Chapter 74 Pneumonia. Gregory J. Moran and David A. Talan PERSPECTIVE PRINCIPLES OF DISEASE

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1 Chapter 74 Pneumonia Gregory J. Moran and David A. Talan PERSPECTIVE Pneumonia is the seventh leading cause of death and the leading cause of death from infectious disease in the United States. 1 The annual incidence of community-acquired pneumonia (CAP) in the United States ranges from 2 to 4 million, resulting in approximately 500,000 hospital admissions. Most cases of CAP are managed in the outpatient setting and the mortality is low (<1%), but pneumonia requiring hospitalization is associated with a much higher mortality rate (approximately 15%). Most deaths occur in elderly or immunosuppressed patients. Pneumonia remains challenging because of an expanding spectrum of pathogens, changing antibiotic resistance patterns, the availability of newer antimicrobial agents, and increasing emphasis on cost-effectiveness and outpatient management. The epidemiology of CAP is changing. As the percentage of the population older than age 65 years continues to increase, the incidence of pneumonia is expected to increase. An increasing number of patients are taking immunosuppressive drugs related to treatment of malignancy, transplantation, or autoimmune disease, resulting in more cases of pneumonia due to other opportunistic pathogens. Patients with acquired immunodeficiency syndrome (AIDS) are at increased risk of infection with Streptococcus pneumoniae, Mycobacterium tuberculosis, or Pneumocystis jirovecii (previously known as Pneumocystis carinii). Antibiotic resistance is more common among S. pneumoniae and other pathogens. In addition, the threat exists of respiratory infections due to biologic terrorism or newly recognized pathogens that have the potential to spread quickly through international travel. Identification of a specific etiology of pneumonia is extremely difficult within the time frame of an emergency department (ED) visit. Even after a thorough inpatient evaluation, a specific pathogen is never identified in many patients with pneumonia. When pneumonia is diagnosed, the priorities in the ED are to initiate appropriate empirical antibiotic therapy based on the most likely pathogens, provide appropriate respiratory support, assess the severity of disease, and recognize indications for hospitalization. PRINCIPLES OF DISEASE Despite the constant presence of potential pathogens in the respiratory tract, the lungs are remarkably resistant to infection. The alveolar surface of the lungs covers an area of approximately 140 m 2. Approximately 10,000 L of air passes through the respiratory tract each day, and typical ambient air can contain hundreds to thousands of microorganisms per cubic meter. Numerous potential respiratory tract pathogens may colonize the oropharynx and upper airways. Although the cough and laryngeal reflexes prevent most large particulate matter from entering the lower respiratory tract, aspiration of oropharyngeal contents may be a common occurrence during normal sleep. Despite these hazards, healthy lungs are usually a virtually sterile environment. The development of clinical pneumonia requires a defect in host defenses, the presence of a particularly virulent organism, or the introduction of a large inoculum of organisms. If the challenge of invading organisms overwhelms host defenses, microbial proliferation leads to inflammation, an immune response, and clinical pneumonia. If host defenses are weak, a minimal challenge may lead to the development of pneumonia. The mouth normally contains numerous microorganisms. Saliva contains approximately 10 8 bacteria/ml, with anaerobic organisms predominating. Bacteroides and Fusobacterium spp. are the most common anaerobic organisms. Streptococci are the most common aerobic organisms, but staphylococci, Haemophilus sp., Moraxella catarrhalis, and Neisseria sp. are also found. Anything that upsets the balance of normal oral flora may permit the growth of more virulent organisms. Systemic illness may alter epithelial binding of oral flora, leading to increased colonization with aerobic gram-negative bacilli. Antimicrobial therapy can also adversely alter normal oral flora. Host defenses can be impaired in many ways. An altered level of consciousness (e.g., intoxication, stroke, seizures, and anesthesia) can suppress protective airway reflexes and lead to aspiration of oropharyngeal contents into the lower respiratory tract. Interventions that bypass the usual defenses of the upper airways, such as endotracheal intubation, nasogastric intubation, and respiratory therapy devices, predispose to infection. Cigarette smoking damages mucociliary function and macrophage activity. Viral infections of the respiratory tract may destroy respiratory epithelium and predispose it to bacterial infection. Increased risk of bacterial pneumonia after influenza or other viral respiratory infections is well described. The elderly are at increased risk of pneumonia related to decline of mucociliary clearance, elastic recoil of the lungs, and humoral and cellular immunity. Human immunodeficiency virus (HIV) infection impairs humoral and cellular immunity. 927

2 PART III Medicine and Surgery / Section Two Pulmonary System 928 If an infectious organism reaches the alveoli and begins replicating, a series of host immune responses occurs that ultimately may lead to the development of clinical pneumonia. As antigens of the infecting organism are identified by the host, cytokines, such as interleukin-1, interleukin-8, and tumor necrosis factor, are produced that mediate the inflammatory response. Transudation of plasma fluids into the lung tissue allows entry of IgM and IgG for bacterial opsonization, complement activation, agglutination, and neutralization. Neutrophils are recruited into the lung to ingest and kill the infecting organisms. Cell-mediated immunity plays an important role in defense against certain pathogens, such as viruses and intracellular organisms such as Mycobacterium and Legionella spp. As fluids and inflammatory cells enter the alveolar spaces to combat the infection, the patient develops the clinical and radiographic signs of pneumonia. Etiologic Agents The challenge with pneumonia lies in identifying the etiologic agent rather than in diagnosis of pneumonia. It is extremely difficult to determine with a high degree of certainty the specific organism responsible for pneumonia, especially within the time frame of an ED evaluation. Empiric therapy must be chosen with activity against the spectrum of likely pathogens based on the overall clinical picture. Difficulty in determining the specific etiology of pneumonia exists even with advanced microbiologic and serologic testing that is not generally available during an ED evaluation. In community-acquired pneumonia, a microbial etiology cannot be determined in one third to one half of cases, even after thorough investigation. In hospitalized adults with CAP, pathogens such as S. pneumoniae and Haemophilus influenzae, referred to as typical pathogens, account for approximately one fourth of cases. Legionella, Mycoplasma, and Chlamydophila spp. (previously known as Chlamydia), referred to as atypical pathogens, are also common. 