Pathophysiology of disease flashcards ( GIẢI PHẪU BỆNH)

Acute Respiratory Distress CARDIOVASCULAR DISORDERS: HEART DISEASE 49.. Pathophysiology of Disease: An Introduction to Clinical Medicine is the leading pathophysiology textbook, provi

Pathophysiology of Disease Flashcards

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Yeong Kwok, MD, Stephen J McPhee, MD,

Gary D Hammer, MD, PhD

University of Michigan, Ann Arbor & University of California, San Francisco

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GENETIC DISEASE

2 Phenylketonuria 2A-B

3 Fragile X–Associated Mental Retardation 3A-B

4 Mitochondrial Disorders: Leber Hereditary

Optic Neuropathy/Mitochondrial

Encephalopathy with Ragged

Red Fibers (LHON/MERRF) 4A-B

5 Down Syndrome 5A-B

DISORDERS OF THE IMMUNE SYSTEM

8 X-Linked Agammaglobulinemia 8A-B

INFECTIOUS DISEASES

11 Infective Endocarditis 11A-B

12 Meningitis 12A-B

14 Diarrhea, Infectious 14A-B

NEOPLASIA

Neuroendocrine Tumor (NET) 16A-B

18 Breast Cancer 18A-B

21 Lymphoma 21A-B

22 Leukemia 22A-B

BLOOD DISORDERS

NERVOUS SYSTEM DISORDERS

28 Amyotrophic Lateral Sclerosis

(Motor Neuron Disease) 28A-B

37 Bullous Pemphigoid 37A-B

39 Poison Ivy/Oak 39A-B

41 Sarcoidosis 41A-B

42 Acne 42A-B

PULMONARY DISEASE

44 Obstructive Lung Disease: Chronic Obstructive

45 Restrictive Lung Disease: Idiopathic

46 Pulmonary Edema 46A-B

48 Acute Respiratory Distress

CARDIOVASCULAR DISORDERS:

HEART DISEASE

49 Arrhythmia 49A-B

50 Heart Failure 50A-B

52 Valvular Heart Disease: Aortic Regurgitation 52A-B

54 Valvular Heart Disease: Mitral Regurgitation 54A-B

DISORDERS OF THE ADRENAL MEDULLA

61 Pheochromocytoma 61A-B

GASTROINTESTINAL DISEASE

62 Achalasia 62A-B

65 Gastroparesis 65A-B

66 Cholelithiasis and Cholecystitis 66A-B

67 Diarrhea, Non-Infectious 67A-B

69 Diverticular Disease (Diverticulosis) 69A-B

70 Irritable Bowel Syndrome 70A-B

LIVER DISEASE

71 Acute Hepatitis 71A-B

73 Cirrhosis 73A-B

DISORDERS OF THE EXOCRINE PANCREAS

RENAL DISEASE

80 Poststreptococcal Glomerulonephritis 80A-B

81 Nephrotic Syndrome: Minimal Change Disease 81A-B

DISORDERS OF THE PARATHYROIDS & CALCIUM & PHOSPHORUS METABOLISM

83 Primary Hyperparathyroidism 83A-B

84 Familial Hypocalciuric Hypercalcemia 84A-B

85 Hypercalcemia of Malignancy 85A-B

86 Hypoparathyroidism and Pseudohypoparathyroidism 86A-B

DISORDERS OF THE HYPOTHALAMUS

& PITUITARY GLAND

94 Obesity 94A-B

96 Panhypopituitarism 96A-B

97 Diabetes Insipidus 97A-B

98 Syndrome of Inappropriate Antidiuretic

THYROID DISEASE

99 Hyperthyroidism 99A-B

100 Hypothyroidism 100A-B

101 Goiter 101A-B

103 Familial Euthyroid Hyperthyroxinemia 103A-B

DISORDERS OF THE ADRENAL CORTEX

104 Cushing Syndrome 104A-B

105 Adrenal “Incidentaloma” 105A-B

107 Hyperaldosteronism (Primary Aldosteronism) 107A-B

108 Type 4 Hyporeninemic Hypoaldosteronism 108A-B

109 Congenital Adrenal Hyperplasia 109A-B

DISORDERS OF THE FEMALE REPRODUCTIVE TRACT

110 Menstrual Disorders: Dysmenorrhea 110A-B

111 Female Infertility 111A-B

112 Preeclampsia-Eclampsia 112A-B

DISORDERS OF THE MALE REPRODUCTIVE TRACT

113 Male Infertility 113A-B

114 Benign Prostatic Hyperplasia 114A-B

INFLAMMATORY RHEUMATIC DISEASES

115 Gout 115A-B

116 Vasculitis 116A-B

117 Systemic Lupus Erythematosus 117A-B

119 Myositis 119A-B

120 Rheumatoid Arthritis 120A-B

Pathophysiology of Disease: An Introduction to Clinical Medicine

is the leading pathophysiology textbook, providing

Pathophysiology of Disease Flashcards provide study aids for

120 of the most common topics germane to medical practice

The

Th Flashcards provide key questions regarding the topics for a

quick review and study aid for a variety of standardized

exami-nations As such, they will be very useful to medical, nursing,

and pharmacy students Each of the Flashcards begins with a

clinical case and then presents key questions to help the reader

think in a step-wise fashion through the various

pathophysi-ologic aspects of the case

Outstanding Features

• 120 common pathophysiology topics useful to learners

in their preparation for a variety of course and certifying

examinations

• Material drawn from the expert source, Pathophysiology of

Disease: An Introduction to Clinical Medicine, now in its new

7th edition

that allows for quick study

assistants (PAs) and nurse practitioners (NPs) in training

Organization

The 120 topics in the

Th Flashcards were selected as core topics

be-cause of their relevance to both clinical practitioners and ers in order to enable understanding of the pathophysiologic ba-

the top of the front side, a CASE is presented On the bottom of

reference to the pathophysiology of the clinical entity illustrated

by the case To allow the user to think through their responses, the Answers to the 3 questions are printed upside down.

