorphous structures
Extracellular Matrix— Wound Strength that lie underneath epithelia of different organs and
endothelial cells. They consist of collagen type IV and
The wound is strengthened by proliferation of fibroblasts laminin.
and myofibroblasts which get structural support from the
extracellular matrix (ECM). In addition to providing 4. ELASTIC FIBRES. While the tensile strength in tissue
structural support, ECM can direct cell migration, comes from collagen, the ability to recoil is provided by elastic
attachment, differentiation and organisation. fibres. Elastic fibres consist of 2 components—elastin
ECM has five main components: collagen, adhesive glycoprotein and elastic microfibril. Elastases degrade the
glycoproteins, basement membrane, elastic fibres, and elastic tissue e.g. in inflammation, emphysema etc.
proteoglycans.
5. PROTEOGLYCANS. These are a group of molecules
1. COLLAGEN. The collagens are a family of proteins having 2 components—an essential carbohydrate polymer
General Pathology and Basic Techniques
which provide structural support to the multicellular (called polysaccharide or glycosaminoglycan), and a protein
organism. It is the main component of tissues such as fibrous bound to it, and hence the name proteo-glycan. Various
tissue, bone, cartilage, valves of heart, cornea, basement proteoglycans are distributed in different tissues as under:
membrane etc. i) Chondroitin sulphate—abundant in cartilage, dermis
Collagen is synthesised and secreted by a complex ii) Heparan sulphate—in basement membranes
biochemical mechanism on ribosomes. The collagen synthesis iii) Dermatan sulphate—in dermis
is stimulated by various growth factors and is degraded by iv) Keratan sulphate—in cartilage
collagenase. Regulation of collagen synthesis and v) Hyaluronic acid—in cartilage, dermis.
degradation take place by various local and systemic factors In wound healing, the deposition of proteoglycans
so that the collagen content of normal organs remains precedes collagen laying.
constant. On the other hand, defective regulation of collagen The strength of wound also depends upon factors like
synthesis leads to hypertrophied scar, fibrosis, and organ the site of injury, depth of incision and area of wound. After
dysfunction. removal of stitches on around 7th day, the wound strength
Depending upon the biochemical composition, 18 types is approximately 10% which reaches 80% in about 3 months.
of collagen have been identified called collagen type I to XVIII,
many of which are unique for specific tissues. Type I collagen TURNOVER OF ECM. ECM is not a static structure but
is normally present in the skin, bone and tendons and the matrix proteins comprising it undergo marked
accounts for 90% of collagen in the body: remodeling during foetal life which slows down in adult
Type I, III and V are true fibrillar collagen which form the tissues. These matrix proteins are degraded by a family of
main portion of the connective tissue during healing of metalloproteinases which act under regulatory control of
wounds in scars. inhibitors of metalloproteinases.
Other types of collagen are non-fibrillar and amorphous
material seen as component of the basement membranes. Factors Influencing Healing
Morphologically, the smallest units of collagen are Two types of factors influence the wound healing: those
collagen fibrils, which align together in parallel bundles to acting locally, and those acting in general.
form collagen fibres, and then collagen bundles.
2. ADHESIVE GLYCOPROTEINS. Various adhesive A. LOCAL FACTORS:
glycoproteins acting as glue for the ECM and the cells consist 1. Infection is the most important factor acting locally which
of fibronectin, tenascin (cytotactin) and thrombospondin. delays the process of healing.

2. Poor blood supply to wound slows healing e.g. injuries to Fracture Healing 171
face heal quickly due to rich blood supply while injury to Healing of fracture by callus formation depends upon some
leg with varicose ulcers having poor blood supply heals clinical considerations whether the fracture is:
slowly. traumatic (in previously normal bone), or pathological (in
3. Foreign bodies including sutures interfere with healing and previously diseased bone);
cause intense inflammatory reaction and infection. complete or incomplete like green-stick fracture; and CHAPTER 6
4. Movement delays wound healing. simple (closed), comminuted (splintering of bone), or
5. Exposure to ionising radiation delays granulation tissue compound (communicating to skin surface).
However, basic events in healing of any type of fracture
formation. are similar and resemble healing of skin wound to some
6. Exposure to ultraviolet light facilitates healing. extent.
7. Type, size and location of injury determines whether Primary union of fractures occurs in a few special
healing takes place by resolution or organisation. situations when the ends of fracture are approximated as is
B. SYSTEMIC FACTORS: done by application of compression clamps. In these cases,
1. Age. Wound healing is rapid in young and somewhat bony union takes place with formation of medullary callus
slow in aged and debilitated people due to poor blood supply without periosteal callus formation. The patient can be made
to the injured area in the latter. ambulatory early but there is more extensive bone necrosis Inflammation and Healing
2. Nutrition. Deficiency of constituents like protein, vitamin and slow healing.
C (scurvy) and zinc delays the wound healing. Secondary union is the more common process of fracture
3. Systemic infection delays wound healing. healing. Though it is a continuous process, secondary bone
union is described under the following 3 headings:
4. Administration of glucocorticoids has anti-inflammatory i) Procallus formation
effect. ii) Osseous callus formation
5. Uncontrolled diabetics are more prone to develop infections iii) Remodelling
and hence delay in healing. These processes are illustrated in Fig. 6.44 and described
6. Haematologic abnormalities like defect of neutrophil func- below:
tions (chemotaxis and phagocytosis), and neutropenia and I. PROCALLUS FORMATION. Steps involved in the
bleeding disorders slow the process of wound healing. formation of procallus are as follows:

1. Haematoma forms due to bleeding from torn blood
HEALING IN SPECIALISED TISSUES
vessels, filling the area surrounding the fracture. Loose
Healing of the skin wound provides an example of general meshwork is formed by blood and fibrin clot which acts as
process of healing by regeneration and repair. However, in framework for subsequent granulation tissue formation.
certain specialised tissues, either regeneration or repair may 2. Local inflammatory response occurs at the site of injury
predominate. Some of these examples are described below. with exudation of fibrin, polymorphs and macrophages. The































Figure 6.44 Fracture healing. A, Haematoma formation and local inflammatory response at the fracture site. B, Ingrowth of granulation tissue
with formation of soft tissue callus. C, Formation of procallus composed of woven bone and cartilage with its characteristic fusiform appearance and
having 3 arbitrary components—external, intermediate and internal callus. D, Formation of osseous callus composed of lamellar bone following
clearance of woven bone and cartilage. E, Remodelled bone ends; the external callus cleared away. Intermediate callus converted into lamellar
bone and internal callus developing bone marrow cavity.

172 external callus is cleared away, compact bone (cortex) is
formed in place of intermediate callus and the bone marrow
cavity develops in internal callus.
COMPLICATIONS OF FRACTURE HEALING. These are
as under:
1. Fibrous union may result instead of osseous union if the
immobilisation of fractured bone is not done. Occasionally,
a false joint may develop at the fracture site (pseudo-
SECTION I
arthrosis).
2. Non-union may result if some soft tissue is interposed
between the fractured ends.
3. Delayed union may occur from causes of delayed wound
healing in general such as infection, inadequate blood supply,
poor nutrition, movement and old age.