2 Testing for common viral agents reveals a viral etiology in approximately 18% of cases, with influenza and parainfluenza viruses most common. 3 Adults who require intensive care unit (ICU) admission have S. pneumoniae as the most common pathogen, with even higher prevalence among fatal cases. Legionella sp., Staphylococcus aureus, and aerobic gram-negative bacilli also appear to be relatively more common among adults with severe CAP. 4 Atypical organisms such as Mycoplasma sp. or viruses account for a relatively higher proportion of pneumonia in patients who have milder illness that is amenable to outpatient therapy. 5 However, atypical organisms occur with significant frequency in patients with severe illness requiring hospitalization, particularly due to Legionella infection. Co-infection, such as with Chlamydophila pneumoniae and S. pneumoniae, is also well recognized. Streptococcus pneumoniae is a gram-positive coccus that is the most common etiology of CAP among adults. It colonizes the nasopharynx in 40% of healthy adults. Although this organism can cause pneumonia in healthy people, patients with a history of diabetes, cardiovascular disease, alcoholism, sickle cell disease, splenectomy, and malignancy or other immunosuppressive illness are at increased risk. A vaccine containing the 23 capsular polysaccharides of pneumococcal types most commonly associated with pneumonia reduces the likelihood of serious pneumococcal infection. It is recommended for people at increased risk because of underlying illness or age older than 65 years. 6 Many ED patients have not received pneumococcal vaccine, and vaccinating eligible patients in this setting seems to be feasible and effective. 7 A heptavalent proteinconjugate pneumococcal vaccine effectively reduces invasive pneumococcal disease and pneumonia in infants and young children. 8 Haemophilus influenzae, the second most frequently isolated organism in CAP among adults, is a pleomorphic gramnegative rod. It is a common pathogen in adults with chronic obstructive pulmonary disease (COPD), alcoholism, malnutrition, malignancy, or diabetes. Although Staphylococcus aureus remains an uncommon cause of CAP, community-associated strains of methicillin-resistant S. aureus (CA-MRSA) are emerging as a cause of severe pneumonia in previously healthy adults and children. This is often associated with influenza. 9 Staphylococcal pneumonias are often necrotizing, with cavitation and pneumatocele formation. Intravenous drug users may develop hematogenous spread of S. aureus that involves both lungs with multiple small infiltrates or abscesses (e.g., tricuspid endocarditis resulting in septic pulmonary emboli). Other pyogenic bacterial etiologies include Moraxella catarrhalis, a gram-negative diplococcus that can be associated with lower respiratory tract infections in patients with COPD. Klebsiella pneumoniae is a gram-negative rod that rarely causes disease in a normal host and accounts for a small percentage of CAPs. It may cause severe pneumonia in debilitated patients with alcoholism, diabetes, or other chronic illness. There is a high incidence of antibiotic resistance since the organism is often hospital acquired. Mycoplasma pneumoniae is one of the most common causes of CAP in previously healthy patients younger than age 40 years. Another important organism in CAP is C. pneumoniae, an intracellular parasite that is transmitted between humans by respiratory secretions or aerosols. Seroprevalence studies indicate that virtually everyone is infected with C. pneumoniae at some time and that reinfection is common. Chlamydophila pneumoniae is a relatively common etiology of CAP, especially in older adults. It accounts for at least 8% of cases, although this is an underestimate due to difficulty in diagnosing infection with this organism. At least 30 species of Legionella have been isolated since the 1976 convention-related outbreak in Philadelphia, from which the organism derives its name. At least 19 are known human pathogens. Legionella is an intracellular organism that lives in aquatic environments. There is no person-to-person transmission. Although it is implicated in point outbreaks related to cooling towers and similar aquatic sources, the organism also lives in ordinary tap water and is underdiagnosed as an etiology of CAP. Legionella prevalence seems to vary greatly by region. Lower respiratory infections due to anaerobic organisms generally result from the aspiration of oropharyngeal contents with large amounts of bacteria. These infections are typically polymicrobial, including Peptostreptococcus, Bacteroides, Fusobacterium, and Prevotella spp. Presentation is often subacute or chronic and may be difficult to distinguish clinically from other etiologies of pneumonia. Clinical factors that suggest an anaerobic infection include risk factors for aspiration, such as central nervous system depression or swallowing dysfunction; severe periodontal disease; fetid sputum; and the presence of a pulmonary abscess or empyema. Viral pneumonias are common in infants and young children and are recognized as an important cause of pneumonia in adults. Respiratory syncytial virus and parainfluenza viruses are the most common causes of pneumonia in infants and small children, occurring mostly during autumn and winter. Influenza viruses are the most common cause of viral pneumonia in adults. Winter influenza outbreaks, usually due to influenza type A, may cause 40,000 deaths annually in the United States. More than 90% occur in people age 65 years or older. 10

