Pneumonia: Definition, Pathophysiology, and Treatment PDF

**DEFINITION** Pneumonia is an infection of the pulmonary parenchyma. Despite significant morbidity and mortality, it is often misdiagnosed, mistreated, and underestimated. Pneumonia has usually been classified as community-acquired (CAP), hospital-acquired (HAP), or ventilator-associated (VAP). A...

**DEFINITION** Pneumonia is an infection of the pulmonary parenchyma. Despite significant morbidity and mortality, it is often misdiagnosed, mistreated, and underestimated. Pneumonia has usually been classified as community-acquired (CAP), hospital-acquired (HAP), or ventilator-associated (VAP). A fourth category, health care-- associated pneumonia (HCAP) was introduced to encompass cases caused by multidrug-resistant (MDR) pathogens typically associated with HAP and cases in unhospitalized individuals at risk of MDR infection. Unfortunately, this category has not reliably predicted infection with resistant pathogens and has been associated with increased use of broad-spectrum antibiotics, particularly those employed for treatment of methicillin-resistant *Staphylococcus aureus* (MRSA) and antipseudomonal β-lactams. Accordingly, use of the HCAP category should be discontinued. Rather than relying on a predefined subset of pneumonia cases, it is better to assess patients individually on the basis of risk factors for infection with a resistant organism. Risk factors for infection with MRSA and *Pseudomonas aeruginosa* include prior isolation of the organism, particularly from the respiratory tract during the preceding year, and/or hospitalization and treatment with an antibiotic in the previous 90 days. Pneumonia caused by macroaspiration of oropharyngeal or gastric contents, usually referred to as aspiration pneumonia, is best thought of as a point on the continuum that includes CAP and HAP. Estimates suggest that aspiration pneumonia accounts for 5--15% of CAP cases, but reliable figures for HAP are unavailable. The airways or pulmonary parenchyma may be involved, and patients usually represent a clinical phenotype with risk factors for macroaspiration and involvement of characteristic anatomic pulmonary locations. **PATHOPHYSIOLOGY** Pneumonia is the result of the proliferation of microbial pathogens at the alveolar level and the host's response to them. Until recently, it was thought that the lungs were sterile and that pneumonia resulted from the introduction of potential pathogens into this sterile environment. Typically, this introduction occurred through microaspiration of oropharyngeal organisms into the lower respiratory tract. Overcoming of innate and adaptive immunity by such microorganisms could result in the clinical syndrome of pneumonia. Recent use of culture-independent techniques of microbial identification has demonstrated a complex and diverse community of bacteria in the lungs that constitutes the lung microbiota. Awareness of this microbiota has prompted a rethinking of how pneumonia develops. Mechanical factors, such as the hairs and turbinates of the nares, the branching tracheobronchial tree, mucociliary clearance, and gag and cough reflexes, all play a role in host defense but are insufficient to effectively block bacterial access to the lower airways. In the absence of a sufficient barrier, microorganisms may reach the lower respiratory tract by a variety of pathways, including inhalation, microaspiration, and direct mucosal dispersion. The constitution of the lung microbiota is determined by three factors: microbial entry into the lungs, microbial elimination, and regional growth conditions for bacteria, such as pH, oxygen tension, and temperature. The key question, however, is how a dynamic homeostasis among bacterial communities results in acute infection. Pneumonia therefore does not appear to be the result of the invasion of a sterile space by a particular microorganism but is more likely an emergent phenomenon dependent upon a number of mechanisms, including self-accelerating positive feedback loops. A possible model for pneumonia is as follows. An inflammatory event resulting in epithelial and or endothelial injury results in the release of cytokines, chemokines, and catecholamines, some of which may selectively promote the growth of certain bacteria, such as *Streptococcus pneumoniae* and *P. aeruginosa*. This cycle of inflammation, enhanced nutrient availability, and release of potential bacterial growth factors may result in a positive feedback loop that further accelerates inflammation and the growth of particular bacteria, which may then become dominant. In cases of CAP and HAP, the trigger may be a viral infection compounded by microaspiration of oropharyngeal organisms. In cases of true aspiration pneumonia, the trigger may simply be the macroaspiration event itself. Once triggered, innate and adaptive immune responses can ideally help contain potential pathogens and prevent the development