Healing of Nervous Tissue
CENTRAL NERVOUS SYSTEM. The nerve cells of the
brain, spinal cord and ganglia once destroyed are not
Figure 6.45 Callus formation in fracture healing. replaced. Axons of CNS also do not show any significant
regeneration. The damaged neuroglial cells, however, may
show proliferation of astrocytes called gliosis.
macrophages clear away the fibrin, red blood cells,
inflammatory exudate and debris. Fragments of necrosed PERIPHERAL NERVOUS SYSTEM. In contrast to the cells
bone are scavenged by macrophages and osteoclasts. of CNS, the peripheral nerves show regeneration, mainly
3. Ingrowth of granulation tissue begins with neovascula- from proliferation of Schwann cells and fibrils from distal
risation and proliferation of mesenchymal cells from end. The process is discussed in Chapter 30. Briefly, it consists
periosteum and endosteum. A soft tissue callus is thus of the following:
formed which joins the ends of fractured bone without much Myelin sheath and axon of the intact distal nerve undergo
strength. Wallerian degeneration up to the next node of Ranvier
General Pathology and Basic Techniques
4. Callus composed of woven bone and cartilage starts towards the proximal end.
within the first few days. The cells of inner layer of the Degenerated debris are cleared away by macrophages.
periosteum have osteogenic potential and lay down collagen Regeneration in the form of sprouting of fibrils takes place
as well as osteoid matrix in the granulation tissue (Fig. 6.45). from the viable end of axon. These fibrils grow along the
track of degenerated nerve so that in about 6-7 weeks, the
The osteoid undergoes calcification and is called woven bone
callus. A much wider zone over the cortex on either side of peripheral stump consists of tube filled with elongated
fractured ends is covered by the woven bone callus and Schwann cells.
united to bridge the gap between the ends, giving spindle- One of the fibrils from the proximal stump enters the old
shaped or fusiform appearance to the union. In poorly neural tube and develops into new functional axon.
immobilised fractures (e.g. fracture ribs), the subperiosteal
osteoblasts may form cartilage at the fracture site. At times, Healing of Muscle
callus is composed of woven bone as well as cartilage, tempo- All three types of muscle fibres have limited capacity to
rarily immobilising the bone ends. regenerate.
This stage is called provisional callus or procallus
formation and is arbitrarily divided into external, intermediate SKELETAL MUSCLE. The regeneration of striated muscle
and internal procallus. is similar to peripheral nerves. On injury, the cut ends of
muscle fibres retract but are held together by stromal
II. OSSEOUS CALLUS FORMATION. The procallus acts connective tissue. The injured site is filled with fibrinous
as scaffolding on which osseous callus composed of lamellar material, polymorphs and macrophages. After clearance of
bone is formed. The woven bone is cleared away by incoming damaged fibres by macrophages, one of the following two
osteoclasts and the calcified cartilage disintegrates. In their types of regeneration of muscle fibres can occur:
place, newly-formed blood vessels and osteoblasts invade, If the muscle sheath is intact, sarcolemmal tubes
laying down osteoid which is calcified and lamellar bone is containing histiocytes appear along the endomysial tube
formed by developing Haversian system concentrically which, in about 3 months time, restores properly oriented
around the blood vessels.
muscle fibres e.g. in Zenker’s degeneration of muscle in
III. REMODELLING. During the formation of lamellar typhoid fever.
bone, osteoblastic laying and osteoclastic removal are taking If the muscle sheath is damaged, it forms a disorganised
place remodelling the united bone ends, which after multinucleate mass and scar composed of fibrovascular
sometime, is indistinguishable from normal bone. The tissue e.g. in Volkmann’s ischaemic contracture.

SMOOTH MUSCLE. Non-striated muscle has limited margins, migration, multilayering and differentiation of 173
regenerative capacity e.g. appearance of smooth muscle in epithelial cells in the same way as in the epidermal cells in
the arterioles in granulation tissue. However, in large healing of skin wounds.
destructive lesions, the smooth muscle is replaced by
permanent scar tissue. Healing of Solid Epithelial Organs

CARDIAC MUSCLE. Destruction of heart muscle is replaced Following gross tissue damage to organs like the kidney, liver CHAPTER 6
by fibrous tissue. However, in situations where the and thyroid, the replacement is by fibrous scar e.g. in chronic
endomysium of individual cardiac fibre is intact (e.g. in pyelonephritis and cirrhosis of liver. However, in
diphtheria and coxsackie virus infections), regeneration of parenchymal cell damage with intact basement membrane
cardiac fibres may occur in young patients. or intact supporting stromal tissue, regeneration may occur.
For example:
In tubular necrosis of kidney with intact basement
Healing of Mucosal Surfaces
membrane, proliferation and slow migration of tubular
The cells of mucosal surfaces have very good regeneration epithelial cells may occur to form renal tubules.
and are normally being lost and replaced continuously e.g. In viral hepatitis, if part of the liver lobule is damaged with
mucosa of alimentary tract, respiratory tract, urinary tract, intact stromal network, proliferation of hepatocytes may
uterine endometrium etc. This occurs by proliferation from result in restoration of liver lobule. Inflammation and Healing