The questions asked on these

learner’s knowledge of the pathophysiology associated with the disorder and thus support their clinical problem- solving

organization of Pathophysiology of Disease: An Introduction tof

Clinical Medicine, 7th edition which is organized by 23 disease

categories:

• ADRENAL MEDULLA • GASTROINTESTINAL TRACT

• HYPOTHALAMUS & PITUITARY • THYROID

• ADRENAL CORTEX • MALE REPRODUCTIVE TRACT

• FEMALE REPRODUCTIVE TRACT • INFLAMMATORY RHEUMATIC

• PARATHYROID, CALCIUM DISEASES

& PHOSPHORUS

Intended Audience

prepare for their Pathophysiology or Introduction to Clinical Medicine course examinations, and the USMLE Part 1 exami-nation Nursing and pharmacy students, NPs and PAs takingtheir internal medicine rotations can review core topics as they prepare for their standardized examinations

1 Osteogenesis Imperfecta, A

A 4-week-old boy is brought in with pain and swelling of

right femur Que stioning of the mother reveals that the boy

and right clavicle—which had been attributed to birth

several family members A diagnosis of type II osteogenesis imperfecta is entertained

1 When and how does type II osteogenesis imperfecta present? To what do these individuals succumb?

2 What are two typical radiologic findings in type II osteogenesis imperfecta? fi

•

Of t

he fo

ur types o

f osteogenesis imper

fec

ta, typ

e II

presen

ts at o

r even befo

re birt

h (diagnos

ed by prenatal

ultrasound)

•

Ther

e are multip

le fractures, bon

y deformities, an

increased fragility

of nonbon

y connecti

ve tissu

e

•

Death usually resul

ts durin

g infancy d

s ffi

•

Presence o

f isolated

“islands” o

f mineralization in t

he

skull (wormia

n bones)

•

Beaded appearance o

f t

he ribs

•

Nonsense-mediated deca

y resul

ts wh

en a mutation

codes fo

r a prematu

re stop codon

•

Th is resul

ts in partially synthesized mRNA p

recurso

that carr

y th

e nonsen

se codon

•

The cell recognizes thes

e mRNA strands an

th

em befo

re protein synthesis tak

es place

•

This prevents t

he buildup

of protein fragmen

ts th

at ca

accumulat

e and damag

2 Phenylketonuria, A

A newborn girl tests positive for phenylketonuria (PKU)

positive, establishing the diagnosis of PKU

1 What are the primary defects in phenylketonuria?

2 Why is dietary modification a less than satisfactory treatment of this condition? fi

•

Th e primary defec

t in PKU is hyperphenylala

•

Most people with PKU have a defec

t in phenylalanine

hydroxylase, an essential enzyme in conver

ting

phenylalanine to tyrosine

•

As a consequence, excessive phenylalanine and

phenylalanine metab

olites bui

ld up, leading t

o

neurologic a

nd other damage

•

Phenylalanine is a

n essenti

al amino acid

, meanin

g that

so

me consumptio

n of i

t is necessary

for life

•

However, in PKU, t

he levels o

f phenylalanine in t

he

diet must b

e strictl

y limited t

o mainta

in a plasma

concentratio

n a

t o

r belo

w 1 mmol/L

•

This limitatio

n mu

st be maintained througho

ut t

aff ecte

d person’s lifetime since even mild ele

vatio

duri

ng adulthoo

d ca

n lead t

o neuropsychological a

nd

cognitive defects

2 Phenylketonuria, B

•

As a

n increasin

g numb

er of treated females with PKU

reach childbearin

g a

ge a

nd beco

me pregna

nt, their

developin

g fetuses a

re a

t risk o

f in u ter

o ex

posur

e to

phenylalanine

•

Th e safe leve

l of plasma phenylalanine fo

r a developin

fet

us is 0.12–0.36 mmol/L, much low

er than th

at for

childre

n o

r adults

•

Newbo

rn infan

ts exposed

to high

er levels

dur

ing

pregnancy exhib

it microcephaly, growth reta

rd

atio

n,

congenital heart diseas

e, a

nd growth retardat

io

n

•

Strict contro

l of maternal phenylalanine concen

tratio

n

before conceptio

n an

d durin

g pregnancy ca

n red

uce th

e

inciden

ce of fetal abnormalities

3 Explain the phenomenon of maternal phenylketonuria.

3 Fragile X–Associated Mental Retardation, A

A young woman is referred for genetic counseling She has

a 3-year-old boy with developmental delay and small joint

X–associated mental retardation She is currently pregnant

history is unremarkable

1 Explain why fragile X–associated mental retardation syndrome exhibits

an unusual pattern of inheritance.

