Pathophysiology- Global Overview of Select Infectious Diseases

Prepared and presented by
Marc Imhotep Cray, M.D.

Companion study tools:
Case-based Q&A:
ICM_ Systems-based Pathophysiologic High Yield Cases.pdf
(Case numbers inside refer to this document.)
Textbook:
Hammer GD & McPhee SJ (Eds.). Pathophysiology of Disease:
An Introduction to Clinical Medicine, 7th Ed. New York, NY:
McGraw-Hill Education, 2014.
2

What is Pathophysiology?
Pathophysiology includes four interrelated topics: etiology,
pathogenesis, clinical manifestations, and treatment implications
 Etiology refers to study of proposed cause or causes
of a particular disease process
o Etiology is a complex concept b/c most diseases are multifactorial
resulting from interplay between genetic constitution and
environmental influences
 Pathogenesis refers to proposed mechanisms
whereby an etiologic stimulus leads to typically
observed clinical manifestations
o Pathogenesis describes direct effects of initiating event, as well as
usual physiologic responses and compensatory mechanisms 3

What is Pathophysiology? cont.
 Clinical manifestations describe signs and
symptoms that typically accompany a particular
pathophysiologic process
o Manifestations may vary depending on stage of disorder,
individual variation, and acuity or chronicity
 Treatment implications An understanding of
etiology, pathogenesis, and clinical consequences of
a disorder may imply that certain treatments could
be helpful
4

Etiologic Classification of Diseases
 Congenital (inborn) diseases or birth defects
 Degenerative diseases
 Iatrogenic diseases
 Idiopathic diseases
 Immunologic diseases
 Infectious diseases
 Inherited diseases
 Metabolic diseases
 Neoplastic diseases
 Nutritional deficiency diseases
 Physical agent–induced diseases
 Psychogenic diseases
5
N.B: Four major causes of death-
injury, infection, degenerative
disease and cancer

Marc Imhotep Cray, M.D. 6
INFLAMMATORY
VASCULAR
NEOPLASTIC
DRUGS
INFECTION
CONGENITAL
AUTOIMMUNE
TRAUMATIC
ENDOCRINE / METABOLIC“VINDICATE”
- SUDDEN ONSET
- CARDINAL SIGNS/SYMPTOMS
- MASS
- HISTORY
- CARDINAL SIGNS/SYMPTOMS
- FROM BIRTH
- SYSTEMIC
- HISTORY
- Sn/Sx
Differential Diagnosis Mnemonic
(Note the relationship to previous slide.)
IS THE PROCESS…

Disorders of the Immune System
Case 10
7

Clinical Case: Make the Diagnosis
8
 A 40-year-old male was seen by his internist with chief
complaints of fever, night sweats, increased episodes of
diarrhea during the past month, and a 30-pound weight
loss over the previous 4 months. On physical exam, he
had oral thrush and cervical lymphadenopathy.
Laboratory findings were significant for a CD4+ cell
count of 100 cells/mL.

Acquired immunodeficiency syndrome
(AIDS) Capsule
AIDS is an infectious disease caused by human
immunodeficiency viruses (HIV)
AIDS is characterized by a profound suppression of immune
system and susceptibility to infections, neurologic disorders,
and malignancies
 Two genetically different, but closely related forms of human pathogens
are recognized: HIV-1 and HIV-2
 Both are RNA viruses belonging to retrovirus family (lentivirus genus)
 HIV expresses cell surface protein gp120, which binds to CD4+ surface
molecule of T helper lymphocytes
 Proviral DNA synthesized by a reverse transcription in infected cells is
integrated into host’s nuclear DNA
Main characteristics of HIV
9

Human Immunodeficiency Virus (HIV)
What is HIV?
 HIV is an RNA retrovirus of lentivirus genus
 This virus causes acquired immunodeficiency
syndrome (AIDS)
Causes
There are two types of HIV:
1. HIV-1:
 Type M: A-J prevalent in Europe, America,
Australia and sub-Saharan Africa
 Type O: mainly in Cameroon
2. HIV-2: predominantly confined to West Africa
10

Prevalence of human immunodeficiency virus (HIV)
infection among the adult population worldwide.
11World Health Organization (WHO) figures from 2006 demonstrate extent of HIV pandemic throughout world.

HIV (2) Structure (simplified)
Ireland KA. Visualizing Human Biology, 3rd ed. New Jersey: Wiley & Sons, 2011.
12

HIV (3)
HIV genes, gene products & structure of HIV-1 virion
Kumar V and Abbas AK. Robbins and Cotran Pathologic Basis of Disease 8th ed. 2014
Modified from: Hammer GD and McPhee JS, Eds. Pathophysiology
of Disease : An Introduction to Clinical Medicine, 7th Ed. 2014
HIV is a group of related retroviruses, whose
RNA encodes for nine genes

Human Immunodeficiency Virus (4)
Etiology and Epidemiology: HIV-1 causes AIDS
Transmission
 Unprotected sexual intercourse
o Homosexual contact is major mode of HIV-1 transmission in
the United States
o Heterosexual transmission is most common in the rest of
world
 Shared contaminated needles (IVDAs)
 Contaminated blood transfusions
 Vertical transmission from mother to child virus
crosses placenta and is transmitted through breast milk 14

