Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults

INTRODUCTION — Community-acquired pneumonia (CAP) is defined as an acute infection of the pulmonary parenchyma in a patient who has acquired the infection in the community, as distinguished from hospital-acquired (nosocomial) pneumonia (HAP).

CAP is a common and potentially serious illness [1,2]. It is associated with considerable morbidity and mortality, particularly in older adult patients and those with significant comorbidities. (See "Morbidity and mortality associated with community-acquired pneumonia in adults".)

The epidemiology, pathogenesis, and microbiology of CAP in adults will be reviewed here. A variety of other important issues related to CAP are discussed separately. These include:

●(See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults".)

●(See "Sputum cultures for the evaluation of bacterial pneumonia".)

●(See "Community-acquired pneumonia in adults: Assessing severity and determining the appropriate site of care".)

●(See "Treatment of community-acquired pneumonia in adults in the outpatient setting".)

●(See "Treatment of community-acquired pneumonia in adults who require hospitalization".)

●(See "Aspiration pneumonia in adults" and "Epidemiology of pulmonary infections in immunocompromised patients".)

●(See "Nonresolving pneumonia".)

●(See "Morbidity and mortality associated with community-acquired pneumonia in adults".)

●(See "COVID-19: Epidemiology, virology, and prevention".)

EPIDEMIOLOGY

Community-acquired pneumonia — The overall incidence of CAP in adults is estimated at approximately 16 to 23 cases per 1000 persons per year; the rate rises with age [3-5]. In the United States, approximately 30 percent of patients with CAP are hospitalized, with an incidence of approximately 5 to 7 CAP hospitalizations per 1000 persons per year [3-5]. There is seasonal variation, with more cases occurring during the winter months. The rates of pneumonia are higher for men than for women and for Black persons compared with White persons. The etiology of CAP varies by geographic region; however, Streptococcus pneumoniae is the most commonly identified bacterial cause of CAP worldwide. Viruses are common causes of CAP as well [6,7]. The microbiology of CAP is discussed in greater detail below. (See 'Microbiology' below.)

In 2005, pneumonia and influenza combined was the eighth most common cause of death in the United States and the seventh most common cause of death in Canada [8,9]. There were over 60,000 deaths due to pneumonia in the United States. Mortality is highest for CAP patients who require hospitalization. Data from the Centers for Medicare and Medicaid Services database estimate the 30-day mortality rate of CAP patients (mostly those >65 years of age) requiring admission to the hospital in the United States to be approximately 12 percent [10]. Overall mortality may also vary according to geographic location (United States/Canada 7.3 percent; Europe 9.1 percent; Latin America 13.3 percent); however, following adjustment for confounding variables, these differences are often reduced [11]. All-cause mortality in patients with CAP is as high as 28 percent within one year. Given the aging population in North America, it is expected that the burden of CAP will increase. (See "Morbidity and mortality associated with community-acquired pneumonia in adults".)

Health care-associated pneumonia — As noted above, community-acquired pneumonia (CAP) is defined as an acute infection of the pulmonary parenchyma in a patient who has acquired the infection in the community, as distinguished from hospital-acquired (nosocomial) pneumonia (HAP).

A third category of pneumonia, designated health care-associated pneumonia (HCAP), was included in prior HAP guidelines [12] (but not current HAP guidelines [13]) to identify patients thought to be at increased risk for multidrug-resistant (MDR) pathogens coming from community settings. HCAP referred to pneumonia acquired in health care facilities such as nursing homes, hemodialysis centers, and outpatient clinics or a hospitalization within the past three months. The rationale for the separate designation of HCAP (and its association with HAP) was that patients with HCAP were thought to be at higher risk for MDR organisms. However, several studies have shown that many patients defined as having HCAP are not at high risk for MDR pathogens [14-16], and that this designation is not a good predictor of who will have an infection with an MDR organism [17]. Furthermore, although interaction with the health care system is potentially a risk for MDR pathogens, underlying patient characteristics are also important independent determinants of risk for MDR pathogens and mortality. It is anticipated that patients previously designated as HCAP will be included in the next update of the Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) CAP guidelines because patients with HCAP frequently present from the community and are initially cared for in emergency departments.

PATHOGENESIS — The lungs are constantly exposed to particulate material and microbes that are present in the upper airways and, by microaspiration, enter the lower respiratory tract. Contrary to longstanding belief, the lower respiratory tract is not sterile. Using culture-independent techniques, investigators have shown that healthy lower airways contain some bacterial species that are also found in the upper respiratory tract, such as Prevotella spp, Veilonella spp, and Streptococcus spp [18]. However, pulmonary host defenses are important for maintaining the microbiome at low levels and devoid of conventional pathogens. These host defenses can be categorized as innate (nonspecific) or acquired (specific). The development of community-acquired pneumonia (CAP) indicates either a defect in host defenses, exposure to a particularly virulent microorganism, or an overwhelming inoculum [19-21].

Microaspiration is the most common mechanism through which the constituents of the microbiota and pathogens reach the lung. Hematogenous spread from a distant infected site, direct spread from a contiguous focus, and macroaspiration are other mechanisms whereby pathogens gain access to the lung.

Local pathogen multiplication — New understanding of the human microbiome indicates that the lower airways and alveolar space in the healthy lung are not free of microorganisms, as previously considered [18]. Bacteria and viruses are part of the normal lung microbiome. The bacteria that constitute the normal alveolar flora are predominantly anaerobic organisms and microaerophilic streptococci. The pathogenesis of some cases of CAP may involve the uncontrolled multiplication of some of these bacteria already present in the alveoli.

Since the common bacterial pathogens associated with CAP are not part of the normal alveolar microbiome, they must arrive and multiply in the alveoli. Local multiplication may be prevented by the killing of organisms by the alveolar macrophage. The presence of a normal alveolar flora may also interfere with the local multiplication of newly arrived pathogenic organisms. The uncontrolled alveolar multiplication of organisms is likely due to a combination of arrival to the alveolar space of a particularly virulent microorganism and abnormal host defenses. In a host prone to aspiration, local multiplication of less virulent bacteria, usually anaerobes from the upper airway, may occur due to an overwhelming inoculum (see "Aspiration pneumonia in adults"). Tobacco use and alcohol consumption are common host conditions that favor development of CAP by altering the normal host defense mechanisms.

Local inflammatory response — If the local alveolar macrophage fails to contain the local multiplication of the pathogenic organism, the macrophage will produce a series of cytokines to bring new phagocytes to the alveolar space. Local production of cytokines will generate an inflammatory response with increased local microvascular permeability. This will facilitate the movement of white blood cells (WBCs), proteins, and fluid into the alveolar space. The arrival of neutrophils, lymphocytes, and antibodies will aid the macrophages in the killing of alveolar pathogens.

Systemic inflammatory response — The production of cytokines and chemokines by activated cells in the alveolar space will spill into the systemic circulation and produce a systemic inflammatory response. The systemic response will aid the local response primarily by activating production of WBCs by the bone marrow, increasing cardiac output, and elevating body temperature. The combination of the local and systemic inflammatory responses can be seen as a normal or physiologic host response to prevent the spread of infection and to control the local alveolar infection. The host local and systemic inflammatory responses explain the majority of the patient's clinical features.

Dysregulated inflammatory response — In some patients, the initial systemic inflammatory response can become dysregulated. This abnormal response will be associated with tissue injury and organ dysfunction. The progression from a physiologic to a dysregulated systemic inflammatory response indicates that pneumonia is now complicated with sepsis [22]. Patients with CAP and sepsis are at risk of progression to organ failure.