•

Th e clinical syndro

me is caus

ed by a

n unusually la

number o

f repeats o

f a triplet sequence (CGG) o

n the

X chromoso

me between ban

ds Xq27 an

d Xq28

•

Th e number o

f repeats o

f this triplet sequence is highl

variab

le an

d can beco

me amplifi

ed (if there a

re fi

>50–55

copies o

f t

he C

GG triplet) durin

g maternal transmission

bu

t no

t durin

g patern

al transmission

•

Eac

h subsequen

t matern

al transmissio

n can amplif

y the

number o

f copies further

•

Clinical diseas

e occu

rs when ther

•

Th us, a transmi

ho herself will no

t be affec

ted wi

th the ff ff

diseas

e since t

he C

GG triplet wi

ll no

t have

bec

om

e

amplifi

ed fi

•

Howeve

r, t

he daughter ca

n pass on th

e X chro

moso

me

to h

er offspri

disea

se since ff ff

th

e numb

er of C

GG triplets can undergo

am

plifi

cati

on fi

3 Fragile X–Associated Mental Retardation, B

•

Genetic anticipatio

n refers to th

e phenomeno

n where

penetrance or exp

ressivity

of a genetic diseas

e seem

s to

increas

e in each successive

generation

•

Fragile X–asso

ciated mental retardatio

•

In both cases, a trip

le repeat nucleic acid seq

uence is

amplifi

ed in eac

h subsequen

t genera

2 What is genetic anticipation? What are two explanations for it?

3 What is an epigenetic change?

•

Epigenetic chan

ge is a

n inheritable phenotypic change

tha

t is not determined b

y t

he D

NA sequence

•

Alteratio

ns

to chromat

in structu

re th

at include

modifi cation o

f D

NA b

y methylation an

cati

on fi

of histon

es b

y methylatio

n and/o

r acetylatio

n are

examples o

f epigenetic chan

ges

4 Mitochondrial Disorders: Leber Hereditary Optic

Neuropathy/Mitochondrial Encephalopathy with Ragged Red Fibers (LHON/MERRF), A

A 16-year-old boy presents with worsening vision for the

with central vision in his right eye, seeing a dark spot in the

over time, and he had also developed loss of central vision

but his mother and another maternal uncle and two

opathy and vascular tortuosity of the retina Genetic testing

es fr

om a mutation o

n mitochondrial DNA

(mtDNA)

•

mtDNA encodes t

he components o

f t

he electron

transport chain involve

d in t

he generation o

f adenosine

triphosphate (ATP)

•

Mutatio

ns in t

he mtD

NA impair t

he ability t

g intensiv

e centra

l nervo

4 Mitochondrial Disorders: Leber Hereditary Optic

Neuropathy/Mitochondrial Encephalopathy with Ragged Red Fibers (LHON/MERRF), B

•

LH

ON is inherite

d through mutatio

ns in mtDNA

(as above)

•

All o

f t

he mtD

NA in o

ur bodies comes exclusivel

is inherited only from

th

e mother

•

A typical cell carries 10–100 s

eparate mtD

NA

molecules, only a fraction o

f whic

h carry t

he mutation

•

Th es

e mtD

NA molecules can ass

erently ff ff

during meiosis

•

Th us, within a

ny given eg

g in an

ected woma

nt D

NA ma

y vary fr

om 10% t

o 90%

•

Furthermore, within a

ny given offsprin

to diff erential assortmen

t durin

g mi

2 How is this disorder inherited?

3 What is the principle of heteroplasmy?

5 Down Syndrome, A

A 40-year-old woman undergoes prenatal screening with

of the amniocentesis show trisomy 21 or Down syndrome.She has several questions about what she might expect

1 What are the common features of the various different karyotypic abnormalities ff resulting in Down syndrome?

2 What are the major categories of abnormalities in Down syndrome, and what is their natural history?

y a variety o

f differe

nt ff ff

karyotyp

ic abnormalities that have

in commo

n a 50%

increas

e in gene dosage o

f t

he genes o

n chromoso

me 21

•

Most often, a

ff ftecte

d individuals have

an extra ff ff

chromoso

me 21, havin

g three copies rath

er th

an t

he

usual two

•

This is d

ue to nondisjunctio

n of chromosome 21 d

uri

the anaphase o

f meiosis

•

Occasionally, D

own syndrome ca

n be caused b

y th

e

inheritance o

f a

n abnorm

al chromoso

me 21, whic

h has

additional translocated genetic mater

ial

on it

•

This abnorm

al chromoso

me is descr

robertsoni

an translocation

•

Congenital heart diseas

e is t

he most significan

t fi

abnormali

ty associated with Do

wn syndrome, an

d th

e majo

r determinan

t o

f longevity in a

ff ect

ed ff ff

individuals

(continued on reverse side)

5 Down Syndrome, B

•

Th er

e is also growth retardatio

•

Th er

e are characteristic changes in appearan

as brachycephal

y, epicanth

al folds, sma

ll ears, and

transverse palmar creases

•

The neurologic eff Th ec

ts are developmenta

l delay a

prematu

re onset o

f Alzheimer disea

se, with

seni

le

plaques present in almost a

ll individuals

ed immune fu

nctio

n with

increased susceptib

ility to infection

s a

nd leukemia

•

Do

wn syndro

me is caused b

y an increased genetic load,

leadin

g to increased expressio

n of specific gene

s fi

•

Th os

e individuals with

ns ca

n have less than

a full

double co

py o

f chromoso

me 21

•

Th is resul

ts in less of a

n increas

e in t

he gene dos

whi

ch can aff ec

t phenotyp

e ff ff

•

In additio

n, so

me individuals with transloc

h so

me cell

s a

re norm

•

This further can decreas

e t

he severity o

f p

heno

expression

3 Explain why trisomy 21 is associated with such a wide range of phenotypes from mild mental retardation to that of “typical” Down syndrome.

6 Allergic Rhinitis, A

A 40-year-old woman comes to the clinic with a

his-tory of worsening nasal congestion and recurrent sinus

infections She had been healthy until about 1 year ago

vacation to Mexico, her rhinorrhea disappeared, only to

return when she came home again She has lived in thesame house for the past 5 years along with her husband

for 1 year On physical examination, she has boggy, len nasal turbinates and a cobblestone appearance of herposterior pharynx

swol-1 What are the major clinical manifestations of allergic rhinitis?