❑

174
Infectious and
Chapter 7
Chapter 7
Parasitic Diseases






SECTION I
INTRODUCTION (including kuru), bovine spongiform encephalopathy (or mad
cow disease) and Creutzfeldt-Jakob disease (associated with
Microorganisms, namely bacteria, viruses, fungi and corneal transplantation). (Dr. Prusiner who discovered prion
parasites, are present everywhere—in the soil, water, atmos- protein was awarded Nobel Prize in medicine in 1997).
phere and on the body surfaces, and are responsible for a Transmission of infectious diseases requires a chain of
large number of infectious diseases in human beings. Some events and is the consequence of inter-relationship between
microorganisms are distributed throughout the world while disease-producing properties of microorganisms and host-
others are limited to certain geographic regions only. In defense capability against the invading organisms. Briefly,
general, tropical and developing countries are specially chain in transmission of infections and factors determining
affected by infectious diseases than the developed countries. this host-microorganism relationship are given below:
There are several examples of certain infectious diseases which
are not so common in the developed world now but they Chain in Transmission of Infectious Diseases
continue to be major health problems in the developing
countries e.g. tuberculosis, leprosy, typhoid fever, cholera, Transmission of infections occurs following a chain of events
measles, pertussis, malaria, amoebiasis, pneumonia etc. pertaining to various parameters as under:
Vaccines have, however, been successful in controlling or i) Reservoir of pathogen. Infection occurs from the source
eliminating some diseases all over the world e.g. smallpox, of reservoir of pathogen. It may be a human being (e.g. in
poliomyelitis, measles, pertussis etc. Similarly, insecticides influenza virus), animal (e.g. dog for rabies), insect (e.g.
have helped in controlling malaria to an extent. However, mosquito for malaria), or soil (e.g. enterobiasis).
infections still rank very high as a cause of death in the world. ii) Route of infection. Infection is transmitted from the
Reasons for this trend are not difficult to seek: reservoir to the human being by different routes, usually from
Development of newer and antibiotic-resistant strains of breach in the mucosa or the skin at both— the portal of exit
General Pathology and Basic Techniques
microorganisms; classic example is that of methicillin- from the reservoir and the portal of entry in the susceptible
resistant Staph. aureus (MRSA). host. In general, the organism is transmitted to the site where
Administration of immunosuppressive therapy to the organism would normally flourish e.g. N. gonorrhoeae
patients with malignant tumours and transplanted organs usually inhabits the male and female urethra and, therefore,
making them susceptible to opportunistic infections the route of transmission would be sexual contact.
Increasing number of patients reporting to hospital for iii) Mode of transmission. The organism may be transmitted
different illnesses but instead many developing hospital- directly by physical contact or by faecal contamination (e.g.
acquired infections. spread of eggs in hookworm infestation), or indirectly by
Lastly, discovery in 1981 of previously unknown deadly fomites (e.g. insect bite).
disease i.e. acquired immunodeficiency syndrome (AIDS)
caused by human immunodeficiency virus (HIV). iv) Susceptible host. The organism would colonise the host
While talking of microbial infective diseases, let us not if the host has good immunity but such a host can pass on
forget the fact that many microorganisms may actually infection to others. However, if the host is old, debilitated,
malnourished, or immunosuppressed due any etiology, he
benefit mankind. Following is the range of host-organism inter- is susceptible to have manifestations of infection.
relationship, which may vary quite widely: Key to management of infection lies in breaking or
1. Symbiosis i.e. cooperative association between two blocking this chain for transmission and spread of infection.
dissimilar organisms beneficial to both.
2. Commensalism i.e. two dissimilar organisms living Factors Relating to Infectious Agents
together benefitting one without harming the other. These are as under:
3. True parasitism i.e. two dissimilar organisms living
together benefitting the parasite but harming the host. i) Mode of entry. Microorganisms causing infectious
diseases may gain entry into the body by various routes e.g.
4. Saprophytism i.e. organisms living on dead tissues.
Besides microorganisms, more recently a modified host through ingestion (external route);
protein present in the mammalian CNS has been identified inoculation (parenteral method);
called prion protein. Prions are transmissible agents similar inhalation (respiration);
to infectious particles but lack nucleic acid. These agents are perinatally (vertical transmission);
implicated in the etiology of spongiform encephalopathy, by direct contact (contagious infection); and

by contaminated water, food, soil, environment or from  TABLE 7.1: Methods of Identification of Microorganisms. 175
an animal host (zoonotic infections).
1. BACTERIA
ii) Spread of infection. Microorganisms after entering the i. Gram stain: Most bacteria
body may spread further through the phagocytic cells, blood ii. Acid fast stain: Mycobacteria, Nocardia
vessels and lymphatics. iii. Giemsa: Campylobacteria
iii) Production of toxins. Bacteria liberate toxins which have 2. FUNGI CHAPTER 7
i. Silver stain: Most fungi
effects on cell metabolism. Endotoxins are liberated on lysis ii. Periodic acid-Schiff (PAS): Most fungi
of the bacterial cell while exotoxins are secreted by bacteria iii. Mucicarmine: Cryptococci
and have effects at distant sites too.
3. PARASITES
iv) Virulence of organisms. Many species and strains of i. Giemsa: Malaria, Leishmania
organisms may have varying virulence e.g. the three strains ii. Periodic acid-Schiff: Amoebae
of C. diphtheriae (gravis, intermedius and mitis) produce the iii. Silver stain: Pneumocystis
same diphtherial exotoxin but in different amounts. 4. ALL CLASSES INCLUDING VIRUSES
i. Culture
v) Product of organisms. Some organisms produce enzy- ii. In situ hybridisation
mes that help in spread of infections e.g. hyaluronidase by iii. DNA analysis
Cl. welchii, streptokinase by streptococci, staphylokinase and iv. Polymerase chain reaction (PCR)
coagulase by staphylococci. Infectious and Parasitic Diseases
species identification and drug sensitivity. Generally, the
Factors Relating to Host organism is looked for at the advancing edge of the lesion in
Microorganisms invade human body when defenses are not the section rather than in the necrotic centre (Fig. 7.1).
adequate. These factors include the following:
DISEASES CAUSED BY BACTERIA,
i) Physical barrier. A break in the continuity of the skin
and mucous membranes allows the microorganisms to enter SPIROCHAETES AND MYCOBACTERIA
the body.
In order to gain an upper hand in human host, bacteria must
ii) Chemical barrier. Mucus secretions of the oral cavity and resist early engulfment by neutrophils. They survive and
the alimentary tract and gastric acidity prevent bacterial damage the host in a variety of ways such as by generation
colonisation. of toxins (e.g. gas-forming anaerobes), by forming a slippery

iii) Effective drainage. Natural passages of the hollow organs capsule that resists attachment to macrophages (e.g.
like respiratory, gastrointestinal, urinary and genital system pneumococci), by inhibition of fusion of phagocytic vacuoles
provide a way to drain the excretions effectively. Similarly, with lysosomes (e.g. tubercle bacilli) etc.
ducts of various glands are the conduits of drainage of Table 7.2 provides an abbreviated classification of
secretions. Obstruction in any of these passages promotes bacterial diseases and their etiologic agents. A few common
infection. and important examples amongst these are discussed below.
iv) Immune defense mechanisms. These include the phago- PLAGUE
cytic leucocytes of blood (polymorphs and monocytes),
phagocytes of tissues (mononuclear-phagocyte system) and Plague is caused by Yersinia (Pasteurella) pestis which is a
the immune system as discussed in Chapter 4. small Gram-negative coccobacillus that grows rapidly on
Some of the common diseases produced by pathogenic most culture media. Direct identification of the organism in
microorganisms are discussed below. Each group of tissues is possible by fluorescence antisera methods.
microorganisms discussed here is accompanied by a Table Plague has been a great killer since 14th century and is
listing diseases produced by them. These lists of diseases known to have wiped out populations of cities. However,
are in no way complete but include only important and the modern Europe is plague free, possibly due to
common examples. No attempts will be made to give details widespread use of arsenic as rat poison. Currently, the world
of organisms as that would mean repeating what is given in over, Vietnam and Tanzania have most cases of plague.
the textbooks of Microbiology. Instead, salient clinico- However, an outbreak in Surat in the state of Gujarat in
pathologic aspects of these diseases are highlighted. Western part of India in 1994 alarmed the world once again
that we are not totally free of this dreaded ‘black death’.
Plague is a zoonotic disease and spreads by rodents,
Methods of Identification
primarily by rats, both wild and domestic; others being
The organisms causing infections and parasitic diseases may squirrels and rabbits. Humans are incidental hosts other than
be identified by routine H & E stained sections in many rodents.
instances. However, confirmation in most cases requires Infection to humans occurs by rat-flea or by inhalation.
either application of special staining techniques or is After the organisms enter the bloodstream, they reach the
confirmed by molecular biologic methods (Table 7.1). In draining lymph nodes where, rather than being phago-
addition, culture of lesional tissue should be carried out for cytosed by phagocytic cells, they proliferate rapidly giving

176











SECTION I
























Figure 7.1 Common stains used for demonstration of microbes. A, Gram’s stain. B, Ziehl-Neelsen (ZN) or AFB stain. C, Giemsa stain. D,
Periodic acid Schiff (PAS) stain. E, Mucicarmine stain. F, Gomori methenamine silver (GMS) stain.


