Infectious Diseases

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Tuberculosis:

1.​ It is a chronic pulmonary and systemic disease caused most commonly by

Mycobacterium tuberculosis and is the leading infectious cause of death worldwide
2.​ Epidemiology:
a.​ Source of transmission:
i.​ Humans with active tuberculosis by sputum
ii.​ Oropharyngeal and intestinal tuberculosis may be contracted by milk
contaminated with Mycobacterium bovis
b.​ The disease flourishes whenever there is:
i.​ Poverty and crowding
ii.​ Chronic debilitating disease and other diseases such as diabetes,
Hodgkin lymphoma, chronic lung disease, chronic renal failure,
malnutrition, alcoholism and immunosuppression
c.​ Infection refers to presence of bacteria in body, which may be:
i.​ Symptomatic (active disease)
ii.​ Asymptomatic (latent infection)
1.​ May cause fever and pleural effusion
2.​ Only evidence of infection is a tiny, fibrocalcific pulmonary nodule
at the site of infection
3.​ If immunity is lowered, latent infection may get activated
3.​ Pathogenesis: outcome of illness depends on T cell-mediated immune response
a.​ Entry of macrophages:
i.​ M. tuberculosis enters macrophages via receptors such as
mannose-binding lectin and type 3 complement receptor (CR3)
b.​ Replication in macrophages:
i.​ The bacterium recruits a host protein called coronin to the membrane of
the phagosome
ii.​ Coronin activates the phosphatase calcineurin, leading to inhibition of
phagolysosome-lysosome fusion
iii.​ Thus, in the first three weeks, the bacteria proliferates in pulmonary
alveolar macrophages and air spaces, resulting in bacteremia and
seeding
iv.​ At this stage, people are asymptomatic or have a mild flu-like illness
c.​ Innate immunity:
i.​ The bacteria release PAMPs such as
1.​ Lipoarabinomannan: binds to TLR2
2.​ Unmethylated CpG nucleotides: bind to TLR9
ii.​ Innate and adaptive immune responses get activated
 d.​ Th1 response:
i.​ About 3 weeks after infection, macrophages become bactericidal due to
mycobacterial antigens displayed to T cells in lymph nodes
ii.​ Differentiation of Th1 cells depends on IL-12 (due to stimulation of TLR2
by mycobacterial ligands) and IL-18 secreted by APCs
e.​ Th1 mediated macrophage activation and bacterial killing: Th1 cells produce
IFN-γ, which performs the following functions
i.​ Stimulates the maturation of phagolysosome
ii.​ Stimulates the production of iNOS
iii.​ Mobilizes antimicrobial peptides (defensins) against bacteria
iv.​ Stimulates autophagy, destroying damaged organelles and intracellular
bacteria
f.​ Granuloma formation and tissue damage:
i.​ Macrophages activated by IFN-γ differentiate into epithelioid cells which
aggregate to form granulomas
ii.​ Some epithelioid cells may fuse to form giant cells
iii.​ In most people, this response is halted before significant tissue damage;
in others, due to old age or immunosuppression, immune response may
lead to caseous necrosis
iv.​ Activated macrophages also secrete TNF and other chemokines, which
recruit monocytes
g.​ Host susceptibility to disease:
i.​ AIDS is the greatest risk factor for progression to active disease
ii.​ Other forms of immunosuppression such as corticosteroids, anti-TNF
therapy, etc along with renal failure and malnutrition also carry risk
iii.​ Mendelian susceptibility to mycobacterial disease:
1.​ Inherited mutations that interfere with Th1 response, such as loss
of IL-12 receptor β1 protein
2.​ There is increased susceptibility to severe tuberculosis and even
symptomatic infection with atypical mycobacteria or BCG vaccine
h.​ Thus, although largely effective, the Th1 immune response comes at the cost of
tissue destruction
i.​ Loss of T-cell immunity (as indicated by tuberculin negativity) is an ominous sign
that resistance to organism has faded
4.​ Clinical features:
a.​ Primary tuberculosis:
i.​ Develops in previously unexposed and therefore unsensitized person
ii.​ Source of infection is exogenous
iii.​ Diagnosis is more difficult as it often resembles an acute bacterial
pneumonia: consolidation, hilar adenopathy and pleural effusion
iv.​ Lymphatic or hematogenous spread may occur, leading to miliary or
meningeal tuberculosis
b.​ Secondary tuberculosis:
i.​ Occurs in a previously sensitized host, may occur months to years later
 ii.​ It is either due to weakened host resistance (common in low-prevalence
areas) or due to exogenous reinfection with a large inoculum that
overwhelms the immune system (common in regions of high contagion)
iii.​ Classically involves apex of upper lobes
iv.​ There is a prompt and marked response which walls off the focus of
infection; thus regional lymph nodes are less prominently involved
v.​ Cavitation occurs readily in this form, leading to erosion of the cavities
into an airway, which is a source of infection
c.​ Symptoms:
i.​ Manifestations are usually insidious in onset
ii.​ Systemic symptoms are due to cytokines such as TNF from macrophages
iii.​ Malaise, anorexia, weight loss and fever (low grade and remittent, i.e,