of pneumonia. However, in the face of continuing inflammation (and especially if a positive feedback loop becomes sustainable), the process may proceed to a full-fledged pneumonia syndrome. Inflammatory mediators such as interleukin 6 and tumor necrosis factor result in fever, and chemokines such as interleukin 8 and granulocyte colony-stimulating factor increase local neutrophil numbers. Mediators released by macrophages and neutrophils may create an alveolar capillary leak resulting in impaired oxygenation, hypoxemia, and radiographic infiltrates. Moreover, some bacterial pathogens appear to interfere with the hypoxic vasoconstriction that would normally occur with fluid-filled alveoli, and this interference may result in severe hypoxemia. Decreased compliance due to capillary leak, hypoxemia, increased respiratory drive, increased secretions, and occasionally infection-related bronchospasm all lead to worsening dyspnea. If severe enough, changes in lung mechanics secondary to reductions in lung volume, compliance, and intrapulmonary shunting of blood may cause respiratory failure. Cardiovascular events with pneumonia, particularly in the elderly and usually in association with pneumococcal pneumonia and influenza, are increasingly recognized. These events, which may be acute or whose occurrence may extend to at least 1 year, include congestive heart failure, arrhythmia, myocardial infarction, or stroke and may be caused by a variety of mechanisms, including increased myocardial load and/or destabilization of atherosclerotic plaques by inflammation. In animal models, direct myocardial invasion by pneumococci may result in scarring and impaired myocardial function and conductivity. **PATHOLOGY** Classic pneumonia evolves through a series of stages. The initial stage is edema with a proteinaceous exudate and often bacteria in the alveoli. Next is a rapid transition to the red hepatization phase. Erythrocytes in the intraalveolar exudate give this stage its name. In the third phase, gray hepatization, no new erythrocytes are extravasating, and those already present have been lysed and degraded. The neutrophil is the predominant cell, fibrin deposition is abundant, and bacteria have disappeared. This phase corresponds with the successful containment of the infection and improvement in gas exchange. In the final phase, resolution, the macrophage reappears as the dominant cell in the alveolar space and the debris of neutrophils, and bacteria and fibrin have been cleared, as has the inflammatory response. This pattern has been described best for lobar pneumococcal pneumonia but may not apply to pneumonia of all etiologies. In VAP, respiratory bronchiolitis may precede the development of a radiologically apparent infiltrate. A bronchopneumonia pattern is most common in nosocomial pneumonias, whereas a lobar pattern is more common in bacterial CAP. Despite the radiographic appearance, viral and *Pneumocystis* pneumonias represent alveolar rather than interstitial processes. **COMMUNITY-ACQUIRED PNEUMONIA** ** ETIOLOGY\ **The list of potential etiologic agents of CAP includes bacteria, fungi, viruses, and protozoa. Newer viral pathogens include metapneumoviruses, the coronaviruses responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), and the recently discovered coronavirus that originated in Wuhan, China, and is designated SARS-CoV-2. First described in December 2019, SARS-CoV-2 and its associated clinical disease, COVID-19, have reached pandemic proportions and are a cause of significant morbidity and mortality. The virus and the disease are discussed in detail in **Chap. 199**. Although most CAP cases are caused by relatively few pathogens, an accurate determination of their prevalence is difficult because laboratory testing methods are often insensitive and indirect **(Table 126-1)**. Separation of potential agents into "typical" bacterial pathogens and "atypical" organisms may be helpful. The former group includes *S. pneumoniae, Haemophilus influenzae*, and, in selected patients, *S. aureus* and gram-negative bacilli such as *Klebsiella pneumoniae* and *P. aeruginosa*. The "atypical" organisms include *Mycoplasma pneumoniae, Chlamydia pneumoniae*, and *Legionella* species as well as respiratory viruses such as influenza virus, adenoviruses, human metapneumoviruses, respiratory syncytial virus, and coronaviruses. With the increasing use of pneumococcal vaccine, the incidence of pneumococcal pneumonia is decreasing. Cases due to *M. pneumoniae* and *C. pneumoniae*, however, appear to be increasing, especially among young adults. Viruses are recognized as increasingly important in pneumonia, and polymerase chain reaction (PCR)--based testing indicates their presence in the respiratory tract of 20--30% of healthy adults and in the same percentage of pneumonia patients, including those who are severely ill. The most common are influenza, parainfluenza, and respiratory syncytial