Infective endocarditis refers to a bacterial or, rarely, a fungal infection
of the cardiac valves. Infection of extracardiac endothelium is
termed “endarteritis” and can cause disease that
is clinically similar to endocarditis. The most common predisposing
factor for infective endocarditis is the presence of structurally
abnormal cardiac valves. Consequently, patients with a history of
rheumatic or congenital heart disease, mitral valve prolapse with
an audible murmur, a prosthetic heart valve, or a history of prior
endocarditis are at increased risk for infective endocarditis. Infection
involves the left side of the heart (mitral and aortic valves) almost
exclusively, except in patients who are injection drug users or,
less commonly, in patients with valve injury from a pulmonary artery
(Swan-Ganz) catheter, in whom infection of the right side of the
heart (tricuspid or pulmonary valve) may occur.
The most common infectious agents causing native valve infective
endocarditis are gram-positive bacteria, including Streptococcus
viridans, S aureus, and enterococci. The specific bacterial
species causing endocarditis can often be anticipated on the basis
of host factors. Injection drug users commonly introduce S
aureus into the blood when nonsterile needles are used
or the skin is not adequately cleaned before needle insertion. Patients
with recent dental work are at risk for transient bacteremia with
normal oral flora, particularly S viridans, with subsequent
endocarditis. Genitourinary tract infections with enterococci may
lead to bacteremia and subsequent seeding of damaged heart valves.
Patients with prosthetic heart valves are also at increased risk
for infective endocarditis resulting from skin flora such as S
epidermidis or S aureus. Before the availability
of antibiotics, infective endocarditis was a progressively fatal
disease. Even with antibiotics, the case fatality rate for endocarditis
approaches 25%, and definitive cure often requires both
prolonged antibiotic administration and urgent surgery to replace
infected cardiac valves.
Several hemodynamic factors predispose patients to endocarditis:
(1) a high-velocity jet stream causing turbulent blood flow, (2)
flow from a high-pressure to a low-pressure chamber, and (3) a comparatively
narrow orifice separating the two chambers that creates a pressure
gradient. The lesions of infective endocarditis tend to form on
the surface of the valve in the cardiac chamber with the lower pressure
(eg, on the ventricular surface of an abnormal aortic valve and
on the atrial surface of an abnormal mitral valve). Endothelium damaged
by turbulent blood flow results in exposure of extracellular matrix
proteins, promoting the deposition of fibrin and platelets, which
form sterile vegetations (nonbacterial thrombotic endocarditis
or marantic endocarditis). Infective endocarditis occurs
when microorganisms are deposited onto these sterile vegetations
during the course of bacteremia (Figure 4–5).
Not all bacteria adhere equally well to these sites. For example, E
coli, a frequent cause of bacteremia, is rarely implicated
as a cause of endocarditis. Conversely, virulent organisms such
as S aureus can invade intact endothelium, causing
endocarditis in the absence of preexisting valvular abnormalities.
Pathogenesis of bacterial valve colonization. Viridans
group streptococci adhere to fibrin-platelet clots that form at
the site of damaged cardiac endothelium (A). The fibrin-adherent
streptococci activate monocytes to produce tissue factor activity
(TFA) and cytokines (B). These mediators activate the
coagulation pathway, resulting in further recruitment of platelets
and growth of the vegetation (C).
(Redrawn, with permission, from Moreillon P et
al. Pathogenesis of streptococcal and staphylococcal endocarditis.
Infect Dis Clin North Am. 2002;16:297.)
Once infected, these vegetations continue to enlarge through
further deposition of platelets and fibrin, providing the bacteria
a sanctuary from host defense mechanisms such as polymorphonuclear
leukocytes and complement. Consequently, once infection takes hold,
the infected vegetation continues to grow in a largely unimpeded
fashion. Prolonged administration (4–6 weeks) of bactericidal
antibiotics is required to penetrate the vegetation and cure this
disease. Bacteriostatic antimicrobial agents, which inhibit but
do not kill the bacteria, are inadequate. Surgical removal of the infected
valve is sometimes required for cure, particularly for infections
with gram-negative bacilli or fungi, if there is mechanical dysfunction
of the valve with resultant congestive heart failure, or in prosthetic
A hallmark of infective endocarditis is persistent bacteremia,
which stimulates both the humoral and cellular immune systems. A
variety of immunoglobulins are expressed, resulting in immune complex
formation, increased serum levels of rheumatoid factor, and nonspecific
hypergammaglobulinemia. Immune complex deposition along the renal
glomerular basement membrane may result in the development of acute glomerulonephritis
and renal failure.
Infective endocarditis is a multisystem disease with protean manifestations.
For these reasons, the symptoms can be nonspecific and the diagnosis
may not be initially included in the differential diagnosis. Table 4–5 summarizes the important
features of the history, physical examination, laboratory results,
and complications of infective endocarditis. Cutaneous findings
suggestive of endocarditis include Osler’s nodes, painful
papules on the pads of the fingers and toes thought to be secondary
to deposition of immune complexes; and Janeway lesions, painless
hemorrhagic lesions on the palms and soles caused by septic microemboli
(Figure 4–6). Symptoms and signs
of endocarditis may be acute, subacute, or chronic. The clinical
manifestations reflect primarily (1) hemodynamic changes from valvular
damage; (2) end-organ symptoms and signs from septic emboli (right-sided
emboli to the lungs, left-sided emboli to the brain, spleen, kidney,
and extremities); (3) end-organ symptoms and signs from immune complex
deposition; and (4) persistent bacteremia with metastatic seeding
of infection (abscesses or septic joints). Death is usually caused
by hemodynamic collapse or by septic emboli to the CNS, resulting
in brain abscesses or mycotic aneurysms and intracerebral
hemorrhage. Risk factors for a fatal outcome include left-sided
valvular infection, bacterial etiology other than S viridans,
medical comorbidities, complications from endocarditis (congestive
heart failure, valve ring abscess, or embolic disease), and, in
one study, medical management without valvular surgery.