•

Common sympto

ms a

re sneezin

g, nas

al itching, clea

r

rhinorrh

ea, and nasal congestion

•

Common sign

s are pale, bluish nasal mucos

a, serous otit

is

media, transvers

e nasal creas

e, a

nd infraorbital cyanosis

•

Sinusitis, heari

ng loss, and otitis media a

re p

ossi

ble

complication

s of otit

is media

•

Allergic rhinitis is caused

b

y a type I (IgE-med

iated)

immedia

te hypersensitivi

ty t

o environmental allergens

•

Nasa

l mucos

a fi lters o

ut particles larg

er than

n be deposite

d on th

y respons

•

Common antigens inclu

de season

al pollen

2 What are the major etiologic factors in allergic rhinitis?

6 Allergic Rhinitis, B

3 What are the pathogenic mechanisms in allergic rhinitis?

•

Surface-bound IgE o

n nas

al mucosa is bound b

y the

inciting antigen

•

Mast cells a

nd basophils, whic

h trigg

er the

inflammatio

n, beco

me activate

•

Mediato

rs o

f t

he immedia

te infl ammator

y respons

suc

h as histamine a

re released, triggerin

g t

he earl

y

phas

e respon

se o

f sneezin

g, nas

al secretion

s, an

d nasal

constriction

•

The last phase o

f t

he immune resp

on

se invo

lves t

influx o

f eosinophils a

nd mononuclear cells, peakin

6–12 hour

s aft er exposur

•

The ma

in sympto

ms o

f this respon

se a

re er

itching, burning, and heat

7 Severe Combined Immunodefi ciency Disease, A

A 2-month-old child is admitted to the ICU with fever,

tory is notable for a similar hospitalization at 2 weeks of

age Physical examination is notable for a temperature of

of recurrent severe infection, the pediatrician suspects an

1 What are the major clinical manifestations of severe combined

immunodefi ciency disease (SCID)? fi

•

SCID, lik

e man

y other primary immunodeficiency fi

disorder

s, presents earl

y in t

he neonatal period

•

In patien

ts with SCID, ther

e is an absence o

f norm

al

thymic tissue, an

d t

he lymph nod

es, spleen, and other

periphera

l lymphoid tissues are

devoid

of lymphocytes

•

In thes

e patien

ts, th

e complet

e or near-complet

nd t

he humoral componen

ts of the

immune syst

em resul

ts in severe infections

•

Th e spectr

um of infectio

ns is broad because thes

patien

ts may als

o suff er fro

m overwhelmin

g infec

by opportunistic path

ogen

s, disseminated

virus

es, an

d

intracellular organisms

•

Failure t

o thri

ve ma

y b

e t

he initial presentin

us candidiasis, chronic diarr

hea, a

nd

pneumoniti

s are common

•

V accination with li

ve vira

l vaccines o

r bacill

ad to disseminated diseas

e

•

Witho

ut immune reco

nstitution b

y bone marro

w

transplantatio

n, SCID is inevitabl

y fat

al with

in 1–2 yea

rs

•

SCID is a het

erogeneous grou

p of disorders

characterized b

y a failur

e in th

e cellula

r maturation

of lympho

id stem cells, resul

tin

g in reduced numbers

an

d functio

n of bot

h B and

T lymphocyt

es and

hypogammaglobulinemia

•

Defective cytokine signaling: X-link

ed SCID (XSCID)

is t

he most prev

alent form, resultin

g from

a genetic

mutatio

n in th

e common

γ chain o

f t

he trimeric ( γαβγ) γ γ r IL fo rs to e recep y th d b hare h is s hic r, w to -2 recep IL-4,

IL-7, IL-9, a

nd IL-15, leadin

g t

o dysfunctio

—These defects inhib

it norm

al maturation o

T lymphocyt

es an

d proliferatio

n of T, B, and natural

killer (NK) cells

•

Defective T-cell recep

tor: Th

e genetic defects f

or several Th

ve SCID have

also been identified, all involvin

g T-cell signalin

g an

maturation

•

Defecti

ve recepto

r gene recombination: Defecti

ve

recombination-activatin

g g

ene (RA G1 a

nd

RA

G2)

produc

ts lead t

o a quantitative an

d functional defi cienc

y fi

of T and

B lymphocytes

•

Defecti

ve nucleoti

de salvag

e pathway:

Appro

ximate

ly

20% of SCID cas

es are caused b

y a defi ciency

of fi

adenosin

e deaminase(ADA), a

n enzyme in t

e for th

e metabolism o

f

adenosine

—Absence o

f t

he AD

A enzyme results in a

n

accumulatio

n o

f toxic adenosin

e metab

oli

tes wi

thin

the cells

—Th es

e metabolites inhib

it norm

al lympho

cyt

proliferatio

n an

d lead to extreme cytopenia o

f b

oth

B a

nd T lymphocytes

—Similarl

y, puri

ne nucleoside phosp

horylase

defi cienc

y caus

es a buildu

p o

f toxic deo

metabolites and inhibits T-cell developmen

t

2 What are the major pathogenetic mechanisms in SCID?

8 X-Linked Agammaglobulinemia, A

An 18-month-old boy is brought to the emergency

depart-ment by his parents with a high fever, shortness of breath,

Since then, he has had four bouts of otitis media, and

because of their severity and recurrence, he was placed

for several months on prophylactic antibiotics He was

Th

quickly progressed into an illness with high fevers and

leth-argy Both of his parents are healthy, and he has a healthy

older sister His father’s family history is unremarkable,

but his maternal uncle died of pneumonia in infancy Examination is remarkable for a normally developed tod-dler who is lethargic and tachypneic His temperature is39°C, and he has decreased breath sounds at both lung

boy’s blood cultures grow out Streptococcus pneumoniae

the next day Immunologic testing shows very low levels

cytometry shows the absence of circulating B lymphocytes

1 What are the major clinical manifestations of X-linked agammaglobulinemia (XLA)?

•

Presen

ts with

in th

e first 2 year

s of lif

e with recurr

sinopulmonary infection

s fro

m most

ly encapsulated

bacter

ia such

as S pne umon iae , ot

her streptococci,

an

d H aem oph ilu

s in fluen za

e fl

and, to

a much lesser

extent, viruses

•

Fungal and opportunistic path

ogen

s are rare

•

Uniq

ue susceptibili

ty to

a rare b

ut deadl

y ente

ro

viral

meningoencephalitis

8 X-Linked Agammaglobulinemia, B

•

Patien

ts with XLA hav

e hypogammaglobulinemia,

pan-wit

h decreased levels o

f I

gG, I

gM, a

nd IgA

•

Th e

y exhib

it poo

r to absen

t responses t

o antig

challenge even though virtuall

y all demonstrate norma

l

functiona

l lymphocyte responses to

T-in v itr

o as we

ll as

in vi vo

tests (e

g, delayed hypersensitivi

ty skin reactions)