  TABLE 7.2: Diseases Caused by Bacteria, Spirochaetes and Mycobacteria.
General Pathology and Basic Techniques
Disease Etiologic Agent
1. Typhoid (enteric) fever (Chapter 20) Salmonella typhi
2. Plague* Yersinia pestis
3. Anthrax* Bacillus anthracis
4. Whooping cough* (pertussis) Bordetella pertussis
5. Chancroid Haemophilus ducreyi
6. Granuloma inguinale* Calymmatobacterium donovani
7. Gonorrhoea Neisseria gonorrhoeae
8. Cholera Vibrio cholerae
9. Shigellosis S. dysenteriae, S. flexneri, S. boydii, S. sonnei
10. Brucellosis B. melitensis, B. abortus, B. suis, B. canis
11. Diphtheria Corynebacterium diphtheriae
12. Lobar pneumonia (Chapter 17) Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae,
Klebsiella pneumoniae
13. Bronchopneumonia (Chapter 17) Staphylococci, Streptococci, K. pneumoniae, H. influenzae
14. Bacterial meningitis (Chapter 30) Escherichia coli, H.influenzae, Neisseria meningitidis, Streptococcus pneumoniae
15. Bacterial endocarditis (Chapter 16) Staphylococcus aureus, Streptococcus viridans
16. Other staphylococcal infections* S. aureus, S. epidermidis, S. saprophyticus
17. Streptococcal infections* S. pyogenes, S. faecalis, S. pneumoniae. S. viridans
18. E. coli infections (Chapter 22) Escherichia coli
(Urinary tract infection)
19. Clostridial diseases*
i) Gas gangrene C. perfringens
ii) Tetanus C. tetani
iii) Botulism C. botulinum
iv) Clostridial food poisoning C. perfringens
v) Necrotising enterocolitis C. perfringens
20. Tuberculosis (page 149) Mycobacterium tuberculosis
21. Leprosy (page 158) Mycobacterium leprae
22. Syphilis (page 161) Treponema pallidum
23. Actinomycosis (page 163) Actinomyces israelii
24. Nocardiosis Nocardia asteroides
*Diseases discussed in this chapter.

177











CHAPTER 7



























Figure 7.2 Forms of plague. Infectious and Parasitic Diseases


rise to tender lymphadenopathy. This occurs within 24-48 Multiple necrotising granulomas.
hours of infection and is accompanied by chills, fever, Characteristic mononuclear inflammatory response.
myalgia, nausea, vomiting and marked prostration. If
untreated, death occurs from disseminated intravascular Masses of proliferating bacilli in sinusoids of lymph
coagulation (DIC) within 1 to 2 days with development of nodes.
widespread petechiae and ecchymoses leading to gangrene, Cellulitis in the vicinity.
and hence the name black death. In other cases, death results PNEUMONIC PLAGUE. This is the most dreaded form
from multi-organ failure due to profound toxaemia. The of plague that occurs by inhalation of bacilli from air-borne
patient and his fluids are highly infectious and can be trans- particles of carcasses of animals or from affected patient’s
mitted by arthropods as well as person-to-person contact, cough. It is characterised by occurrence of broncho-
giving rise to secondary cases. pneumonia, with the following conspicuous microscopic
Virulence of the organism Y. pestis is attributed to the features:
elaboration of plague toxins: pesticin and lipopolysaccharide Necrosis of alveolar walls.
endotoxin. Intense hyperaemia and haemorrhages.
MORPHOLOGIC FEATURES. Following forms of plague Numerous bacilli in the alveolar lumina.
are recognised (Fig. 7.2): Characteristic mononuclear inflammatory response
1. Bubonic plague, the most common with very scanty neutrophils.
2. Pneumonic plague TYPHOIDAL PLAGUE. This form of plague is
3. Typhoidal plague unassociated with regional lymphadenopathy. The lesions
4. Septicaemic plague in typhoidal plague are as follows:
BUBONIC PLAGUE. This form is characterised by rapid Necrotic foci in visceral lymphoid tissue.
appearance of tender, fluctuant and enlarged regional Necrotic areas in parenchymal visceral organs.
lymph nodes, several centimeters in diameter, and may G.I. manifestations with diarrhoea and pain abdomen.
have discharging sinuses on the skin. SEPTICAEMIC PLAGUE. This is a form of progressive,
Microscopically, the features are as under: fulminant bacterial infection associated with profound
Effaced architecture of lymph nodes due to necrosis septicaemia in the absence of apparent regional
in and around the affected nodes. lymphadenitis.