Table 4–5 Diagnosis of Infective Endocarditis and Its Complications. |Favorite Table|Download (.pdf)
Table 4–5 Diagnosis of Infective Endocarditis and Its Complications.
|History||Physical Examination||Laboratory Data||Complications|
|Fever, chills, fatigue, malaise (nonspecific
constitutional symptoms; can be acute, subacute, or chronic)||“Ill appearing”||Positive blood cultures||Systemic|
|Fever||↑ White blood cell count||Persistent bacteremia|
|Tachycardia||↑ Erythrocyte sedimentation rate||Sepsis syndrome|
|Hypotension||↑ Rheumatoid factor|
|Headaches||Papilledema||Head CT or MRI||CNS|
|Back pain||Focal vertebral spinal tenderness||Spinal MRI||Cerebral emboli|
|Focal weakness||Focal neurologic exam (weakness, hyperreflexia, positive
Babinski’s sign, etc)||Mycotic aneurysm (with or without hemorrhage)|
|Dyspnea||↑ Jugular venous pressure||Chest radiograph||Cardiovascular (with left-sided endocarditis)|
|Orthopnea||Cardiac murmurs||Electrocardiogram||Mitral regurgitation|
|Pedal edema||Quincke’s pulses (AR)||Transthoracic echocardiogram||Aortic regurgitation|
|Water-hammer pulses (AR)||Transesophageal echocardiogram||Congestive heart failure|
|Rales||Valve ring abscess|
|Pleuritic chest pain, cough||Crackles||Chest radiograph||Pulmonary (with right-sided
|Septic pulmonary emboli|
|Flank pain||Flank tenderness||↑ BUN, ↑ creatinine||Renal|
|Discolored (brown) urine||Pyuria||Immune-complex glomerulonephritis|
|Renal sonogram||Renal artery emboli|
|Abdominal pain||Focal abdominal tenderness||Abdominal sonogram||GI|
|Hepatomegaly||Abdominal CT||Liver abscesses|
|Intestinal artery emboli (intestinal ischemia)|
|Rashes||Janeway lesions (painless hemorrhagic macules
on hands and soles)||Skin biopsies (low yield for diagnosis)||Skin, miscellaneous|
|Focal painful lesions||Septic emboli|
|Visual complaints||Splinter hemorrhages (nail beds)||Immune complex vasculitis|
|Osler’s nodes (painful nodules)|
|Roth spots (funduscopic examination)|
Osler’s node causing pain within pulp of the
big toe in a woman hospitalized with acute bacterial endocarditis.
(Osler’s nodes are painful: remember “O” for
Ouch and Osler.) Note the multiple painless flat Janeway lesions
over the sole of the foot.
(Used with permission from David A. Kasper, DO,
MBA. Originally published in: Chumley H. Bacterial endocarditis.
In: Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H, Tysinger J [editors]. The
Color Atlas of Family Medicine. New York, NY: McGraw-Hill;
- 5. Which patients are at highest
risk for infective endocarditis?
- 6. What are the leading bacterial
agents of infective endocarditis?
- 7. What features characterize infective
endocarditis in intravenous drug users? In patients with prosthetic
- 8. What hemodynamic features predispose
to infective endocarditis?
- 9. What is the outcome of untreated
- 10. What are the risk factors for
a fatal outcome? What are the most common causes of death in untreated
Symptoms commonly associated with both bacterial and viral meningitis
include acute onset of fever, headache, neck stiffness (meningismus),
photophobia, and confusion. Bacterial meningitis causes significant
morbidity (neurologic sequelae, particularly sensorineural hearing
loss) and mortality and thus requires immediate antibiotic therapy.
With rare exceptions, only supportive care with analgesics is necessary
for viral meningitis.
Because the clinical presentations of bacterial and viral meningitis
may be indistinguishable, laboratory studies of the cerebrospinal
fluid are critical in differentiating these entities. Cerebrospinal
fluid leukocyte pleocytosis (white blood cells in the cerebrospinal
fluid) is the hallmark of meningitis. Bacterial meningitis is generally
characterized by neutrophilic pleocytosis (predominance of polymorphonuclear
neutrophils in the cerebrospinal fluid). Common causes of lymphocytic
pleocytosis include viral infections (eg, enterovirus, West Nile
virus), fungal infections (eg, cryptococcus in HIV-infected persons),
and spirochetal infections (eg, neurosyphilis or Lyme neuroborreliosis).
Noninfectious causes such as cancer, connective tissue diseases,
and hypersensitivity reactions to drugs can also cause lymphocytic
pleocytosis. The cerebrospinal fluid in bacterial meningitis is
generally characterized by marked elevations in protein concentration,
an extremely low glucose level, and, in the absence of previous antibiotic
treatment, a positive Gram stain for bacteria. However, there is
often significant overlap between the cerebrospinal fluid findings
in bacterial and nonbacterial meningitis, and differentiating these
entities at presentation is a significant clinical challenge.
The microbiology of bacterial meningitis in the United States has
changed dramatically following the introduction of the Haemophilus
influenzae conjugate vaccine. The routine use of this vaccine
in the pediatric population has essentially eliminated H
influenzae as a cause of meningitis, resulting in a shift in
median age among patients with bacterial meningitis from 9 months
to 25 years.
Bacterial agents causing meningitis vary according to host age
(Table 4–6). In infants younger
than 3 months, E coli, Listeria, and group B streptococci
are the most common causes of meningitis. For children 3 months
to 18 years of age, S pneumoniae and N
meningitidis are the most common causes, with H
influenzae a concern among nonimmunized children. For adults
aged 18–50 years, S pneumoniae and N meningitidis are
the leading causes of meningitis, whereas the elderly are at risk
for those pathogens as well as for Listeria. Additional
bacteria must be considered for postneurosurgery patients (S
aureus, P aeruginosa), patients with ventricular shunts
(S epidermidis, S aureus, gram-negative
bacilli), pregnant patients (Listeria), or neutropenic
patients (gram-negative bacilli, including P aeruginosa).
Subacute or chronic meningitides may be caused by M tuberculosis,
fungi (eg, Coccidioides immitis, Cryptococcus neoformans),
and spirochetes such as Treponema pallidum (the
bacterium causing syphilis) or Borrelia burgdorferi (the
bacterium causing Lyme disease). The diagnosis of meningitis caused by these organisms may be delayed
because many of these pathogens are difficult to culture and require
special serologic or molecular diagnostic techniques.
Table 4–6 Common Causes of Bacterial Meningitis in the United States by Host Age. |Favorite Table|Download (.pdf)
Table 4–6 Common Causes of Bacterial Meningitis in the United States by Host Age.
|Pathogen||< 3 Months||3 Months–18 Years||18–50 Years||> 50 Years|
|Group B streptococci||X|
|Aerobic gram-negative bacilli||X||X|
The pathogenesis of bacterial meningitis involves a sequence of
events in which virulent microorganisms overcome the host defense
mechanisms (Table 4–7).