appears each afternoon)
iv.​ With progressive pulmonary involvement, increasing amounts of sputum
appear, first mucoid, then purulent; some degree of hemoptysis is seen
v.​ Pleuritic pain may appear to due extension of infection to pleural surface
vi.​ Extrapulmonary symptoms depend on the site involved
d.​ Lab diagnosis:
i.​ Acid-fast smears of sputum
ii.​ Culture (3-6 weeks on solid agar, within 2 weeks in liquid media) of
sputum
iii.​ PCR amplification can lead to rapid diagnosis and also detection of
resistance (it is less sensitive in children and smear-negative TB)
iv.​ Latent TB is detected from assay of T-cells specific for or delayed
hypersensitivity to TB antigens
1.​ IFN-γ release assays (IGRA):
a.​ In vitro test where lymphocytes are stimulated with proteins
from M. tuberculosis
b.​ Production of IFN-γ is measured to assay the level of T-cell
mediated immunity
c.​ False-positive results are uncommon
2.​ Tuberculin/Mantoux skin test:
a.​ Intracutaneous injection of purified protein derivative (PPD)
b.​ Visible and palpable induration is seen, which peaks at
47-72 hours
c.​ False-positive reaction is seen in infection with atypical
mycobacteria and in prior vaccination with BCG
3.​ They do not distinguish between active and latent infection
4.​ False-negative reactions may be seen in viral infections,
sarcoidosis, malnutrition, Hodgkin lymphoma, immunosuppression
and most importantly, active TB
e.​ HIV-infected individuals:
i.​ Pulmonary manifestations are more variable
 ii.​ Increased frequency of false-negative sputum smears and tuberculin tests
(anergy) and absence of granulomas
iii.​ Absence of bronchial wall destruction results in excretion of fewer bacilli
5.​ Morphology:
a.​ Primary tuberculosis:
i.​ Inhaled bacteria typically implant in distal air spaces of the lower part of
upper lobe or upper part of lower lobe, close to the pleura
ii.​ Ghon focus: gray-white area of inflammation with consolidation; its center
underogoes caseous necrosis
iii.​ Ghon complex: combination of parenchymal lung lesion and nodal
involvement (with caseation of nodes)
iv.​ Ghon complex undergoes progressive fibrosis, followed by radiologically
detectable calcification
v.​ Granulomas may coalesce to become macroscopically visible
b.​ Secondary tuberculosis:
i.​ Initial lesion is a small focus of consolidation, which is firm and gray-white
in color
ii.​ In immunocompetent individuals, initial parenchymal focus undergoes
progressive fibrous encapsulation
iii.​ Bacteria are not visible in acid-fast staining in late, fibrocalcific stages
iv.​ Secondary lesion may heal with fibrosis either spontaneously or after
therapy or the the disease may progress and extend along several
pathways
c.​ Progressive pulmonary tuberculosis: in older adults and immunocompromised
individuals
i.​ Apical lesion expands into adjacent lung and erodes bronchi and vessels
ii.​ Caseous center is evacuated leaving a cavity that is poorly walled off by
fibrous tissue
iii.​ Erosion of blood vessels causes hemoptysis
d.​ Miliary pulmonary disease:
i.​ Microscopic or small (2mm) foci of yellow-white consolidation
ii.​ These lesions may expand or coalesce, resulting in consolidation of large
regions or even whole lobes
iii.​ Serous pleural effusions, tuberculous empyema or obliterative fibrous
pleuritis may develop
e.​ Endobronchial, endotracheal and laryngeal tuberculosis: mucosal lining may be
studded with minute or microscopic granulomatous lesions
f.​ Systemic miliary tuberculosis: dissemination in arteries; mostly affect liver, bone
marrow, spleen, adrenals, meninges, kidneys, fallopian tubes and epididymis
g.​ Pott disease: isolated disease of vertebrae; paraspinal cold abscess may track
along tissue planes and present as abdominal or pelvic mass
h.​ Lymphadenitis/scrofula:
i.​ Most common extrapulmonary site
ii.​ Multifocal, with systemic symptoms in HIV-positive people
 i.​ Intestinal tuberculosis:
i.​ Due to ingestion of infected milk or swallowing of coughed-up infective
material
ii.​ Granulomatous inflammation leads to ulceration of mucosa, particularly in
ileum
iii.​ Healing creates strictures
6.​ Nontuberculous mycobacterial (NTM) infections:
a.​ Most frequently due to Mycobacterium avium complex (MAC), M. abscessus
complex and M. kansasii
b.​ Newer molecular methods help distinguish between various causative agents,
which are difficult to differentiate by conventional methods
c.​ These agents are ubiquitous in the environment, water and soil
d.​ NTM biofilm on medical devices is a common source in recent times
e.​ Most common manifestation is chronic pulmonary disease in vulnerable
individuals (immunosuppression, chronic disease, mendelian susceptibility)
f.​ Radiological characteristics:
i.​ Fibrocavitary lesions in upper lobes
ii.​ Nodular bronchiectasis with multifocal clusters of small nodules
g.​ Morphology:
i.​ Hallmark in HIV patients ins abundant acid-fast bacilli within macrophages
ii.​ Enlargement of lymph nodes, liver and spleen with yellowish pigmentation
to these organs