3 Metapneumovirus is a paramyxovirus that seems to be an important cause of viral pneumonia in children and adults. 11 Cytomegalovirus (CMV) primarily causes pneumonia in immunosuppressed patients, such as transplant recipients. Varicella-zoster virus causes pneumonia that seems to be more common and more severe in adults. Predisposing factors include smoking or pregnancy. Severe acute respiratory syndrome (SARS) is a respiratory illness due to a coronavirus identified in Southeast Asia. SARS is associated with a high case fatality rate (approximately 10 15% overall and higher in the elderly). Fungal infections due to organisms such as Histoplasma capsulatum, Blastomyces dermatitides, and Coccidioides immitis commonly present as pulmonary disease. These organisms are present in the soil in various geographic areas of the United States: H. capsulatum in the Mississippi and Ohio River valleys, C. immitis in desert areas of the Southwest, and B. dermatitides in a poorly defined area extending beyond that of H. capsulatum. These infections should be considered in people in appropriate geographic areas, especially in those who are near activities that disturb the soil, such as construction or dirt bike riding. Clinical presentation varies from an acute or chronic pneumonia to asymptomatic granulomas and hilar adenopathy. Pneumocystis pneumonia (PCP) occurs in compromised hosts, principally people with AIDS or malignancy. Although P. jirovecii is often classified as a protozoan, biochemical evidence indicates that it is more closely related to fungi. PCP is one of the most common presentations leading to a diagnosis of HIV infection and AIDS. Patients with pulmonary complaints should be questioned about HIV risk factors, and clinicians should search for signs of HIV-related immunosuppression, such as weight loss, lymphadenopathy, and oral thrush. PCP typically presents subacutely with fatigue, exertional dyspnea, nonproductive cough, pleuritic chest pain, and fever. Mycobacterium tuberculosis is a slow-growing bacterium transmitted between people by droplet nuclei produced from coughing and sneezing. Mycobacterium tuberculosis survives within macrophages as a facultative intracellular parasite and may remain dormant in the body for many years. Active tuberculosis (TB) develops within 2 years of infection in approximately 5% of patients, and another 5% develop reactivation disease at some later time. Reactivation is more likely to occur in people with impaired cell-mediated immunity, such as patients with diabetes, renal failure, immunosuppressive therapy, malnutrition, or AIDS. Approximately one third of the world s population is infected with M. tuberculosis. Approximately 8 million new cases of active disease develop annually, resulting in 3 million deaths worldwide. An estimated 10 to 15 million people in the United States (3 5% of the population) are infected with TB. Multidrug-resistant strains of M. tuberculosis are found in increasing numbers, especially among immigrants from Southeast Asia and AIDS patients. Unusual Causes of Pneumonia Hantaviruses are endemic in several areas of the United States and can cause a syndrome of severe respiratory distress and shock. Infection occurs from inhalation of aerosols contaminated with rodent urine and feces. Patients are typically healthy adults with a prodrome of fever, myalgia, and malaise followed several days later by the onset of respiratory distress. Hypoxia may progress rapidly, requiring ventilatory support. Characteristic laboratory findings include thrombocytopenia, hemoconcentration, and leukocytosis with atypical lymphocytes. Chest radiographs show bilateral interstitial lung infiltrates that are more pronounced in dependent areas. Treatment 929 is supportive, including the use of extracorporeal membrane oxygenation. There is no known effective antiviral therapy. Plague, caused by Yersinia pestis, is endemic in many areas of the world, including the southwestern United States. It is an agent that could be used for biologic terrorism, 12 but it also occurs naturally in people bitten by fleas from infected rodents or carnivores. Hematogenous spread may lead to pneumonia that is highly contagious and has a high mortality. A number of zoonotic organisms cause pneumonia. Tularemia, caused by the bacterium Francisella tularensis, is spread by contact with body fluids of an infected mammal (especially rabbits) or the bite of an infected arthropod. Illness usually begins with an ulcerated skin lesion and painful regional lymphadenopathy. Some patients have a typhoidal form with only fever, malaise, and weight loss. Pneumonia may occur with either form, presenting as a nonproductive cough and patchy infiltrates on a chest radiograph. Psittacosis can spread to humans from birds infected with Chlamydophila psittaci. Illness often begins rapidly with chills, high fever, myalgias, and nonproductive cough. Severe headache is often the major complaint. Splenomegaly is often present. Q fever is caused by the rickettsial organism Coxiella burnetii. It is most common in people with occupational exposure to cattle or sheep or parturient animals, including cats. Severe headache occurs in approximately 75% of cases. Q fever is rarely fatal. Other zoonotic pulmonary infections include Rhodococcus equi associated with exposure to horses and Bordetella bronchiseptica associated with exposure to ill dogs ( kennel cough ). CLINICAL FEATURES The ED evaluation should focus on establishing the diagnosis of pneumonia and determining the presence of epidemiologic and clinical features that would influence decisions regarding hospitalization and antibiotics. Key history includes the character and pattern of symptoms, the setting in which the pneumonia is acquired, geographic or animal exposures, and host factors that predispose to certain types of infections and are associated with outcome. Pneumonia generally presents as a cough productive of purulent sputum, shortness of breath, and fever. In most healthy older children and adults, the diagnosis can be reasonably excluded on the basis of history and physical examination, with suspected cases confirmed by chest radiography. The absence of any abnormalities in vital signs or chest auscultation substantially reduces the likelihood of pneumonia. However, no single isolated clinical finding is highly reliable in establishing or excluding a diagnosis of pneumonia. 13 Elder or debilitated patients with pneumonia often present with nonspecific complaints but not the classic symptoms. Pneumonia commonly presents in the elderly as acute confusion or a deterioration of baseline function. Elder patients are more likely to have advanced illness at the time of presentation and may present with sepsis in the absence of a previous syndrome suggestive of pneumonia. Rarely, patients with lower lobe pneumonia present with a complaint of abdominal or back pain. The diagnosis may be more difficult in infants and small children who are unable to give an adequate history. Pneumonia may present in infants as a fever associated with irritability, tachypnea, tachycardia, intercostal retractions, nasal flaring, or grunting. Cough may be minimal or absent. Pneumonia can be divided based on clinical patterns into typical pneumonia caused by pyogenic bacteria, such as S. pneumoniae or H. influenzae, and atypical pneumonia caused by organisms such as Mycoplasma and Chlamydophila spp. This division is artificial, and a clear differentiation between these two types of pneumonia on clinical grounds alone is impossi- Chapter 74 / Pneumonia