15
HIV (5) Reproduction/ infection
process
Modified from: Ireland KA. Visualizing Human
Biology, 3rd ed. New Jersey: Wiley & Sons, 2011
1. Virus attaches to host cell at CD4 receptor
2. Viral RNA is injected into cell and using reverse
transcriptase makes a complementary DNA strand
(cDNA)
3. Viral cDNA makes a second strand of DNA
double-stranded viral DNA enters nucleus and is
inserted into host DNA where it can remain
dormant for many years as a provirus
4. Viral cDNA is transcribed into viral RNA and
exported into cytoplasm.
5. Viral RNA is translated into new viral particles
6. Assembled virus buds from cell membrane and is
released
Helper T-
Lymphocyte
(CD4+ Cell)

Human immunodeficiency virus-1 (HIV-1) seen
budding from infected cells (arrows)
Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 2012
16

HIV (6) HIV-1 pathogenesis
17
 HIV-1 attaches via envelope glycoprotein gp120 to CD4 molecule
and a second coreceptor (chemokine receptor) on helper T
lymphocytes, monocytes-macrophages, and mucosal dendritic
cells
 HIV-1 may infect both activated and nonactivated CD4+ cells in
draining lymph node
 Virus remains latent in nonactivated (resting) T cells but
replicates in and kills T cells activated by infection or cytokines or
both Note: chemokine=any of a family of low
molecular weight (8–10 kD) cytokines that
induce chemotaxis or chemokinesis in leukocytes
(or in particular populations of leukocytes).

HIV (7) AIDS pathogenesis
18
AIDS is consequence of infection with HIV-1 which
infects multiple cell lines, including lymphocytes,
monocytes, macrophages, and dendritic cells
 With HIV infection, there is an absolute reduction of
CD4 T lymphocytes, an accompanying deficit in CD4+
T-lymphocyte function and an associated increase
in CD8+ cytotoxic T lymphocytes (CTLs)
 “Reversal of the OKT4/T8 Ratio”

HIV (8) AIDS pathogenesis cont.
19
 In addition to cell-mediated immune defects (T
lymphocytes ) B-lymphocyte function (humoral-
mediated immunity) is altered  such that many
infected individuals have marked
hypergammaglobulinemia but impaired specific
antibody responses
Resultant immunosuppression predisposes patients to
constellation of opportunistic infections that
characterizes AIDS

20
 Clinical Manifestations: HIV disease is characterized by
 an acute phase with a “flu-like” or infectious mononucleosis-
like syndrome, followed by
 an asymptomatic phase of clinical latency characterized by
fatigue, weight loss, night sweats, or lymphadenopathy with a
median time of 7-10 years to development of AIDS
Symptomatic phase and AIDS is end-stage disease
 AIDS is characterized by a CD4+ T lymphocyte count below
200 cells/mL (normal = 800–1200/mL)
 Opportunistic protozoal, fungal, bacterial, & viral infections
 Malignancies
 Neurological disorders

HIV (10)
 Diagnostic Test:
 Bloods: CBC, Lytes, LFTs, lipids, glucose, lymphocyte subsets
 HIV specific:
o Enzyme-linked immunosorbent assay (ELISA)
o Western blot test
o Immunofluorescence assay (IFA)
o Nucleic acid testing
 Virology screen: HIV antibody, HIV viral load, HIV
genotype, hepatitis serology, cytomegalovirus (CMV)
antibody, syphilis screen
 Other infection, e.g. tuberculosis if indicated
21

Natural History (NH) & Phases of HIV infection
1. Early, acute phase: Self-limited acute illness 3 to 6 weeks after
infection
 High level of virus production and widespread infection of lymphoid
organs
2. Middle, chronic phase: No symptoms or persistent lymphadenopathy
for several years
3. Minor infections
4. Final, crisis: Long-lasting fever, severe opportunistic infections,
secondary neoplasms, and neurologic disorders
 This usually develops after 7 to 10 years of chronic phase
Four major stages of HIV infection:
22

23
Four major stages of HIV infection cont.
1) With acute HIV infection, individual may remain asymptomatic or develop an acute illness
that resembles influenza or infectious mononucleosis Sx usually develop within 2 to 6
weeks after infection
 During this stage, antibodies to HIV are generally undetectable
2) Seroconversion usually occurs during clinical latency, an asymptomatic period that would
last approx. 7 to 10 years in an untreated patient
 Low-level (but persistent) replication of HIV causes a gradual decrease in CD4+ T cells,
and minor opportunistic infections may occur
3) During crisis phase, escalation of viral replication leads to a more rapid T-cell decline
 clinically apparent as weight loss, fever, fatigue, and lymphadenopathy
4) Acquired immunodeficiency syndrome (AIDS) is diagnosis for a person who is HIV-
positive and has a T-cell count below 200 cells/ uL ( or 200/ mm3) or presents with one of
AIDS defining opportunistic infections /malignancies

NH: Typical course of HIV
infection (1)
Kumar V and Abbas AK. Robbins and Cotran Pathologic Basis of
Disease 8th ed. Philadelphia: Saunders, 2014
Acute HIV infection may present
as a self-limited, febrile viral
syndrome characterized by:
 fatigue
 pharyngitis
 myalgias
 maculopapular rash
 lymphadenopathy and
 significant viremia
 without detectable anti-HIV
antibodies
24

NH: Typical course of HIV infection (2)
Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 2012
25

NH: Typical course of untreated HIV infection (3)
 During early period after primary
infection, there is widespread
dissemination of virus and a sharp
decrease in number of CD4 T cells in
peripheral blood
 An immune response to HIV ensues, with a
decrease in detectable viremia followed by
a prolonged period of clinical latency
 Sensitive assays for viral RNA show that virus
is present in plasma at all times
 CD4 T-cell count continues to decrease
during following years until it reaches a
critical level below which there is a
substantial risk of opportunistic diseases
26
Fauci AS, Lane HC: Human immunodeficiency virus disease: AIDS and related
disorders. In Longo DL, Fauci AS, Kasper DL, et al (editors). Harrison’s
Principles of Internal Medicine, 18th ed. McGraw-Hill, 2012