Leprosy:

1.​ Also called Hansen disease, it is a slowly progressive infection caused by

Mycobacterium leprae
2.​ Pathogenesis:
a.​ It has low communicability; source of infection is unknown, but respiratory
secretions or soil are likely
b.​ Its proliferation is best at 32-34oC, in cool tissues of skin and extremities
c.​ Its virulence is based on the properties of its cell wall; cell-mediated immunity is
manifested by DTH reactions to dermal injections of bacterial extract called
lepromin
d.​ It causes two distinct patterns of disease, determined by T-cell response:
i.​ Tuberculoid:
1.​ Less severe, due to strong immune response; bacilli are few,
hence called paucibacillary leprosy
2.​ Dry, scaly lesions that lack sensation are seen
3.​ There is asymmetric involvement of large peripheral nerves
4.​ Patients have a Th1 response, associated with production of IL-2
and IFN-γ, as well as Th17 response
5.​ Antibody production is low
6.​ Disease has extremely slow course
 7.​ Morphology:
a.​ Localized flat, red skin lesions, with irregular shapes,
indurated, elevated, hyperpigmented margins and
depressed pale centers (central healing)
b.​ Neuronal involvement dominates
c.​ Nerves become enclosed within granulomatous reactions
d.​ Nerve degeneration causes skin anesthesias and skin and
muscle atrophy; this may lead to chronic skin ulcers
e.​ Contractures, paralysis and autoamputation of fingers or
toes ensues
f.​ Facial nerve involvement can lead to paralysis of eyelids,
with keratitis and corneal ulcerations
ii.​ Lepromatous:
1.​ Associated with weak Th1 response, with relative increase in Th2;
weak cell-mediated immunity allows bacteria to be readily
visualized in tissue section, hence called multibacillary leprosy
2.​ Widespread invasion into Schwann cells and into endoneurial and
perineural macrophages damages PNS
3.​ In advanced disease, bacteria are present in sputum and blood
4.​ Antibodies are produced, but they form complexes with free
antigens and cause erythema nodosum, vasculitis and
glomerulonephritis
5.​ Morphology:
a.​ Involves skin, PNS, anterior eye chamber, upper airways,
testes, hand and feet
b.​ Vital organs and CNS are usually spared because of high
temperature
c.​ Lesions contain large aggregates of lipid-laden
macrophages (lepra cells), often filled with masses (globi)
of acid-fast bacilli
d.​ Nodular lesions on face and eyes coalesce to yield
characteristic leonine facies
e.​ Skin lesions are hypesthetic or anesthetic
f.​ Peripheral nerves, especially ulnar and peroneal nerves,
are symmetrically invaded with minimal inflammation
g.​ Lymph nodes contain aggregates of bacteria-filled foamy
macrophages
h.​ Aggregates of macrophages seen in spleen and liver in
advanced disease
i.​ Testes are involved usually, with destruction of
seminiferous tubules and sterility