Table 4–7 Pathogenetic Sequence of Bacterial Neurotropism. |Favorite Table|Download (.pdf)
Table 4–7 Pathogenetic Sequence of Bacterial Neurotropism.
|Neurotropic Stage||Host Defense||Strategy of Pathogen|
|1. Colonization or mucosal invasion||Secretory IgA ||IgA protease secretion|
|Ciliary activity ||Ciliostasis|
|Mucosal epithelium||Adhesive pili|
|2. Intravascular survival||Complement||Evasion of alternative pathway by polysaccharide capsule|
|3. Crossing of blood-brain barrier||Cerebral endothelium||Adhesive pili|
|4. Survival within CSF||Poor opsonic activity||Bacterial replication|
Most cases of bacterial meningitis begin with bacterial colonization
of the nasopharynx (Figure 4–7,
panel A). An exception is Listeria, which enters
the bloodstream through ingestion of contaminated food. Pathogenic
bacteria such as S pneumoniae and N meningitidis secrete
an IgA protease that inactivates host antibody and facilitates mucosal
attachment. Many of the causal pathogens also possess surface characteristics
that enhance mucosal colonization. N meningitidis binds
to nonciliated epithelial cells by finger-like projections known
Pathogenic steps leading to pneumococcal meningitis.
The pneumococcus adheres to and colonizes the nasopharynx. IgA1
protease protects the pneumococcus from host antibody (A).
Once in the bloodstream, the bacterial capsule helps the pneumococcus
to evade opsonization (B). The pneumococcus accesses
the cerebrospinal fluid through receptors on the endothelial surface
of the blood-brain barrier (C).
(Redrawn, with permission,
from Koedel U et al. Pathogenesis and pathophysiology of pneumococcal
meningitis. Lancet Infect Dis. 2002;2:731.)
Once the mucosal barrier is breached, bacteria gain access to
the bloodstream, where they must overcome host defense mechanisms
to survive and invade the CNS (Figure 4–7, panel
B). The bacterial capsule, a feature common to N meningitidis, H
influenzae, and S pneumoniae, is the most
important virulence factor in this regard. Host defenses counteract the
protective effects of the pneumococcal capsule by activating the
alternative complement pathway, resulting in C3b activation, opsonization,
phagocytosis, and intravascular clearance of the organism. This
defense mechanism is impaired in patients who have undergone splenectomy,
and such patients are predisposed to the development of overwhelming
bacteremia and meningitis with encapsulated bacteria. Activation
of the complement system membrane attack complex is an essential
host defense mechanism against invasive disease by N meningitidis, and
patients with deficiencies of the late complement components (C5–9)
are at increased risk for meningococcal meningitis.
The mechanisms by which bacterial pathogens gain access to the
CNS are largely unknown. Experimental studies suggest that receptors
for bacterial pathogens are present on cells in the choroid plexus,
which may facilitate movement of these pathogens into the subarachnoid
space (Figure 4–7, panel C). Invasion
of the spinal fluid by a meningeal pathogen results in increased
permeability of the blood-brain barrier, with leakage of albumin
into the subarachnoid space, where local host defense mechanisms
are inadequate to control the infection. Normally, complement components
are minimal or absent in the cerebrospinal fluid. Meningeal inflammation
leads to increased, but still low, concentrations of complement,
inadequate for opsonization, phagocytosis, and removal of encapsulated
meningeal pathogens. Immunoglobulin concentrations are also low
in the cerebrospinal fluid, with an average blood to cerebrospinal
fluid IgG ratio of 800:1. Although the absolute quantity of immunoglobulin
in the cerebrospinal fluid increases with infection, the ratio of
immunoglobulin in the cerebrospinal fluid relative to that in the
serum remains low.
The ability of meningeal pathogens to induce a marked subarachnoid
space inflammatory response contributes to many of the pathophysiologic
consequences of bacterial meningitis. Although the bacterial capsule
is largely responsible for intravascular and cerebrospinal fluid
survival of the pathogens, the subcapsular surface components (ie,
the cell wall and lipopolysaccharide) of bacteria are more important determinants
of meningeal inflammation. The major mediators of the inflammatory
process are thought to be IL-1, IL-6, matrix metalloproteinases,
and tumor necrosis factor (TNF). Within 1–3 hours after
intracisternal inoculation of purified lipopolysaccharide in an
animal model, there is a brisk release of TNF and IL-1 into the
cerebrospinal fluid, preceding the development of inflammation.
Indeed, direct inoculation of TNF and IL-1 into the cerebrospinal
fluid produces an inflammatory cascade identical to that seen with
experimental bacterial infection.
Cytokine and proteolytic enzyme release leads to loss of membrane
integrity, with resultant cellular swelling. The development of
cerebral edema contributes to an increase in intracranial pressure,
potentially resulting in life-threatening cerebral herniation (Figure 4–8). Vasogenic cerebral
edema is principally caused by the increase in blood-brain
barrier permeability. Cytotoxic cerebral edema results
from swelling of the cellular elements of the brain because of toxic
factors from bacteria or neutrophils. Interstitial cerebral
edema reflects obstruction of flow of cerebrospinal fluid,
as in hydrocephalus. The literature suggests that oxygen free radicals
and nitric oxide may also be important mediators in cerebral edema.
Other complications of meningitis include cerebral vasculitis with
alterations in cerebral blood flow. The vasculitis leads to narrowing
or thrombosis of cerebral blood vessels, resulting in ischemia and
possible brain infarction.
Pathophysiological alterations leading to neuronal injury
during bacterial meningitis. BBB, blood-brain barrier; CBV, cerebral blood
(Redrawn, with permission, from Koedel U et al. Pathogenesis
and pathophysiology of pneumococcal meningitis. Lancet Infect Dis.
Understanding the pathophysiology of bacterial meningitis has
therapeutic implications. Although bactericidal antibiotic therapy
is critical for adequate treatment, rapid bacterial killing releases
inflammatory bacterial fragments, potentially exacerbating inflammation
and abnormalities of the cerebral microvasculature. In animal models,
antibiotic therapy has been shown to cause rapid bacteriolysis and
release of bacterial endotoxin, resulting in increased cerebrospinal
fluid inflammation and cerebral edema.
The importance of the immune response in triggering cerebral
edema has led researchers to study the role of adjuvant anti-inflammatory
medications for bacterial meningitis. The use of corticosteroids
has been shown to decrease the risk of sensorineural hearing loss
among children with H influenzae meningitis and
mortality among adults with pneumococcal meningitis, and these agents
are routinely given at the time of initial antibiotic therapy.
Among patients who develop community-acquired bacterial meningitis,
an antecedent upper respiratory tract infection is common. Patients
with a history of head injury or neurosurgery, especially those
with a persistent cerebrospinal fluid leak, are at particularly
high risk for meningitis. Manifestations of meningitis in infants
may be difficult to recognize and interpret; therefore, the physician
must be alert to the possibility of meningitis in the evaluation
of any febrile neonate.