Virulence factors — Some microorganisms have developed specific mechanisms to overcome pulmonary host defenses and establish infection [19-21]. Examples include:

●Chlamydia pneumoniae produces a ciliostatic factor.

●Mycoplasma pneumoniae can shear off cilia.

●Influenza virus markedly reduces tracheal mucus velocity within hours of onset of infection and for up to 12 weeks postinfection.

●S. pneumoniae and Neisseria meningitidis produce proteases that can split secretory immunoglobulin (Ig)A. In addition, the pneumococcus produces other virulence factors, including the capsule that inhibits phagocytosis, pneumolysin, a thiol-activated cytolysin that interacts with cholesterol in host cell membranes, neuraminidase, and hyaluronidase.

●Mycobacterium spp, Nocardia spp, and Legionella spp are resistant to the microbicidal activity of phagocytes.

Predisposing host conditions — In addition to microbial virulence factors, diseases and conditions in the host may lead to impairment of pulmonary defense and increased risk of CAP (table 1). These include [23]:

●Older age (marked increase in pneumonia incidence among adults >65 years old)

●Chronic lung diseases and/or other disorders that impair airway clearance:

•Chronic obstructive pulmonary disease (COPD)

•Cystic fibrosis

•Bronchiectasis

•Heart failure

•Bronchial obstruction due to stenosis, tumor, or foreign body

•Lung cancer

•Previous episode of pneumonia (presumably due to scarring)

•Immotile cilia syndrome and Kartagener syndrome (ciliary dysfunction, situs inversus, sinusitis, bronchiectasis)

●Conditions that increase risk of macroaspiration of stomach contents and/or microaspiration of upper airway secretions:

•Any alteration in level of consciousness (eg, stroke, seizure, anesthesia, drug or alcohol intoxication)

•Dysphagia due to esophageal lesions and motility problems

•Wearing dentures while sleeping [24]

●Immunocompromising conditions, such as:

•Diabetes mellitus [25]

•HIV infection (especially for pneumococcal pneumonia) (see "Bacterial pulmonary infections in patients with HIV", section on 'Community-acquired pneumonia')

•Solid organ or hematopoietic stem cell transplantation

•Immunosuppressive medication use (eg, tumor necrosis factor-alpha inhibitors, chemotherapy)

●Metabolic disorders:

•Malnutrition

•Uremia

•Acidosis

●Lifestyle factors and environmental exposures:

•Smoking tobacco

•Alcohol consumption

•Opioid use [26]

•Toxic inhalations

•Overcrowding in jails and shelters [27,28]

•Homelessness [29]

●Instrumentation of the respiratory tract (eg, intubation or bronchoscopy) [30]

●Viral respiratory tract infection, especially influenza; influenza can cause viral pneumonia and predispose patients to bacterial pneumonia (see "Seasonal influenza in adults: Clinical manifestations and diagnosis", section on 'Pneumonia')

Combinations of risk factors, such as smoking, congestive heart failure, and COPD, are additive in terms of risk, a concept known as risk factor stacking [29,31].

Risk factors for CAP caused by specific pathogens are discussed separately. (See "Microbiology, epidemiology, and pathogenesis of Legionella infection", section on 'Risk factors' and "Pneumonia caused by Chlamydia pneumoniae in adults", section on 'Epidemiology' and "Mycoplasma pneumoniae infection in adults", section on 'Epidemiology' and "Pneumococcal pneumonia in patients requiring hospitalization", section on 'Epidemiology'.)

Drugs

●Acid-reducing agents – Several studies have shown an increased risk of CAP among patients taking gastric acid–suppressive therapy, including proton pump inhibitors and H2 blockers. This is discussed in detail separately. (See "Antiulcer medications: Mechanism of action, pharmacology, and side effects", section on 'Adverse effects' and "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders", section on 'Pneumonia'.)

●Antipsychotic drugs – Several studies have shown an association between use of antipsychotic drugs and CAP, although the mechanism remains unclear. In one case-control study, use of antipsychotic drugs was associated with an almost 60 percent increase in the risk of pneumonia among older persons requiring hospitalization [32]. In another case-control study, current use of atypical (odds ratio [OR] 2.61, 95% CI 1.48-4.61) or typical (OR 1.76, 95% CI 1.22-2.53) antipsychotic use was associated with a dose-dependent increased risk for CAP compared with past use [33]. Atypical antipsychotic use was also associated with an increase in the risk of fatal CAP (OR 5.97, 95% CI 1.49-23.98).

●ACE inhibitors – In a meta-analysis of randomized trials and observational studies, ACE inhibitors were associated with a reduced risk of pneumonia [34]. However, an accompanying editorial noted that this effect was seen only in observational studies (but not in randomized trials), there was a high likelihood of reporting bias, respiratory infection was not a primary outcome of most of the studies, and there was substantial heterogeneity among the studies [35].

●Glucocorticoids – Some studies, but not others, have suggested an association between inhaled glucocorticoids for chronic obstructive pulmonary disease and pneumonia. (See "Role of inhaled glucocorticoid therapy in stable COPD", section on 'Adverse effects' and "Major side effects of inhaled glucocorticoids", section on 'Lung infection'.)

●Sedatives – Sedatives increase the risk of aspiration pneumonia by reducing consciousness. (See "Aspiration pneumonia in adults", section on 'Predisposing conditions'.)

MICROBIOLOGY

Typical versus atypical bacteria — Bacteria have traditionally been divided into two groups, "typical" and "atypical" agents.

●"Typical" organisms include S. pneumoniae, Haemophilus influenzae, Staphylococcus aureus, group A streptococci, Moraxella catarrhalis, anaerobes, and aerobic gram-negative bacteria.

●"Atypical" pneumonia refers to pneumonia caused by Legionella spp, M. pneumoniae, C. pneumoniae, and Chlamydia psittaci; although imprecise, we use this term because of its acceptance among clinicians.

In the individual patient, there are no findings from history, physical examination, or routine laboratory studies that allow the clinician to distinguish pneumonia caused by atypical versus typical organisms.

Common pathogens — There are more than 100 microbes (bacteria, viruses, fungi, and parasites) that can cause community-acquired pneumonia (CAP). Most cases of CAP in which an organism is identified are caused by one of only four or five microorganisms (table 2), but the distribution of pathogens varies with the clinical setting [36]. A microbiologic diagnosis was confirmed in 38 to 87 percent of cases of CAP in studies that used specialized tests to detect various pathogens [6,7,37-41] but in a lower percentage of cases in studies that did not used specialized tests (table 2) [42,43]. In clinical practice, an etiologic agent is identified even less frequently. As an example, in a review of 17,435 cases of CAP in the Medicare database for United States emergency departments, an etiologic diagnosis was reported in only 7.6 percent of cases [44].

The true prevalence of the various etiologic agents in CAP is uncertain. Studies investigating the etiology of CAP have been performed in different regions, in various patient populations and clinical settings, and using a variety of microbiologic techniques. Because direct culture of infected lung tissue requires invasive techniques, studies primarily use laboratory tests that provide indirect evidence of etiology. These indirect methods include sputum cultures (which may be contaminated with oropharyngeal flora), blood cultures, polymerase chain reaction, urinary antigen tests, and serology. Studies that used serologic testing may have overestimated the incidence of CAP caused by specific pathogens, such as M. pneumoniae and C. pneumoniae [37-40,45], since positive serologic results may represent recent infection rather than active infection. In addition to the use of indirect methods, interpretation of the results is hampered by the failure to identify an organism in a large proportion of cases and the frequency of mixed infections. Pneumococcal vaccination rates also vary across regions, limiting the extent to which prevalence studies can be pooled or generalized from one region to another.