Syphilis
1.​ It is a chronic STD caused by Treponema pallidum subspecies pallidum
2.​ The causative bacteria are too slender to be visualized by Gram staining, so silver stains
or immunofluorescence techniques are used
3.​ Transplacental transmission occurs readily, leading to congenital syphilis
4.​ T. pallidum cannot be easily grown in culture
5.​ Pathogenesis:
a.​ Proliferative endarteritis affecting small vessels with surrounding plasma cell-rich
infiltrate is characteristic of all stages; much of the pathology is associated with
ischemia due to vascular lesions
b.​ Immune response may deal with local lesions, but do not reliably eliminate
systemic infection
c.​ Superficial sites of infection (chancres and rashes) have intense inflammatory
infiltrate; CD4+ T cells in it are Th1 cells, which activate macrophages
d.​ Treponemal-specific antibodies are seen, which activate complement and
opsonize the bacteria
e.​ TprK, a protein in the outer membrane of T. pallidum, accumulates structural
diversity due to recombination between silent donor sites and tprK gene, allowing
the organism to persist
6.​ The three stages of syphilis are:
a.​ Primary syphilis:
i.​ Occurs 3 weeks after infection
ii.​ Chancre: single firm, nontender, raised, red lesion at the site of invasion
on penis, cervix, vagina or anus
iii.​ Heal with or without therapy
iv.​ Spirochetes are plentiful in these and disseminate through hematologic or
lymphatic route
v.​ Morphology:
1.​ Gross:
a.​ Chancre erodes to create a clean-based shallow ulcer
b.​ Hard chancre: the contiguous induration creates a
button-like mass directly adjacent to the eroded skin
c.​ Regional lymph nodes are enlarged
2.​ Microscopy:
a.​ Intense infiltrate of plasma cells
b.​ Proliferative endarteritis, which results in intimal fibrosis
b.​ Secondary syphilis:
i.​ Occurs 2-10 weeks after primary chancre
ii.​ Marked by painless, superficial lesions of skin and mucosal surfaces
iii.​ Skin lesions are usually seen in palms or soles and may be
maculopapular, scaly or pustular
iv.​ Condyloma lata: moist areas of skin may have broad-based elevated
plaques
v.​ Silvery-gray superficial erosion may form on mucous membranes
vi.​ Lymphadenopathy, mild fever, weight loss and malaise may be seen
 vii.​ Asymptomatic or symptomatic neurosyphilis can occur
viii.​ Secondary syphilis lasts several weeks and then enters latent stage
ix.​ Morphology:
1.​ Gross:
a.​ Widespread mucocutaneous lesions are seen in oral
cavity, palms and soles
b.​ Rash usually consists of discrete red-brown macules
c.​ Red lesions in mouth or vagina contain most organisms
and are most infectious
2.​ Microscopy:
a.​ Plasma cell infiltrate and obliterative endarteritis similar to
primary chancre is seen, but inflammation is less intense
c.​ Tertiary syphilis:
i.​ Occurs after latent period of 5 years
ii.​ Patients show three main manifestations, which may occur alone or in
combination
1.​ Cardiovascular syphilis:
a.​ Most commonly occurs as syphilitic aortitis
b.​ Leads to progressive dilation of aortic root and arch, which
causes aortic valve insufficiency and aneurysms of
proximal aorta
c.​ Morphology:
i.​ Endarteritis of vasa vasorum of proximal aorta
ii.​ Occlusion of vasa vasorum results in scarring of
media, leading to loss of elasticity
iii.​ There may be narrowing of coronary artery ostia,
leading to myocardial ischemia
2.​ Neurosyphilis:
a.​ Asymptomatic neurosyphilis is suspected on detection of
CSF abnormalities such as pleocytosis, elevated proteins
or decreased glucose, confirmed by detection of antibodies