Most patients with meningitis have a rapid onset of fever, headache,
lethargy, and confusion. Fewer than half complain of neck stiffness,
but nuchal rigidity is noted on physical examination in 30–70%.
Other clues seen in a variable proportion of cases include altered
mental status, nausea or vomiting, photophobia, Kernig’s
sign (resistance to passive extension of the flexed leg with
the patient lying supine), and Brudzinski’s sign (involuntary
flexion of the hip and knee when the examiner passively flexes the
patient’s neck). More than half of patients with meningococcemia
develop a characteristic petechial or purpuric rash, predominantly
on the extremities.
Although a change in mental status (lethargy, confusion) is common
in bacterial meningitis, up to one third of patients present with
normal mentation. From 10% to 30% of patients have
cranial nerve dysfunction, focal neurologic signs, or seizures.
Coma, papilledema, and Cushing’s triad (bradycardia, respiratory
depression, and hypertension) are ominous signs of impending herniation (brain
displacement through the foramen magnum with brain stem compression),
heralding imminent death.
Any patient suspected of having meningitis requires emergent
lumbar puncture for Gram stain and culture of the cerebrospinal
fluid, followed immediately by the administration of antibiotics
and corticosteroids. Alternatively, if a focal neurologic process
(eg, brain abscess) is suspected, antibiotics should be initiated
immediately, followed by brain imaging (computed tomography or magnetic
resonance imaging) and lumbar puncture performed only if there is
no radiologic contraindication.
- 11. What is the typical presentation
of bacterial meningitis?
- 12. What are the major etiologic agents
of meningitis, and how do they vary with age or other characteristics
of the host?
- 13. What is the sequence of events
in development of meningitis, and what features of particular organisms
predispose to meningitis?
- 14. What are the diverse causes of
cerebral edema in patients with meningitis?
- 15. Why is rapid bacteriolysis theoretically
dangerous in meningitis?
- 16. What are the associated clinical
manifestations of untreated bacterial meningitis?
The respiratory tract is the most common site of infection by pathogenic
microorganisms. Pneumonia accounts for 1.2 million hospitalizations
each year in the United States, with an estimated 58,000 deaths.
Pneumonia, together with influenza, is the leading cause of death
from an infectious disease in the United States.
Diagnosis and management of pneumonia require knowledge of host
risk factors, potential infectious agents, and environmental exposures.
Pneumonia is an infection of the lung tissue caused by a number
of different bacteria, viruses, parasites, and fungi, resulting
in inflammation of the lung parenchyma and accumulation of an inflammatory
exudate in the airways. Infection typically begins in the alveoli,
with secondary spread to the interstitium, resulting in consolidation
and impaired gas exchange. Infection can also extend to the pleural
space, causing pleurisy (inflammation of the pleura,
characterized by pain on inspiration). The exudative response of the
pleura to pneumonia is termed parapneumonic effusion, which
itself can become infected and develop into frank pus (empyema).
Despite technologic advances in diagnosis, a specific causative agent
is not identified in as many as 50% of cases of community-acquired
pneumonia. Even in cases in which a microbiologic diagnosis is made,
there is usually a delay of several days before the pathogen can
be identified and antibiotic susceptibility determined. Symptoms
are nonspecific and do not reliably differentiate the various causes
of pneumonia. Therefore, knowledge of the most common etiologic
organisms is crucial in determining rational empiric antibiotic
regimens. Bacterial causes of community pneumonia vary by comorbid
disease and severity of pulmonary infection (Table
Table 4–8 Common Etiologic Agents of Community-Acquired Pneumonia as Determined by Severity of Illness. |Favorite Table|Download (.pdf)
Table 4–8 Common Etiologic Agents of Community-Acquired Pneumonia as Determined by Severity of Illness.
|Mild to Moderate Infection (Not in ICU)||Severe Infection (Requiring ICU)|
|Enteric gram-negative bacilli||X||X|
S pneumoniae is the most common organism isolated
in community-acquired pneumonia in both immunocompetent and immunocompromised
individuals. Several additional organisms require special consideration
in specific hosts or because of public health importance (Table 4–9). Understanding and identifying
patient risk factors (eg, smoking, HIV infection) and host defense
mechanisms (cough reflex, cell-mediated immunity) focuses attention
on the most likely etiologic agents, guides empiric therapy, and
suggests possible interventions to decrease further risk. For example,
patients who have suffered strokes and have impaired ability to
protect their airways are at risk for aspirating oropharyngeal secretions.
Precautions such as avoiding thin liquids in these patients may
decrease the risk of future lung infections. Likewise, an HIV-infected
patient with a low CD4 lymphocyte count is at risk for pneumocystic
pneumonia and should be given prophylactic antibiotics.
Table 4–9 Common Risk Factors and Causes of Pneumonia in Specific Adult Hosts. |Favorite Table|Download (.pdf)
Table 4–9 Common Risk Factors and Causes of Pneumonia in Specific Adult Hosts.
Agents||Pathogenetic Mechanism and Comments|
|Acute Symptoms||Subacute Chronic Symptoms|
|HIV infection||S pneumoniae||Fungi||Cell-mediated immune dysfunction|
|H influenzae||M tuberculosis||Impaired humoral response|
|Solid organ or bone marrow transplantation ||Cytomegalovirus||Nocardia||Cell-mediated immune dysfunction|
|Aspergillus species||Fungi||Neutropenia (bone marrow transplant)|
|Legionella species||M tuberculosis|
|Chronic obstructive lung disease or smoking||S pneumoniae||Decreased mucociliary clearance|
|Structural lung disease (bronchiectasis)||P aeruginosa|
|Alcoholism||K pneumoniae||Mixed anaerobic infection (lung abscess)||Aspiration of oropharyngeal contents|
|Injection drug abuse||S aureus||Hematogenous spread|
|Environmental or animal exposure||Legionella species (infected water)||C immitis (Southwest USA)||Inhalation|
|C psittaci (birds)||H capsulatum (east of Mississippi)|
|C burnetii (animals)||C neoformans (birds)|
|Hanta virus (rodents)|
|Institutional exposure (hospital, nursing
home, etc)||Gram-negative bacilli ||Microaspirations|
|P aeruginosa||Bypass of upper respiratory tract defense
|Acinetobacter species||Hematogenous spread (intravenous catheters)|
|Postinfluenza||S aureus||Disruption of respiratory epithelium|
|S pyogenes||Ciliary dysfunction|
|Inhibition of PMNs|
Although pneumonia is a relatively common disease, it occurs infrequently
in immunocompetent individuals. This can be attributed to the effectiveness
of host defenses, including anatomic barriers and cleansing mechanisms in the nasopharynx and upper airways
and local humoral and cellular factors in the alveoli. Normal lungs
are sterile below the first major bronchial divisions.