27
Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri:
Saunders-Elsevier, 2013.
Common Agents of Infection In Patients with AIDS
As indicated above,
 AIDS is characterized by a
profound suppression of
immune system and
susceptibility to
o infections
o neurologic disorders &
o malignancies

HIV/AIDS (12)
Consequences & Complications
 Increased risk of opportunistic infections:
o Toxoplasmosis
o CMV, e.g. retinitis
o Pneumocystis jiroveci pneumonia
o Cryptococcal meningitis
o Mycobacterium avium complex
o Candida
o Aspergillosis
 Increased risk of malignancies:
o Kaposi’s sarcoma
o Non-Hodgkin’s lymphoma
o Cervical cancer
o Anal cancer
28

Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic
Foundations of Medicine, 2012
 HIV-1 mediated destruction of
cellular immune system results in
 AIDS
 Infectious and neoplastic
complications of AIDS can affect
practically every organ system
Consequences of HIV
infection and AIDS

Pneumocystis jiroveci (carinii).
HIV-associated Kaposi sarcoma in nodular stage.
HIV-associated Kaposi sarcoma in macular stage.
Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri: Saunders-Elsevier, 2013.
30

Clinical Manifestations
 HIV affects all body systems, particularly integumentary,
pulmonary, gastrointestinal (GI), neurologic, and ocular
systems
 GI manifestations develop in nearly all persons with
HIV b/c of major effect of HIV infection on GI system
 Pulmonary and cutaneous symptoms develop in ~
50% to 75% of all persons with HIV, and
 Neurologic Sx develop in 50% to 60%
31

One of most significant systemic symptoms is
malnutrition or wasting syndrome
 In Africa, HIV is known as “slim disease” b/c of
wasting
Malnutrition is defined as unintended, involuntary loss
of greater than 10% body weight
Systemic symptoms attributable to HIV infection
malnutrition include major muscle wasting, weight loss,
and loss of vitamins, minerals, and other nutrients 32

HIV (16) Wasting syndrome cont.
33
HIV malnutrition is result of a combination of factors,
including
 an elevated metabolic rate with increased resting
energy expenditure (REE)
 chronic inflammation
 malabsorption
 anorexia
 decreased intake of food, and
 effect of multiple opportunistic insults

Treatment
 Conservative: patient education including
o Transmission reduction advice
o Contact tracing
o Psychological support
 Medical: highly active antiretroviral therapy (HAART): either 2
× NRTIs combined with 1 × NNRTI or 2 × NRTIs combined with
1 × PIs or 1 × II:
o Nucleoside reverse transcriptase inhibitor (NRTI),e.g. zidovudine
o Non-nucleoside reverse transcriptase inhibitor (NNRTI), e.g. nevirapine
o Protease inhibitor (PI), e.g. indinavir
o Integrase inhibitor (II), e.g. raltegravir
34

HIV (18) Antiretroviral therapy
Stages in life cycle of HIV in which antiretroviral therapy is effective are shown.
Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri: Saunders-Elsevier, 2013. 35

Infectious Diseases
Cases 11, 12 , 13, 14 & 15
36

37
A 30-year-old man presents to the emergency room with sudden
high fever and shaking chills. A new murmur localized to the
mitral valve is heard. The patient has bilateral nail-bed
hemorrhages, painful nodules on the tips of his fingers and toes,
an erythematous rash on his palms and soles, and white spots
surrounded by hemorrhage in his retina. You immediately begin
the patient on broad spectrum antibiotics and order blood
cultures and an echocardiogram to confirm the diagnosis.

Infective Endocarditis (IE)
What is infective endocarditis?
 It is an infection of endocardium usually involving heart
valves, with ‘vegetation’ of infectious agent
 Mitral valve is more commonly affected but tricuspid valve
is implicated in IV drug users (IVDAs)
Risk factors
 IV drug abuse
 Cardiac lesions
 Rheumatic heart disease
 Dental treatment: requires antibiotic prophylaxis
38

Infective endocarditis (2)
Pathophysiology and Pathogenesis
 Infective endocarditis is a rare infection that usually affects
patients who already have a structural valve abnormality
 Reason why heart valves are targeted is b/c valves of heart
have limited blood supply and consequently WBCs cannot
reach valves through blood
 Hemodynamic factors that predispose pts. to development of
endocarditis include:
o (1) a high-velocity jet stream causing turbulent flow
o (2) flow from a high- to a low-pressure chamber, and
o (3) a comparatively narrow orifice separating two
chambers that creates a pressure gradient 39

40
Pathophysiology and Pathogenesis cont.
 Lesions of endocarditis tend to form on surface of valve in
lower pressure cardiac chamber
 The predisposed, damaged endothelium of an abnormal valve-
or jet stream-damaged endothelium-promotes deposition of
fibrin and platelets forming sterile vegetations
 When bacteremia occurs (such as after dental work)
microorganisms can be deposited on these sterile vegetations

41
Causative agents
 A variety of organisms are known to have an affinity for
endocardium and cardiac valves in particular
 Most common bacterial culprits are several strains of
Streptococcus and Staphylococcus aureus
Bacterial organisms:
o Streptococcus viridans
o Staphylococcus aureus
o Staphylococcus epidermidis
o Diphtheroids
o Microaerophilic streptococci
o HACEK group: Hemophilus, Actinobacillus, Cardiobacterium,
Eikenella and Kingella