Despite these problems, studies have identified some consistent trends and conclusions regarding the etiology of CAP in adults, which are listed below:

●S. pneumoniae has been the most commonly detected bacterial species in most studies. However, the detection of S. pneumoniae from patients with CAP in the United States has declined significantly, likely due in part to the use of pneumococcal vaccines in adults and the universal use of pneumococcal conjugate vaccines in children (leading to herd immunity). (See 'S. pneumoniae' below.)

●The coronavirus disease 2019 (COVID-19) pandemic has dramatically changed the epidemiology of CAP. And overall, there is increasing recognition that respiratory viruses are common causes of CAP, either as the sole pathogen or as a coinfecting organism. Using molecular methods, viruses are detected in approximately one-third of cases of CAP in adults in nonepidemic settings. (See 'Viruses' below.)

●The "atypical" pathogens (M. pneumoniae, Legionella spp, C. pneumoniae, C. psittaci) are not often identified in clinical practice because there are no widely available specific, rapid, or standardized tests for their detection with the exception of Legionella pneumophila. Of these, M. pneumoniae is the most commonly identified pathogen, especially in pneumonia treated on an ambulatory basis. Legionella spp are less common causes of CAP but are important because they can cause severe CAP and can result in outbreaks of pneumonia. C. pneumoniae was formerly thought to be common based upon studies that used serologic techniques (which do not distinguish between current and past infection), but more recent studies that used molecular techniques identified C. pneumoniae in <1 percent of cases of CAP.

Atypical bacteria, chiefly M. pneumoniae and Legionella spp, have been detected in approximately 3 to 15 percent of patients with CAP requiring hospitalization using techniques other than serology (eg, molecular techniques, Legionella urinary antigen, Mycoplasma culture) [6,7,46]. Other studies have detected atypical bacteria in 20 to 30 percent of cases, but these studies may have overestimated the incidence because serologic techniques were used [45,47,48]. In addition, some of the cases may have occurred as part of sporadic outbreaks. (See 'M. pneumoniae' below and 'C. pneumoniae' below and 'Legionella' below.)

●Staphylococcus aureus, Enterobacteriaceae, and Pseudomonas aeruginosa are important pathogens in selected groups of patients (eg, postinfluenza, prior antimicrobial treatment, or pulmonary comorbidities) [49,50].

●The etiology of pneumonia in a region is dynamic, as evidenced by the emergence of avian influenza viruses, severe acute respiratory syndrome coronaviruses, and Middle East respiratory syndrome coronavirus (MERS-CoV). (See 'Influenza viruses' below and 'Middle East respiratory syndrome coronavirus' below and 'Other viruses' below.)

The frequency of other etiologic agents, such as Mycobacterium tuberculosis, C. psittaci (psittacosis), Coxiella burnetii (Q fever), Francisella tularensis (tularemia), and endemic fungi (histoplasmosis, coccidioidomycosis, blastomycosis), varies with the epidemiologic setting. (See 'Epidemiologic clues' below.)

Pathogen detection based on illness severity — The most commonly identified pathogens depend in part upon the severity of illness as judged by the site of care (outpatient versus inpatient versus intensive care unit [ICU]) (table 3) [6,7,37-39,42,45,48,51].

Outpatients — Among patients treated in the outpatient setting, the most frequently detected pathogens are S. pneumoniae, M. pneumoniae, and respiratory viruses (eg, influenza, parainfluenza, respiratory syncytial virus [RSV]) (table 3) [39,48]. Legionella pneumoniae and H. influenzae are less common.

Inpatients — Among patients who require hospitalization but not admission to an ICU, the most frequently detected pathogens are S. pneumoniae, respiratory viruses (eg, influenza, parainfluenza, RSV, rhinovirus), and, less often, H. influenzae, M. pneumoniae, and Legionella spp (table 3) [6,7,37-39,42,45,51]. Among patients who require admission to an ICU, S. pneumoniae is the most commonly detected pathogen, but Legionella, enteric gram-negative bacilli, S. aureus, H. influenzae, and respiratory viruses are also important.

In the Etiology of Pneumonia in the Community (EPIC) study, a prospective multicenter population-based active surveillance study conducted by the United States Centers for Disease Control and Prevention (CDC) between 2010 and 2012 that included 2259 adults requiring hospitalization for CAP that used specialized techniques, one or more viruses were detected in 23 percent of cases, bacteria in 11 percent, bacteria and viruses in 3 percent, and fungi or mycobacteria in 1 percent; an etiology was not identified in 62 percent of cases [7]. The most commonly identified organisms were rhinovirus (in 9 percent), influenza virus (in 6 percent), and S. pneumoniae (in 5 percent). The incidences of influenza virus and S. pneumoniae were nearly five times as high among individuals ≥65 years of age than among younger adults, and the incidence of rhinovirus was nearly 10 times as high among individuals ≥65 years of age than among younger adults. A caveat is that polymerase chain reactions (PCRs) for respiratory viruses was performed from nasopharyngeal or oropharyngeal swabs; positive results may have represented upper respiratory tract infection in some cases. The majority of patients were admitted to a hospital ward; 21 percent required ICU admission.

A study of 323 adults with CAP admitted to two tertiary hospitals in the United Kingdom used both bacterial cultures and comprehensive multiplex molecular testing for bacteria and viruses on lower respiratory tract specimens that were collected within 48 hours of admission [6]. Using molecular methods, a pathogen was identified in 87 percent of cases. Culture-based methods detected a pathogen in only 39 percent of cases. Of 127 culture-positive specimens, 125 (98 percent) were also positive for the same bacterial species by PCR. H. influenzae and S. pneumoniae were the most common agents detected, followed by a wide variety of typical and atypical pathogens. Viruses were present in 30 percent of cases; 82 percent of these were detected in specimens that also tested positive for bacteria. All patients included in this trial were able to produce a mucopurulent sputum specimen, which may have led to an overestimate of diagnostic yield. An additional caveat is that contamination of specimens with upper respiratory tract secretions could cause false-positive results [52]. However, even when a cutoff of ≥100,000 colony forming units/mL was applied to the bacterial species that commonly colonize the oropharynx, 72 percent of patients were considered to have a bacterial cause of CAP, compared with 81 percent when no cutoff was applied [6].

Epidemiologic clues — The presenting clinical manifestations cannot reliably differentiate between different etiologies, but there are a few epidemiologic and/or clinical clues that can be helpful and must be taken into account when considering the etiology of CAP (table 1):

●Know the local epidemiology and the patient's travel history (eg, endemic fungi, such as Histoplasma, Coccidioides, Blastomyces, and Paracoccidioides spp; hantavirus). (See 'Fungi' below.)

●Be aware of national and international outbreaks (eg, influenza [including avian influenza H5N1 and H7N9], SARS, or MERS) in the geographic region that the patient resides in and/or has visited. (See 'Influenza viruses' below and 'Middle East respiratory syndrome coronavirus' below and 'Other viruses' below.)

●Be aware of local outbreaks of Legionella spp, M. pneumoniae, or C. pneumoniae infections. (See 'Legionella' below and 'M. pneumoniae' below and 'C. pneumoniae' below.)

●Elicit history of specific exposures (eg, Histoplasma spp and bat or bird droppings, C. psittaci and birds). (See 'Histoplasma capsulatum' below.)