Pulmonary pathogens reach the lungs by one of four routes: (1)
direct inhalation of infectious respiratory droplets, (2) aspiration
of oropharyngeal contents, (3) direct spread along the mucosal membrane
surface from the upper to the lower respiratory system, and (4)
hematogenous spread. The pulmonary antimicrobial defense mechanisms
are shown in Figure 4–9. Incoming
air with suspended particulate matter is subjected to turbulence
in the nasal passages and then to abrupt changes in direction as
the airstream is diverted through the pharynx and along the branches
of the tracheobronchial tree. Particles larger than 10 mm are trapped
in the nose or pharynx; those with diameters of 2–9 mm
are deposited on the mucociliary blanket; only smaller particles
reach the alveoli. M tuberculosis and Legionella
pneumophila are examples of bacteria that are deposited
directly in the lower airways through inhalation of small airborne
particles. Bacteria trapped in the upper airways can colonize the
oropharynx and subsequently be transported into the lungs either
by “microaspiration” or by overt aspiration through
an open epiglottis (eg, in patients who lose consciousness after
excessive alcohol intake).
Pulmonary defense mechanisms. Abrupt changes in direction
of airflow in the nasal passages can trap potential pathogens. The
epiglottis and cough reflex prevent introduction of particulate
matter in the lower airway. The ciliated respiratory epithelium
propels the overlying mucous layer (right) upward toward the mouth.
In the alveoli, cell-mediated immunity, humoral factors, and the
inflammatory response defend against lower respiratory tract infections.
(Redrawn, with permission, from Storch GA. Respiratory system.
In: Mechanisms of Microbial Disease, 4th ed. Schaechter
M et al [editors]. Lippincott Williams & Wilkins, 2007.)
The respiratory epithelium has special properties for fighting
off infection. Epithelial cells are covered with beating cilia blanketed
by a layer of mucus. Each cell has about 200 cilia that beat up
to 500 times/min, moving the mucus layer upward toward
the larynx. The mucus itself contains antimicrobial compounds such
as lysozyme and secretory IgA antibodies. Chronic cigarette smokers
have decreased mucociliary clearance secondary to damage of cilia
and must, therefore, rely more heavily on the cough reflex to clear
aspirated material, excess secretions, and foreign bodies.
Bacteria that reach the terminal bronchioles, alveolar ducts, and
alveoli are inactivated primarily by alveolar macrophages and neutrophils.
Opsonization of the microorganism by complement and antibodies enhances
phagocytosis by these cells.
Impairment at any level of host defenses increases the risk of
developing pneumonia. Children with cystic fibrosis have defective
ciliary activity and are prone to develop recurrent sinopulmonary
infections, particularly with S aureus and P aeruginosa. Patients
with neutropenia, whether acquired or congenital, are also susceptible
to lung infections with gram-negative bacteria and fungi. Antigenic
stimulation of T cells leads to the production of lymphokines that
activate macrophages with enhanced bactericidal activity. HIV-infected patients
have depleted CD4 T lymphocyte counts and are pre-disposed to a
variety of bacterial (including mycobacterial) and fungal infections.
Most patients with pneumonia have fever, cough, tachypnea, tachycardia,
and an infiltrate on chest x-ray film. Extrapulmonary manifestations
that may provide clues to the etiologic agents include pharyngitis
(Chlamydia pneumoniae), erythema nodosum rash (fungal
and mycobacterial infections), and diarrhea (Legionella).
The following questions aid in guiding empiric therapy for a
patient who presents with symptoms consistent with pneumonia: (1)
Is this pneumonia community acquired or healthcare acquired (eg,
hospital, nursing home)? (2) Is this patient immunocompromised (HIV
infected, a transplant recipient)? (3) Is this patient an injection
drug user? (4) Has this patient had a recent alteration in consciousness
(suggestive of aspiration)? (5) Are the symptoms acute (days) or
chronic (weeks to months)? (6) Has this patient lived in or traveled
through geographic areas associated with specific endemic infections (histoplasmosis,
coccidioidomycosis)? (7) Has this patient had recent zoonotic exposures
associated with pulmonary infections (psittacosis, Q fever)? (8)
Could this patient have a contagious infection of public health
importance (tuberculosis)? (9) Could this patient’s pulmonary
infection be associated with a common source exposure (Legionella or
- 17. What are the important pathogens
for patients with community-acquired pneumonia based on severity
of illness and site of care?
- 18. What host features influence the
likelihood of particular causes of pneumonia?
- 19. What are the four mechanisms by
which pathogens reach the lungs?
- 20. What are the defenses of the respiratory
epithelium against infection?
Each year throughout the world more than 5 million people—most
of them children younger than 1 year—die of acute infectious
diarrhea (see also Chapter 13). Although death
is a rare outcome of infectious diarrhea in the United States, morbidity
is substantial. It is estimated that there are more than 200 million
episodes each year, resulting in 1.8 million hospitalizations at
a cost of $6 billion per year. The morbidity and mortality
attributable to diarrhea are largely due to loss of intravascular
volume and electrolytes, with resultant cardiovascular failure.
For example, adults with cholera can excrete more than 1 L of fluid
per hour. Contrast this with the normal volume of fluid lost daily
in the stools (150 mL), and it is clear why massive fluid losses
associated with infectious diarrhea can lead to dehydration, cardiovascular
collapse, and death.
Gastrointestinal (GI) tract infections can present with primarily
upper tract symptoms (nausea, vomiting, crampy epigastric pain),
small intestine symptoms (profuse watery diarrhea), or large intestine
symptoms (tenesmus, fecal urgency, bloody diarrhea). Sources of
infection include person-to-person transmission (fecal-oral spread
of Shigella), water-borne transmission (Cryptosporidium),
food-borne transmission (Salmonella or S
aureus food poisoning), and overgrowth after antibiotic
administration (Clostridium difficile).
A wide range of viruses, bacteria, fungi, and protozoa can infect
the GI tract. However, in the majority of cases, symptoms are self-limited,
and diagnostic evaluation is not performed. Patients presenting
to medical attention are biased toward the subset with more severe
symptoms (eg, high fevers or hypotension), immunocompromise (eg,
HIV or neutropenia), or prolonged duration (eg, chronic diarrhea
defined as lasting 14 days). An exception is large outbreaks of
food-borne illness, in which epidemiologic investigations may detect
patients with milder variants of disease.