Signs and symptoms
 fever, chills, night sweats, malaise, Roth spots, Janeway
lesions, splinter hemorrhages, and Osler nodes
Remember as FROM JANE:
 Fever
 Roth’s spots (seen on fundoscopy)
 Osler’s nodes (painful nodules seen on fingers and toes)
 Murmur (new)
 Janeway lesions (painless papules seen on palms and soles)
 Anemia
 Nails: splinter hemorrhages
 Emboli
42

Sn and Sx cont.
 Osler node causing pain within pulp of big
toe in a woman hospitalized with acute
bacterial endocarditis
 (Osler nodes are painful: remember “O” for
Ouch and Osler.)
 Note multiple painless flat Janeway lesions
over sole of foot
Hammer GD & McPhee SJ (Eds.).
Pathophysiology of Disease: An
Introduction to Clinical Medicine, 7th
Ed. New York, NY: McGraw-Hill
Education, 2014.
43

44
 In addition to classic Sx & Sn described above, pts. w IE can
develop multisystem complaints, including:
 headaches
 back pain
 focal neurologic Sx
 shortness of breath
 pulmonary edema
 chest pain
 cough
 decreased urine output
 hematuria
 flank pain
 abdominal pain
Sx & Sn reflect:
(1) hemodynamic changes from valvular damage
(2) end-organ damage by septic emboli (right-sided
endocarditis causes emboli to lungs & left-sided
endocarditis causes emboli to brain, spleen, kidney,
GI tract, and extremities)
(3) immune complex deposition causing acute
glomerulonephritis, and
(4) persistent bacteremia and distal seeding of infection,
resulting in abscess formation

45
 Mitral valve endocarditis from subacute bacterial infection with
Streptococcus viridans (friable vegetations are denoted by arrows)
 Left ventricle contains numerous abscesses formed by seeding from
vegetations traveling in coronary arteries

Diagnostic Test:
 Blood cultures: take 3 separate cultures from 3
different peripheral sites (before empiric abx Tx started)
 Bloods for elevated WBC and anemia
 Urinalysis for microscopic hematuria
 CXR septic lesions
 Transesophageal/ transthoracic ECHO for vegetations
46

Classification of infective endocarditis
Duke Criteria:
2 major criteria or 1 major and 3 minor criteria or 5 minor criteria
 Major criteria:
o 2 separate positive blood cultures
o Endocardial involvement
 Minor criteria: FIVE
o Fever >38°C
o IV drug user or predisposing heart condition
o Immunological phenomena, e.g. Osler’s nodes or Roth’s spots
o Vascular phenomena, e.g. mycotic aneurysm or Janeway
lesions
o Echocardiograph findings
47

48
Acute vs Subacute infective endocarditis
Acute infective endocarditis may develop in any individual if host resistance
is low, if organism is highly virulent & if bacterial invasion is sufficiently large
 usually affects individuals with previously normal valves and leads to death in a large
percentage of patients
 Intravenous drug abusers (IVDAs) are particularly susceptible to acute infective
endocarditis Staphylococcus aureus & Staphylococcus epidermidis
Subacute infective endocarditis has a more insidious onset and generally
affects individuals with some preexisting valvular lesion, including:
 Rheumatic heart disease, congenital heart abnormalities, mitral valve prolapse,
calcified valves, and prosthetic valves are important predisposing factors
 Offending organisms are less virulent commonly Streptococcus viridans

Complications
 Heart failure
 Arrhythmias
 Abscess formation in cardiac muscle
 Emboli formation: may cause stroke, vision loss or
spread infection to other regions of body
49

Treatment
Depends on causative agent Check hospital antibiotic guidelines
 Conservative: maintain good oral hygiene
 Medical: empirical therapy is benzylpenicillin and
gentamicin
o Streptococci: benzylpenicillin and amoxicillin
o Staphylococci: dicloxacillin, vancomycin (for MRSA) and
gentamicin
o Aspergillus: miconazole
 Surgical: valve repair or valve replacement
50

51
A 21-year-old man presents to the emergency department
complaining of a severe headache.
Physical examination reveals a fever to 102°F, nuchal rigidity, and
photophobia.
You perform a lumbar puncture, which initially reveals purulent
CSF infiltrated with neutrophils, increased protein content, and
decreased glucose content.
While you await culture results, you admit the patient to
the hospital and begin empiric broad spectrum antibiotics to
treat his condition.

Meningitis
What is Meningitis?
 Inflammation of meninges (membranes covering brain and
spinal cord [see next slide]), usually due to infection
Etiology:
 Viral meningitis tends to occur in epidemics in winter (U.S.) it
is relatively mild
 Bacterial meningitis is life-threatening
o Mainly caused by Haemophilus Influenzae type B (HIB) (most
common worldwide), Neisseria meningitides
(Meningococcus) Type B & C and Streptococcus pneumoniae
N.B. Meningitis is both an acute and chronic disease.
Bacteria and viruses cause acute disease, while
Mycobacterium tuberculosis and fungi (Cryptococcus
and Coccidioides) cause the chronic form. 52

Meningitis (2)
53
Etiology cont.
 Bacteria that cause meningitis usually reach CNS by way of bloodstream or
by extension from cranial structures such as paranasal sinuses or ears
 Some of organisms responsible for causing meningitis may be normal
inhabitants of nasopharynx
 Pathogens can also gain access to CNS through breaks in barrier system
as occur w penetrating head wounds or skull fractures or following
neurosurgery in which dura is penetrated
 Overall mortality rate for meningitis is highest for individuals 65 years of
age and older (23%) whereas that for infants is 7%
 Survivors of meningococcal disease have an 11% to 19% chance of ongoing
neurologic deicits