●Methicillin-resistant S. aureus (MRSA) is an important cause of severe, occasionally necrotizing CAP. Risk factors for CAP caused by MRSA are discussed below. (See 'S. aureus' below.)

●MRSA and multidrug-resistant gram-negative bacilli, such as P. aeruginosa and extended-spectrum beta-lactamase–producing gram-negative bacilli, should be considered in patients who have certain comorbidities, who have recently received antibiotics, and/or who have had exposure to health care settings. (See 'Gram-negative bacilli' below and 'S. aureus' below and "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired and ventilator-associated pneumonia in adults", section on 'MDR risk factors'.)

●Patients who are severely ill with influenza pneumonia should be evaluated for secondary bacterial pneumonia, which is most likely to be caused by S. pneumoniae, S. aureus (including MRSA), or group A Streptococcus. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis".)

●Never forget M. tuberculosis as a cause of pneumonia, particularly in patients who reside in or have visited endemic regions.

●Pneumocystis jirovecii (formerly P. carinii) is often forgotten as a cause of CAP now that antiretroviral therapy has resulted in a decrease in the number of cases of Pneumocystis pneumonia (PCP) in HIV-infected patients. However, it continues to cause pneumonia in patients with risk factors.

●Consider potential agents of bioterrorism that can cause respiratory symptoms. These include B. anthracis (inhalation anthrax), Yersinia pestis (pneumonic plague), F. tularensis (tularemia), C. burnetii (Q fever), Legionella spp, influenza virus, hantavirus, and ricin (table 4). (See 'CAP and bioterrorism agents' below.)

Bacteria — In many studies of patients with CAP, bacteria have been the most commonly detected organisms. The true incidence of these infections is uncertain because of the difficulty in distinguishing colonizing organisms from pathogens.

S. pneumoniae — S. pneumoniae has traditionally been the most common cause of CAP. In the preantibiotic era, S. pneumoniae was responsible for >75 percent of cases of pneumonia [2,53,54]. However, more recent studies have isolated the organism in only 5 to 15 percent of cases in the United States [7,42,55-57] but in a higher proportion of cases in some other countries [2,6,37]. Factors that are likely to have contributed to the decline in S. pneumoniae as a cause of CAP in the United States include the use of pneumococcal vaccines in adults, the universal use of pneumococcal conjugate vaccines in children (leading to herd immunity), and a reduction in cigarette smoking [2,58].

It is important to note that the rate of isolation of S. pneumoniae increases when more invasive methods are used for obtaining specimens, such as transtracheal aspiration, which eliminates contaminating oropharyngeal flora; this method was used in the past but is no longer used. It is believed that many culture-negative cases are caused by pneumococcus. One factor arguing for the predominance of S. pneumoniae as a cause of CAP is that in patients with CAP who have positive blood cultures, 58 to 81 percent of bloodstream isolates are S. pneumoniae [59,60]; however, only 7 to 10 percent of patients with CAP have positive blood cultures [7,59,60]. One group has estimated that, for every case of bacteremic pneumococcal pneumonia, there are at least three additional cases of non-bacteremic pneumococcal pneumonia [61]. The data supporting this conclusion are presented in greater detail separately.

H. influenzae — Nontypeable H. influenzae is an important cause of pneumonia in older adults and in patients with underlying pulmonary disease, such as cystic fibrosis and chronic obstructive pulmonary disease (COPD). The clinical features are indistinguishable from CAP caused by other organisms. (See "Epidemiology, clinical manifestations, diagnosis, and treatment of Haemophilus influenzae".)

M. pneumoniae — M. pneumoniae is the most common cause of atypical pneumonia in series from the United States and other parts of the world, accounting for up to 15 percent of cases of pneumonia treated in the ambulatory setting based mostly on serologic methods [48]. However, studies that use serologic techniques may overestimate the incidence. (See 'Common pathogens' above.)

M. pneumoniae is transmitted from person to person by infected respiratory droplets during close contact. Infection rates are highest in school-aged children, military recruits, and college students. Substantial rates of macrolide resistance have been observed in certain regions, such as Asia [62]. (See "Mycoplasma pneumoniae infection in adults".)

C. pneumoniae — The incidence of C. pneumoniae in adults with CAP has varied in different studies from 0 to 20 percent [37-39,45], although the validity of these data is in question due to problems with diagnostic testing [63,64]. One problem is the use of a serologic test in many studies, which lacks both sensitivity and specificity for C. pneumoniae. In addition, positive serologic results may represent either current or past infection. More recent studies that used molecular techniques identified C. pneumoniae in <1 percent of cases of CAP [6,7]. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults", section on 'Multiplex molecular assays' and "Pneumonia caused by Chlamydia pneumoniae in adults", section on 'Diagnosis'.)

Transmission of the organism is thought to be person to person and has been implicated in outbreaks of pneumonia in residents of long-term care facilities and military recruits [65-68]. Unlike other respiratory infections, which have peak rates in the winter months, C. pneumoniae infection does not vary significantly by season. Pneumonia and bronchitis are the most common respiratory infections associated with C. pneumoniae. (See "Pneumonia caused by Chlamydia pneumoniae in adults".)

Legionella — Legionella accounts for 1 to 10 percent of cases of CAP. Legionella can occur as a sporadic infection or cause outbreaks. Travel-associated legionellosis is becoming more common. In most instances, Legionella is transmitted to humans by inhalation of aerosols containing the bacteria. Outbreaks have been associated with exposure to a variety of aerosol-producing devices, including showers, a grocery store mist machine, cooling towers of air conditioning systems, whirlpool spas, and fountains (see "Microbiology, epidemiology, and pathogenesis of Legionella infection"). Sporadic legionellosis constitutes the majority of Legionella cases and the source for these cases is often unknown. In Connecticut, investigators found an association between residence of cases in proximity to rivers and watersheds [69].

Gram-negative bacilli — Gram-negative bacilli, especially Klebsiella pneumoniae, Escherichia coli, Enterobacter spp, Serratia spp, Proteus spp, P. aeruginosa, and Acinetobacter spp, are uncommon causes of CAP except in patients with severe pneumonia requiring admission to an ICU where, as a group, they are among the most commonly isolated organisms after S. pneumoniae and in patients with significant underlying disease (table 3) [70,71]. (See "Treatment of community-acquired pneumonia in adults who require hospitalization", section on 'Likely pathogens'.)

●Klebsiella pneumoniae – K. pneumoniae is responsible for approximately 6 percent of cases of CAP in Asia [45] but is less common in other regions (table 2). K. pneumoniae must be considered as a cause of severe CAP in patients who have significant underlying disease, such as COPD, diabetes, and alcohol abuse. In a study of 112 immunocompetent patients with severe CAP, multivariate analysis found K. pneumoniae was an independent risk factor for mortality [71]. (See "Clinical features, diagnosis, and treatment of Klebsiella pneumoniae infection", section on 'Community-acquired pneumonia'.)

●Pseudomonas aeruginosa – Risk factors for community-acquired P. aeruginosa pneumonia include bronchiectasis (eg, due to cystic fibrosis) and the use of repeated antibiotic courses or prolonged glucocorticoids in patients with other structural lung abnormalities, such as COPD and pulmonary fibrosis [49,50,72]. Immunocompromise (eg, neutropenia, HIV infection, solid organ or hematopoietic stem cell transplantation) and previous hospitalization are other risk factors for Pseudomonas pneumonia. (See "Pseudomonas aeruginosa pneumonia".)