A comprehensive approach to GI tract infections starts with the
classic host-agent-environment interaction model. A number of host
factors influence GI tract infections. Patients at extremes of age
and with comorbid conditions (eg, HIV infection) are at higher risk
for symptomatic infection. Medications that alter the GI microenvironment
or destroy normal bacterial flora (eg, antacids or antibiotics)
also predispose patients to infection. Microbial agents responsible
for GI illness can be categorized according to type of organism
(bacterial, viral, protozoal), propensity to attach to different
anatomic sites (stomach, small bowel, colon), and pathogenesis (enterotoxigenic,
cytotoxigenic, enteroinvasive). Environmental factors can be divided
into three broad categories based on mode of transmission: (1) water
borne, (2) food borne, and (3) person to person. Table
4–10 summarizes these relationships and provides a
framework for assessing the pathogenesis of GI tract infections.
Table 4–10 Approach to GI Tract Infections. |Favorite Table|Download (.pdf)
Table 4–10 Approach to GI Tract Infections.
|Environment||Water borne||Fecal contamination of water supply||Vibrio cholerae|
|Food borne||Contaminated food (bacteria or toxin)||S aureus|
|Person to person (fecal oral spread)||Child care centers||Shigella|
|Host||Age||Infants, elderly||Enterohemorrhagic E coli|
|Gastric acidity||Antacid use||Salmonella|
|GI flora||Antibiotic use||Clostridium difficile|
|Small intestine||Secretory diarrhea||V cholerae|
|Large intestine||Inflammatory diarrhea||Shigella|
GI tract infections can involve the stomach, causing nausea and
vomiting, or affect the small and large bowel, with diarrhea as
the predominant symptom. The term “gastroenteritis” classically
denotes infection of the stomach and proximal small bowel. Organisms
causing this disorder include Bacillus cereus, S aureus, and
a number of viruses (rotavirus, norovirus). B cereus and S
aureus produce a preformed neurotoxin that,
even in the absence of viable bacteria, is capable of causing disease,
and these toxins represent major causes of food poisoning. Although
the exact mechanisms are poorly understood, it is thought that neurotoxins
act locally, through stimulation of the sympathetic nervous system
with a resultant increase in peristaltic activity, and centrally,
through activation of emetic centers in the brain.
The spectrum of diarrheal infections is typified by the diverse
clinical manifestations and mechanisms through which E coli can
cause diarrhea. Colonization of the human GI tract by E
coli is universal, typically occurring within hours after
birth. However, when the host organism is exposed to pathogenic
strains of E coli not normally present in the bowel
flora, localized GI disease or even systemic illness may occur.
There are five major classes of diarrheogenic E coli:
enterotoxigenic (ETEC), enteropathogenic (EPEC), enterohemorrhagic
(EHEC), enteroaggregative (EAEC), and enteroinvasive (EIEC) (Table 4–11). Features common to
all pathogenic E coli are evasion of host defenses,
colonization of intestinal mucosa, and multiplication with host
cell injury. This organism, like all GI pathogens, must survive
transit through the acidic gastric environment and be able to persist in
the GI tract despite the mechanical force of peristalsis and competition
for scarce nutrients from existing bacterial flora. Adherence can
be nonspecific (at any part of the intestinal tract) or, more commonly,
specific, with attachment occurring at well-defined anatomic areas.
Table 4–11 Escherichia coli in Diarrheal Disease. |Favorite Table|Download (.pdf)
Table 4–11 Escherichia coli in Diarrheal Disease.
|Developed Countries||Developing Countries|
|ETEC||Returning travelers||Age < 5 years||Watery diarrhea||Small intestine||Heat-labile and heat-stable toxin|
|EIEC||Rare||All ages||Dysentery (bloody diarrhea, mucus, fever)||Large intestine > small intestine||Shigella-like enterotoxin|
|EHEC||Children, elderly||Rare||Hemorrhagic colitis; hemolytic uremic syndrome||Large intestine||Shiga toxins (Stx1 & Stx2)|
|EPEC||Rare||Age < 2 years||Watery diarrhea||Small intestine||Unknown|
|EAEC||Rare||Children||Persistent watery diarrhea||Small intestine||Enteroaggregative heat-stable enterotoxin|
Once colonization and multiplication occur, the stage is set for
host injury. Infectious diarrhea is clinically differentiated into
secretory, inflammatory, and hemorrhagic types, with different pathophysiologic
mechanisms accounting for these diverse presentations. Secretory (watery)
diarrhea is caused by a number of bacteria (eg, Vibrio cholerae, ETEC,
EAggEC), viruses (rotavirus, norovirus), and protozoa (Giardia, Cryptosporidium).
These organisms attach superficially to enterocytes in the lumen
of the small bowel. Stool examination is notable for the absence
of fecal leukocytes, although in rare cases there is occult blood
in the stools. Some of these pathogens elaborate enterotoxins, proteins
that increase intestinal cyclic adenosine monophosphate (cAMP) production, leading
to net fluid secretion. The classic example is cholera. The bacterium V
cholerae produces cholera toxin, which causes prolonged
activation of epithelial adenylyl cyclase in the small bowel, leading
to secretion of massive amounts of fluid and electrolytes into the
intestinal lumen (Figure 4–10). Clinically,
the patient presents with copious diarrhea (“rice-water
stools”), progressing to dehydration and vascular collapse
without vigorous volume resuscitation. ETEC, a common cause of acute
diarrheal illness in young children and the most common cause of
diarrhea in travelers returning to the United States from developing
countries, produces two enterotoxins. The heat-labile toxin (LT)
activates adenylyl cyclase in a manner analogous to cholera toxin,
whereas the heat-stable toxin (ST) activates guanylyl cyclase activity.
Pathogenesis of Vibrio cholerae and
enterotoxigenic E coli (ETEC) in diarrheal disease. V
cholerae and ETEC share similar pathogenetic mechanisms
in causing diarrheal illness. The bacteria gain entry to the small
intestinal lumen through ingestion of contaminated food (left). They
elaborate an enterotoxin that is composed of one A subunit and five
B subunits. The B subunits bind to the intestinal cell membrane
and facilitate entry of part of the A subunit (right).
Subsequently, this results in a prolonged activation of adenylyl
cyclase and the formation of cyclic adenosine monophosphate (cAMP),
which stimulates water and electrolyte secretion by intestinal endothelial
(Redrawn, with permission, from Vaughan M. Cholera
and cell regulation. Hosp Pract. 1982;17(6):145–152.
Inflammatory diarrhea is a result of bacterial invasion
of the mucosal lumen, with resultant cell death. Patients with this
syndrome are usually febrile, with complaints of crampy lower abdominal
pain as well as diarrhea, which may contain visible mucous. The
term dysentery is used when there are significant numbers
of fecal leukocytes and gross blood. Pathogens associated with inflammatory
diarrhea include EIEC, Shigella, Salmonella,
Campylobacter, and Entamoeba histolytica. Shigella, the
prototypical cause of bacillary dysentery, invades the enterocyte
through formation of an endoplasmic vacuole, which is lysed intracellularly.