Meninges
BMA Illustrated Medical Dictionary. Dorling Kindersley, 2013.
Netter FH. The Netter Collection of Medical, Illustrations: Nervous System,
Part I: BRAIN, Volume 7, 2nd Ed. Saunders-Elsevier, 2013.
54

55
Meningitis (3) gross
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

56
Meningitis (4) microscopic

Pyogenic (bacterial) Meningitis (5)
57
Etiology : Causative agents
 Group B streptococci, E coli, Listeria in neonates and infants
 H influenzae and N meningitidis in children and young adults
 Pneumococcus, Listeria, and gram-negative rods in older adults
Pathology: Purulent exudate within leptomeninges, engorged meningeal
vessels, neutrophils within subarachnoid space
Clinical Manifestations: Headache, neck stiffness, fever, irritability
other clues seen in a variable proportion include N/V, photophobia, Kernig sign
and Brudzinski sign
Lab findings: Lumbar puncture shows cloudy CSF with neutrophils, increased
protein, decreased glucose and increased opening pressure
Treatment: Antibiotics and supportive care

58
Pathogenic steps leading to
pneumococcal meningitis
A.Pneumococcus adheres to and colonizes
nasopharynx
 IgA1 protease protects pneumococcus from
host antibody
B. Once in bloodstream, bacterial capsule
helps pneumococcus to evade opsonization
C. Pneumococcus accesses CSF through
receptors on endothelial surface of blood-
brain barrier (BBB)
Hammer GD & McPhee SJ (Eds.). Pathophysiology of Disease:
An Introduction to Clinical Medicine, 7th Ed. McGraw-Hill, 2014.

Pathophysiological alterations leading to
neuronal injury during bacterial meningitis.
59
Hammer GD & McPhee SJ (Eds.). Pathophysiology of Disease: An Introduction to
Clinical Medicine, 7th Ed. McGraw-Hill, 2014.

Viral (aseptic) meningitis (6)
60
Most common form of acute meningitis
Clinical Manifestations: Headache, photophobia, neck stiffness, fever, irritability
Pathology: May be no abnormality or a mild lymphocytic infiltrate in
subarachnoid space and mild edema may be present
Causes: HSV virus, coxsackie virus, echoviruses, and arboviruses
Lab findings: Lumbar puncture shows lymphocytosis, mildly elevated protein,
and normal glucose
Treatment: Self-limiting illness; acyclovir for HSV meningitis
N.B. Viral encephalitis refers to infection of brain and/or meninges
(meningoencephalitis)
 It can be caused by many organisms, including arboviruses, herpes,
cytomegalovirus, rabies, and poliovirus
 Histopathologically, glial nodules, inclusion bodies in neurons, and
perivascular mononuclear cell infiltrates are seen

61
Meningitis: Common Cause & CSF Findings

62
A 68-year-old man presents to the emergency department
complaining of a fever, dyspnea, and a cough productive of green
sputum. Physical examination reveals an ill-appearing man,
breathing heavily. On lung examination, you note bronchial breath
sounds and dullness to percussion over the right lower lung lobe.
A chest x-ray demonstrates circumscribed opacity over the region
of his right lower lung lobe. You obtain sputum and blood cultures
and then admit this patient to the hospital for antibiotic treatment.

Bacterial Pneumonia
63
Etiology
 Lobar pneumonia: Pneumococcus (Streptococcus pneumoniae)
accounts for 90%-95% of cases
 Bronchopneumonia: Staphylococcus aureus, Haemophilus influenzae,
Klebsiella pneumoniae, Streptococcus pyogenes
Pathology
 Lobar: Generally intra-alveolar exudate leading to consolidation 4
stages: (1) congestion: heavy red lung, intra-alveolar fluid; (2) red
hepatization: RBCs, fibrin and neutrophils within alveoli; (3) gray
hepatization: fibrin and neutrophils within alveoli; (4) resolution: intra-
alveolar exudate is reabsorbed
 Bronchopneumonia: Often is bilateral and multilobar neutrophil
exudate extends from bronchi and bronchioles into adjacent alveoli

Bacterial Pneumonia (2)
64
Clinical Manifestations:
 Sx Malaise, fever, dyspnea, and productive cough
 Sn Bronchial breath sounds and rales on auscultation and
dullness to percussion over affected lung areas
Complications include abscess, empyema, or sepsis
Imaging: CXR shows radio-opaque lobe for lobar pneumonia or
patchy opacities for bronchopneumonia
Treatment: Antibiotics; respiratory support
N.B. Hospital-acquired pneumonias may be caused by gram-negative
microorganisms (Klebsiella, Escherichia coli, Pseudomonas) as well as gram-
positive organisms (S aureus) and can be fatal

67
Acute community-acquired typical pneumonias
Johnson AG, et.al. Microbiology and Immunology
(Board Review Series) 5th ed. Philadelphia, PA:
Lippincott Williams & Wilkins, 2010

68
A 21-year-old woman presents to the university health clinic
complaining of general weakness and a low-grade fever of 3 days
duration. Upon directed history, you learn that she has had an
occasional cough and dyspnea and that her two roommates have
been suffering from similar symptoms. When a chest x-ray reveals
patchy infiltrates, you prescribe her a course of azithromycin and
schedule her for a follow-up visit to make sure that her symptoms
have resolved.