b.​ Antibodies are given for a longer time if it spreads to CNS,
so all patients of tertiary syphilis must be tested for
neurosyphilis
c.​ Symptomatic neurosyphilis may take form of
meningovascular syphilis, tabes dorsalis or general paresis
3.​ Benign tertiary syphilis:
a.​ Characterized by gumma on skin, bones and mucus
membranes of upper airway and mouth
b.​ They are nodular elevations due to development of DTH
c.​ Skeletal involvement shows pain, tenderness, swelling and
pathologic fractures
d.​ Gummas in skin and mucous membranes may produce
ulceration
 e.​ Morphology:
i.​ Gross:
1.​ Gummas are white-gray and rubbery
2.​ Hepar lobatum: scarring as a result of
gummas in liver
ii.​ Microscopy:
1.​ They have center of coagulated, necrotic
material and margins composed of plump,
palisading macrophages and fibroblasts
surrounded by mononuclear leukocytes
2.​ Treponemes are scant in gummas
4.​ Congenital syphilis:
a.​ Occurs most frequently in maternal primary or secondary
syphilis, when spirochetes are most numerous
b.​ Intrauterine and perinatal death are common
c.​ Manifestation are divided into those that occur in first 2
years of life (infantile syphilis) and those that occur after
(tardive syphilis)
d.​ Manifested by nasal discharge and congestion (snuffles)
e.​ A desquamating or bullous rash, leading to sloughing of
skin, is seen commonly in hands, feet and around the
mouth and anus
f.​ Hepatomegaly and skeletal abnormalities are common
g.​ Late manifestation of congenital syphilis is the Hutchinson
triad: interstitial keratitis, Hutchinson teeth and VIII nerve
deafness
h.​ Morphology:
i.​ More severe rash
ii.​ Syphilitic osteochondritis and periostitis occur
commonly in nose and lower legs
iii.​ Saddle nose deformity: destruction of vomer leads
to collapse of bridge of nose
iv.​ Saber shin: periostitis of tibia lead to new bone
growth on anterior surface and anterior bowing
v.​ Diffuse fibrosis is seen in liver and hepatic cells
isolate into small nests accompanied by
lymphoplasmocytic infiltrate and vascular changes
vi.​ Pneumonia alba: in syphilitic stillborn, lungs appear
pale and airless
7.​ Serologic tests: mainstay of diagnosis of syphilis
a.​ Nontreponemal tests:
i.​ Measure antibody to a cardiolipin-cholesterol-lecithin antigen
ii.​ Tests include rapid plasma reagin (RPR) and Venereal Disease Research
Laboratory (VDRL)
 iii.​ They are nonspecific, but cheap, easy and yield quantifiable results
b.​ Treponemal antibody tests:
i.​ Measure antibodies specific to T. pallidum
ii.​ Tests include fluorescent treponemal antibody absorption test and the T.
pallidum enzyme immunoassay test
c.​ Rapid point-of-care tests:
i.​ Designed for use with fingerstick blood (less sensitive than serum)
ii.​ Inexpensive and simple to perform
iii.​ Not commonly used due to low sensitivities and specificities
d.​ Interpretation:
i.​ Both treponemal and nontreponemal tests are moderately sensitive for
primary syphilis
ii.​ Both are very sensitive to secondary syphilis
iii.​ Treponemal tests are very sensitive for tertiary and latent syphilis;
nontreponemal tests are somewhat less sensitive
iv.​ Nontreponemal antibodies fall with successful treatment and so change in
titers can be used to monitor therapy
v.​ Treponemal tests are non-quantitative and remain positive even after
therapy
vi.​ Either test can be used for initial screening, but positive test must be
confirmed by performing other test also
vii.​ Cause of false-positives, which can occur in both methods, can be
pregnancy, autoimmune disease and infections other than syphilis