•

Th e basic defect is a

rrested cellular ma

turation a

t t

lymphocyt

pre-B-e stage

•

Normal number

s of pre-B lymphocyt

es are in t

he bo

ne

marro

w with absen

t circulatin

g B lymphocytes

•

Lympho

id tissues lack fully diff erentiated B lym

pho

cyt

(antibody-secretin

g plasma cells), a

nd lym

ph no

des lack

develop

ed germinal cente

rs

•

The defecti

ve gene produc

t, BTK (Bruto

kinase), is a B-cell

–specifi

c signaling pro

•

Gene deletion

s and point mutation

f the

BTK

gene blo

ck norm

al BTK func

necessar

y f

or B-cell matura

tion

2 What are the major pathogenetic mechanisms in XLA?

9 Common Variable Immunodefi ciency, A

An 18-year-old man presents with complaints of fever,

facial pain, and nasal congestion consistent with a

diag-nosis of acute sinusitis His medical history is notable for

multiple sinus infections, two episodes of pneumonia,

and chronic diarrhea, all suggestive of a primary

1 What are the major clinical manifestations of common variable

immunodefi ciency? fi

•

Common variable immunod

eficiency is t

he most fi

commo

n serio

us primary immune deficiency dis

order fi

in adults

•

Patien

ts usually present within t

he first 2 decades o

lif

e with recurrent sinopulmonary infection

s, includin

g

sinusitis, otit

is, bronchitis, a

nd pneumonia

•

Common pathogen

s are encapsulated bac

ter

ia such as

Str epto coc cus pn eum on ia e,H aem oph ilu

s in fluen za

e fl

, and

Mor axella cata rrh alis

•

Bronchiectasis ca

t serio

us

respiratory infection

s, leadin

g t

o infectio

n with more

virulen

t pathogen

s, includin

g Stap hyl ococcus a ure

us

and

Pse udomonas ae

ru ginos

a, w

hich in turn, ca

n wo

rsen t

he

long-term prognosis

•

Associated noninfectious disorders inclu

de

gastrointestina

l malabsorption, autoimmune dis

ord

ers,

an

d neoplasms (lymphoreticular, gastr

ic, an

d skin)

•

Autoimmune diso

rder

s occ

ur in 20–30% of patien

ts

and may prece

de t

he recurren

t infections

•

Monthl

y infusio

ns o

f intraveno

us immunoglo

bu

lin ca

n

reconstitu

te humoral immuni

ty, decrea

ve quali

ty o

f life

9 Common Variable Immunodefi ciency, B

•

Common variable immunode

ficienc

y is heterogeneo

marked reduction

in antibod

y production is t

he primary

disorder

•

Th e vast majori

ty of patients demonstra

te a

in vi tro

defec

t in terminal diff er

entiation

of B cells ff ff

•

Antibody-secretin

g plasma cells a

re conspicuously

sparse in lymphoid tissues

•

No single gene defect ca

n b

e held accountabl

e for the

multitude o

f defec

ts known

to cause comm

on variable

immunodefi cienc

y fi

•

In ma

ny patients, t

he defect is intrinsic to th

e

B-lymphocyt

e population

—Approximate

ly 15% o

f patients with commo

n

variabl

e immunodefi cienc

y disea

se demonstra

defecti

ve B-cell surface exp

ressio

n of t

he

transmembrane activato

r an

d calci

um modulat

or

and cyclophilin liga

nd interacto

r (TACI), a memb

er

of t

he TNF recepto

r famil

y, which keeps a

ff ect

ed ff ff

patien

ts from responding t

o B-cell–activa

f t

he B-ce

ll surface ma

rk

er

CD19, which no

rmally complexes with

CD21 an

d

CD81 t

o facilitat

e cellular activation thro

ugh B-cell

recepto

rs, leads to defi cien

t humoral func

y als

o lead t

o

immune defects, wi

th subsequent impairmen

t of B-cell

differentiatio

n ff ff

—Mutatio

n o

f t

he inducible T-cell costimulat

or (I

COS)

gene, expressed b

y activate

d T cells and

tion/antibod

y production, is

responsib

le in so

me cases

—Mo

re than 50% of patients also have som

e

T-lymphocyt

e dysfunctio

n as determine

neous responses t

10 Acquired Immunodefi ciency Syndrome (AIDS), A

A 31-year-old male injection drug user presents to the

emergency department with shortness of breath He

describes a 1-month history of intermittent fevers and night

sweats and a nonproductive cough He has become

pro-gressively more short of breath, and now he feels dyspneic

at rest He appears to be in moderate respiratory distress

His vital signs show a temperature of 39°C, heart rate of

112 bpm, respiratory rate of 20/minute, and oxygen tion of 88% on room air Physical examination is otherwise unremarkable, including a normal lung exam Chest x-ray film reveals a diff

pneumocystis pneumonia, an opportunistic infection

1 What are the major clinical manifestations of AIDS?

•

Candidiasis of t

he esophagus, bronch

i, trachea, o

r lungs

•

Cryptococcosis, cocci

dioidomycosis, o

r histoplasmosis,

extrapulmonary

•

Cryptosporidiosis o

r isosporiasis, chronic intestinal

(

>1-month duration)