Interstitial Pneumonia
69
Etiology:
Mycoplasma pneumoniae; viruses (influenza, RSV, adenovirus);
Chlamydia psittaci; Coxiella burnetii; Legionella pneumophila
Pathology:
Lung: Often multilobar; patchy infiltration of mononuclear
inflammatory exudate into alveolar
walls; may see pink hyaline membranes lining alveoli
Clinical Manifestations: Malaise; fever; muscle aches; occasional
cough (clinical picture appears less severe than typical
pneumonias)
Imaging: CXR reveals patchy infiltration

Interstitial Pneumonia (2)
70
Lab findings:
 Leukocytosis, elevated cold agglutinin levels in M
pneumoniae infection
Treatment:
 Antibiotics; supportive care
N.B Pneumocystis carinii pneumonia (PCP) is most common
opportunistic infection seen in AIDS patients
 It demonstrates an interstitial pattern of lung pathology
and can be diagnosed by silver stain of a bronchial lavage

Mp X-ray looks worse than patient
http://www.intechopen.com/books/respiratory-disease-
and-infection-a-new-insight/pneumonia-in-children
X-ray of 25-year old FM w cough
due to Mycoplasma Pneumonia
http://www.medicalgrapevineasia.com/mg/2012/11/20/the-
mycoplasma-story/

72
Johnson AG, et.al. Microbiology and Immunology
(Board Review Series) 5th ed. Philadelphia, PA:
Acute community-acquired atypical pneumonias

Bacterial pneumonias: most common
causative agents
73
 Bronchopneumonia is caused by
 staphylococci,
 streptococci,
 pneumococci,
 Haemophilus influenzae,
 Pseudomonas aeruginosa, and
 coliform bacteria
 Lobar pneumonia is most frequently (90%–95%) caused by
pneumococci (Streptococcus pneumoniae)
 encapsulated gram-positive coccus known for causing rust-
colored sputum

Common causes of pneumonia (2)
74
Neonates
(< 4 Wks.)
Children
(4 Wks.–18 Yrs.)
Adults
(18–40 Yrs.)
Adults
(40–65 Yrs.)
Elderly
Group B
streptococci
E. coli
Viruses (RSV)
Mycoplasma
C. trachomatis
(infants–3 yr.)
C. pneumoniae
(school-aged
children)
S. pneumoniae
Mycoplasma
C. pneumoniae
S. pneumoniae
S. pneumoniae
H. influenzae
Anaerobes
Viruses
Mycoplasma
S. pneumoniae
Influenza virus
Anaerobes
H. influenzae
Gram-negative
rods
Redrawn and modified from: Le T and Bhushan V. First Aid for the USMLE Step 1 2015
Note: Most common pneumonias in childhood are Viral pneumonias
Most commonly implicated viruses are Influenza, parainfluenza,
respiratory syncytial virus, rhinovirus, and adenovirus

Common causes of pneumonia (3)
75
Special groups
Alcoholic/IV drug user S. pneumoniae, Klebsiella, S. aureus
Aspiration Anaerobes (e.g., Peptostreptococcus, Fusobacterium,
Prevotella, Bacteroides)
Atypical Mycoplasma, Legionella, Chlamydia
Cystic fibrosis Pseudomonas, S. aureus, S. pneumoniae
Immunocompromised S. aureus, enteric gram-negative rods, fungi, viruses, P.
jirovecii (with HIV)
Nosocomial (hospital
acquired)
S. aureus, Pseudomonas, other enteric gram-negative rods
Postviral S. aureus, H. influenzae, S. pneumoniae
Redrawn from: Le T and Bhushan V. First Aid for the USMLE Step 1 2016. New York, NY: McGraw-Hill Education, 2016.

76
A 21-year-old woman presents with the complaint of diarrhea.
She returned from Mexico the day before her visit. The day before
that, she had an acute onset of profuse watery diarrhea.
She denies blood or mucus in the stools. She has had no
associated fever, chills, nausea, or vomiting. She has no other
medical problems and is taking no medications. Examination is
remarkable for diffuse, mild abdominal tenderness to palpation
without guarding or rebound tenderness. Stool is guaiac negative.
Infectious diarrhea is suspected.

Infectious Diarrhea (Diarrheas & Dysentery)
77
 Diarrheas are characterized by frequent and fluid stools that
result from small intestine disease involving fluid and
electrolyte loss (Watery diarrhea)

 Dysentery is an inflammatory disease of large intestine with
blood or pus in stool (Bloody diarrhea)
 However, clinicians frequently only apply term dysentery to infections
by a Shigella bacteria or an amoeba=Entamoeba histolytica
 Thus, diarrhea can be classified
 On basis of nature of diarrhea reflects pathology
 Site of infection

Infectious Diarrhea (2)
78
 Sources of infectious agents are
 Food
 Water
 Zoonotic, or
 Person-to-person transfer by fecal–oral route
 Toxins play a major role in development of symptoms
observed w some bacteria and rotavirus infections
incubation times depend on whether
 a preformed toxin
 colonization and toxin synthesis, or
 tissue invasion is involved

79
 Many infections are self-limiting, but some, particularly in
children without proper rehydration, can be fatal
 Since it is impossible to clinically diagnose causative agents
recent food and travel history as well as examination of
stool is important
 Specific diagnosis is dependent on laboratory analysis of
stool involving Gram staining for bacteria, staining for
polymorphonuclear neutrophils (PMNs), and bacterial
culture and immunologic-based tests for specific pathogens

80
 Other important considerations related to diagnosis are
whether pathogen is associated with an epidemic
 infection is frequently location dependent in
developed countries, viral infections are most
common
 An identification scheme initially based on nature of
diarrhea and presence or absence of vomiting is
described in the following slides (i.e., watery vs bloody
w or w/o vomiting)

81
A. Watery diarrheas with vomiting
 Causative pathogens are viruses and several
bacteria majority of which synthesize
enterotoxins involved in pathogenesis of disease
 Some produce fever, but all have relatively short
incubation times ranging from several hours to a
few days due to associated toxins or virus
multiplication in small intestine

Johnson AG, et.al. Microbiology and Immunology (Board Review Series) 5th
ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010.
Watery diarrheas with vomiting

83
Pathogenesis of Vibrio cholerae and enterotoxigenic E coli
(ETEC) in diarrheal disease
Hammer GD & McPhee SJ (Eds.). Pathophysiology of Disease: An Introduction to Clinical Medicine, 7th Ed. New York,
NY: McGraw-Hill Education, 2014.

