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, 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 viridians group streptococci, 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 skin bacteria such as 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 viridians group streptococci, 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 uniformly fatal disease. Even with antibiotics, the case fatality rate for endocarditis approaches 25%, and definitive cure often requires both prolonged intravenous 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 urosepsis, 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 if there is mechanical dysfunction of the valve with resultant heart failure, abscess formation around the valve ring, or prosthetic valve infections.
A hallmark of infective endocarditis is sustained high-grade 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. Table 4–4 summarizes the important features of the history, physical examination, laboratory results, and complications of infective endocarditis. Cutaneous findings suggestive of endocarditis include Osler 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 central nervous system (CNS), resulting in brain abscesses or mycotic aneurysms and intracerebral hemorrhage. Risk factors for a fatal outcome include patients with left-sided valvular infection, bacterial infection other than viridans group streptococci, medical comorbidities, complications from endocarditis (heart failure, valve ring abscess, or embolic disease), and delayed valvular surgery (for those with large vegetations and significant valvular destruction).
Osler node causing pain within pulp of the big toe in a woman hospitalized with acute bacterial endocarditis. (Osler 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 et al, eds. The Color Atlas of Family Medicine. McGraw-Hill, 2009:205–9.)
Which patients are at highest risk for infective endocarditis?
What are the leading bacterial agents of infective endocarditis?
What features characterize infective endocarditis in intravenous drug users? In patients with prosthetic heart valves?
What hemodynamic features predispose to infective endocarditis?
What is the outcome of untreated bacterial endocarditis?
What are the risk factors for a fatal outcome? What are the most common causes of death in untreated infective endocarditis?
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 resulted in a more than 95% decrease in the incidence of H influenzae meningitis in the United States.
Bacterial agents causing meningitis vary according to host age (Table 4–5). Additional bacteria must be considered for postneurosurgery patients (S aureus, gram-negative bacilli, 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 4–5Proportion of cases of bacterial meningitis in the United States by host age, 2003–2007. ||Download (.pdf) Table 4–5 Proportion of cases of bacterial meningitis in the United States by host age, 2003–2007.
| ||Age |
|Pathogen ||<2 Months ||2 Months–17 Years ||18–50 Years ||>50 Years |
|Group B streptococci ||>85% ||~5% ||<5% ||<5% |
|H influenzae ||<5% || ||<5% ||<5% |
|Listeria monocytogenes ||<5% ||<5% ||<5% ||~10% |
|N meningitidis || ||~40% ||~20% ||~5% |
|S pneumoniae ||<5% ||~50% ||~65% ||~75% |
The pathogenesis of bacterial meningitis involves a sequence of events in which virulent microorganisms overcome the host defense mechanisms (Table 4–6).
Table 4–6Pathogenetic sequence of bacterial neurotropism. ||Download (.pdf) Table 4–6 Pathogenetic sequence of bacterial neurotropism.
|Neurotropic Stage ||Host Defense ||Strategy of Pathogen |
|1. Colonization or mucosal invasion ||Respiratory mucous ||Enzymatic degradation |
| ||Secretory IgA ||IgA protease secretion |
| ||Ciliary activity ||Ciliostasic enzymes |
| ||Mucosal epithelium ||Binding molecules and adhesive pili |
|2. Intravascular survival ||Complement ||Production of polysaccharide capsule and enzymatic degradation |
|3. Crossing of blood-brain barrier ||Cerebral endothelium ||Binding to endothelial receptors and adhesive pili |
|4. Survival within CSF ||Complement and antibodies (low levels in uninfected patients) ||Rapid bacterial replication prior to complement production and recruitment of neutrophils |
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 as pili.
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 polysaccharide 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, 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.
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, 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. In contrast, experimental injection of purified pneumococcal capsular polysaccharide proteins directly into the cerebrospinal fluid does not result in significant inflammation in animals.
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. Neuronal cell death or apoptosis is caused both by the immune inflammatory response and by direct toxicity of bacterial components, and clinically may be associated with cognitive impairment as a long-term sequela of meningitis. Cerebrovascular complications including infarction or hemorrhage are common and may be due to localized intravascular coagulation.
Pathophysiological alterations leading to neuronal injury during bacterial meningitis. BBB, blood-brain barrier; CBV, cerebral blood volume. (Redrawn, with permission, from Koedel U et al. Pathogenesis and pathophysiology of pneumococcal meningitis. Lancet Infect Dis. 2002;2:731.)