4 PART III Medicine and Surgery / Section Two Pulmonary System 930 ble. Certain clinical factors are often said to be suggestive of atypical organisms. Factors studied prospectively and found not to be more frequent with atypical pneumonias than with pyogenic bacterial etiologies include gradual onset, viral prodrome, absence of rigors, nonproductive cough, lower degree of fever, absence of pleurisy or consolidation, low leukocyte count, and an ill-defined infiltrate on a chest radiograph. 2 Although it is impossible to determine with a high degree of certainty the specific etiology of pneumonia without results of microbiologic or serologic tests, certain clinical factors suggest that a specific pathogen should be considered. The classic presentation of pneumococcal pneumonia is the abrupt onset of a single shaking chill followed by fever, cough productive of rust-colored sputum, and pleuritic chest pain. Many patients do not exhibit the classic pattern. Patients often have a preceding upper respiratory illness, and the onset of pneumonia may be insidious, especially in the elderly or with underlying lung disease. Patients with a history of asplenia, sickle cell disease, AIDS, multiple myeloma, or agammaglobulinemia are at increased risk of pneumococcal bacteremia and sepsis with high mortality rates. Extrapulmonary complications (e.g., meningitis, endocarditis, or arthritis) may rarely be present. Adults with chronic lung disease who develop pneumonia due to H. influenzae typically present with an insidious worsening of baseline cough and sputum production, and bacteremia is rare. Klebsiella pneumoniae may cause severe pneumonia in elderly or debilitated patients. Sputum is often described as currant jelly because of the necrotizing, hemorrhagic nature of the infection. Abscess formation, empyema, and bacteremia are common with this organism, and mortality is high. Atypical pneumonia is caused by organisms such as M. pneumoniae, C. pneumoniae, viruses, Legionella sp., or rickettsiae such as C. burnetii. Mycoplasmal infection usually begins as a flulike illness with headache, malaise, and fever. Cough is usually nonproductive but may sometimes produce clear or purulent sputum. Skin lesions, including maculopapular, vesicular, urticarial, or erythema multiforme-type rashes, are common, especially in younger patients. Although bullous myringitis is described as a classic finding, it is not specific for mycoplasmal infection and is present in only a few cases. Common physical findings include pharyngeal erythema, cervical adenopathy, and scattered rales and rhonchi. Rare extrapulmonary manifestations include pericarditis, glomerulonephritis, aseptic meningitis, and Guillain-Barré syndrome. Patients generally do not appear toxic, and most can be treated as outpatients. Although mucopurulent sputum generally indicates the presence of pyogenic bacterial pneumonia or bronchitis, it may also be present with mycoplasmal or viral pneumonia. Viral pneumonia in adults is often preceded by symptoms of upper respiratory infection, such as rhinitis or sore throat. Cough is usually nonproductive, and pleuritic chest pain is less common than with bacterial pneumonia. Most C. pneumoniae infections in young adults cause a minor, self-limited upper respiratory illness that is subacute in onset. This organism is also associated with bronchitis, wheezing, sinusitis, pharyngitis, and atherosclerosis. Development of radiographically evident pneumonia is more common in the elderly, in contrast to the common perception that atypical pneumonias occur in the young. Some patients with Legionella infection have a mild, selflimited atypical pneumonia presentation. Older patients, smokers, and those with chronic disease or immunosuppression are more prone to develop the more acute and severe systemic illness of legionnaires disease. Gastrointestinal symptoms, such as diarrhea and abdominal cramping, are sometimes prominent. In addition to age, the presence of underlying illness, and presenting symptoms, the setting of acquisition of pneumonia may provide clues to likely etiologies. CAP that occurs in otherwise healthy individuals is likely to be due to viruses, Mycoplasma sp., or S. pneumoniae. Staphylococcus aureus, including CA-MRSA, can cause severe pneumonia associated with influenza. Hospitalized patients may develop pneumonia due to agents that are uncommon in CAP, such as Enterobacteriaceae, Pseudomonas aeruginosa, and S. aureus. Healthy patients in an institutional setting, such as a dormitory or military barracks, are likely to have pneumonia due to Mycoplasma sp. or viruses. Patients with underlying lung disease, especially COPD, constitute an important group likely to develop pneumonia. The lower respiratory tract of these patients is commonly colonized with organisms such as S. pneumoniae, H. influenzae, and M. catarrhalis. Cystic fibrosis patients are prone to pneumonia due to P. aeruginosa or S. aureus. Defective mucociliary clearance in both of these groups makes them highly susceptible to repeated episodes of pneumonia. Patients with immunosuppression due to hematologic malignancy, patients receiving chemotherapy for malignancy, and transplant recipients are prone to pulmonary infections with a wide variety of organisms. In addition to the usual pathogens, these patients may develop pneumonia secondary to viruses such as CMV, varicella, or herpes simplex virus. They are also more likely to develop pneumonia due to aerobic gram-negative bacilli, fungi such as Candida sp. or H. capsulatum, and P. jirovecii. Patients in nursing homes or other extended-care facilities are at increased risk for infection with resistant organisms such as P. aeruginosa, K. pneumoniae (including strains producing extended-spectrum β-lactamases), Acinetobacter species, and hospital-associated strains of MRSA. Other risk factors for infection with multidrug-resistant pathogens include (1) hospitalization for 2 or more days in an acute care facility within 90 days of infection; (2) patients who attended a hemodialysis clinic; and (3) patients who received intravenous antibiotic therapy, chemotherapy, or wound care within 30 days of infection. Any patient with pneumonia that fulfills any one of these historical features, including patients from a nursing home or long-term care facility, is designated as having health care associated pneumonia (HCAP). HCAP is associated with a greater likelihood of resistant pathogens such as Pseudomonas and MRSA, and mortality is higher than that for CAP. 14 DIAGNOSTIC STRATEGIES Although many chest radiographs are obtained unnecessarily for patients with upper respiratory tract infections or bronchitis, it is difficult to identify a set of specific criteria to direct test ordering that is better than the clinical judgment of an experienced physician. A routine chest radiograph for all patients who present with cough is not necessary; chest radiography may be reserved for patients who have other suggestive findings (e.g., fever, tachycardia, oxygen desaturation, or an abnormal lung examination). Among patients suspected to have pneumonia, these clinical findings are prospectively validated and are better predictors of a radiographic infiltrate than physician judgment. 15 Patients with serious underlying disease, patients with severe sepsis or shock, and patients in whom hospitalization is considered should have chest radiography performed. Computed tomography (CT) of the chest is more sensitive than plain radiography for detecting the presence of pulmonary consolidation, although the natural history of CTpositive, plain radiograph-negative pneumonia is not clear. 16 Young, healthy adults with a presumptive diagnosis of pneu-