84
B. Watery diarrhea with no vomiting
 One bacterium (Clostridia Perfringens) and two protozoa
(Giardia lamblia & Cryptosporidium parvum) are in this
group
 Variety of toxins contribute to bacterial disease  has a
short (less than 24 hours) incubation period
 Protozoa have longer (1 to 4 weeks) incubation periods
with disease that is usually moderate but it can become
chronic and serious in immunocompromised individuals
 No fever is associated with these infections

85
Watery diarrhea with no vomiting
Johnson AG, et.al. Microbiology and Immunology (Board Review Series) 5th ed. Philadelphia, PA:

86
C. Bloody diarrhea with vomiting
 Two types of Escherichia coli cause this form of diarrhea
 Enterohemorrhagic E. coli (EHEC) strains release a
verotoxin that is cytotoxic to intestinal villi and colon
epithelial cells
 Enteroinvasive E. coli (EIEC) strains invade and destroy
colon epithelial cells
 Both have incubation periods of 2 to 5 days
Note: There are 4 different strains of E coli, namely:
Enteropathogenic E. coli (EPEC)
Enterotoxigenic E. coli (ETEC) ‘‘Traveler’s’’ diarrhea
Enterohemorrhagic E. coli (EHEC)’
Enteroinvasive E. coli (EIEC)

Bloody diarrhea with vomiting

88
D.Bloody diarrhea with no vomiting
 Both bacillary and amebic dysentery cause this form of diarrhea
 Gram-positive and Gram-negative rods and a protozoan are
involved
 PMNs in stool and fever occur with most infections
 Tissue invasion is common

89
Bloody diarrhea with no vomiting

Sepsis, Bacteremia, Septicemia & Septic Shock: Definitions
90
 Sepsis Infection of a wound or body tissues with bacteria that leads to
formation of pus or to multiplication of the bacteria in blood. (not a clinical
definition)
 Bacteremia Presence of bacteria in bloodstream. Occurs briefly after many
minor surgical operations invasive medical and dental procedures. The
immune system usually prevents bacteria from multiplying and causing
damage.
 Septicemia A potentially life-threatening condition in which there is rapid
multiplication of bacteria and in which bacterial toxins are present in the
blood.
 Septic Shock A life-threatening condition in which there is tissue damage
and a dramatic drop in blood pressure as a result of septicemia.
Source: The British Medical Association Illustrated Medical Dictionary. Dorling Kindersley, 2013.

91
Septicemia Capsule:
 Septicemia usually arises through escape of bacteria from a focus of
infection such as an abscess
 Septicemia is more likely to occur in:
 people with an immunodeficiency disorder, cancer, or diabetes mellitus
 those who take immunosuppressant drugs, and
 drug addicts who inject
 Symptoms include a fever, chills, rapid breathing, headache, and clouding
of consciousness
 Sufferer may go into life-threatening septic shock
 Treatment Glucose and/or saline are given by intravenous infusion, and
antibiotics by bolus injection or IV infusion
 Surgery may be necessary to remove original infection
 If treatment is given before septic shock develops, prognosis is good

Sepsis & Septic Shock
92
Epidemiology
 Sepsis is a leading cause of death in United States
more than 34,000 deaths occurring annually and overall case fatality
rate approaching 20%
 Medical costs of sepsis In U.S. > $17 billion
 Rates of sepsis continue to rise secondary to medical advances
 widespread use of indwelling intravascular catheters,
increased implantation of prosthetic material (e.g., cardiac
valves and artificial joints), and administration of
immunosuppressive drugs and chemotherapeutic agents
 These interventions serve to increase risk of infect. & subsequent sepsis

Sepsis & Septic Shock (2)
93
Study of sepsis has been facilitated by establishment of
standardized case definitions ( See table slide 88)
Systemic inflammatory response syndrome ( SIRS ) is a
nonspecific inflammatory state that may be seen w
infection as well as w noninfectious states (e.g.
pancreatitis, pulmonary embolism, and myocardial
infarction)
 Leukopenia and hypothermia, included in SIRS case definition,
are predictors of a poor prognosis when associated w sepsis

94
 Sepsis is defined as presence of SIRS associated w an
infectious precipitant
 Severe sepsis occurs when there is objective evidence
of organ dysfunction (e.g., renal failure, hepatic failure,
altered mentation) usually associated w tissue
hypoperfusion
 Final stage of sepsis is septic shock defined as
hypotension (SBP <90 mm Hg or a 40 mm Hg decrease
below baseline SBP) unresponsive to fluid
resuscitation

Hammer GD & McPhee SJ (Eds.). Pathophysiology of Disease: An Introduction to
Clinical Medicine, 7th Ed. New York, NY: McGraw-Hill Education, 2014.
Clinical definition
of sepsis

96
Confusion about meaning of terms bacteremia, sepsis, septic shock, and SIRS prompted
planning of a consensus conference to provide definitions for clinical and research purposes.
See: Levy MM, et al: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference,
Crit Care Med 31(4):1250–1256, 2003.