•

Cytomegalovir

us (CMV) disea

se (oth

er than liver,

spleen, o

r nodes), eg, retini

tis

•

HIV-related encephalopathy

or progressive multifoc

al

leukoencephalopathy

•

Herpes simplex: chronic ulcer

s, or bronchitis,

pneumonitis, o

r esophagitis

•

Cancers: Kaposi sarco

ma, invasive cervica

l ca

ncer,

lymphoma (Burkitt, immunobl

astic, primary

m co

mplex o

rMy cob acte

rium

kansas

ii, o

r extrapulmonary

M yco bacte riu

m tu

berculos

is,

other extrapu

lmonary

M yco bacte riu

i p

neumonia o

r toxoplasmosis o

f

brain

•

Recurre

nt pneumonia or

Sa lmone lla

septicem

ia

•

HIV-related wasting syndrome

10 Acquired Immunodefi ciency Syndrome (AIDS), B

•

HIV reverse transcriptas

e conver

NA, whic

h integrates into

th

e host chromosome

•

Once integrate

d, t

he HIV provir

us may rema

in late

nt

or beco

me transcriptionall

y acti

ve, depending o

n the

activation state o

f t

he host cell

•

Although only 2% o

f mononuclear cells a

re found

peripherally, lym

ph nodes fro

m HIV-infected

individuals ca

n contain large amoun

ts of virus

sequestered amon

g infected follicular dendritic cells in

the germinal cente

rs

•

For patien

ts infected through vaginal o

r rect

al mucosa,

gut-associated lymphoid tissue is a majo

r site

of viral

replicatio

n and persistence

•

Th e persistence o

f vir

us in these secondary lympho

structures triggers cellular activation a

nd massive,

irrevocabl

e depletio

n of CD4 T-lymphocyt

e reservoirs,

as well

as disea

se latency due t

o severa

l mechanisms:

—Direct HIV-med

iate

d infection and d

estruc

tion o

f

CD4 T lymphocyt

es durin

g viral replica

tion

—Depletio

n b

y fusio

n an

d formati

um formation)

—Toxici

ty o

f viral protein

s to CD4 T lymp

—Loss of T-lymphocy

te costimula

to

ry facto

rs, suc

h as

CD28

—Induction o

f apoptosis (programmed

d T cells

•

CD8 cytotoxic T-lymphocyt

e activi

ty is initially br

isk

and eff ecti

ve a

t controllin

g viremia b

ut later ind

uces th

generation o

f vira

l escap

e mutations

•

Ultimatel

y, vira

l proliferatio

n outstrips host r

ppressio

n leads to

d

isea

se

progression

2 What are the major steps in development of AIDS after infection with HIV?

11 Infective Endocarditis, A

A 55-year-old man who recently emigrated from China

presents to the emergency department with fever He states

that he has had recurring fevers over the past 3 weeks,

associated with chills, night sweats, and malaise Today, he

prompting him to come to the emergency department

His medical history is remarkable for “being very sick as a

extracted for severe dental caries He is taking no

medica-tions On physical examination, he is febrile to 38.5°C, and

his blood pressure is 120/80 mm Hg, heart rate 108 bpm,

and respiratory rate 16/min, with an oxygen saturation

of 97% on room air Skin examination is remarkable for

He has multiple splinter hemorrhages in the nailbeds and painless hemorrhagic macules on the palms of the hands.Ophthalmoscopic examination is remarkable for retinalhemorrhages Chest examination is clear to auscultationand percussion Cardiac examination is notable for a grade

sternal border, with radiation to the axilla Abdominal andback examinations are unremarkable

1 Which patients are at highest risk for infective endocarditis?

•

Th e most common p

redisposing fac

es related

to

rheumatic hea

rt disea

se, congenital heart disease,

prosthetic valve

, or pri

or endocarditis

•

Injection dr

ug us

e is also a

n importa

nt risk fac

to

r fo

r

endocarditis

•

The patient’s history o

f signifi Thcan

t illness as a child a

er ft

a sore throat suggests t

he possibility

of rheumatic he

art

disease

11 Infective Endocarditis, B

•

Th e most common inf

re gram-positive bacteria, including

viridan

s grou

p streptococci

, Staph ylococcu

s au reu

s, a

nd

enterococci

•

Giv

en th

e histo

ry o

f recen

t denta

l wor

k, t

he most

likely pathogen in this patient w

h are norm

y bloodborn

e aft er

denta

l ft

manipulation

•

Certain pathogen

s are mo

re common in certain gr

ou

ps

such

asS aureu sin in

jectio

n drug users and

L

iste

ria

monocyto gen

es in t

he elderly

•

Th e hemodyna

mic facto

rs that predispose patients t

the development o

f endocarditis include (1) a high

-velocity jet stream causing t

- to

a low-pressure chamber, an

d (3) a

comparativel

y narrow orifi

ce separatin

g two chamber

tha

t creates a pressur

e gradient

•

Th e lesio

ns o

f endocarditis tend t

o form on th

e cardiac chamber Th

e Th

predisposed, damaged endotheli

thelium—pro

motes

th

e depositio

n of fibrin a

nd platelets, formin

g ster

vegetations

•

Wh

en bacteremia occu

n be deposite

d on these st

erile

vegetations

2 What are the leading bacterial agents of infective endocarditis?

3 What hemodynamic features predispose to infective endocarditis?

12 Meningitis, A

A 25-year-old man presents to the emergency department

with fever and in a confused, irrational state He is

accom-panied by his wife, who provides the history She states that

he had been well until approximately 1 week ago, when he

developed symptoms of upper respiratory tract infection

that were slow to improve On the morning of admission,

he complained of progressive severe headache and nausea

He vomited once He became progressively lethargic as the

day progressed, and she brought him to the hospital He

has no other medical problems and takes no medications

On examination, he is febrile to 39°C, with a blood pressure of 95/60 mm Hg, heart rate of 100 bpm, andrespiratory rate of 18/min He is lethargic and confused, lying with his hand over his eyes Funduscopic examina-

Brudzinski sign Heart, lung, and abdominal examinations are unremarkable Neurologic examination is limited by the patient’s inability to cooperate but appears to be non-focal Kernig sign (resistance to passive extension of the

fl exed leg with the patient lying supine) is negative.fl

1 What is the typical presentation of bacterial meningitis?

2 What are the major etiologic agents of meningitis, and how do they vary with age or other characteristics of the host?

•

Sympto

ms common

ly associated with both bacteria

l an

d

vira

l meningitis inclu

de acute onset o

f fever, headach

e, neck

stiffness (meningism

us), photophob

ia, an

confusion

(continued on reverse side)