●Acinetobacter spp – Acinetobacter spp are well recognized as pathogens causing nosocomial pneumonia. In addition, Acinetobacter baumannii is emerging as a cause of severe CAP with high mortality. Multidrug resistance is an increasing problem with Acinetobacter infection. (See "Acinetobacter infection: Treatment and prevention" and "Acinetobacter infection: Treatment and prevention", section on 'Pneumonia'.)

●Moraxella catarrhalis – Moraxella is a gram-negative diplococcus that can cause lower respiratory tract infections in adults with COPD and in immunocompromised persons. In a review of 58 patients with M. catarrhalis bacteremia, 70 percent had predisposing factors, such as neutropenia, malignancy, or COPD, either alone or in combination [73]. Many patients with this infection are malnourished. Not infrequently, it is a copathogen [74].

S. aureus — In an international multicenter study of inpatients with CAP, MRSA was detected in 95 of 3193 patients (3 percent) who underwent microbiologic testing within 24 hours of admission, with varying prevalence in different continents and countries [75]. Among all S. aureus isolates, 51 percent were MRSA and 49 percent were methicillin-susceptible S. aureus (MSSA). In a study in the United States of 2259 inpatients with CAP, S. aureus was isolated from 37 patients (1.7 percent), including 15 (0.7 percent) with MRSA and 22 (1 percent) with MSSA [76].

S. aureus pneumonia that is community acquired is usually seen in older adults and in younger patients who are recovering from influenza (post-influenza pneumonia) [77-81]. However, the pneumococcus remains the most frequent pathogen in this setting. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis", section on 'Pneumonia'.)

During the 2003 to 2004 influenza season, 17 cases of S. aureus CAP were reported to the CDC from nine states; 15 cases were community-associated methicillin-resistant S. aureus (CA-MRSA) [78]. All isolates had community-associated genetic characteristics; 12 of 13 available S. aureus isolates had the Panton-Valentine leukocidin (PVL) gene. Influenza virus infection was also documented in 12 (71 percent) of cases. All patients were hospitalized and death occurred in five (29 percent); four of the deaths were in patients with MRSA infection. Another outbreak of 10 cases of severe CA-MRSA pneumonia occurred in association with influenza during the 2006 to 2007 influenza season [79]. Six of the patients died.

In a study of 627 patients who presented to emergency departments in 12 cities in the United States between the winter of 2006 and the spring of 2007 and who were hospitalized with CAP, S. aureus was cultured from the blood and/or respiratory tract in 24 patients (4 percent); of these S. aureus infections, 9 (2 percent) were caused by methicillin-susceptible S. aureus and 14 (2.4 percent) were caused by methicillin-resistant S. aureus [43]. Isolation of MRSA (as compared with any other or no pathogen) was associated with a patient history of MRSA, nursing home admission in the previous year, close contact with someone with a skin infection during the previous month, multiple infiltrates or cavities on chest radiograph, and comatose state, intubation, receipt of pressor agents, or death in the emergency department.

CA-MRSA is often associated with severe necrotizing pneumonia [77-79,82-86]. Several studies suggested that the tendency to necrotizing pneumonia may be mediated by PVL, which is typically present in CA-MRSA strains [77-79,83-85,87-89]. However, subsequent reports have disproven the role of PVL as a virulence factor in MRSA pneumonia [90-94].

Other bacteria

●Group A Streptococcus – Group A Streptococcus (GAS; S. pyogenes) can cause a fulminant pneumonia with early empyema formation even in young, immunocompetent hosts. In a prospective surveillance study for invasive GAS infection, pneumonia accounted for 11 percent of cases with a mortality rate of 38 percent compared with 26 percent for necrotizing fasciitis and 12 percent for the entire cohort of invasive disease [95].

The largest outbreak of GAS pneumonia in the United States occurred in 2002 among military recruits at the recruiting depot in San Diego [96,97]. Twenty-seven percent of 127 cases of pneumonia were definitely or probably due to GAS, and another 17 percent were coinfected with GAS and another pathogen [96,97]. The epidemic occurred despite prophylaxis against GAS but was ended after the administration of additional prophylaxis [97].

●Anaerobes – Anaerobic organisms cause the pneumonia that sometimes develops following aspiration and are also involved in necrotizing polymicrobial infections that result in lung abscess. Anaerobic pathogens in pulmonary infections should be suspected when there is putrid sputum or putrid empyema fluid (diagnostic of anaerobes), infection associated with aspiration, which usually results in an infiltrate in a dependent pulmonary segment (superior segment of a lower lobe or posterior segment of an upper lobe), or infection-associated necrosis (abscess or necrotizing pneumonia). Most infections are polymicrobial with predominance of anaerobes (eg, Bacteroides melaninogenicus, Fusobacterium spp, Peptostreptococcus spp) and/or oral streptococci (eg, Streptococcus milleri). Given the difficulty with obtaining appropriate pretreatment specimens and the tedious microbiology required, most cases are treated empirically. (See "Aspiration pneumonia in adults" and "Lung abscess in adults".)

●Neisseria meningitidis – N. meningitidis is an uncommon cause of CAP. Meningococcal pneumonia has no distinguishing clinical features compared to other causes of CAP. However, pneumonia due to N. meningitidis should be reported to the health department and prophylaxis given as for meningitis or septicemia. (See "Clinical manifestations of meningococcal infection".)

●Mycobacterium tuberculosis – M. tuberculosis is an important cause of CAP in developing countries and in some regions of the United States [98,99]. Missed diagnosis is common, as illustrated in report from Baltimore in which 16 of 33 patients (48 percent) with culture-confirmed pulmonary tuberculosis (TB) were initially treated for presumed CAP [99]. (See "Clinical manifestations and complications of pulmonary tuberculosis".)

●Burkholderia pseudomallei – B. pseudomallei is an important cause of CAP in endemic regions (South and Southeast Asia, China, and Northern Australia). Occurrence outside of these regions is rare and usually linked to travel. (See "Melioidosis: Epidemiology, clinical manifestations, and diagnosis".)

Other bacteria that can cause CAP include F. tularensis (tularemia), C. burnetii (Q fever), and Bacillus anthracis (anthrax). These microorganisms are described below. (See 'CAP and bioterrorism agents' below.)

Viruses — The frequency of specific viral pathogens varies with the diagnostic studies used for detection [100]. The use of the PCR has increased the diagnostic yield compared with conventional tests, such as viral culture and antigen detection assays [101-103]. As an example, in a randomized trial that included 107 inpatients with CAP, real-time PCR increased the diagnostic yield compared with conventional diagnostic procedures (43 compared with 21 percent) with 26 viral etiologies identified by PCR compared with only 16 by conventional methods [101]. In other studies that used PCR with or without other methods, viruses were detected in up to one-third of cases of CAP in adults [6,7,37,51,102,104]. Since respiratory virus can be present in the upper airways without causing illness, studies using multiplex PCR may overestimate the frequency of viruses as a cause of CAP. Using PCR, nasopharyngeal swabs are positive for respiratory tract viruses in 20 to 30 percent of healthy adults [105].

Influenza remains the clinically most significant viral cause of CAP in adults; other common viral pathogens include RSV, parainfluenza viruses, and adenovirus (table 2) [102]. Other viruses that have been detected in patients with CAP include rhinoviruses, coronaviruses, and human metapneumovirus (hMPV) [102]. However, in a study that used multiplex PCR, in 30 of 32 patients in whom rhinovirus or a coronavirus was implicated, another organism was also identified [106]. A possible reason for this is that rhinovirus and coronavirus were not causing the pneumonia but impairing upper airway defenses so that pathogens can establish themselves in the lower respiratory tract. In another study, bacterial coinfection was associated with approximately 40 percent of viral respiratory tract infections requiring hospitalization [107]. In a separate study, the rate of mixed viral-bacterial infection was approximately 20 percent; such mixed infections have been found to be associated with more severe CAP and longer hospitalization than CAP caused by bacteria alone [108].