97
Relationship of infection,
systemic inflammatory response
syndrome (SIRS), sepsis, severe
sepsis, and septic shock
Abbreviations:
ARDS, acute respiratory distress syndrome
CI, cardiac index
DIC, disseminated intravascular coagulation
MODS, multiple-organ dysfunction syndrome
Dipiro JT et al, editors: Pharmacotherapy: A Pathophysiologic Approach, 8th Ed.
New York: McGraw-Hill, 2011.

Etiology of Circulatory Shock
98
Cardiogenic Shock
Myocardial infarction
Cardiomyopathy
Valvular heart disease
Ventricular rupture
Congenital heart defects
Papillary muscle rupture
Obstructive Shock
Pulmonary embolism
Cardiac tamponade
Tension pneumothorax
Dissecting aortic aneurysm
Hypovolemic Shock
Acute hemorrhage
Dehydration from vomiting, diarrhea
Overuse of diuretics
Burns
Pancreatitis
Distributive Shock
Anaphylaxis
Neurotrauma
Spinal cord trauma
Spinal anesthesia
Sepsis

Comparison of Clinical Findings In Different
Types of Shock
99

100
Etiology
 Although evidence of infection is a diagnostic criterion for
sepsis only 28% of patients w sepsis have bacteremia, and
only 10% will have primary bacteremia, defined as positive
blood cultures w/o an obvious source of bacterial seeding
 Common sites of infection among pts. w sepsis syndrome (in
decreasing order of frequency) include
 respiratory tract
 genitourinary tract
 abdominal sources (gall bladder, colon)
 device-related infections, and
 wound or soft tissue infections

101
Etiology cont.
Bacteriology of sepsis:
 Gram-negative bacteria ( Enterobacteriaceae & Pseudomonas ) ,
previously most common cause of sepsis, have been supplanted
by gram-positive organisms now cause more than 50% of
cases
o Staphylococci are most common bacteria cultured from
bloodstream, b/c of an increase in prevalence of chronic
indwelling venous access devices and implanted prosthetic
material

102
Pathophysiology
of septic shock

103
Signs and Symptoms Associated with Sepsis
Early Sepsis
Fever or hypothermia
Rigors, chills
Tachycardia
Tachypnea
Nausea, vomiting
Hyperglycemia
Myalgias
Lethargy, malaise
Proteinuria
Hypoxia
Leukocytosis
Hyperbilirubinemia
Late Sepsis
Lactic acidosis
Oliguria
Leukopenia
DIC
Myocardial depression
Pulmonary edema
Hypotension (shock)
Hypoglycemia
Azotemia
Thrombocytopenia
ARDS
Gl hemorrhage
Coma
 Clinical manifestations of sepsis
include:
 Those related to systemic
response to infections
(tachycardia, tachypnea,
alterations in temp. and WBC
count) and
 Those related to specific organ
system dysfunction
(cardiovascular, respiratory,
renal, hepatic, and hematologic
abnormalities)

Septic Shock: KEY POINTS
104
 Septic shock results from a severe systemic inflammatory
response to infection
 Gram-positive bacteria, Gram-negative bacteria, and fungal
infections are common causes of septic shock
 In gram-negative shock, endotoxins in bacterial cell walls stimulate
massive immune system activation
 Septic shock from any organism is characterized by release of
large numbers of immune mediators (e.g., cytokines) resulting in
widespread inflammation
 The clotting cascade, complement system, and kinin system are
activated as part of immune response

Septic Shock: KEY POINTS (2)
105
 Widespread inflammation leads to profound peripheral
vasodilation w hypotension, maldistribution of bld flow w
cellular hypoxia, and increased capillary permeability w edema
formation
 Initially, septic shock is characterized by abnormally high cardiac
output resulting from immune-mediated vasodilation and
sympathetic activation of heart
 Patient is usually febrile and warm
 Even though cardiac output is high, cellular hypoxia is present
b/c of maldistribution of blood flow
 Reduced cellular oxygen utilization is manifested as a high SvO2

Septic Shock: KEY POINTS (3)
106
 Therapy for septic shock is aimed at improving
distribution of blood flow and managing infection with
antibiotics
 Administration of fluid and drugs to increase cardiac
and vascular performance is done to improve
distribution of blood low

107
THE END
See next slide for further study tools and resources.

Sources and further study:
108
 Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri: Saunders-Elsevier,
2013.
 Dipiro JT et al, eds. Pharmacotherapy: A Pathophysiologic Approach, 8th Ed. New York:
McGraw-Hill, 2011.
 Kishiyama JL. Ch. 3 Disorders of the Immune System, Pgs. 31-59 and Bloch KC. Ch. 4
Infectious Diseases, Pgs. 61-87 In: Hammer GD and McPhee eds. JS. Pathophysiology of
Disease : An Introduction to Clinical Medicine, 7th Ed. New York: McGraw-Hill Education,
2014
 Johnson AG et al. Bacterial Diseases. In: Microbiology and immunology. 4th Ed. Baltimore:
Lippincott Williams & Wilkins, 2010.
 Le T and Bhushan V. First Aid for the USMLE Step 1 2016, New York: McGraw-Hill, 2016.
eLearning (IVMS Cloud)
o Infectious Disease
o Microbial biology & Immune System
Textbooks:
 Ryan KJ and Ray CG Eds. Sherris Medical Microbiology, 5th Ed. New York: McGraw-Hill, 2010.
 Carroll KC etal. Jawetz, Melnick, & Adelberg’s Medical Microbiology 27th Ed. New York:
McGraw-Hill, 2016.

Pathophysiology- Global Overview of Select Infectious Diseases

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