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. The benefit of adjuvant corticosteroids for other types of meningitis is unproven.
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 frequently noted on physical examination. Other clues seen in a variable proportion of cases include nausea or vomiting, photophobia, Kernig sign (resistance to passive extension of the flexed leg with the patient lying supine), and Brudzinski 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 the Cushing 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.
Despite advances in treatment, the case fatality rate of meningitis remains approximately 15%, and neurologic impairment is common among survivors. Morbidity and mortality may be decreased by rapid initiation of appropriate antibiotics. Any patient suspected of having meningitis requires prompt medical assessment and emergent lumbar puncture for Gram stain and culture of the cerebrospinal fluid, followed immediately by the administration of antibiotics (and corticosteroids if pneumococcal meningitis is suspected).
What is the typical presentation of bacterial meningitis?
What are the major etiologic agents of meningitis, and how do they vary with age or other characteristics of the host?
What is the sequence of events in development of meningitis, and what features of particular organisms predispose to meningitis?
What are the diverse causes of cerebral edema in patients with meningitis?
Why is rapid bacteriolysis theoretically dangerous in meningitis?
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 million hospitalizations each year in the United States, and >50,000 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 pleuritis (inflammation of the pleura, characterized by pain on inspiration). The exudative inflammatory response of the pleura to pneumonia is termed a parapneumonic effusion; when bacterial infection is present in the pleura, this is termed empyema.
Despite technologic advances in diagnosis, no causative agent is identified in approximately 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 4–7).
Table 4–7Common etiologic agents of community-acquired pneumonia as determined by severity of illness. ||Download (.pdf) Table 4–7 Common etiologic agents of community-acquired pneumonia as determined by severity of illness.
| || ||Hospitalized |
|Etiologic Agent ||Outpatient ||Mild-to-Moderate Infection (Not in ICU) ||Severe Infection (Requiring ICU) |
|S pneumoniae ||X ||X ||X |
|M pneumoniae ||X ||X || |
|C pneumoniae ||X ||X || |
|H influenzae ||X ||X ||X |
|Respiratory viruses1 ||X ||X || |
|Legionella species || ||X ||X |
|Gram-negative bacilli || || ||X |
|Anaerobes (aspiration) || ||X || |
|S aureus || || ||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 4–8). 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 pneumocystis pneumonia and should be given prophylactic antibiotics.
Table 4–8Common risk factors and causes of pneumonia in specific adult hosts. ||Download (.pdf) Table 4–8 Common risk factors and causes of pneumonia in specific adult hosts.
| ||Etiologic Agents || |
|Risk Factor ||Acute Symptoms ||Subacute Chronic Symptoms ||Pathogenetic Mechanism |
|HIV infection ||S pneumoniae ||Fungi (eg, Aspergillus, Histoplasma, Cryptococcus) ||Cell-mediated immune dysfunction |
| ||H influenzae ||M tuberculosis, atypical mycobacteria ||Impaired humoral response |
| ||P jirovecii || || |
|Solid organ or bone marrow transplantation ||Cytomegalovirus ||Nocardia ||Cell-mediated immune dysfunction |
| || ||Fungi ||Neutropenia (bone marrow transplant) |
| ||Legionella species ||M tuberculosis || |
| ||P jirovecii || || |
| ||P aeruginosa || || |
|Chronic obstructive lung disease or smoking ||S pneumoniae || ||Decreased mucociliary clearance |
| ||H influenzae || || |
| ||Moraxella catarrhalis || || |
| ||P aeruginosa || || |
|Structural lung disease (bronchiectasis) ||P aeruginosa || || |
| ||Burkholderia cepacia || || |
| ||S aureus || || |
|Alcoholism ||K pneumoniae ||Mixed anaerobic infection (lung abscess) ||Aspiration of oropharyngeal contents |
| ||Oral anaerobes || || |
|Injection drug abuse ||S aureus || ||Hematogenous spread |
|Environmental or animal exposure ||Legionella species (infected water) ||C immitis (Southwest United States) ||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 mechanisms (intubation) |
| ||S aureus || || |
| ||Acinetobacter species || ||Hematogenous spread (intravenous catheters) |
|Postinfluenza ||S aureus || ||Disruption of respiratory epithelium |
| ||S pyogenes || ||Ciliary dysfunction |
| || || ||Inhibition of PMNs |
Pneumonia is disproportionally a disease of the elderly and impaired host; 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 into the lower airways, (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. (C, complement.) (Redrawn, with permission, from Storch GA. Respiratory system. In: Schaechter M et al, eds. Mechanisms of Microbial Disease, 4th ed. 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 therefore compensate through 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 predisposed 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 considerations 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 influenza outbreak)? (10) Does the illness necessitate hospitalization or intensive care admission (eg, pneumonia due to Legionella, S pneumonia, S aureus)?