5 931 Figure Posteroanterior chest radiograph reveals a left upper lobe pneumonia. A variety of organisms can produce this pattern, most commonly S. pneumoniae, H. influenzae, or gram-negative bacilli, but also C. pneumoniae, Mycoplasma, or Legionella sp. Chapter 74 / Pneumonia monia, who will be treated as outpatients, may have a chest radiograph deferred unless there is a suspicion of immunocompromise or other unusual features of disease. A chest radiograph should be obtained subsequently if there is a poor initial response to treatment. Routine performance of chest radiography for patients with exacerbation of chronic bronchitis or COPD is of low yield and may be limited to patients with other signs of infection or congestive heart failure. Studies of infants with fever show that a routine chest radiograph is of low yield in the absence of other symptoms or signs of lower respiratory tract infection (e.g., abnormal auscultation or elevated respiratory rate). 17 Although the causative agent cannot be determined solely by the results of chest radiography, certain radiographic patterns may suggest the possibility of specific pathogens. In pyogenic bacterial pneumonias, radiographs usually show an area of segmental or subsegmental infiltration and air bronchograms (Fig. 74-1). Lobar consolidation is present in a few cases of bacterial pneumonia, often due to pneumococcus or Klebsiella. A dense lobar infiltrate with a bulging fissure appearance on a chest radiograph is often described with pneumonia due to Klebsiella, but this finding is nonspecific, and most cases present as a subtler bronchopneumonia. Pneumonia resulting from spread of infection along the intralobular airway results in fluffy or patchy infiltrates in the involved areas of the lung. A wide variety of bacteria and agents such as Chlamydophila sp., Mycoplasma sp., Legionella sp., viruses, and fungi may cause this pattern. An interstitial pattern on a chest radiograph (Fig. 74-2) typically is caused by Mycoplasma sp., viruses, or P. jirovecii. Tiny nodules disseminated throughout both lungs represent a miliary pattern typical of granulomatous pneumonias, such as TB or fungal disease. The location of infiltrates may also give a clue to the etiology. Aspiration pneumonia occurs in dependent areas of the lung, most commonly the superior segments of the lower lobes or posterior segments of the upper lobes. Pneumonias produced by hematogenous spread (e.g., S. aureus) tend to be peripheral. Apical infiltrates suggest TB. The presence of additional radiographic features in association with infiltrates may suggest a specific etiology. An infiltrate associated with hilar or mediastinal adenopathy suggests the presence of TB or fungal disease or may indicate pneumo- Figure Posteroanterior chest radiograph reveals patchy interstitial infiltrates. Viruses and Mycoplasma are the most likely etiologies in an otherwise healthy patient, but many bacterial organisms may also produce this pattern. nia associated with a neoplasm. Bacteria most likely associated with cavitation (Fig. 74-3) are anaerobes, aerobic gramnegative bacilli, and S. aureus. Cavitation also may be present in fungal disease or TB and with noninfectious processes (e.g., malignancy and pulmonary vascular disease). Pneumato-

6 932 PART III Medicine and Surgery / Section Two Pulmonary System A Figure Posteroanterior (A) and lateral (B) chest radiographs reveal a lung abscess in the left lower lobe with a distinct air-fluid level. B celes or spontaneous pneumothorax may be seen in AIDS patients with PCP. Pleural effusions occur with a wide variety of organisms, including many types of pyogenic bacterial pneumonias, Chlamydophila sp., Legionella sp., and TB. Anaerobic infections associated with an effusion are especially prone to development of empyema. The diagnosis and aspiration of pleural effusions can be aided by use of ED bedside ultrasonography. Radiographic findings are nonspecific for predicting a particular infectious etiology. Mycoplasma pneumonia may present as a dense infiltrate, or pneumococcal pneumonia may present as a diffuse interstitial infiltrate. Immunocompromised patients are particularly prone to having atypical radiographic appearances. Rarely, patients with a clinical picture strongly suggestive of pneumonia have a normal chest radiograph, and some are found to have an infiltrate within the next 24 to 48 hours. The absence of findings on a chest radiograph should not preclude the use of antimicrobial therapy in appropriate patients with a clinical diagnosis of pneumonia. Whether the state of hydration can affect the radiographic appearance of pneumonia is controversial. Although severe dehydration theoretically could result in a diminished exudative response by decreasing blood volume and hydrostatic pressure, this has not been shown experimentally. 18,19 Laboratory studies also are nonspecific for identifying the etiology of pneumonia. Although the finding of a white blood cell count (WBC) greater than 15,000/mm 3 increases the probability of the patient having a pyogenic bacterial etiology rather than a viral or atypical etiology, the predictive value of this finding depends on the stage of the illness and likely prevalences of various etiologies. This is neither sensitive nor specific enough to aid decisions regarding therapy in an individual patient. A WBC may be helpful if it yields evidence of immunosuppression, such as neutropenia, or if it reveals lymphopenia that may indicate immunosuppression from AIDS. Basic metabolic panels may help identify patients with renal or hepatic dysfunction or metabolic acidosis associated with sepsis. These findings predict a complicated course and influence decisions regarding disposition, choice of antimicrobial agents, and dosages. The assessment of respiratory function with pulse oximetry is important in the evaluation of patients with pneumonia since clinical assessment of oxygenation can be inaccurate. 