Bacteria then proliferate in the cytoplasm and invade adjacent epithelial cells.
Production of a cytotoxin, the Shiga toxin, leads to
local cell destruction and death. EIEC resembles Shigella both
clinically and with respect to the mechanism of invasion of the enterocyte
wall; however, the specific cytotoxin associated with EIEC has not
yet been identified.
Hemorrhagic diarrhea, a variant of inflammatory
diarrhea, is primarily caused by EHEC. Infection with E
coli O157:H7 has been associated with a number of deaths
from the hemolytic-uremic syndrome, with several well-publicized outbreaks
related to contaminated foods. EHEC causes a broad spectrum of clinical
disease, with manifestations including (1) asymptomatic infection,
(2) watery (nonbloody) diarrhea, (3) hemorrhagic colitis (bloody,
noninflammatory diarrhea), and (4) hemolytic-uremic syndrome (an
acute illness, primarily of children, characterized by anemia and
renal failure). EHEC does not invade enterocytes; however, it does produce
two Shiga-like toxins (Stx1 and Stx2) that closely resemble the
Shiga toxin in structure and function. After binding of EHEC to
the cell surface receptor, the A subunit of the Shiga toxin catalyzes
the destructive cleavage of ribosomal RNA and halts protein synthesis,
leading to cell death.
Clinical manifestations of GI infections vary depending on the on
site of involvement (Table 4–10).
For instance, in staphylococcal food poisoning, symptoms develop
several hours after ingestion of food contaminated with neurotoxin-producing S aureus.
The symptoms of staphylococcal food poisoning are profuse vomiting,
nausea, and abdominal cramps. Diarrhea is variably present with
agents causing gastroenteritis. Profuse watery (noninflammatory,
nonbloody) diarrhea is associated with bacteria that have infected
the small intestine and elaborated an enterotoxin (eg, Clostridium
perfringens, V cholerae). In contrast, colitis-like symptoms
(lower abdominal pain, tenesmus, fecal urgency) and an inflammatory
or bloody diarrhea occur with bacteria that more commonly infect
the large intestine. The incubation period is generally longer (>
3 days) for bacteria that localize to the large intestine, and colonic
mucosal invasion can occur, causing fever, bacteremia, and systemic
- 21. How many individuals in the
world die yearly of infectious diarrhea?
- 22. What are different modes of spread
of infectious diarrhea? Give an example of each.
- 23. What are the different mechanisms
by which infectious organisms cause diarrhea?
Sepsis is a leading cause of death in the United States, with more
than 34,000 deaths occurring annually and an overall case fatality
rate approaching 20%. The medical costs of sepsis in the
United States exceed $17 billion annually. Rates of sepsis
continue to rise secondary to medical advances such as the widespread
use of indwelling intravascular catheters, increased implantation
of prosthetic material (eg, cardiac valves and artificial joints),
and administration of immunosuppressive drugs and chemotherapeutic
agents. These interventions serve to increase the risk of infection
and subsequent sepsis.
The study of sepsis has been facilitated by establishment of standardized
case definitions (Table 4–12). The systemic inflammatory response
syndrome (SIRS) is a nonspecific inflammatory
state that may be seen with infection as well as with noninfectious
states such as pancreatitis, pulmonary embolism, and myocardial
infarction. Leukopenia and hypothermia, included in the SIRS case
definition, are predictors of a poor prognosis when associated with
sepsis. Sepsis is defined as the presence of SIRS associated
with an infectious precipitant. Severe sepsis occurs
when there is objective evidence of organ dysfunction (eg, renal
failure, hepatic failure, altered mentation), usually associated
with tissue hypoperfusion. The final stage of sepsis is septic
shock, defined as hypotension (systolic blood pressure <
90 mm Hg or a 40 mm Hg decrease below the baseline systolic blood
pressure) unresponsive to fluid resuscitation.
Table 4–12 Clinical Definition of Sepsis. |Favorite Table|Download (.pdf)
Table 4–12 Clinical Definition of Sepsis.
|I. Systemic inflammatory response syndrome (SIRS)|
|Two or more of the following:|
|(1) Temperature of > 38 °C or < 36 °C|
|(2) Heart rate of > 90/min|
|(3) Respiratory rate of > 20/min or
PaCO2 < 32 mm Hg|
|(4) WBC count of > 12 × 109/L
or < 4 × 109/L, or
> 10% immature forms (bands)|
|SIRS plus evidence of infection|
|III. Severe sepsis|
|Sepsis plus organ dysfunction, hypotension,
or hypoperfusion (including lactic acidosis, oliguria, acute alteration
in mental status)|
|IV. Septic shock|
|Hypotension (despite fluid resuscitation) plus
Although evidence of infection is a diagnostic criterion for sepsis,
only 28% of patients with sepsis have bacteremia, and slightly
more than 10% will have primary bacteremia, defined as
positive blood cultures without an obvious source of bacterial seeding.
Common sites of infection among patients with sepsis syndrome (in
decreasing order of frequency) include the respiratory tract, the
genitourinary tract, abdominal sources (gall-bladder, colon), device-related
infections, and wound or soft tissue infections.
The bacteriology of sepsis has evolved in the last decade. Gram-negative
bacteria (Enterobacteriaceae and Pseudomonas),
previously the most common cause of sepsis, have been surplanted
by gram-positive organisms, which now cause more than 50% of
cases. Staphylococci are the most common bacteria cultured from
the bloodstream, presumably because of an increase in the prevalence
of chronic indwelling venous access devices and implanted prosthetic
material. For similar reasons, the incidence of fungal sepsis due
to Candida species has risen dramatically in the
last decade. Sepsis associated with P aeruginosa, Candida, or
mixed (polymicrobial) organisms is an independent predictor of mortality.
The different stages of sepsis (SIRS to septic shock) represent
a continuum, with patients often progressing from one stage to the
next within days or even hours after admission. Sepsis generally
starts with a localized infection. Bacteria may then invade the bloodstream
directly (leading to bacteremia and positive blood cultures) or
may proliferate locally and release toxins into the bloodstream.
These toxins can arise from a structural component of the bacteria
(eg, endotoxin) or may be exotoxins, which are proteins synthesized
and released by the bacteria. Endotoxin is defined
as the lipopolysaccharide (LPS) moiety
contained in the outer membrane of gram-negative bacteria. Endotoxin
is composed of an outer polysaccharide chain (the O side chain), which
varies between species and is not toxic, and a highly conserved
lipid portion (lipid A), which is embedded in the outer bacterial
membrane. Injection of either purified endotoxin or lipid A is highly
toxic in animal models, causing a syndrome analogous to septic shock
in the absence of viable bacteria.