What are the important pathogens for patients with community-acquired pneumonia based on severity of illness and site of care?
What host features influence the likelihood of particular causes of pneumonia?
What are the four mechanisms by which pathogens reach the lungs?
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 infection).
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 4–9 summarizes these relationships and provides a framework for assessing the pathogenesis of GI tract infections.
Table 4–9Approach to GI tract infections. ||Download (.pdf) Table 4–9 Approach to GI tract infections.
|Paradigm ||Categories ||Epidemiology ||Examples |
|Environment ||Water borne ||Fecal contamination of water supply ||Vibrio cholerae |
| ||Food borne ||Contaminated food (bacteria or toxin) ||S aureus |
| || || ||Salmonella |
| ||Person to person (fecal oral spread) ||Child care centers ||Shigella |
| || || ||Rotavirus |
|Agent ||Bacterial || ||Campylobacter |
| ||Viral || ||Norovirus |
| ||Parasitic || ||Entamoeba histolytica |
|Host ||Age ||Infants, elderly ||Enterohemorrhagic E coli |
| ||Comorbidity ||HIV ||Cryptosporidium |
| ||Gastric acidity ||Antacid use ||Salmonella |
| ||GI flora ||Antibiotic use ||Clostridium difficile |
|Site ||Stomach ||Gastroenteritis ||B cereus |
| ||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. Causative organisms 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. 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 (and several newer proposed subgroups): enterotoxigenic (ETEC), enteropathogenic (EPEC), enterohemorrhagic (EHEC), enteroaggregative (EAEC), and enteroinvasive (EIEC) (Table 4–10). 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 4–10Escherichia coli in diarrheal disease. ||Download (.pdf) Table 4–10 Escherichia coli in diarrheal disease.
| ||Susceptible Populations || || || |
|Class ||Developed Countries ||Developing Countries ||Clinical Syndrome ||Site ||Toxins |
|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 and 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, EAEC), 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 cells. (Redrawn, with permission, from Vaughan M. Cholera and cell regulation. Hosp Pract. 1982;17(6):145–52.)
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 through a similar toxin, termed Shigella-like enterotoxin.
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 tract infections vary depending on the site of involvement (Table 4–9). 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 symptoms.
How many individuals in the world die yearly of infectious diarrhea?
What are different modes of spread of infectious diarrhea? Give an example of each.
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 4–11). 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 4–11Clinical definition of sepsis. ||Download (.pdf) Table 4–11 Clinical definition of sepsis.
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
Sepsis plus organ dysfunction, hypotension, or hypoperfusion (including lactic acidosis, oliguria, acute alteration in mental status)
Hypotension (despite fluid resuscitation) plus hypoperfusion abnormalities
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.
Sepsis was initially considered to be a result of overstimulation of the host inflammatory response and uncontrolled release of inflammatory mediators. The failure of a number of pharmacologic interventions aimed at blocking endotoxin or the resultant inflammatory cascade suggests that other factors, such as host immunosuppression, play 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 (Figure 4–11).
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 shock.
Vascular 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. Clinical guidelines emphasize the use of a systematic approach to the recognition and early treatment of sepsis. Initial responses should include obtaining cultures of blood and other body fluids, empiric administration of broad-spectrum antibiotics, determination of serum lactate as a marker of hypoperfusion, and use of intravenous fluid and vasopressor therapy for patients with sustained hypotension.
What is the mortality rate of sepsis and septic shock in the United States?
What factors contribute to hospital-related sepsis?
Which organisms are most commonly associated with sepsis?
What is the role of the host immune system in the pathogenesis of sepsis?
What activates the immune response?
What are some distinctive hemodynamic features of septic shock versus noninfectious shock syndromes?