viruses. Whether they are true etiologic pathogens, co-pathogens, or simply colonizers cannot always be determined. Atypical organisms cannot be cultured on standard media or seen on Gram's stain, but their frequency and importance have significant implications for therapy. They are intrinsically resistant to all β-lactams and require treatment with a macrolide, a fluoroquinolone, or a tetracycline. In the 10--15% of CAP cases that are polymicrobial, the etiology usually includes a combination of typical and atypical pathogens. page3800image10948160 **TABLE 126-1 Microbial Causes of Community-Acquired Pneumonia, by Site of Care**  Earlier literature suggested that aspiration pneumonia was caused primarily by anaerobes, with or without aerobic pathogens. A shift, however, has been noted recently: if aspiration pneumonia is acquired in a community or hospital setting, the likely pathogens are those usually associated with CAP or HAP. Anaerobes may still play a role, especially in patients with poor dentition, lung abscess, necrotizing pneumonia, or empyema. *S. aureus* pneumonia is known to complicate influenza virus infection. However, MRSA has been reported as a primary etiologic agent of CAP. Although cases caused by MRSA are relatively uncommon, clinicians must be aware of its potentially serious consequences, such as necrotizing pneumonia. Two factors have led to this problem: the spread of MRSA from the hospital setting to the community and the emergence of genetically distinct strains of MRSA in the community. Community-associated MRSA (CA-MRSA) strains may infect healthy individuals who have had no association with health care. Despite a careful history, physical examination, and radiographic studies, the causative pathogen is often difficult to predict with certainty, and in more than half of cases a specific etiology is not determined. Nevertheless, epidemiologic and risk factors may suggest certain pathogens **(Table 126-2)**. **TABLE 126-2 Epidemiologic Factors Suggesting Possible Causes of Community-Acquired Pneumonia** page3802image4777728 ** EPIDEMIOLOGY\ **More than 5 million CAP cases occur annually in the United States. Along with influenza, CAP is the eighth leading cause of death in this country. CAP causes more than 55,000 deaths annually and results in more than 1.2 million hospitalizations; ∼70% of patients are treated as outpatients and 30% as inpatients. The mortality rate among outpatients is usually \65 years of age. Moreover, 18% of hospitalized CAP patients are readmitted within 1 month of discharge. The overall yearly CAP cost is estimated at \$17 billion. The overall incidence among adults is ∼16--23 cases per 1000 persons per year, with the highest rates at the extremes of age. The risk factors for CAP in general and for pneumococcal pneumonia in particular have implications for treatment. They include alcoholism, asthma, immunosuppression, institutionalization, and age \>70 years. In the elderly, decreased cough and gag reflexes and reduced antibody and Toll-like receptor responses increase the likelihood of pneumonia. Risk factors for pneumococcal pneumonia include dementia, seizure disorders, heart failure, cerebrovascular disease, alcoholism, tobacco smoking, chronic obstructive pulmonary disease (COPD), and HIV infection. CA-MRSA pneumonia is more likely in patients with skin colonization or infection with CA-MRSA and after viral infection. Enterobacteriaceae tend to infect patients who have recently been hospitalized or given antibiotics or who have comorbidities such as alcoholism, heart failure, or renal failure. *P. aeruginosa* is a particular problem in patients with severe structural lung disease (e.g., bronchiectasis, cystic fibrosis, or severe COPD). Risk factors for *Legionella* infection include diabetes, hematologic malignancy, cancer, severe renal disease, HIV infection, smoking, male gender, and a recent hotel stay or trip on a cruise ship. ** CLINICAL MANIFESTATIONS\ **The clinical presentation of pneumonia can vary from indolent to fulminant and from mild to fatal in severity. Manifestations of worsening severity include both constitutional findings and those limited to the lung and associated structures. The patient is frequently febrile and/or tachycardic and may experience chills and/or sweats. Cough may be nonproductive or productive of mucoid, purulent, or blood-tinged sputum. Gross hemoptysis is suggestive of necrotizing pneumonia (e.g., that due to CA-MRSA). Depending on severity, the patient may be able to speak in full sentences or may be short of breath. With pleural involvement, the patient may experience pleuritic chest pain. Up to 20% of patients may have gastrointestinal symptoms such as nausea, vomiting, or diarrhea. Other symptoms may include fatigue, headache, myalgias, and arthralgias. Findings on physical examination vary with the degree of pulmonary consolidation and the presence or absence of a significant pleural effusion. An