Until recently, sepsis was attributed solely to overstimulation
of the host inflammatory response and uncontrolled release of inflammatory
mediators. Although this undoubtedly occurs in a subset of patients,
the failure of medical interventions aimed at blocking this response
(eg, monoclonal antibodies directed against endotoxin, blockade
of IL-1 and TNF, bradykinin antagonists, inhibition of cyclooxygenase with
ibuprofen) suggests a more complex process. Studies have shown that,
as sepsis persists, host immunosuppression plays a critical role.
Specific stimuli such as organism, inoculum, and site of infection
stimulate CD4 T cells to secrete cytokines with either
inflammatory (type 1 helper T-cell) or anti-inflammatory (type 2
helper T-cell) properties (Figure 4–11).
Among patients who die of sepsis, there is significant loss of cells
essential for the adaptive immune response (B lymphocytes, CD4 T
cells, dendritic cells). Genetically programmed cell death, termed apoptosis, is
thought to play a key role in the decrease in these cell lines and
downregulates the surviving immune cells. The clinical consequences
of sepsis include hemodynamic changes (tachycardia, tachypnea), inappropriate
vasodilation, and poor tissue perfusion, with resultant organ dysfunction
Pathogenic sequence of the events in septic shock. Activation
of macrophages by endotoxin and other proteins leads to release
of inflammatory mediators and immune modulation resulting in host
tissue damage and, in some cases, death.
(Redrawn, with permission, from Horn DL et al.
What are the microbial components implicated in the pathogenesis
of sepsis? Clin Infect Dis. 2000;31:852.)
All forms of shock result in inadequate tissue perfusion and subsequent
cell dysfunction and death (see Chapter 11).
In noninfectious forms (such as cardiogenic shock and hypovolemic
shock), systemic vascular resistance is elevated as
a compensatory mechanism to maintain blood pressure. In the hypoperfused
tissues, there is enhanced extraction of oxygen from circulating
red blood cells, leading to decreased pulmonary artery oxygenation.
In contrast, early in septic shock there is hypovolemia from inappropriate
arterial and venous dilation (low systemic vascular resistance)
and leakage of plasma into the extravascular space. Even with correction
of the hypovolemia, systemic vascular resistance remains low despite
a compensatory increase in cardiac output. Inefficient oxygen
extraction and tissue hypoperfusion result in an increased pulmonary
artery oxygen content.
A hyperdynamic circulatory state, described as distributive shock to
emphasize the maldistribution of blood flow to various tissues,
is the common hemodynamic finding in sepsis. The release of vasoactive
substances (including nitric oxide) results in loss of normal mechanisms
of vascular autoregulation, producing imbalances in blood flow with
regional shunting and relative hypoperfusion of some organs. Animal
studies have documented predictable changes in organ blood flow, with
a marked reduction in blood flow to the stomach, duodenum, small
bowel, and pancreas; a moderate reduction in blood flow to the myocardium
and the skeletal muscles; and relative preservation of perfusion
to the kidneys and CNS.
Myocardial depression is a common finding in early septic shock.
Initially, patients have low cardiac filling pressures and low cardiac
output secondary to volume depletion and vasodilation. After fluid
replacement, cardiac output is normal or increased but ventricular
function is abnormal. From 24 to 48 hours after the onset of sepsis,
left and right ventricular ejection fractions are reduced, and end-diastolic
and end-systolic volumes are increased. This myocardial depression has
been attributed to direct toxic effects of nitric oxide, TNF, and
IL-1. Reduced ejection fraction and consequent myocardial depression
are reversible in patients who survive the initial period of septic
and Multiorgan Dysfunction
Most patients who die of septic shock have either refractory hypotension
or multiple-organ failure. Refractory hypotension can occur from
two mechanisms. First, some patients cannot sustain high cardiac
output in response to the septic state and develop progressive high-output
cardiac failure. Second, circulatory failure may be associated with
severe vasodilation and hypotension refractory to intravenous fluid resuscitation
and vasopressor therapy.
The development of multiple-organ failure represents the terminal
phase of a hypermetabolic process that begins during the initial
stages of shock. Organ failure results from microvascular injury
induced by local and systemic inflammatory responses to infection.
Maldistribution of blood flow is accentuated by impaired erythrocyte
deformability, with microvascular obstruction. Aggregation of neutrophils
and platelets may also reduce blood flow. Demargination of neutrophils
from vascular endothelium results in further release of inflammatory
mediators and subsequent migration of neutrophils into tissues.
Components of the complement system are activated, attracting more
neutrophils and releasing locally active substances such as prostaglandins
and leukotrienes. The net result of all of these changes is microvascular collapse
and, ultimately, organ failure.
The outcome of sepsis depends on the number of organs that fail:
The mortality among patients with multiorgan failure (three or more
organ systems) averages 70%. Respiratory failure develops
in 18% of patients with sepsis. At the most severe end
of the spectrum is acute respiratory distress syndrome, characterized
by refractory hypoxia, decreased lung compliance, noncardiogenic
pulmonary edema, and pulmonary hypertension. Renal failure, seen
in 15% of cases, is usually a multifactorial process, with
additive injury from intra-renal shunting, renal hypoperfusion,
and administration of nephrotoxic agents (antibiotics and radiologic
imaging dye). Other organs affected by sepsis include the CNS (altered mentation,
coma) and the blood (disseminated intravascular coagulation).
The clinical manifestations of sepsis include those related to the
systemic response to infections (tachycardia, tachypnea, alterations
in temperature and leukocyte count) and those related to specific
organ system dysfunction (cardiovascular, respiratory, renal, hepatic,
and hematologic abnormalities). Sepsis sometimes begins with very
subtle clues that can be easily confused with more common and less
serious illnesses. Awareness of these early signs of sepsis can
lead to early recognition and intervention. Nonspecific signs can
include isolated tachypnea (without dyspnea), isolated tachycardia
(with normal blood pressure), irritability or lethargy, and otherwise unexplained
fever, rigors, or myalgias. Nonspecific laboratory abnormalities
can include respiratory alkalosis, leukocytosis, and mild liver
- 24. What is the mortality rate
of sepsis and septic shock in the United States?
- 25. What factors contribute to hospital-related
- 26. Which organisms are most commonly
associated with sepsis?
- 27. What is the role of the host immune
system in the pathogenesis of sepsis?
- 28. What activates the immune response?
- 29. What are some distinctive hemodynamic
features of septic shock versus noninfectious shock syndromes?