Although viruses are commonly found in the nasopharynx of adults with CAP, it is often unclear whether these viruses are the sole agents causing CAP. In addition to possibly predisposing patients to infections with other organisms, the presence of a respiratory virus may also represent prolonged shedding (especially in immunocompromised hosts), upper respiratory tract infection, or colonization.

However, some studies have suggested that viruses like rhinovirus are likely to play a pathogenic role in CAP in adults. As an example, one study evaluated whether viruses are detected in the nasopharynx by PCR more commonly in patients with pneumonia than in asymptomatic individuals sampled at the same time and in the same geographic area [109]. Viruses were detected rarely in asymptomatic adults but frequently in adults with CAP (2.1 versus 24.5 percent). Viruses were detected more often in both asymptomatic children (24.4 percent) and children with CAP (68.8 percent) compared with adults. Detection of influenza, RSV, and hMPV were rare in asymptomatic adults and children. Associations of rhinovirus and adenovirus with CAP varied with age. Asymptomatic rhinovirus detection declined with increasing age. This led to a strong association of rhinovirus with CAP in adults, a more modest association in older children, and no association in younger children. In children, RSV and hMPV were highly associated with CAP. Adenovirus in the nasopharynx was only associated with CAP in children <2 years of age but not in older children.

In a study of 259 patients with a pneumonia syndrome, 44 viruses were detected in 42 patients: 26 (16.2 percent) had rhinovirus, 7 had coronavirus, 4 had parainfluenza virus, 3 had RSV, 1 had hMPV, and 1 had influenza [55]. A virus was the only pathogen detected in 30; 3 of 30 patients had clinical characteristics suggestive of bacterial pneumonia. The procalcitonin level was 0.81, significantly lower than in patients with bacterial infection. In 28 of 42 patients (66.6 percent), there was reasonable evidence that the viral pathogen detected in the nasopharynx did indeed cause the pneumonia.

Influenza viruses — Influenza A or B viruses cause an acute respiratory illness that occurs in outbreaks and epidemics worldwide, mainly in the winter season. Avian influenza viruses (eg, H5N1 and H7N9 avian influenza) have emerged to cause disease in humans. (See "Influenza: Epidemiology and pathogenesis" and "Avian influenza: Epidemiology and transmission".)

Influenza viruses can cause pneumonia, although they are far more likely to cause upper respiratory tract infection and to predispose to secondary pulmonary infection by bacteria. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis", section on 'Pneumonia'.)

Primary influenza pneumonia occurs when influenza virus infection directly involves the lung, typically producing a severe pneumonia. Influenza pneumonia occurs most frequently in certain groups of patients with underlying chronic illnesses who are classified as "high risk" for this infection (table 5).

Patients who are severely ill with influenza should be evaluated for a secondary bacterial pneumonia, which is most likely to be caused by S. pneumoniae, S. aureus (including MRSA), or group A streptococci. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis".)

The first association of avian influenza H5N1 with clinical respiratory disease occurred in Hong Kong in 1997 when 18 human cases occurred during a poultry outbreak of highly pathogenic H5N1 influenza in live bird markets. The clinical features of avian influenza are variable, being determined in part by the strain. In the 1997 outbreak, 58 percent of patients had pneumonia. (See "Avian influenza: Epidemiology and transmission".)

Another avian influenza virus, H7N9, emerged in China in 2013 and has caused severe pneumonia in some patients. (See "Avian influenza: Epidemiology and transmission", section on 'Avian influenza H7N9'.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) — COVID-19, the disease caused by SARS-CoV-2, is discussed separately. (See "COVID-19: Epidemiology, virology, and prevention".)

Parainfluenza viruses — Parainfluenza viruses are important respiratory pathogens in immunocompromised adults, causing potentially life-threatening lower respiratory tract infections. (See "Parainfluenza viruses in adults".)

Respiratory syncytial virus — RSV causes acute respiratory tract illness in persons of all ages. Traditionally a viral pathogen of children, RSV can also cause CAP in adults and can be particularly severe in older adults and immunocompromised individuals (eg, hematopoietic cell transplant recipients). (See "Respiratory syncytial virus infection: Clinical features and diagnosis".)

Adenovirus — Adenovirus pneumonia was first described among military recruits in whom it causes an "atypical pneumonia." The usual symptoms are fever, malaise, and cough (often with substernal discomfort). Increased peribronchial markings with patchy alveolar infiltrates are found on chest radiography. Pneumonia occasionally results in fatalities. (See "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection".)

Human metapneumovirus — HMPV was first described in 2001 in the Netherlands. HMPV can cause upper and lower respiratory tract infection in patients of all age groups, but symptomatic disease most often occurs in young children or older adults. It is an emerging pathogen as a cause of CAP in adults. (See "Human metapneumovirus infections".)

Middle East respiratory syndrome coronavirus — A novel coronavirus, Middle East respiratory syndrome coronavirus, causing severe respiratory illness, emerged in 2012 in Saudi Arabia. Additional cases and clusters of MERS-CoV infections have been detected subsequently in Saudi Arabia, other Arabian Peninsula countries, and other countries. MERS should be considered in patients who have traveled to the Arabian Peninsula within 14 days of presentation. (See "Middle East respiratory syndrome coronavirus: Virology, pathogenesis, and epidemiology" and "Middle East respiratory syndrome coronavirus: Clinical manifestations and diagnosis", section on 'Diagnosis'.)

Although most clusters of MERS have been characterized by limited human-to-human transmission, an outbreak of MERS in South Korea in 2015 was associated with superspreading events. Superspreading events are outbreaks in which specific individuals are responsible for a disproportionately large number of transmission events [110]. (See "Middle East respiratory syndrome coronavirus: Virology, pathogenesis, and epidemiology", section on 'Human-to-human transmission'.)

Rhinovirus — Rhinoviruses are among the most common pathogens that affect humans and are implicated in 30 to 50 percent of acute respiratory tract infections [111]. The advent of multiplex PCR for the etiologic diagnosis of CAP has led to the current prominence of rhinoviruses in the CAP field. As an example, a 2005 study showed that inclusion of PCR on nasopharyngeal and oropharyngeal swabs of patients with CAP improved the diagnostic yield by 16 percent [106]. The most common virus detected was rhinovirus, in 18 of 105 patients (17 percent).

The evidence is accumulating that rhinovirus is likely to play a role in CAP in adults. Nevertheless, some experts have questioned the role of rhinoviruses in the pathogenesis of pneumonia [111,112], arguing that the frequency of rhinovirus infections in the population makes assessment of causal role in pneumonia difficult [111].

In the EPIC study, a prospective multicenter population-based active surveillance study of 2259 adults requiring hospitalization for CAP, rhinovirus was the most commonly identified organism (in 9 percent) [7]. The incidence of rhinovirus was nearly 10 times as high among CAP patients ≥65 years of age than among younger CAP patients. A caveat is that PCR for rhinovirus was performed from nasopharyngeal or oropharyngeal swabs; positive results may have represented upper respiratory tract infection in some cases. Nevertheless, a related study suggested that rhinovirus is strongly associated with CAP in adults (but not in children) [109]. Rhinovirus was detected in 21 of 192 adults with CAP (10.9 percent) but in only 2 of 238 asymptomatic adults (0.8 percent). (See 'Viruses' above.)

