Epidemiology And Etiology
Pneumonia is the number one cause of death among infectious diseases in the United States and was the seventh leading cause of death overall in 2002.10,11 There are approximately 5 million cases of pneumonia in the US each year, with 1.3 million of these evaluated in the nation’s EDs.12 While the majority of patients are treated at home, over a million are hospitalized annually with pneumonia.
The causative organisms for pneumonia vary with age, comorbidities, severity of disease, clinical setting, and geographic location. In many cases, an etiology of pneumonia cannot be identified at all. Streptococcus pneumoniae is the most frequently identified bacterial etiologic agent.13-16 Other commonly identified bacterial pathogens include Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydia pneumoniae, Staphylococcus aureus, Moraxella catarrhalis, Legionella pneumophila, and gram-negative bacilli. Viruses, such as influenza A and B, parainfluenza, adenovirus, respiratory syncytial virus (RSV), hantavirus, and human metapneumovirus, are additional pathogens to consider.17- 19 Numerous studies have reported a significant portion of patients with mixed infection, as well.17,18 Fungi are uncommon overall, but more likely in endemic areas. Histoplasma capsulatum is found in the Mississippi and Ohio River valleys, Coccidioides immitis is found in the southwestern US, and Blastomyces dermatitides is found in a similar geographic area as Histoplasma, plus the southeastern US.
The true prevalence of specific causative organisms is unknown. Published studies fail to identify the causative organism in 40-60% of cases, despite rigorous clinical testing.5,14 There are many factors that explain this failure — no single test or array of tests can identify all potential pathogens, currently available diagnostic tests have limited sensitivity and specificity, and some infections may be caused by pathogens that have yet to be discovered.
In the past, physicians have characterized pneumonia as either “typical” or “atypical.” Patients with “typical” pneumonia presented with acute onset of fever, chills, and cough with productive sputum. Typical pneumonias are caused by S pneumoniae, H influenzae, and M catarrhalis, and may be treated with ß-lactam antibiotics (ie, penicillins or cephalosporins). Patients with “atypical” pneumonia have fever, dry cough, sore throat, and headache. Such symptoms are associated with Mycoplasma pneumoniae and with viruses, and atypical pneumonias may be treated with macrolides or doxycycline.
A number of studies have shown that this dual classification can be misleading — patients with typical pathogens can present with signs and symptoms of atypical pneumonia and vice versa.17,18,20-22 In a prospective study of 395 consecutive patients hospitalized with pneumonia, Ruiz et al found that clinical symptoms classically associated with pneumococcal pneumonia, such as chills and pleuritic chest pain, had sensitivity and specificity in the range of 50%. In a prospective observational study of 343 ambulatory and hospitalized patients in Argentina, 65% of patients initially believed to have typical pneumonia were ultimately diagnosed with an atypical pathogen, and 23% of those patients initially suspected of having a typical pneumonia actually had an atypical pathogen.23
Basing therapy upon the typical/atypical approach could lead to errors in treatment decisions and antibiotic choices. The American Thoracic Society (ATS) has recommended stratifying patients into groups based on age, comorbidities, and severity of symptoms, in order to determine the likely etiology and therefore the appropriate antibiotic choice. This approach has been prospectively validated.17 All patients with CAP should be considered as potentially infected with S pneumoniae, Chlamydia, Mycoplasma, or Legionella. Additional factors in the history and clinical presentation should be considered to broaden the differential of potential pathogens, thereby broadening antibiotic coverage. (Table 2)
Streptococcus pneumoniae is the most commonly identified bacterial pathogen in CAP and is isolated most frequently in bacteremic CAP patients.24,25 Pneumococcal infections are more common in the winter. Pneumococcal infections appear more frequently and have greater severity in young children (<5 years) and in the elderly, as well as in patients with comorbidities, particularly immune system compromise.
Penicillin-resistant S pneumoniae and drug-resistant S pneumoniae (DRSP) have become increasingly common in the United States.26 The mechanism of resistance to penicillin is in the penicillin-binding protein, rather than beta-lactamase production.27 Macrolide resistance is conferred by 2 mechanisms — the mef gene causes active efflux of drug from the cell, and the erm gene blocks drug from binding to its target, rRNA. Risk factors associated with DRSP include recent ß-lactam therapy, exposure to a child in day care, multiple medical problems, and immunosuppression. 7 (Table 3)
H influenzae is a small, pleomorphic, gram-negative rod. Since the introduction of the H influenzae type b vaccine, rates of serious infections in children due to this organism have decreased significantly.28 However, infections due to nontypeable H influenzae are still common, and the organism is identified as a causative agent in up to 11% of patients hospitalized for CAP.29 Chronic pulmonary disease, asplenia, exposure to day care, and HIV and other types of immunocompromise are risk factors for infection. 14,30,31
Moraxella catarrhalis is a gram-negative diplococcus. Risk factors for developing CAP due to this organism include older age, COPD, congestive heart failure, corticosteroid therapy, malignancy, and diabetes.32,33 Approximately 90% of isolates produce ß-lactamase.34
Staphylococcus aureus is a gram-positive coccus. S aureus pneumonia classically develops as a complication of acute influenza infection.35 However, S aureus may cause a primary bacterial pneumonia that is similar in presentation to other typical bacterial pneumonias.