20 Pulse oximetry should be obtained in any patient suspected to have pneumonia. Sputum Gram s stain rarely results in a change in therapy or outcome. Correlation between identification of pneumococcus on Gram s stain and sputum culture results is poor, even when commonly used criteria for an adequate sputum specimen (<5 squamous epithelial cells and >25 WBC/high-power field) are applied. Gram s stains are even less likely to show gram-negative pathogens, such as H. influenzae, and should not be relied on to rule out a gram-negative etiology. Empirical antimicrobial agents are usually highly clinically effective if chosen based on clinical information without sputum analysis. Guidelines for management of CAP from the Infectious Disease Society of America (IDSA) and American Thoracic Society (ATS) support limiting sputum Gram s stain and culture to those patients with more severe disease or risk factors for unusual pathogens. 1 Routine blood cultures are of essentially no value in nonimmunocompromised adults with pneumonia, in whom there is a very low prevalence of noncontaminant bacteremia, and management is rarely changed based on the results. 21,22 The follow-up of false-positive blood cultures is costly and laborintensive, and it may lead to unnecessary use of antibiotics such as vancomycin or linezolid when results are initially reported as gram-positive cocci. Blood cultures should be obtained from immunocompromised patients, those with severe sepsis or shock, or those with risk factors for endovascular infection (e.g., prosthetic valves, intravenous drug use, or cavitary infiltrates). 1 When cultures are drawn, they should be obtained prior to the initiation of antibiotics (although antibiotics should not be delayed for this reason). Patients with a pleural effusion greater than 5 cm on lateral upright posterior-anterior chest radiograph should have a diagnostic thoracentesis performed, 1 with fluid sent for cell count, differential, ph (ph < 7.2 predicts the need for a thoracostomy tube), Gram s stain, and culture. For most patients, thoracentesis can be safely deferred until after hospital admis-

7 sion. Patients in significant respiratory distress, however, or with evidence of tension and mediastinal shift require emergent diagnostic and therapeutic thoracentesis. Serologic tests are available for the diagnosis of many organisms, including C. pneumoniae, Legionella sp., and fungi. The use of serologic tests to determine the etiology of pneumonia may be helpful retrospectively, but they usually require acute and convalescent serum titers and are of little use in the ED. Urine antigen tests for S. pneumoniae and Legionella are available, and in some facilities results can be obtained within the time frame of an ED evaluation. It is not clear, however, that a positive result should prompt a change of empirical treatment. 1 Rapid diagnostic tests for viral antigens are available for several viruses, including RSV and influenza. These tests may be useful for infection control decisions in hospitalized patients, and they may provide an indication for influenza therapy and family prophylaxis. In the future, rapid testing using technology such as the polymerase chain reaction may provide emergency physicians with a reliable method to determine the specific etiology of pneumonia. Pneumonia Associated with Human Immunodeficiency Virus Infection The approach to an HIV-infected patient with pulmonary complaints must consider the likelihood of opportunistic lung infections. Although the use of highly active antiretroviral therapy (HAART) is decreasing the incidence of opportunistic infections among HIV-infected patients, individuals who are not under regular care often present to the ED. In the setting of a patient with risk factors for HIV but an unknown serologic status, a decision must be made as to the likelihood of AIDS and the need to search aggressively for opportunistic pathogens. Respiratory infections are the most common type of opportunistic infection in AIDS patients. In addition to P. jirovecii, there is also an increased incidence of pneumonia due to M. tuberculosis and common bacterial pathogens such as S. pneumoniae and H. influenzae. The incidence of pneumococcal pneumonia is 7 to 10 times higher in HIV-infected people and the incidence of H. influenzae pneumonia is approximately 100 times higher than in non-hiv-infected individuals. Other less important causes of pneumonia in HIV-infected patients include Mycobacterium avium complex, CMV, aerobic gram-negative bacilli, Cryptococcus neoformans, and Rhodococcus equi. Although some patients have known HIV infection or AIDS, many patients are unaware of their HIV status, and many are reluctant to volunteer that they have risk factors for HIV. The first crucial step in the diagnosis of PCP is the recognition that a patient may be at risk. If the possibility of HIV infection is established, the likelihood of immunosuppression must be determined. The potential for opportunistic pulmonary infection can be predicted by a recent absolute CD4 lymphocyte count less than 200/mm 3. This count is often known by patients with recognized HIV infection or may be surmised by a peripheral total lymphocyte count less than 1000/mm In patients who do not know their HIV status, the presence of findings such as weight loss, hairy leukoplakia, and oral candidiasis strongly suggests immunosuppression. Although patients with PCP may present with typical features of subacute onset of nonproductive cough, fever, shortness of breath, diffuse interstitial infiltrates on chest radiography, and arterial hypoxemia, 10 to 20% of patients subsequently proven to have PCP lack these findings. PCP usually has a subacute presentation characterized by nonproductive 933 cough, exertional dyspnea, and weight loss. Tachypnea and tachycardia are usually present. The classic radiographic findings in PCP are bilateral interstitial infiltrates that begin in the perihilar region. Radiographic manifestations of PCP can vary considerably, however, ranging from a normal appearance to dense consolidation. Lobar infiltrates, pleural effusions, hilar adenopathy, parenchymal nodules, and cavitary disease are also described. Hypoxemia, hypocapnia, and an increased arterial-alveolar oxygenation gradient are usually present. Serum lactate dehydrogenase is significantly elevated in AIDS patients with PCP compared to patients with non-pcp pneumonia. The demonstration of oxygen desaturation with mild exercise may be helpful in patients with more subtle presentations. Confirmation of the diagnosis of PCP requires sputum induction and staining and, in some cases, further invasive procedures, such as bronchoscopy with bronchoalveolar lavage or biopsy. In most settings, patients suspected to have PCP are admitted to the hospital and given presumptive therapy against PCP. There is a broad differential diagnosis for pulmonary infiltrates in AIDS patients (Fig. 74-4). The bacterial