178 ANTHRAX aerosols results in rapid development of malignant
pustule in the bronchus. This is followed by development
Anthrax is a bacterial disease of antiquity caused by Bacillus
anthracis that spreads from animals to man. The disease is of primary extensive necrotising pneumonia and
widely prevalent in cattle and sheep but human infection is haemorrhagic mediastinitis which is invariably fatal.
rare. However, much of knowledge on human anthrax has 3. Intestinal anthrax is rare in human beings and is quite
been gained owing to fear of use of these bacteria for military similar to that seen in cattle. Septicaemia and death often
purpose by rogue countries or for “bio-terrorism” (other results in this type too. The lesions consist of mucosal
microbial diseases in this list include: botulism, pneumonic oedema, small necrotic ulcers, massive fluid loss and
plague, smallpox). A few years back, the human form of haemorrhagic mesenteric lymphadenitis.
SECTION I
disease attracted a lot of attention of the media and the Besides, anthrax septicaemia results in spread of
civilised world due to its use in the form of anthrax-laced infection to all other organs.
letters sent by possible terrorist groups as a retaliatory
biological weapon against the US interest subsequent to LABORATORY DIAGNOSIS. Anthrax can be diagnosed by
punitive attacks by the US on Afghanistan as an aftermath a few simple techniques:
of September 11, 2001 terrorist attacks in the US. In India, i) Smear examination: Gram stained smear shows rod-shaped,
anthrax in animals is endemic in South due to large spore-forming, gram-positive bacilli. Endospores are
unprotected and uncontrolled live-stock population. detectable by presence of unstained defects or holes within
the cell.
ETIOPATHOGENESIS. The causative organism, Bacillus
anthracis, is a gram-positive, aerobic bacillus, 4.5 μm long. It ii) Culture: Anthrax bacteria grow on sheep blood agar as
is a spore-forming bacillus and the spores so formed outside flat colonies with an irregular margin (medusa head).
the body are quite resistant. The disease occurs as an Anthrax contaminated work surfaces, materials and
exogenous infection by contact with soil or animal products equipment must be decontaminated with 5% hypochlorite
or 5% phenol.
contaminated with spores.
Depending upon the portal of entry, three types of human
anthrax is known to occur: WHOOPING COUGH (PERTUSSIS)
i) Cutaneous form by direct contact with skin and is most Whooping cough is a highly communicable acute bacterial
common. disease of childhood caused by Bordetella pertussis. The use
ii) Pulmonary form by inhalation, also called as “wool- of DPT vaccine has reduced the prevalence of whooping
sorters’ disease” and is most fatal. cough in different populations.
General Pathology and Basic Techniques
The causative organism, B. pertussis, has strong tropism
iii) Gastrointestinal form by ingestion and is rare. for the brush border of the bronchial epithelium. The
The mechanism of infection includes spread of bacilli organisms proliferate here and stimulate the bronchial
from the portal of entry to the regional lymph nodes through epithelium to produce abundant tenacious mucus. Within
lymphatics where the bacteria proliferate. There is delayed 7-10 days after exposure, catarrhal stage begins which is the
accumulation of polymorphs and macrophages. most infectious stage. There is low grade fever, rhinorrhoea,
Macrophages also play a role in expression of bacterial conjunctivitis and excess tear production. Paroxysms of
toxicity; bacterial toxin is quite lethal to macrophages. cough occur with characteristic ‘whoop’. The condition is self-
limiting but may cause death due to asphyxia in infants. B.
MORPHOLOGIC FEATURES. The characteristic lesions pertussis produces a heat-labile toxin, a heat-stable endotoxin,
of anthrax are haemorrhage, oedema and necrosis at the and a lymphocytosis-producing factor called histamine-
portal of entry.
sensitising factor.
1. Cutaneous anthrax is the most common and occurs in
two forms: one type is characterised by necrotic lesion due Microscopically, the lesions in the respiratory tract consist
to vascular thrombosis, haemorrhage and acellular of necrotic bronchial epithelium covered by thick
necrosis, while the other form begins as a pimple at the mucopurulent exudate. In severe cases, there is mucosal
point of entry of B. anthracis into the abraded exposed skin, erosion and hyperaemia. The peripheral blood shows
more often in the region of hands and the head and neck. marked lymphocytosis upto 90% (Fig. 7.3) and
The initial lesion develops into a vesicle or blister enlargement of lymphoid follicles in the bronchial mucosa
containing clear serous or blood-stained fluid swarming and peribronchial lymph nodes.
with anthrax bacilli which can be identified readily by
smear examination. The bursting of the blister is followed GRANULOMA INGUINALE
by extensive oedema and black tissue necrosis resulting
in formation of severe ‘malignant pustule’. Regional Granuloma inguinale is a sexually-transmitted disease
lymph nodes are invariably involved along with profound affecting the genitalia and inguinal and perianal regions
septicaemia. caused by Calymmatobacterium donovani. The disease is
common in tropical and subtropical countries such as New
2. Pulmonary anthrax (wool-sorters’ disease) occurring Guinea, Australia and India. The organism inhabits the
from inhalation of spores of B. anthracis in infectious
intestinal tract. The infection is transmitted through vaginal

follicles. Impetigo is yet another staphylococcal skin infection 179
common in school children in which there are multiple
pustular lesions on face forming honey-yellow crusts. Breast
abscess may occur following delivery when staphylococci are
transmitted from infant having neonatal sepsis or due to
stasis of milk. CHAPTER 7
2. Infections of burns and surgical wounds. These are quite
common due to contamination from the patient’s own nasal
secretions or from hospital staff. Elderly, malnourished, obese
patients and neonates have increased susceptibility.

3. Infections of the upper and lower respiratory tract.
Small children under 2 years of age get staphylococcal
infections of the respiratory tract commonly. These include
pharyngitis, bronchopneumonia, staphylococcal
pneumonia and its complications.
4. Bacterial arthritis. Septic arthritis in the elderly is caused
Figure 7.3 Marked peripheral blood lymphocytosis in whooping by Staph. aureus.
cough. Infectious and Parasitic Diseases
5. Infection of bone (Osteomyelitis). Young boys having
or anal intercourse and by autoinoculation. The incubation history of trauma or infection may develop acute
period varies from 2 to 4 weeks. Initially, the lesion is in the staphylococcal osteomyelitis (Chapter 28).
form of a papule, a subcutaneous nodule or an ulcer. Within
a few weeks, it develops into a raised, soft, painless, reddish 6. Bacterial endocarditis. Acute and subacute bacterial
ulcer with exuberant granulation tissue. Depending upon endocarditis are complications of infection with Staph. aureus
and Staph. epidermidis (Chapter 16).
whether the individual is heterosexual or homosexual, the
lesions are located on the penis, scrotum, genito-crural folds 7. Bacterial meningitis. Surgical procedures on central
and inguinal folds, or in the perianal and anal area respecti- nervous system may lead to staphylococcal meningitis
vely. Regional lymphadenopathy generally does not occur. (Chapter 30).

Microscopically, the margin of the ulcer shows epithelial
hyperplasia. The ulcer bed shows neutrophilic abscesses.
The dermis and subcutaneous tissues are infiltrated by
numerous histiocytes containing many bacteria called
Donovan bodies, and lymphocytes, plasma cells and
neutrophils. These organisms are best demonstrated by
silver impregnation techniques.

STAPHYLOCOCCAL INFECTIONS
Staphylococci are gram-positive cocci which are present
everywhere—in the skin, umbilicus, nasal vestibule, stool
etc. Three species are pathogenic to human beings: Staph.
aureus, Staph. epidermidis and Staph. saprophyticus. Most
staphylococcal infections are caused by Staph. aureus.
Staphylococcal infections are among the commonest
antibiotic-resistant hospital-acquired infection in surgical
wounds.
A wide variety of suppurative diseases are caused by
Staph. aureus which includes the following (Fig. 7.4):
1. Infections of skin. Staphylococcal infections of the skin
are quite common. The infection begins from lodgement of
cocci in the hair root due to poor hygiene and results in
obstruction of sweat or sebaceous gland duct. This is termed
folliculitis. Involvement of adjacent follicles results in larger
lesions called furuncle. Further spread of infection
horizontally under the skin and subcutaneous tissue causes
carbuncle or cellulitis. Styes are staphylococcal infection of the
sebaceous glands of Zeis, the glands of Moll and eyelash Figure 7.4 Suppurative diseases caused by Staphylococcus aureus.