increased respiratory rate and use of accessory muscles of respiration are common. Palpation may reveal increased or decreased tactile fremitus, and the percussion note can vary from dull to flat, reflecting underlying consolidated lung and pleural fluid, respectively. Crackles, bronchial breath sounds, and possibly a pleural friction rub may be heard. The clinical presentation may be less obvious in the elderly, who may initially display new- onset or worsening confusion but few other manifestations. Severely ill patients may have septic shock and evidence of organ failure. In cases of CAP, symptoms can range from almost nonexistent to severe, and chest radiographic findings are often in gravity- dependent parts of the lung. ** DIAGNOSIS\ **When confronted with possible CAP, the physician must ask two questions: is this pneumonia, and, if so, what is the likely pathogen? The former question is answered by clinical and radiographic methods, whereas the latter requires laboratory techniques. **Clinical Diagnosis** The differential diagnosis includes infectious and noninfectious entities, including acute bronchitis, exacerbations of chronic bronchitis, heart failure, and pulmonary embolism. The importance of a careful history cannot be overemphasized. The diagnosis of CAP requires a compatible history, such as cough, sputum production, fever and dyspnea, and a new infiltrate on chest radiography. Unfortunately, the sensitivity and specificity of findings on physical examination are only 58% and 67%, respectively. Chest radiography is often necessary to differentiate CAP from other conditions. Radiographic findings may suggest increased severity (e.g., cavitation or multilobar involvement). Occasionally, radiographic results suggest an etiologic diagnosis, such as pneumatoceles in *S. aureus* infection or an upper-lobe cavitating lesion in tuberculosis. CT may be of value in suspected loculated effusion or cavitary cases or in postobstructive pneumonia caused by a tumor or foreign body. For outpatients, clinical and radiologic assessments are usually all that is required before treatment is started since most laboratory results are not available soon enough to influence initial management. In certain cases, the availability of rapid point-of-care outpatient tests can be important; for example, rapid diagnosis of influenza infection can prompt specific anti- influenza treatment and secondary prevention measures. **Etiologic Diagnosis** The etiology of pneumonia usually cannot be determined solely on the basis of clinical or radiographic presentation. Data from more than 17,000 emergency department CAP cases showed an etiologic determination in only 7.6%. Except for CAP patients admitted to the ICU, no data exist to show that treatment directed at a specific pathogen is statistically superior to empirical therapy. The benefit of establishing a microbial etiology may be questioned, particularly in light of the cost of diagnostic testing. However, a number of reasons exist for attempting an etiologic diagnosis. Identification of a specific or unexpected pathogen allows narrowing of the initial empirical regimen, with a consequent decrease in antibiotic selection pressure and in the risk of resistance. Pathogens with important public safety implications, such as *Mycobacterium tuberculosis* and influenza virus, may be found. Finally, without susceptibility data, trends in resistance cannot be followed accurately, and appropriate empirical therapeutic regimens are harder to devise. **GRAM'S STAIN AND CULTURE OF SPUTUM** The main purpose of the sputum Gram's stain is to ensure suitability of a specimen for culture. (To be suitable, a sputum sample must have \>25 neutrophils and \7 mmol/L (U); respiratory rate ≥30/min (R); blood pressure--- systolic ≤90 mmHg or diastolic ≤60 mmHg (B); and an age of ≥65 years. Patients with a score of 0 (a 30-day mortality rate of 1.5%) can be treated as outpatients. With a score of 1 or 2, the patient should be hospitalized unless the score is entirely or in part attributable to an age of ≥65 years; in such cases, hospitalization may not be necessary. Among patients with scores of ≥3, mortality rates are 22% overall; these patients may require ICU admission. The PSI has greater efficacy than CURB-65 but is more difficult to calculate. If a patient is unable to maintain oral intake, if compliance is thought to be an issue when assessed on the basis of mental condition or living situation (e.g., cognitive impairment or homelessness), or if the patient's O2 saturation on room air is \2--4 μg/mL for intermediate, and ≥8 μg/mL for resistant. A change in susceptibility thresholds dramatically decreased the proportion of pneumococcal isolates considered nonsusceptible. For meningitis, MIC thresholds remain at the former lower levels. Fortunately, resistance to penicillin appeared to plateau even before the change in MIC thresholds. Of isolates in the United States, \