pathogens most commonly responsible for pneumonia in these patients are the same pathogens most frequently encountered in immunocompetent individuals with CAP, but they may have an atypical appearance on chest x-ray. Because AIDS patients with pulmonary TB cannot be distinguished reliably from AIDS patients with other pulmonary infections at presentation, consider TB in all HIV-infected patients with respiratory complaints and initiate respiratory isolation. AIDS patients are also at risk for pneumonia due to other mycobacterial species (e.g., M. avium complex). Nevertheless, the finding of acid-fast bacilli in the sputum should prompt empirical therapy against M. tuberculosis until another mycobacterial species is definitively identified. AIDS patients are also at increased risk for pneumonia due to Cryptococcus neoformans or other fungi associated with geographic exposure. Kaposi s sarcoma may also present with pulmonary infiltrates. DIFFERENTIAL DIAGNOSIS CONSIDERATIONS The differentiation between upper and lower respiratory tract infections may be difficult. A chest radiograph helps differentiate between upper respiratory tract infection or bronchitis and pneumonia, but it is probably not necessary for all patients with cough and sputum production unless other factors are present that suggest the possibility of pneumonia or obscure its clinical diagnosis (e.g., toxic appearance, extremes of age, underlying illness, and abnormal chest examination). Many noninfectious etiologies may result in inflammatory lung processes, including exposure to mineral dusts (e.g., silicosis), chemical fumes (e.g., chlorine and ammonia), toxic drugs (e.g., bleomycin), radiation, thermal injury, or oxygen toxicity. Immunologic diseases (e.g., sarcoidosis, Goodpasture s syndrome, and collagen vascular disease) or hypersensitivity to environmental agents (e.g., farmer s lung disease) may also result in pneumonia. Tumors may be confused with pneumonia radiographically or may present initially as a postobstructive infection or adenopathy with peripheral infiltrates. Lymphangitic spread of lung malignancy may resemble interstitial pneumonia. Aspiration It is important to recognize the distinction between the acute aspiration of gastric contents or other liquids and bacterial pneumonia that may develop later as a complication of Chapter 74 / Pneumonia

8 934 PART III Medicine and Surgery / Section Two Pulmonary System Figure Posteroanterior chest radiograph of an HIV-infected patient reveals interstitial disease mixed with patchy alveolar infiltrates. Pneumocystis jirovecii is the most common etiology, but bacterial pathogens and tuberculosis must also be considered. aspiration. Aspiration of liquids into the lung disrupts surfactant and causes an inflammatory response that may lead to hypoxia and respiratory failure. Aspiration of acidic gastric contents is particularly damaging to lungs and is common in patients who are unconscious from intoxication or anesthesia or who have neurologic deficits. Patients may present initially with coughing or shortness of breath or may appear well initially and then develop respiratory dysfunction during the next several hours. Acute aspiration of acidic fluid into the lungs may produce fever, leukocytosis, purulent sputum, and radiographic infiltrates that mimic bacterial pneumonia. Although many of these patients go on to develop bacterial pneumonia, prophylactic administration of antibiotics is controversial. Some studies indicate that prophylactic antibiotics do not seem to be beneficial and may select for resistant organisms. 24 Antibiotics should be initiated if the patient develops signs of bacterial pneumonia, including new fever, expanding infiltrate appearing more than 36 hours after aspiration, or unexplained deterioration. Systemic corticosteroids for acute aspiration are of no benefit. MANAGEMENT The possibility of communicable disease should suggest early isolation. 25 Patients with a history of TB exposure, suggestive symptoms (e.g., persistent cough, weight loss, night sweats, and hemoptysis), or belonging to a group at high risk for TB (e.g., homeless, intravenous drug user, alcoholic, HIV risk, and immigrant from high-risk area) should be given a mask and placed in respiratory isolation before evaluation, including chest radiography. 26 EDs that frequently care for patients at risk for TB should consider triage protocols to identify these individuals rapidly before patients, visitors, or staff are unnecessarily exposed. 27 Antimicrobials should be administered in the ED for patients who are being admitted to the hospital. Timely administration of antimicrobials has been associated with improved outcomes for hospitalized pneumonia patients 28, although confounding factors limit the conclusions of these studies. A rush to treatment without a diagnosis of pneumonia, however, can result in inappropriate antibiotic use. Although the Centers for Medicare and Medicaid Services have used specific time cutoffs for antibiotic administration as a quality measure, the IDSA/ATS guidelines for management of pneumonia do not support the use of a specific time cutoff. The antibiotics selected should cover the likely etiologies based on clinical, laboratory, radiologic, and epidemiologic information. However, the regimen should also be as selective as possible to avoid drug toxicity, emergence of resistance to broad-spectrum agents, and excessive cost. The prevalence of drug-resistant S. pneumoniae (DRSP) is increasing. In most areas of the United States, high-level penicillin resistance occurs in approximately 15 to 20% of outpatient pneumococcal sputum isolates. DRSP that is resistant to penicillin is usually resistant to other β-lactams, macrolides, tetracyclines, and trimethoprim-sulfamethoxazole (TMP-SMX). Many extended-spectrum or respiratory fluoroquinolones are available, such as levofloxacin, moxifloxacin, and gemifloxacin. Because oral bioavailability of fluoroquinolones is high, oral therapy provides serum and tissue levels essentially equivalent to parenteral therapy. 29 These agents are active against DRSP and other typical or atypical pneumonia pathogens. It is not clear, however, that in vitro resistance is related to adverse clinical outcome. Most cephalosporins and macrolides achieve adequate levels in serum and tissues to successfully treat S. pneumoniae respiratory tract infections, even if the laboratory reports that the organism is resistant. CA-MRSA has rapidly emerged as the most common pathogen isolated in community-acquired skin and soft tissue infections. It is also increasingly recognized as a cause of severe, rapidly progressing pneumonia with sepsis, often in children or healthy young adults with influenza. 9 Antimicrobials with consistent in vitro activity against CA-MRSA isolates include vancomycin, TMP-SMX, daptomycin, tigecycline, linezolid, ceftaroline, and ceftobipirole. Although vancomycin is used most often for documented MRSA infections, there is concern that vancomycin may be losing efficacy in light of increasing minimum inhibitory concentrations for vancomycin. 30 Daptomycin is inactivated by pulmonary surfactant and would not be appropriate for empiric therapy. Empirical coverage of