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as an important pathogen in the general population. CA-MRSA carries virulence genes that make it genetically distinct from hospital-associated S aureus (HA-MRSA).36 CA-MRSA usually presents as a skin or soft tissue infection, but it has also caused a number of cases of severe pneumonia.37-39 The CDC has reported clusters of CA-MRSA skin infections among athletes, military recruits, children, prisoners, men who have sex with men, and among people in certain geographic areas. Risk factors associated with CA-MRSA include close skin-to-skin contact, cuts or abrasions, contact with contaminated items and surfaces, crowded living conditions, and poor hygiene.40 (Table 4)
Legionella is an intracellular, gram-negative rod that lives in aquatic environments. Infection results from inhalation of aerosolized contaminated water, as opposed to person-to-person transmission. Legionella is more commonly identified in patients with severe CAP and in those with comorbid medical conditions.41
Mycoplasma pneumoniae is unique among bacteria in that it lacks a cell wall, which explains why penicillin and cephalosporins are not effective against this organism. Mycoplasma is found frequently in ambulatory patients and younger patients.42,43 The most common presentation is bronchitis, rather than pneumonia.
Chlamydia pneumoniae is an obligate intracellular parasite. Although only recently identified as a cause of pneumonia, C pneumoniae appears to be quite prevalent, with a majority of adults showing serologic evidence of previous infection.44 Reinfection is common. While Chlamydia generally causes mild disease, severe cases have been reported, particularly in the elderly.45,46
Pseudomonas spp, Klebsiella pneumoniae, Escherichia coli, and other gram-negative rods (GNR) rarely cause CAP in the general population and usually occur only in those patients with risk factors.7 (Table 5) Recent hospitalization, recent antibiotic use, coexisting pulmonary disease, immunocompromise, and corticosteroid use are associated with GNR infection.29 Pneumonia due to GNR is more likely to be severe and carries a higher risk of death.17,47 In a prospective study of 559 patients hospitalized with pneumonia, patients with a gram-negative bacterial etiology had a significantly higher mortality than those without gramnegative bacteria (32% vs 9%).29
Viruses are identified as causative agents in 5-20% of patients with CAP.48,49 Influenza, RSV, parainfluenza, and adenovirus are the most commonly identified causes of viral pneumonia among adults.18 Secondary bacterial infections may complicate acute influenza, and it can be difficult to reliably differentiate viral from bacterial pneumonia in these situations. S pneumoniae is the most common bacterial superinfection5 — S aureus is another important and well-known cause. Human metapneumovirus was recently discovered (in 2001) and was subsequently identified as a major cause of pediatric respiratory tract infections, including CAP.50 Varicella zoster and herpes simplex virus can also cause CAP.
Tuberculosis is usually caused by Mycobacterium tuberculosis, an acid-fast intracellular aerobic bacillus, although Mycobacterium bovis and Mycobacterium africanus may cause TB, as well. With the advent of aggressive public health measures and effective antibiotics early in the 20th century, the US enjoyed a steady decline in the disease, until the late 1980s. The arrival of HIV, development of multidrug- resistant strains, and increased immigration from countries with high rates of TB have led to a resurgence of tuberculosis cases, starting in 1985. In 1987, the Department of Health and Human Services instituted aggressive public health initiatives.51 Since 1993, the incidence of TB has declined by 44% and is now at a historic low level.52
Tuberculosis is transmitted by respiratory droplets. Risk factors include close contact with known cases of pulmonary TB, HIV infection, birth in a country with a high prevalence of TB, homelessness, residence in long-term care facilities and correctional facilities, and injection drug use.53 (Table 6)
CAP In The Immunocompromised Host
Immunocompromised patients with pulmonary complaints and/or fever pose a special challenge. Although common community-acquired pneumonia is possible, unusual pathogens, serious infections, and complications related to the underlying disease must be excluded. Evaluations for these patients should be thorough and the threshold to admit low.
In addition to conventional bacteria and viruses associated with CAP, cancer patients are commonly infected with fungi, Pneumocystis jiroveci (PCP, formerly Pneumocystis carinii), Nocardia asteroides, and tuberculosis. Neutropenia places the cancer patient at particular risk for gram-negative infection; use of aggressive prophylactic antibiotics has resulted in an increased prevalence of gram-positive pathogens in these patients.54
Patients with HIV are at increased risk for bacterial pneumonia when compared to seronegative controls.55 Despite highly active antiretroviral therapy, PCP remains common among HIV patients.56 HIV patients are also more likely to have Toxoplasma gondii, Histoplasma capsulatum, and tuberculosis.
Patients with a history of solid organ transplant present with varying pathogens, depending on the time elapsed since the transplant.57 In the first month after transplant, most infections are nosocomial. In the 1- to 6- month period, patients may have opportunistic infections with CMV, Pneumocystis, and aspergillus, as well as the usual organisms associated with CAP. Beyond 6 months, most patients are maintained on minimal immunosuppressive therapy, so that opportunistic infections become unusual and classic CAP organisms predominate.