12 Meningitis, B

•

In adults, t

he most likely bac

terial pathogen

s are

Neis seria m en in git id isan

d S trep toc occus p neu mon ia e

•

In newborns younge

r than

3 month

s, th

e most commo

n

pathogens a

re thos

e to which th

e infa

nt is exposed

in

the maternal genitourinary canal, includin

g E sch eri ch

ia

col ian

d other gram-negati

ve bacilli, gro

up B and oth

er

streptococci, an

d L iste ria m on ocy togen es

•

Between th

e ages o

f 3 month

s a

nd 15 yea

rs,

N

mening itid

is an dS pn eum on iae

are t

he most common

pathogen

s H aem oph ilu

s in fluen za

e fl

, previo

ge gro

up

, is now

primaril

y a concern in t

he unimmunized ch

colonizatio

n of t

he host

’s nasopharynx

•

Th is is followed b

y local invasio

n of t

he m

epithelium and subsequent bacteremia

•

Cerebral endothelial ce

ll injury follo

ws an

d results in

increased blood-brain barrier permeabilit

y, facilitating

meningeal invasion

•

The resulta

nt infl Th am

matory respon

se in t

subarachnoid space causes cerebral edema, vasculi

tis,

an

d infarction, ultimate

ly leading t

o decreas

ed

cerebrospinal fluid fl flow, hydrocephalus, wors

cerebral edema, increa

sed intracranial

pressur

e, a

nd

decreased cerebral blood flow fl

13 Pneumonia, A

A 68-year-old man presents to the hospital emergency

department with acute fever and cough He has had cough

productive of green sputum for 3 days, with shortness of

sweats His medical history is notable for chronic

obstruc-tive pulmonary disease His medications include albuterol,

patient lives at home and is active On examination, he is

febrile to 38°C, with a blood pressure of 110/50 mm Hg,

heart rate of 98 bpm, and respiratory rate of 20/min Oxygensaturation is 92% on room air He is a thin man in moderate respiratory distress Examination is notable for rales in the

l-trates A diagnosis of pneumonia is made, and the patient is admitted to the hospital for administration of intravenousantibiotics

1 What are the important pathogens for patients with community-acquired

pneumonia based on severity of illness and site of care?

•

Th e most likely pa

thogen

Strep toc occus pne um onia e,

Haem oph ilu

s in fluen za

e fl

,and

M oraxe lla cata rrh alis

•

Oth

er potentia

l pathogen

s include

Mycop las ma

pne umoniae ,Ch lam ydo ph ila pn eumo niae , Le gio nella

pne um ophi la

,a

nd respiratory viruses

•

T uberculosis, an

aerob

es, an

d fungi should also b

e

considered, although these a

re less likely in this pa

tient

with such an acu

te presentation

•

Staphylococcu

s au reu

s a

nd

Pse udomonas ae

ru

ginos

a

should be added to th

e differential diagnosis, part

icula

if t

he patient had been recently hospitalize

CU admission

13 Pneumonia, B

•

An immunoco

mpromised stat

e, resulti

ng in immune

dysfunctio

n a

nd increas

ed risk o

f infection

•

Chronic lun

g diseas

e, resulting in decreas

ed mucociliary

clearance

•

Alcoholism o

r oth

er reductio

n o

f t

he lev

el o

f

consciousness, wh

ich increases t

he risk

of aspiration

•

Injectio

n drug abus

e, whic

h increas

us spre

ad of pathogens

•

Environmental

or animal exposure, resulti

ng in

inhalatio

n of specific pathogens fi

•

Residence in an institution, with its associa

ted r

isk o

f

microaspiratio

ns, and exposur

e via instrumenta

tio

n

(catheter

s an

d intubation)

•

Recent influenza infectio

n, leadin

g to disruptio

of respiratory epithelium, ciliary

dysfuncti

on, a

nd

inhibitio

n of polymorphonuclear neutroph

ils (PMN

s)

•

Inhalatio

n of infectious droplets into th

e lower airways

•

Aspiratio

n of oropharynge

al contents

•

Spread along th

e mucos

al membra

ne surface

•

Hematogenous sp

read

2 What host features influence the likelihood of particular causes of pneumonia? fl

3 What are the four mechanisms by which pathogens reach the lungs?

ut t

he world, more than

5 million

people—most o

f them children younger than

1 year—die o

f acute infectious diarrhea

•

Pathogens suc

h as

Vibr

io c hol erae

are water-born

e and

transmitted via a conta

minated water supply

•

Several pathogen

s, includin

gStaph ylococcu

s au reu

s a

nd

Baci llus ce reu

s, a

re transmitted b

y contaminated food

•

So

me pathogen

s, such

asS hig ella

and

Rota vir

us,

are

transmitt

ed by person-to-perso

ly seen in institu

tional set

tin

gs suc

h

as child care centers

A 21-year-old woman presents with the complaint of

diarrhea She returned from Mexico the day before her

pro-fuse 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

mild abdominal tenderness to palpation without guarding

or rebound tenderness Stool is guaiac negative Infectious diarrhea is suspected

1 How many individuals in the world die yearly of infectious diarrhea?

2 What are diff erent modes of spread of infectious diarrhea? Give an example ff

of each.