180 streptococcal complications such as RHD and acute
glomerulonephritis.
3. Group C and G streptococci are responsible for respiratory
infections.
4. Group D or Streptococcus faecalis, also called enterococci
are important in causation of urinary tract infection, bacterial
endocarditis, septicaemia etc.
5. Untypable α-haemolytic streptococci such as Streptococcus
viridans constitute the normal flora of the mouth and may
SECTION I
cause bacterial endocarditis.
6. Pneumococci or Streptococcus pneumoniae are etiologic
agents for bacterial pneumonias, meningitis and septicaemia.

CLOSTRIDIAL DISEASES
Clostridia are gram-positive spore-forming anaerobic
microorganisms found in the gastrointestinal tract of
herbivorous animals and man. These organisms may
undergo vegetative division under anaerobic conditions, and
sporulation under aerobic conditions. These spores are
passed in faeces and can survive in unfavourable conditions.
On degeneration of these microorganisms, the plasmids are
liberated which produce many toxins responsible for the
following clostridial diseases depending upon the species
(Fig. 7.6):
Figure 7.5 Diseases caused by streptococci. 1. Gas gangrene by C. perfringens
2. Tetanus by C. tetani
8. Septicaemia. Staphylococcal septicaemia may occur in 3. Botulism by C. botulinum
patients with lowered resistance or in patients having 4. Clostridial food poisoning by C. perfringens
underlying staphylococcal infections. Patients present with 5. Necrotising enterocolitis by C. perfringens.
features of bacteraemia such as shaking chills and fever
General Pathology and Basic Techniques
(Chapter 6). GAS GANGRENE. Gas gangrene is a rapidly progressive
and fatal illness in which there is myonecrosis of previously
9. Toxic shock syndrome. Toxic shock syndrome is a serious healthy skeletal muscle due to elaboration of myotoxins by
complication of staphylococcal infection characterised by some species of clostridia. In majority of cases (80-90%), the
fever, hypotension and exfoliative skin rash. The condition source of myotoxins is C. perfringens Type A; others are C.
affects young menstruating women who use tampons of novyi and C. septicum. Generally, traumatic wounds and
some brands which when kept inside the vagina cause surgical procedures are followed by contamination with
absorption of staphylococcal toxins from the vagina. clostridia and become the site of myonecrosis. The incuba-
tion period is 2 to 4 days. The most common myotoxin
STREPTOCOCCAL INFECTIONS produced by C. perfringens Type A is the alpha toxin which

Streptococci are also gram-positive cocci but unlike is a lecithinase. The prevention of gas gangrene lies in
staphylococci, they are more known for their non- debridement of damaged tissue in which the clostridia thrive.
suppurative autoimmune complications than suppurative The lesion has serosanguineous discharge with odour and
inflammatory responses. Streptococcal infections occur contains gas bubbles. There is very scanty inflammatory
throughout the world but their problems are greater in reaction at the site of gas gangrene.
underprivileged populations where antibiotics are not TETANUS. Tetanus or ‘lock jaw’ is a severe acute neuro-
instituted readily. logic syndrome caused by tetanus toxin, tetanospasmin,
The following groups and subtypes of streptococci have which is a neurotoxic exotoxin elaborated by C. tetani. The
been identified and implicated in different streptococcal spores of the microorganism present in the soil enter the body
diseases (Fig. 7.5): through a penetrating wound. In underdeveloped countries,
1. Group A or Streptococcus pyogenes, also called β-haemo- tetanus in neonates is seen due to application of soil or dung
lytic streptococci, are involved in causing upper respiratory on the umbilical stump. The degenerated microorganisms
tract infection and cutaneous infections (erysipelas). In liberate the tetanus neurotoxin which causes neuronal
addition, beta haemolytic streptococci are involved in stimulation and spasm of muscles. The incubation period of
autoimmune reactions in the form of rheumatic heart disease the disease is 1-3 weeks. The earliest manifestation is lock-
(RHD). jaw or trismus. Rigidity of muscles of the back causes
2. Group B or Streptococcus agalactiae produces infections in backward arching or opisthotonos. Death occurs due to
the newborn and is involved in non-suppurative post- spasm of respiratory and laryngeal muscles.

NECROTISING ENTEROCOLITIS. Necrotising entero- 181
colitis or ‘pig bel’ is caused by beta-enterotoxin produced by
C. perfringens Type C. The condition occurs especially in
undernourished children who suddenly indulge in
overeating such as was first reported participation in pig
feasts by poor children in New Guinea and hence the name CHAPTER 7
‘pig bel’. Adults do not develop the condition due to good
antibody response.
Ingestion of contaminated pork by malnourished children
who normally take protein-deficient vegetarian diet causes
elaboration of beta-enterotoxin. The symptoms appear within
48 hours after ingestion of contaminated meat. These include:
severe abdominal pain, distension, vomiting and passage of
bloody stools. Milder form of disease runs a course similar
to other forms of gastroenteritis while fulminant ‘pig bel’
may result in death of the child.

Grossly, the disease affects small intestine segmentally.
The affected segment of bowel shows green, necrotic Infectious and Parasitic Diseases
pseudomembrane covering the necrotic mucosa and there
is associated peritonitis. Advanced cases may show
perforation of the bowel wall.
Microscopically, there is transmural infiltration by acute
Figure 7.6 Diseases caused by clostridia.
inflammatory cell infiltrate with changes of mucosal
infarction, oedema and haemorrhage (Chapter 20). The
BOTULISM. Botulism is characterised by symmetric pseudomembrane consists of necrotic epithelium with
paralysis of cranial nerves, limbs and trunk. The condition entangled bacilli.
occurs following ingestion of food contaminated with
neurotoxins of C. botulinum and less often by contamination
of a penetrating wound. The spores of C. botulinum are DISEASES CAUSED BY FUNGI
capable of surviving in unfavourable conditions and
contaminate vegetables and other foods, especially if Of the large number of known fungi, only a few are infective
improperly stored or canned. The symptoms of botulism to human beings. Many of the human fungal infections are
begin to appear within 12 to 36 hours of ingestion of food opportunistic i.e. they occur in conditions with impaired host
containing the neurotoxins (type A to type G). The toxins immune mechanisms. Such conditions include defective
resist gastric digestion and are absorbed from the upper neutrophil function, administration of corticosteroids,
portion of small intestine and enter the blood. On reaching immunosuppressive therapy and immunodeficiency states
the cholinergic nerve endings, the toxin binds to membrane (congenital and acquired). A list of common fungal infections
receptors and inhibits release of acetylcholine resulting in of human beings is given in Table 7.3. A few important
paralysis and respiratory failure. representative examples are discussed below.