Viral hemorrhagic fever:

1.​ Severe life-threatening multisystem syndrome in which there is vascular damage leading
to widespread hemorrhage and shock
2.​ It is caused by four genera of enveloped RNA viruses: arenaviridae, bunyaviridae,
filoviridae and flaviviridae
3.​ They can cause a mild acute disease characterized by fever, headache, myalgia, rash,
neutropenia and thrombocytopenia
4.​ Disease can sometimes be severe with sudden hemodynamic deterioration and shock
5.​ These viruses pass through an animal or insect host; humans are incidental hosts, who
get infected through contact with infected host (commonly rodents) or insect vectors
(mosquitoes and ticks)
6.​ Some of these cause hemorrhagic fever, that can spread from person-to-person, eg:
Ebola, Marburg and Lassa
7.​ Damage to blood vessels is prominent is these infections, which may be caused by:
a.​ Direct infection and damage to endothelial cells
b.​ Infection of macrophage and dendritic cells leading to production of inflammatory
cytokines
8.​ Ebola virus:
a.​ It spread person-to-person through mucosal secretions
 b.​ It has specific mechanisms by which it evades immune response:
i.​ VP24: blocks type I IFN signaling by preventing tyrosine kinase
dimerization and nuclear translocation of STAT-1
ii.​ VP35: binds to double-stranded viral RNA in infected host cells,
preventing detection from host
iii.​ GP: surface protein that is found in non-virus associated soluble form,
which acts as a decoy for binding host antibodies
9.​ Morphology:
a.​ Hemorrhagic manifestations: petechiae due to thrombocytopenia or platelet
dysfunction, endothelial injury, DIC and deficiency of clotting factors due to liver
damage
b.​ In Congo-Crimean fever, hemorrhage is prominent
c.​ Necrosis of tissues secondary to vascular lesions and hemorrhages may be
seen, but immune response is minimal
d.​ In Ebola virus infection, there is widespread hemorrhage and viral replication in
mani organs:
i.​ Liver: hepatocellular necrosis and scant inflammation
ii.​ Spleen: lymphocyte apoptosis, viral replication in dendritic cells,
fibroblasts and monocytes

Dengue:

1.​ It is a flavivirus transmitted by Aedes mosquito

2.​ Clinical manifestations include fever, headache, macular rash, severe myalgias
(breakbone fever)
3.​ Severe dengue or dengue hemorrhagic fever has bleeding, liver failure, reduced
consciousness, organ failure and plasma leakage leading to shock and respiratory
distress
4.​ In severe dengue there is widespread hemorrhage with hepatic necrosis and
mononuclear infiltrates, septal thickening and hyaline membrane formation in lung
5.​ The immune response determines, in part, the severity of the infection:
a.​ There are 4 serotypes of the virus
b.​ Infection with each serotype provides protective immunity to that serotype and
also stimulates a cross-reactive antibody response that is weak and
non-protective for other serotypes
c.​ Severe dengue occurs in people who have had a previous infection with a
different serotype than the one associated with their severe illness
d.​ Antibody-dependent enhancement, where cross-reactive antibodies enhance
uptake of virus into macrophages via Fc receptors, is through to increase
infectivity of the virus
e.​ Severe dengue occurs in infants who have maternal antibodies against dengue

Novel coronavirus SARS-CoV-2 (COVID-19)

 1.​ Caused a pandemic in 2020
2.​ Initial animal-to-human transmission was followed by person-to-person spread soon
thereafter
3.​ Sequencing of its entire genome gave rise to rapid molecular diagnostic assay
4.​ Vast majority of patients recover after a flu-like illness
5.​ Severe and sometimes fatal illness with respiratory compromise is seen in older
individuals and those with comorbid conditions
a.​ Bilateral ground-glass opacities on chest imaging
b.​ Diffuse alveolar damage
c.​ Inflammation with mainly mononuclear cells

Mucormycosis (zygomycosis):

1.​ It is an opportunistic infection caused by environmental fungi, including Mucor spp.,

Rhizopus spp. and Cunninghamella spp., which belong to the subphylum Mucormycotina
2.​ Mucromycotina are widely distributed in nature and cause no harm in immunocompetent
individuals
3.​ Major predisposing factors are neutropenia, corticosteroid use, diabetes mellitus, iron
overload and breakdown of cutaneous barrier
4.​ Pathogenesis:
a.​ Transmitted by airborne sexual spores
b.​ Inhalation of spore is the most common route, but may also infect through
ingestion and percutaneous exposure
c.​ Macrophages provide initial defense by phagocytosis of sporangiospores
d.​ Hyphal components are recognized by TLR, which leads to release of IL-6 and
TNF
e.​ Neutrophils have a key role in killing by directly damaging hyphal walls
f.​ If macrophages and neutrophils are compromised, risk of infection is increased
g.​ Different Mucor species have different resistances to immune response
h.​ Availability of free iron increases risk of infection, as seen in people with diabetes
and patients receiving chronic iron chelation treatment (deferoxamine acts as a
siderophore for fungi)
5.​ Morphology:
a.​ They form nonseptate hyphae, with frequent right-angle branching demonstrated
by H/E or special fungal stains
b.​ Primary sites of infection are nasal sinuses, lungs and GIT, depending on route of
infection
c.​ In diabetic patients, it may spread from nasal sinuses to orbit and brain, giving
rise to rhinocerebral mucormycosis
d.​ They can cause local tissue necrosis, invade arterial walls and penetrate
periorbital tissues and cranial vault
e.​ Meningoencephalitis follows, sometimes complicated by cerebral infarction when
fungi invade arteries and induce thrombosis
 f.​ Lung lesions combine areas hemorrhagic pneumonia with vascular thrombi and
distal infarctions