In a single-center study in Finland conducted from June 2008 to May 2012, three nasopharyngeal swabs and bronchoalveolar lavage fluid were obtained from adults with CAP who were started on mechanical ventilation during the first 48 hours following ICU admission [103]. Of the 49 patients studied, a bacterium was detected in 43 percent and a virus in 49 percent; in 10 percent of patients, a virus was the only pathogen detected. Rhinoviruses were found in 31 percent of patients.

Other viruses

●Severe acute respiratory syndrome – In November 2002, an outbreak of SARS started in Guangdong Province in southern China and spread worldwide, affecting more than 8000 persons. SARS was due to a novel coronavirus that jumped the species barrier from civet cats to man. The case-fatality rate of the 2003 Hong Kong outbreak was 11 percent, but higher mortality was seen in older adults (≥60 years of age) and pregnant women. Superspreading events, which are outbreaks in which specific individuals are responsible for a disproportionately large number of transmission events, likely contributed to the SARS outbreak [110]. (See "Severe acute respiratory syndrome (SARS)" and "Severe acute respiratory syndrome (SARS)", section on 'Transmission'.)

●Other coronaviruses – Human coronaviruses were first described in association with respiratory infections in 1935 but were ignored until the advent of SARS. HCoV-229E and HCoV-OC43 caused upper and lower respiratory tract infections prior to the SARS outbreaks. Since that time, human coronaviruses HCoV-NL63 and CoV-HKU1 have been identified as additional etiologic agents in CAP.

HCoV-NL63 was recovered from 19 of 525 (3.6 percent) of respiratory specimens collected from laboratories across Canada in 2001 and 2002 [113], primarily causing infections of the upper respiratory tract. In contrast, CoV-HKU1 accounted for 2.4 percent (10 of 418) of CAP cases in Hong Kong [114]. (See "Coronaviruses".)

●Hantavirus – In May 1993, an outbreak of severe respiratory illness caused by a previously unknown virus, hantavirus, occurred in the southwestern United States. The illness was preceded by prodromal flu-like symptoms, followed by noncardiogenic pulmonary edema. The virus accounting for the initial cases, Sin Nombre virus, is spread to humans from infected mice. Subsequently, other hantaviruses have been found to cause hantavirus pulmonary syndrome, and the disease has been described in other parts of the United States, western Canada, and South America. It is important to recognize that hantavirus does not cause pneumonia but instead causes an acute respiratory distress syndrome (ARDS)-like picture due to the host response to this virus. (See "Epidemiology and diagnosis of hantavirus infections" and "Hantavirus cardiopulmonary syndrome".)

●Varicella – Varicella pneumonia is the most frequent complication of varicella infection in normal healthy adults, with a reported incidence of about 1 in 400 cases. The case-fatality rate is between 10 and 30 percent. (See "Clinical features of varicella-zoster virus infection: Chickenpox".)

Fungi — Fungal infection is an unusual cause of CAP in immunocompetent patients, but certain fungi (eg, Histoplasma capsulatum, Coccidioides spp, Blastomyces dermatitidis) can cause pneumonia in immunocompetent or immunocompromised patients who reside in or have visited endemic areas. The specific epidemiology of some fungal infections is therefore important as a diagnostic clue. Fungal infection is more common in immunocompromised patients, particularly those with neutropenia, those receiving chronic immunosuppressive therapy (eg, organ transplant recipients), and those infected with HIV.

A retrospective study examined the microbiologic etiology of 94 cases of community-acquired pulmonary fungal infection hospitalized in Taiwan [115]. The criteria for diagnosis were a lung lesion on chest radiographs and either the presence or isolation of fungi from a tissue biopsy, pleural effusion, or blood. The most frequently isolated fungi were Aspergillus species (56 percent), followed by Cryptococcus species (31 percent), and Candida species (4 percent).

Cryptococcus spp — Cryptococcus organisms are found in the soil throughout the world, and a significant percent of the population has most likely been exposed to these organisms. Primary infections occur in both immunocompetent and immunocompromised persons. In immunocompetent individuals, primary infections are most commonly asymptomatic and usually discovered as an incidental finding on chest radiograph. In contrast, cryptococcal pneumonia in immunocompromised patients is usually symptomatic with the most common signs and symptoms being cough, fever, and dyspnea. (See "Microbiology and epidemiology of Cryptococcus neoformans infection" and "Cryptococcus neoformans infection outside the central nervous system".)

Histoplasma capsulatum — H. capsulatum is found worldwide; within the United States, infection is most common in the Midwestern states located in the Ohio and Mississippi River Valleys. H. capsulatum proliferates best in soil contaminated with bird or bat droppings. Less than 5 percent of exposed individuals develop symptomatic disease after a low-level exposure. However, the majority of patients develop symptomatic infection following more extensive exposure, as occurs with activities that disturb heavily contaminated soil or areas with large amounts of bird or bat droppings.

Symptomatic patients with acute histoplasmosis generally present with a flu-like illness with pulmonary complaints and radiographic abnormalities, including bronchopneumonia or signs of interstitial pneumonitis. (See "Pathogenesis and clinical features of pulmonary histoplasmosis".)

Coccidioides spp — Coccidioidomycosis is the infection caused by the dimorphic fungi of the genus Coccidioides (C. immitis and C. posadasii). These fungi are endemic to certain deserts of the Western Hemisphere, including southern Arizona, central California, southwestern New Mexico, and west Texas in the United States. They are also found in parts of Mexico and Central and South America. (See "Primary pulmonary coccidioidal infection", section on 'Epidemiology' and "Primary pulmonary coccidioidal infection", section on 'Microbiology'.)

A prospective observational study of 55 adults with CAP in Arizona found serologic evidence for coccidioidomycosis (valley fever) as the etiologic agent in 16 patients (29 percent) [116]. This study suggests that valley fever is a common cause of CAP after exposure in a disease-endemic region and that patients exposed in these regions that develop CAP should undergo laboratory evaluation for this organism.

The most common presenting symptoms of primary coccidioidal infection are chest pain, cough, and fever. Although initial infections usually have a respiratory component, chest radiographs are unremarkable in up to one-half of all patients. Common radiographic abnormalities include unilateral infiltrate and ipsilateral hilar adenopathy. (See "Primary pulmonary coccidioidal infection".)

Other fungi — Other fungi that can cause CAP include Aspergillus spp and Pneumocystis jirovecii (formerly P. carinii). Infection with these fungi occurs primarily in the setting of immunosuppression. Pulmonary aspergillosis is particularly associated with severe neutropenia, while P. jirovecii is particularly associated with HIV infection and other defects in cell-mediated immunity. (See "Epidemiology and clinical manifestations of invasive aspergillosis" and "Clinical presentation and diagnosis of Pneumocystis pulmonary infection in patients with HIV" and "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in patients without HIV".)

B. dermatitidis can cause pneumonia in both immunocompetent and immunocompromised hosts. (See "Clinical manifestations and diagnosis of blastomycosis", section on 'Pulmonary involvement' and "Mycology, pathogenesis, and epidemiology of blastomycosis", section on 'Epidemiology'.)

Mixed infections — The role of more than one causative microorganism in CAP is difficult to establish. A prospective study of 1511 consecutive hospitalized patients examined the incidence of mixed respiratory pathogens in patients with CAP [117]. Microbiologic evaluation included sputum and blood cultures (and pleural fluid, transbronchial aspirates, protected specimen brush, and bronchial alveolar lavage when available), paired serologies (for influenza, parainfluenza, respiratory syncytial, and adenoviruses and C. pneumoniae, M. pneumoniae, L. pneumophila, and C. burnetii), and urine antigen (for S. pneumoniae and L. pneumophila). Of 610 patients in whom an etiology was identified, 82 (13 percent) had more than one microorganism. S. pneumoniae was identified in 44 of 82 mixed infections (54 percent).