14 Diarrhea, Infectious, B

•

Sec ret ory

(watery

f

bacter

ia (eg, V c hol erae , en

terotoxigenic

Esch eric hia

col i[

ETEC], enteroaggregative

E coli

[EAEC]),

viruses (rotavir

us, norovirus), a

nd proto

zoa (Gi ardia ,

Cry ptosp ori dium

)

•

Th es

e organisms attach sup

cially t

o enterocy

in t

he lumen o

f t

he sma

ll bowel where some, such as

cholera an

d ETEC, elaborate

en teroto xins,

protein

s that

increas

e intestinal cyclic adenosine monop

hosphate

(cAMP) production, leading t

o net fluid loss fl

•

In

fl amma to ry diarrhe

is a resul

t of bacterial invasio

of t

he mucosal lumen, with resultan

t cell death

•

Pathogens associated with infl ammatory diarrhe

include enteroinvasive

E col

i (

EIEC),

Shig ella

,

Sa lmone lla ,C ampylo bac ter,

and

E ntam oeb

a h isto lyt ica

Shi gel la

, t

he prototypical caus

e of bacillary dysente

ry,

invades t

he enterocy

te through formatio

n of a

n

endoplasmic vacuole

, whic

h is lys

ed intracellula

rly

•

Bacter

ia th

en prolifera

te in t

he cytoplasm a

nd in

vade

adjacent epithelia

l cells Production o

local cell destructio

n an

d

death

•

Hemo rrhagic

diarrhea, a va

ria

nt o

f infl amm

ator

y fl

diarrh

ea, is primaril

y caused b

y enterohemo

er,

it do

es

produce tw

o Shiga-lik

e toxins (Stx1 an

d Stx2) t

hat

resembl

e th

e Shiga toxin in struc

tu

re and

a toxin catalyzes t

he destr

ucti

ve

cleavag

e of ribosomal RNA a

nd hal

ts protein s

yn

thesis,

leadin

g to cell death

3 What are the diff erent mechanisms by which infectious organisms cause diarrhea? ff

15 Sepsis, Sepsis Syndrome, Septic Shock, A

A 65-year-old woman is admitted to the hospital with

community-acquired pneumonia She is treated with

intra-venous antibiotics and is given oxygen by nasal cannula

A Foley catheter is placed in her bladder On the third

hospital day, she is switched to oral antibiotics in

antici-pation of discharge On the evening of hospital day 3, she

develops fever and tachycardia Blood and urine cultures

pres-sure 85/40 mm Hg, heart rate 110 bpm, and respiratory

rate 20/min Oxygen saturation is 94% on room air Headand neck examinations are unremarkable Lung examina-

base Cardiac examination is notable for a rapid but regularrhythm, without murmurs, gallops, or rubs Abdominalexamination is normal Extremities are warm Neurologic

ICU for management of presumed sepsis and given

positive for gram-negative rods

1 What factors contribute to hospital-related sepsis?

•

Factors th

at contribute

to hospital-related sepsis are:

—Invasi

ve monitorin

g devices

—Indwellin

g catheters

—Extensiv

e surgical procedures

—Increased number

s of immunoco

mpro

mised

patien

ts

15 Sepsis, Sepsis Syndrome, Septic Shock, B

•

Gram-negati

ve bacter

ia,En tero bac teriaceae

such as

Esc her ich

ia coli

and

Pseu domona sae ru ginos

a, a

re

common causes o

f sepsis

•

Staphylococci a

re no

w th

e most commo

n bacteria

cultured fr

om t

he bloodstream, presumably because

of a

n increas

e in t

he prevalence o

f chronic indwelling

veno

us access devices a

nd implanted prosthetic mate

rial

•

For similar reason

s, th

e incidence of fungal s

epsis d

ue to

Can did

a sp

ecies h

as ris

en dramaticall

ted with

P aeru ginos

a, Ca nd

ida

, or mix

ed

(polymicrobial) organisms is a

n independent p

redic

to

r

of mortality

•

Speci

fi c stimuli such as o

rganism, inocu

lum, a

nd si

of infecti

on stimulat

e C D4 T cells

to secrete cytokines

wit

h eith

er infl ammatory (type 1 helper T-cell) or a

inflammatory (type 2 helper T-cell) pro

ho die o

f sepsis, there is significan

t fi

loss o

f cells essentia

l fo

r th

e adaptive immune resp

onse

(B lymphocyt

es, CD4 T cell

s, dendrit

ic cells)

•

Genetically programmed

cell death, terme

t t

o play

a key ro

he survivin

g immune cells

2 Which organisms are most commonly associated with sepsis?

3 What is the role of the host immune system in the pathogenesis of sepsis?

A 54-year-old man presents with several weeks of facial

flushing and diarrhea His symptoms began intermittently

fl

but are becoming more constant A 24-hour urine

collec-tion reveals an elevated level of 5-hydroxyindoleacetic acid

(5-HIAA), a metabolite of serotonin An abdominal CT scan shows a 2-cm mesenteric mass in the ileum and likely metastatic tumors in the liver

1 What products produced by NETs reflect their embryonic origin? fl

•

Neuroendocri

ne tumors ari

se fr

om neuroendocrine

cells, speci

fi call

y the enterochro

n cells, which ffi

migra

te during embryogenesis t

o t

he submucosal layer

of t

he intestines and

th

e pulmonary bronchi

•

Carcinoid tumo

rs are most common

ly found in t

he

intestines a

nd lungs

•

Since carcino

id tumors are derived fro

m

neuroendocri

ne tissue, they can secrete ma

ny peptides

th

at ha

ve systemic effec

ts ff ff

•

Th is secretion is d

ue to th

e inappropria

te activa

of laten

t synthetic abili

ty that all neuro

endocrine cells

possess

•

Production o

f serotonin (metabolized to

5-hydroxyindoleacetic acid [5-HIAA]) is c

•

Bronchial carcinoid

s rare

ly produce 5-HI

rm

on

(ACTH), resultin

g in Cushin

g syndrome

•

Man

y other peptides ca

n be produced, including:

calcitonin, gastrin, g

licentin, glucag

on, grow

th

hormo

ne, insulin, melanocyte-stimulatin

g h

ormo

ne

(MSH), motilin, neuro

peptide K, neuro

ten

sin,

somatostat

in, pancreat

ic polypeptide, subst

ance K,

substance, P , and vasoactive intestina

l pepti

de