CLOSTRIDIAL FOOD POISONING. Clostridial food
poisoning is caused by enterotoxin elaborated by C.  TABLE 7.3: Diseases Caused by Fungi.
perfringens. Out of five serotypes of C. perfringens, type A Disease Etiologic Agent
and C produce alpha-enterotoxin that causes food poisoning. 1. Mycetoma*
These serotypes of organism are omnipresent in the Madurella mycetomatis
environment and thus clostridial poisoning occurs 2. Aspergillosis (Chapter 17) Aspergillus fumigatus,
throughout the world. Food poisoning from C. perfringens is A. flavus, A. niger
mostly from ingestion of meat and its products which have 3. Blastomycosis Blastomyces dermatitidis
been allowed to dry resulting in dehydration and anaerobic 4. Candidiasis* Candida albicans
conditions suitable for growth of C. perfringens. The 5. Coccidioidomycosis Coccidioides immitis
contaminated meat contains vegetative form of the organism 6. Cryptococcosis Cryptococcus neoformans
and no preformed enterotoxin (unlike botulism where pre- 7. Histoplasmosis Histoplasma capsulatum
formed neurotoxin of C. botulinum is ingested). On ingestion
of the contaminated meat, alpha-enterotoxin is produced in 8. Rhinosporidiosis (Chapter 18) Rhinosporidium seeberi
the intestine. Symptoms of the food poisoning appear within 9. Superficial mycosis* Microsporum, Trichophyton,
12 hours of ingestion of contaminated meat and recovery Epidermophyton
occurs within 2 days. *Conditions discussed in this chapter.

182 MYCETOMA
Mycetoma is a chronic suppurative infection involving a
limb, shoulder or other tissues and is characterised by
draining sinuses. The material discharged from the sinuses
is in the form of grains consisting of colonies of fungi or
bacteria. Mycetomas are of 2 main types:
Mycetomas caused by actinomyces (higher bacteria)
comprising about 60% of cases (page 163).
SECTION I
Eumycetomas caused by true fungi comprising the
remaining 40% of the cases.
Most common fungi causative for eumycetoma are
Madurella mycetomatis or Madurella grisea, both causing black
granules from discharging sinuses. Eumycetomas are
particularly common in Northern and tropical Africa,
Southern Asia and tropical America. The organisms are
inoculated directly from soil into barefeet, from carrying of
contaminated sacks on the shoulders, and into the hands from
infected vegetation.
Figure 7.8 Candidiasis of the ulcer in the skin.
MORPHOLOGIC FEATURES. After several months of
infection, the affected site, most commonly foot, is swollen Various predisposing factors are: impaired immunity,
and hence the name ‘madura foot’. The lesions extend prolonged use of oral contraceptives, long-term antibiotic
deeply into the subcutaneous tissues, along the fascia and therapy, corticosteroid therapy, diabetes mellitus, obesity,
eventually invade the bones. They drain through sinus pregnancy etc.
tracts which discharge purulent material and grains. The
surrounding tissue shows granulomatous reaction MORPHOLOGIC FEATURES. Candida produces super-
(Fig. 7.7). ficial infections of the skin and mucous membranes, or
may invade deeper tissues as described under:
CANDIDIASIS 1. Oral thrush. This is the commonest form of muco-
General Pathology and Basic Techniques
Candidiasis is an opportunistic fungal infection caused most cutaneous candidiasis seen especially in early life. Full-
commonly by Candida albicans and occasionally by Candida fledged lesions consist of creamy white pseudomembrane
tropicalis. In human beings, Candida species are present as composed of fungi covering the tongue, soft palate, and
normal flora of the skin and mucocutaneous areas, intestines buccal mucosa. In severe cases, ulceration may be seen.
and vagina. The organism becomes pathogenic when the 2. Candidal vaginitis. Vaginal candidiasis or monilial
balance between the host and the organism is disturbed. vaginitis is characterised clinically by thick, yellow, curdy
discharge. The lesions form pseudomembrane of fungi on
the vaginal mucosa. They are quite pruritic and may
extend to involve the vulva (vulvovaginitis) and the
perineum.
3. Cutaneous candidiasis. Candidal involvement of nail
folds producing change in the shape of nail plate
(paronychia) and colonisation in the intertriginous areas
of the skin, axilla, groin, infra- and inter-mammary,
intergluteal folds and interdigital spaces are some of the
common forms of cutaneous lesions caused by Candida
albicans (Fig. 7.8).
4. Systemic candidiasis. Invasive candidiasis is rare and
is usually a terminal event of an underlying disorder
associated with impaired immune system. The organisms
gain entry into the body through an ulcerative lesion on
the skin and mucosa or may be introduced by iatrogenic
means such as via intravenous infusion, peritoneal dialysis
or urinary catheterisation. The lesions of systemic
candidiasis are most commonly encountered in kidneys
as ascending pyelonephritis and in heart as candidal
Figure 7.7 Madura foot. Brown granule lying in necrotic tissue in endocarditis.
the discharging sinus.

SUPERFICIAL MYCOSIS neoplasms are discussed in Chapter 8. A few common and 183
important viral diseases are described below.
Dermatophytes are the most important example of cutaneous
mycosis caused by Microsporum, Trichophyton and VIRAL HAEMORRHAGIC FEVERS
Epidermophyton. These superficial fungi are spread by direct
contact or by fomites and infect tissues such as the skin, hair Viral haemorrhagic fevers are a group of acute viral infections
and nails. Examples of diseases pertaining to these tissues which have common features of causing haemorrhages, CHAPTER 7
are as under: shock and sometimes death. Viruses causing haemorrhagic
Tinea capitis characterised by patchy alopecia affecting fevers were earlier called arthropod-borne (or arbo) viruses
the scalp and eyebrows. since their transmission was considered to be from
Tinea barbae is acute folliculitis of the beard. arthropods to humans. However, now it is known that all
Tinea corporis is dermatitis with formation of such viruses are not transmitted by arthropod vectors alone
erythematous papules. and hence now such haemorrhagic fevers are classified
The diagnosis of dermatophytosis is made by light according to the routes of transmission and other
microscopic examination of skin scrapings after addition of epidemiologic features into 4 groups:
sodium or potassium hydroxide solution. Other methods Mosquito-borne (e.g. yellow fever, dengue fever, Rift
include fungal culture and demonstration of fungus in tissue Valley fever)
sections. Tick-borne (e.g. Crimean haemorrhagic fever, Kyasanur
Forest disease) Infectious and Parasitic Diseases
DISEASES CAUSED BY VIRUSES Zoonotic (e.g. Korean haemorrhagic fever, Lassa fever)
Marburg virus disease and Ebola virus disease by
Viral diseases are the most common cause of human illness. unknown route.
However, many of the viral infections remain asymptomatic Of these, mosquito-borne viral haemorrhagic fevers in
while others produce viral disease. Another peculiar feature which Aedes aegypti mosquitoes are vectors, are the most
of viral infection is that a single etiologic agent may produce common problem the world over, especially in developing
different diseases in the same host depending upon host countries. Two important examples of Aedes mosquito-borne
immune response and age at infection e.g. varicella-zoster viral haemorrhagic fevers are yellow fever and dengue fever,
virus is causative for chickenpox as well as herpes zoster. which are discussed below.
Viruses are essentially intracellular parasites. Depending
upon their nucleic acid genomic composition, they may be Yellow Fever
single-stranded or double-stranded, RNA or DNA viruses.
A list of common viruses and diseases caused by them is Yellow fever is the oldest known viral haemorrhagic fever
given in Table 7.4. Oncogenic viruses and their role in restricted to some regions of Africa and South America.