The clinical importance of mixed infections on outcome is difficult to assess, although there is a suggestion that patients with mixed infections have a more severe illness as illustrated in a prospective study of 493 patients with CAP in whom an extensive microbiologic workup was performed [118]. Compared with patients with monomicrobial pneumonia, patients with mixed pneumonia were more likely to have complications of the pneumonia (39.3 versus 18.6 percent); however, they were also more likely to have an underlying comorbid illness (64 versus 45 percent).

CAP and bioterrorism agents — Several biological agents may be used for bioterrorism and can cause a CAP syndrome. In the event of a possible bioterrorist event, local emergency response systems should be activated by dialing 911 in the United States or equivalent emergency telephone numbers in other countries. Local and state public health authorities should also be notified immediately. In addition, in the United States, the local Federal Bureau of Investigation office should be contacted promptly. (See "Identifying and managing casualties of biological terrorism", section on 'Public health notification'.)

Bioterrorism agents that can cause CAP include B. anthracis (inhalation anthrax), Yersinia pestis (pneumonic plague), F. tularensis (tularemia), C. burnetii (Q fever), Legionella spp, influenza virus, and hantavirus (table 4) [119]:

●Bacillus anthracis (anthrax) – On October 2, 2001, a 63-year-old male from Florida became the first case of inhalation anthrax in the United States since 1968 and was the first due to an act of biological terrorism. Anthrax was deliberately spread through the postal system by sending letters with a powder containing B. anthracis, a gram-positive bacillus that forms spores. Two of the 22 persons infected in the postal attack developed inhalational anthrax. (See "Microbiology, pathogenesis, and epidemiology of anthrax".)

Inhalation anthrax is the deadliest form of the disease. The incubation period following exposure is one to six days. The classic chest radiograph findings are mediastinal widening with pleural effusions. A World Health Organization expert committee estimated that if 50 kg of anthrax was released over an urban population of five million, there would be 250,000 casualties, 100,000 of whom would be expected to die without treatment [120]. (See "Clinical manifestations and diagnosis of anthrax".)

●Yersinia pestis (plague) – Biological weapons programs in the United States and the Soviet Union following World War II developed techniques for aerosolizing Y. pestis, the agent of plague. The hypothetical intentional release of aerosolized plague would cause widespread illness; the case-fatality rate for primary pneumonic plague is close to 100 percent if treatment is not initiated within 24 hours.

The time to onset of symptoms following exposure is two to three days. The most common chest radiograph findings are bilateral infiltrates, often with pleural effusions. (See "Clinical manifestations, diagnosis, and treatment of plague (Yersinia pestis infection)".)

●Francisella tularensis (tularemia) – Tularemia is caused by the gram-negative bacilli, F. tularensis. During the 1950s and 1960s, both the United States and the Soviet Union biological weapons program developed aerosolized F. tularensis. It has been estimated that dispersal of 50 kg of virulent F. tularensis over a metropolitan area with five million people would result in 250,000 incapacitating casualties, including 19,000 deaths [121].

Tularemia has a longer incubation period than either inhalation anthrax or plague. The classic chest radiographic findings are bilateral infiltrates with hilar adenopathy. (See "Tularemia: Clinical manifestations, diagnosis, treatment, and prevention".)

●C. burnetii (Q fever) – C. burnetii is the etiologic agent of Q fever and is a CDC category B biological agent. As a biological warfare agent, C. burnetii can be easily dispersed as an aerosol with a high infectivity rate and pneumonia as the major manifestation. Further information regarding Q fever can be found on the United States Centers for Disease Control and Prevention website [122,123].

Ricin is a toxin naturally found in castor beans that could be used as an agent of bioterrorism. Although ricin does not cause CAP, inhalational ricin may cause respiratory distress, fever, cough, and pulmonary edema. (See "Identifying and managing casualties of biological terrorism", section on 'Toxins of concern'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topic (see "Patient education: Community-acquired pneumonia in adults (The Basics)")

●Beyond the Basics topic (see "Patient education: Pneumonia in adults (Beyond the Basics)")

SUMMARY

●Community-acquired pneumonia (CAP) is a common and potentially serious illness. It is associated with considerable morbidity and mortality, particularly in older adult patients and those with significant comorbidities. (See 'Introduction' above.)

●The overall incidence of CAP in adults is estimated at approximately 16 to 23 cases per 1000 persons per year; the rate rises with age. There is seasonal variation, with more cases occurring during the winter months. The rates of pneumonia are higher for men than for women and for Black persons compared with White persons. (See 'Epidemiology' above.)

●The lungs are constantly exposed to particulate material and microbes that are present in the upper airways and, by microaspiration, enter the lower respiratory tract. Contrary to longstanding belief, the lower respiratory tract is not sterile. Healthy lower airways contain some bacterial species that are also found in the upper respiratory tract, such as Prevotella spp, Veilonella spp, and Streptococcus spp. The development of CAP indicates either a defect in host defenses, exposure to a particularly virulent microorganism, or an overwhelming inoculum. (See 'Pathogenesis' above.)

●In addition to microbial virulence factors, diseases and conditions in the host may lead to impairment of pulmonary defense and increased risk of CAP (table 1). (See 'Predisposing host conditions' above.)

●The presenting clinical manifestations cannot reliably differentiate between different etiologies, but there are a few epidemiologic and/or clinical clues that can be helpful and must be taken into account when considering the etiology of CAP (table 1). (See 'Epidemiologic clues' above.)

●There are more than 100 microbes (bacteria, viruses, fungi, and parasites) that can cause CAP. Most cases of pneumonia are caused by one of only four or five microorganisms. The most commonly identified pathogens depend in part upon the severity of illness as judged by the site of care (outpatient versus inpatient versus intensive care unit) (table 3). (See 'Microbiology' above.)

●In many studies of patients with CAP, bacteria have been the most commonly detected organisms. The true incidence of these infections is uncertain because of the difficulty in distinguishing colonizing organisms from pathogens. S. pneumoniae is the most commonly identified bacterial cause of CAP. However, it has decreased markedly due to pneumococcal vaccines (table 3 and table 2). (See 'Bacteria' above.)

●Using molecular methods, viruses are detected in approximately one-third of cases of CAP in adults. Influenza is the most significant viral cause of CAP in adults. SARS-CoV-2 is an important cause during the pandemic. Mixed viral-bacterial infection is relatively common. (See 'Viruses' above.)

●Fungal infection is an unusual cause of CAP in the immunocompetent patient, but certain fungi (eg, Histoplasma capsulatum, Coccidioides spp) can cause pneumonia in immunocompetent or immunocompromised patients who reside in or have visited endemic areas. The specific epidemiology of some fungal infections is therefore important as a diagnostic clue. Fungal infection is more common in immunocompromised patients, particularly those with neutropenia, those receiving chronic immunosuppressive therapy (eg, organ transplant recipients), and those infected with HIV. (See 'Fungi' above.)

ACKNOWLEDGMENT — We are saddened by the death of John G Bartlett, MD, who passed away in January 2021. UpToDate gratefully acknowledges his tenure as the founding Editor-in-Chief for UpToDate in Infectious Diseases and his dedicated and longstanding involvement with the UpToDate program.