9 Table 74-1 Community-Acquired Pneumonia in Older Children and Adults: Outpatient Treatment 935 CLINICAL SETTING ANTIBIOTIC REGIMEN* COMMENTS Previously healthy, no antimicrobials in last 3 mo Comorbidities, or antimicrobials in last 3 mo Doxycycline 100 mg PO bid Azithromycin Levofloxacin 750 mg PO daily for 5 days Cefpodoxime 200 mg PO bid + azithromycin 500 mg PO daily *Doses are for 70-kg adult with normal renal and hepatic function. DRSP, Drug-resistant S. pneumoniae. Preferred for adolescent/young adult when likelihood of mycoplasma is high; variable activity vs. S. pneumoniae. Treats common typical bacterial and atypical pathogens. Variety of dosing regimens: 500 mg once followed by 250 mg daily for 4 days; 500 mg PO daily for 3 days; 2 g PO extended-release suspension once. Can substitute clarithromycin. Can substitute moxifloxacin or gemifloxacin. Treats common typical and atypical bacterial pathogens; active vs. DRSP. Use if recently received β-lactam or macrolide. Use if recently received fluoroquinolones. Can substitute cefdinir, cefprozil, or amoxicillin/clavulanate for cefpodoxime. Variable activity against DRSP. Chapter 74 / Pneumonia MRSA should be strongly considered for patients with severe pneumonia associated with sepsis, especially those with concurrent influenza, contact with someone infected with MRSA, or radiographic evidence of necrotizing pneumonia. Appropriate agents for outpatient treatment of adults with CAP include macrolides, doxycycline, and fluoroquinolones with enhanced activity against S. pneumoniae (Table 74-1). 1 In patients properly identified at low risk for complications and who will have careful outpatient follow-up, use of a macrolide or doxycycline is reasonable. For patients at higher risk of DRSP due to recent antibiotic use or comorbidities such as chronic heart, lung, liver, or renal disease, a respiratory fluoroquinolone should be considered. For patients who have received a fluoroquinolone within the previous few months, a combination of a macrolide plus a β-lactam agent (e.g., high-dose amoxicillin [1 g three times daily], amoxicillin-clavulanate [2 g orally twice daily], or cefpodoxime) is appropriate. Except for the administration of fluoroquinolones, these recommendations also apply to school-age children and adolescents, in whom mycoplasmal infection is common. For patients whose illness is severe enough to require hospital admission and parenteral antibiotics, options include a combination of a β-lactam agent (e.g., ceftriaxone, cefotaxime, ampicillin-sulbactam, or ertapenem) and a macrolide (e.g., intravenous or oral azithromycin) or an extended-spectrum fluoroquinolone alone. These regimens are associated with lower mortality in elderly patients hospitalized for CAP compared with monotherapy with a third-generation cephalosporin. These regimens treat the most common bacterial pathogens, such as S. pneumoniae, M. catarrhalis, and H. influenzae, and atypical pathogens, such as Mycoplasma, Chlamydophila, and Legionella spp. Intravenous azithromycin alone is another option, although this drug does not achieve significant serum levels and lacks significant activity against many aerobic gram-negative bacilli and DRSP. Azithromycin alone might be an appropriate choice for people with milder illness who are less likely to be bacteremic. If anaerobic organisms are suspected (e.g., aspiration), clindamycin or metronidazole could be added to the regimen, or the regimen could include an antibiotic with anaerobic activity, such as ertapenem, ampicillin-sulbactam, or piperacillin-tazobactam. Some quinolones, such as moxifloxacin, are also active against anaerobes (Table 74-2). Seriously ill patients who present with severe sepsis or septic shock require aggressive fluid resuscitation and may benefit from more intensive management with vasopressors, transfusion, and inotropic agents as part of early goal-directed therapy. 31 Severely ill and compromised patients are at relatively greater risk of infection due to S. pneumoniae, aerobic gram-negative bacilli, S. aureus (including MRSA), and, in some areas, Legionella sp. For pneumonia patients admitted to an ICU, adequate activity against DRSP may be more important. Outcomes with severe pneumococcal pneumonia may be better with combination therapy compared with a single agent such as a fluoroquinolone alone. 32 A third-generation cephalosporin or β-lactam/β-lactamase inhibitor can be combined with a fluoroquinolone. Addition of an aminoglycoside should be considered if septic shock is present. Patients with recent hospitalization, neutropenia, or underlying bronchiectasis are at increased risk of infection with P. aeruginosa. Empirical therapy should include two agents with extended gram-negative activity, including P. aeruginosa. Empirical regimens include cefepime, imipenem, meropenem, or piperacillin-tazobactam, plus either ciprofloxacin (high dose) or an aminoglycoside and a macrolide. For lifethreatening pneumonia in populations at risk for MRSA, and for patients recently exposed to fluoroquinolones who may have fluoroquinolone-resistant S. pneumoniae, consider vancomycin or linezolid. The regimen should also cover atypical pathogens and gram-negative bacilli. Since HCAP is associated with higher mortality and a greater likelihood of unusual pathogens, it is appropriate to give broader spectrum empirical therapy, usually with a combination of antimicrobials to increase the chance that at least one antibiotic will be active against the causative pathogen. Appropriate combinations include an antipseudomonal β-lactam agent, such as piperacillin-tazobactam, cefepime, imipenem, or meropenem, with either an aminoglycoside or a fluoroquinolone and vancomycin or linezolid for MRSA. 33 For patients with AIDS, it is important to treat P. jirovecii and bacterial pathogens such as S. pneumoniae. TMP-SMX is the treatment of choice; the usual regimen is 20 mg/kg of TMP and 100 mg/kg of SMX daily in four divided doses, to be continued for 21 days. 34 For most adult patients, a regimen of three ampules (80 mg of TMP and 400 mg of SMX per ampule) every 6 hours is appropriate. For patients allergic to sulfa, pentamidine can be given, 4 mg/kg over 1 hour. Toxicities of pentamidine include acute hypotension and hypoglycemia. Because pentamidine has no activity against S. pneumoniae or other bacterial pathogens, it is important to add a cephalosporin or other antibacterial agent to the initial