 TABLE 7.4: Diseases Caused by Viruses.
Disease Etiologic Agent
1. Viral haemorrhagic fevers* Arthropod-borne (arbo) viruses
2. Influenza [Bird flu, H5N1, Swine flu (H1N1)]* Influenza virus type A
3. Viral encephalitis Arthropod-borne (arbo) viruses
4. Rabies* Rabies virus (arboviruses)
5. Poliomyelitis Poliovirus
6. Smallpox (Variola) Variola virus
7. Chickenpox (varicella)* Varicella-zoster virus
8. Herpes simplex and herpes genitalis* Herpes simplex virus (HSV-I and HSV-II)
9. Herpes zoster* Varicella-zoster virus
10. Lymphogranuloma venereum* Chlamydia trachomatis
11. Cat-scratch disease* Bartonella henselae
12. Viral hepatitis (Chapter 21) Hepatotropic viruses
13. Cytomegalovirus inclusion disease Cytomegalovirus (CMV)
14. Infectious mononucleosis (Chapter 14) Epstein-Barr virus (EBV)
15. Measles (Rubeola) Measles virus
16. German measles (Rubella) Rubella virus
17. Mumps (Chapter 19) Mumps virus
18. Viral respiratory infections Adenovirus, echovirus, rhinovirus, coxsackie virus, influenza A,B and C etc.
19. Viral gastroenteritis Rotaviruses, Norwalk-like viruses
*Diseases discussed in this chapter.

184 Monkeys carry the virus without suffering from illness and iii) coagulopathy with thrombocytopenia; and
the virus is transmitted from them to humans by Aedes aegypti iv) haemoconcentration.
as vector. The main abnormalities in investigations in DHF are
Yellow fever is characterised by the following clinical
features: Sudden onset of high fever, chills, myalgia, as under:
i) Leucopenia with relative lymphocytosis, sometimes
headache, jaundice, hepatic failure, renal failure, bleeding with atypical lymphocytes
disorders and hypotension.
ii) Thrombocytopenia
MORPHOLOGIC FEATURES. Major pathologic changes iii) Elevated haematocrit due to haemoconcentration
SECTION I
are seen in the liver and kidneys. iv) X-ray chest showing bilateral pleural effusion
Liver. The characteristic changes include: v) Deranged liver function tests (elevated transaminases,
i) midzonal necrosis; hypoalbuminaemia and reversed A:G ratio)
ii) Councilman bodies; and vi) Prolonged coagulation tests (prothrombin time,
iii) microvesicular fat. activated partial thromboplastin time and thrombin time)
Diagnosis of DHF is confirmed by:
Kidneys. The kidneys show the following changes: serologic testing for detection of antibodies;
i) coagulative necrosis of proximal tubules; detection of virus by immunofluorescence method and
ii) accumulation of fat in the tubular epithelium; and monoclonal antibodies; and
iii) haemorrhages. rapid methods such as reverse transcriptase-PCR and
Patients tend to recover without sequelae and death fluorogenic-ELISA.
rate is less than 5%, death resulting from hepatic or renal
failure, and petechial haemorrhages in the brain. At autopsy, the predominant organ changes observed
are as follows:
Dengue Haemorrhagic Fever (DHF) i) Brain: intracranial haemorrhages, cerebral oedema,
dengue encephalitis.
The word dengue is derived from African word ‘denga’ ii) Liver: enlarged; necrosis of hepatocytes and Kupffer
meaning fever with haemorrhages. Dengue is caused by virus cells, Reye’s syndrome in children.
transmitted by bites of mosquito Aedes aegypti; the iii) Kidneys: petechial haemorrhages and features of renal
transmission being highest during and after rainy season failure.
when mosquitos are numerous. DHF was first described in iv) Muscles and joints: perivascular mononuclear cell
1953 when it struck Philippines. An outbreak of DHF infiltrate.
occurred in Delhi and neighbouring cities in 1996 claiming
General Pathology and Basic Techniques
several lives. Since then, some cases of DHF have been Chikungunya Virus Infection
reported in post-monsoon period every year in North India.
Dengue occurs in two forms: The word chikungunya means “that which bends up” and
is derived from the language in Africa where this viral
1. Dengue fever or break-bone fever in an uncomplicated way disease was first found in human beings. Chikungunya virus
is a self-limited febrile illness affecting muscles and joints infection is primarily a disease in nonhuman primates but
with severe back pain due to myalgia (and hence the name the infection is transmitted to humans by A. aegypti
‘break-bone’ fever). mosquito. The disease is endemic in parts of Africa and Asia
2. Dengue haemorrhagic fever (DHF), on the other hand, is a and occurs sporadically elsewhere. A massive outbreak
severe and potentially fatal form of acute febrile illness occurred in 2004 in Indian Ocean region affecting people in
characterised by cutaneous and intestinal haemorrhages due Sri Lanka, Maldives, Mauritius and parts of India.
to thrombocytopenia, haemoconcentration, hypovolaemic Clinically, the disease is characterised by abrupt onset of
shock and neurologic disturbances. DHF is most common in fever, severe arthralgia (producing bending posture of
children under 15 years of age. patient due to pain and hence the name), migratory
Dengue virus infects blood monocytes, lymphocytes and polyarthritis affecting small joints, chills, headache, anorexia,
endothelial cells. This initiates complement activation and nausea, abdominal pain, rash, petechiae and ocular
consumptive coagulopathy including thrombocytopenia. The symptoms such as photophobia.
entire process takes place rapidly and may evolve over a Major laboratory findings include leucopenia, mild
period of a few hours. If patient is treated appropriately at thrombocytopenia, elevated transaminases and raised CRP.
this stage, there is rapid and dramatic recovery. But in
untreated cases, dengue shock syndrome develops and death INFLUENZA VIRUS INFECTIONS
occurs.
Influenza virus infection is an important and common form
MORPHOLOGIC FEATURES. The predominant organ of communicable disease, especially prevalent as a seasonal
changes in DHF are due to following: infection in the developed countries. Its general clinical
i) focal haemorrhages and congestion; features range from a mild afebrile illness similar to common
ii) increased vascular permeability resulting in oedema cold by appearance of sudden fever, headache, myalgia,
in different organs; malaise, chills and respiratory tract manifestations such as
cough, soar throat to a more severe form of acute respiratory