Malaria:

1.​ Caused by intracellular parasite Plasmodium and transmitted by female mosquitoes

2.​ Various species are P. falciparum (which causes cerebral malaria), P. ovale, P. vivax, P.
knowlesi and P. malariae
3.​ Combination of mosquito control and antimalarial drugs are used to decrease incidence
4.​ Pathogenesis:
a.​ P. ovale, P. vivax, P. knowlesi and P. malariae cause low levels of parasitemia,
mild anemia, splenic rupture and nephrotic syndrome
b.​ P. falciparum causes high levels of parasitemia that may lead to severe anemia,
cerebral symptoms, renal failure, pulmonary edema and death
c.​ Life cycle of plasmodium involves only humans and mosquitoes
d.​ Exoerythrocytic stage:
i.​ The infectious stage is sporozoite, which is found in salivary glands of
female mosquitoes and released into human’s blood when mosquito
takes a blood meal
ii.​ The sporozoites attach to receptors on hepatocytes, such as serum
proteins thrombospondin and properdin
iii.​ In hepatocytes, they multiply and give rise to merozoites (asexual,
haploid), which are released by rupture
1.​ In P. falciparum infection, rupture occurs in 8-12 weeks
2.​ In P. ovale and P. vivax infection, latent hypnozoites persist which
cause relapse of malaria after week or months of initial infection
e.​ Erythrocytic stage:
i.​ Once released from liver, merozoites use a lectin-like molecule to bind to
sialic acid residues on glycophorin molecules on the surface of red cells
and invade by active membrane penetration
ii.​ The parasite grows in membrane-bound digestive vacuoles, hydrolyzing
hemoglobin through secreted enzymes
iii.​ Trophozoite is the first stage in red cells, characterized by single
chromatin mass
iv.​ The next stage is schizont, characterized by multiple chromatin masses,
which develop into merozoites
v.​ Upon rupture of RBCs, merozoites infect more RBCs
vi.​ Paroxysmal fever, chills and rigor are seen when merozoites are
released, due to release of cytokines such as TNF
vii.​ Periodicity of fever varies with species of malarial parasite
viii.​ Most parasites in RBCs develop into merozoites, while some develop into
sexual forms called gametocytes, which infect mosquitoes
ix.​ P. falciparum:
1.​ It can infect RBC of any age
 2.​ Cerebral malaria:
a.​ The major cause of death in children with malaria
b.​ P. falciparum can clump together to form rosettes and stick
to endothelial cells (sequestration), which causes
manifestations
c.​ Adhesive polypeptides like P. falciparum erythrocyte
membrane protein 1 (PfEMP1) forms knobs on surface of
RBCs and bind to ligands on endothelial cells such as
CD36, thrombospondin, VCAM-1, ECAM-1 and E-selectin
3.​ GPI-linked proteins like merozoite surface antigen are released
from infected red cells and induce cytokine production
5.​ Host resistance to malaria:
a.​ Inherited: pathogenic in homozygous form, but confer selective advantage in
heterozygous form
i.​ Hemoglobinopathies: point mutations in globin genes like HbS, HbC
ii.​ Mutations leading to globin deficiencies like thalassemia
iii.​ Mutations in red cell enzymes: G6PD deficiency
iv.​ Mutations in red cell membrane defects: absence of DARC, band 3,
spectrin
b.​ Acquired resistance:
i.​ Seen in areas endemic for malaria; it is immune mediated
ii.​ Specific antibodies and T lymphocytes reduce disease manifestations
iii.​ P. falciparum uses antigenic variation to escape host immune response to
PfEMP1 and other surface proteins
iv.​ CTLs may also play an important role
6.​ Morphology:
a.​ The standard diagnostic test is Giemsa-stained peripheral blood smear, which
identifies the asexual stages
b.​ PCR is more sensitive, but it is not accepted as gold standard
c.​ Splenomegaly is seen due to recognition of infected RBCs by macrophages
d.​ In chronic lesions, spleen becomes fibrotic and brittle, with a thick capsule and
fibrous trabeculae
e.​ The parenchyma is gray or black because of phagocytes containing granular,
brown-black, faintly birefringent hemozoin pigment
f.​ Liver becomes enlarged and contains pigmented phagocytes
g.​ Kidney are enlarged and congested with hemoglobin casts in tubules
h.​ In cerebral malaria, brain vessels are plugged with parasitized red cells; ring
hemorrhages are seen around these vessels that are related to local hypoxia
incident to vascular stasis and small focal inflammation (malarial or Dürk
granulomas)
i.​ Nonspecific focal hypoxic lesions in the heart due to progressive anemia and
stasis
j.​ Pulmonary edema and DIC may cause death
Cysticercosis:

1.​ Taenia solium is the cestode that causes cysticercosis

2.​ It occurs because of deposition of larval cysts called cysticerci resulting in inflammatory
response
3.​ They consist of:
a.​ Scolex/head: has suckers and hooklets that attach to the intestinal wall
b.​ Neck
c.​ Proglottids: contain the male and female reproductive organs
4.​ Most distal proglottids are the most mature and contain eggs, that can detach and be
shed in feces
5.​ It can be transmitted to humans in two ways:
a.​ Cysticerci are ingested in undercooked pork and attach to the intestinal wall
where they develop into mature adult tapeworms
i.​ Produce mild abdominal symptoms
ii.​ Life cycle is completed
iii.​ Disseminated disease does not develop
b.​ When intermediate hosts ingest food or water contaminated with human feces,
the egg becomes an oncosphere that hatches and penetrates the gut wall,
disseminating hematogenously and transition into a cysticercus that can encyst in
many organs
i.​ Most serious manifestation is neurocysticercosis, due to deposition in
brain; can lead to convulsions, increased ICP and neurological
disturbances
ii.​ Adult tapeworms are not produced, as cysts lodged in places other than
intestine cannot mature
iii.​ Viable cysts evade the immune by producing taeniaestatin and
paramyosin, which inhibit complement activation, thus symptoms are not
produced
iv.​ When cysticerci die and degenerate, inflammatory reaction is seen
6.​ Morphology:
a.​ Can be found in any organ, but most common in brain, muscles, skin and heart
b.​ Cysts are ovoid and white to opalescent, often grape-sized and contain an
invaginated scolex with hooklets that are bathed in clear cyst fluid
c.​ When cysts degenerate, there is inflammation, followed by focal scarring and
calcification visible by radiography

Hydatid disease:
​
1.​ Caused by ingestion of eggs of Echinococcus species:
a.​ E. granulosus: definitive host is dog, intermediate host in sheep
b.​ E. multilocularis: definite host is fox, intermediate host are rodents
2.​ Humans are accidental hosts, who get infected by ingestion of food contaminated with
eggs shed by dogs or foxes
3.​ Eggs hatch in the duodenum and larvae invade the organs
4.​ Mostly asymptomatic, but:
a.​ Large cysts in liver can cause abdominal pain, obstruction
b.​ Pulmonary cysts can cause pain, cough and hemoptysis
5.​ Caution is warranted in case of surgical removal, since anaphylaxis or dissemination can
occur from spillage of cyst contents
6.​ Morphology:
a.​ Most commonly seen in liver, lungs, bones or brain
b.​ Larvae lodge in the capillaries and incite an inflammatory reaction composed of
mononuclear leukocytes and eosinophils
c.​ Many such larvae are destroyed but other encyst
d.​ Structure of cyst:
i.​ Inner nucleated, germinative layer, enclosing an opalescent fluid
ii.​ Outer opaque non-nucleated layer, which is distinctive and has
innumerable delicate laminations
e.​ Outside the opaque layer, there is inflammatory reaction that has fibroblasts,
giants cells, mononuclear and eosinophilic cells; a dense fibrous capsule forms
f.​ Daughter cysts appear from mother cysts, which appear first as minute
projections of germinative layer that develop central vesicles and form tiny brood
capsules
g.​ Hydatid sand: degenerating scolices of the worm produce a fine, sand-like
sediment