Community-Acquired Pneumonia

Epidemiology

Community-acquired pneumonia (CAP) remains a common and persistent cause of morbidity and mortality. Despite the development of multiple new antimicrobials, there is little evidence to document that either the incidence or morbidity of pneumonia has declined over the last 40 years (Table 4-1).

Unlike health care–associated pneumonia (HCAP) or hospital-acquired pneumonia (HAP), the diagnosis of CAP can sometimes be more easily made. Patients usually have an infiltrate on chest radiograph, with at least two of the most common symptoms of lower respiratory tract infection, including:

• Fever
• Cough
• Sputum production
• Dyspnea
• Sweats
• Hemoptysis
• Chest pain.

Other signs and symptoms include:

• Myalgia
• Headache
• Anorexia
• Malaise
• Diarrhea
• Abdominal discomfort
• Occasionally, nausea and vomiting.

A wide variety of diagnostic and therapeutic approaches have been suggested in evaluating the patient with pneumonia. Often, a brief history of the risk factors and epidemiology of the infection will narrow the focus. In addition, the duration of symptoms prior to presentation may be helpful in the differential diagnosis. Initially, one should make sure that the patient meets the diagnostic criteria. Although this is usually straightforward, caution must be used in patients with serious underlying diseases and in those who have been hospitalized in the preceding weeks. Similarly, patients who are residents of chronic-care facilities should be treated as if they have HCAP rather than CAP. The pattern of the infiltrate on chest radiograph may be helpful in the differential diagnosis. However, no pattern should be viewed as diagnostic for a particular pneumonia. Even the lobar infiltrates may represent “atypical” pneumonia.

The epidemiologic risk factors and associations for CAP are listed in Table 4-2. S pneumoniae is the most commonly identified pathogen in all patients but M pneumoniae and C pneumoniae are frequently found in younger adults and adolescents. However, recent epidemiology suggests a rising incidence of viral pneumonia. In etiologic studies, no pathogen is identified in as many as 50% of cases. It is often stated that the initial chest roentgenogram may be normal, particularly in dehydrated patients. While this can be true, one should be careful about making a diagnosis of pneumonia without some abnormality on the film. It is now recognized that computed tomography (CT) scanning enhances the radiographic diagnosis of CAP by 25%. One of the major controversies of treating pneumonia concerns the issue of how aggressive the diagnostic workup should be prior to initiating antibiotics. Many guidelines have indicated that with prior knowledge of epidemiologic risk factors and the appearance of the chest radiograph, a precise microbiologic diagnosis is not necessary.

The development of the broad-spectrum antibiotics has made the empiric treatment of pneumonia easier. In addition, most studies have not demonstrated improved survival in patients when a precise microbiologic diagnosis has been made compared with those treated empirically. Finally, the yield for diagnostic workup has not been that high. Currently, expectorated sputum is diagnostic by Gram’s stain and culture in at most 40% to 50% of cases. Molecular testing by mPCR is more sensitive; in one study of CAP patients, mPCR successfully identified a pathogen in 87% of cases, compared to 39% of cases using culture-based methods.

The counter argument that supports the need for an etiologically oriented evaluation has been outlined in a position paper by the Infectious Disease Society of America (IDSA). The rationale for establishing a precise diagnosis includes:

• To allow for organism-specific therapy
• To promote focused antibiotic selection, which limits the risk of toxicity, costs, and emergence of resistance
• To identify specific pathogens that may precipitate epidemiologic investigations
• A precise etiologic diagnosis is valuable when the patient does not respond to therapy.

In addition, although the backbone of an etiologic diagnosis is the expectorated sputum, a number of additional and newer technologies are now available. Some of these include:

• Testing for pathogen genomic and non-genomic DNA/RNA by mPCR, which allows for simultaneous detection of nearly all of the most common bacterial, viral, and fungal pathogens, as well as for detection of antimicrobial resistance genes. The use of rapid antigen testing for identification of SARS-CoV-2 has allowed for point-of-care diagnosis and treatment during the COVID-19 pandemic.
• Sputum for acid-fast organisms in patients at risk and those with indolent presentations. Amplification methods that are reliable in patients with positive acid smears are available for this purpose.
• Test of Legionella infection with urinary antigen is an easy way to screen for L pneumophila serogroup 1. The latter accounts for 75% of all cases. Sputum culture and direct fluorescent antibody (DFA) stains on sputum are other methods whose sensitivity is dependent upon the quality of the specimen. Serology can be useful to confirm the diagnosis, but since 4-fold changes in titers are needed, they are of value only in retrospect. Urinary assay for pneumococcus antigen is becoming more available and should prove to be of good value.
• Fungal cultures and stains of respiratory secretions will pick up Coccidioides, Blastomyces, Cryptococcus, Aspergillus, Zygomycetes (Table 4-3); fungal antigens in blood (G-test)
• Giemsa or Gomori’s methenamine silver stain is available for P carinii
• Viral cultures for influenza, adenovirus, respiratory syncytial virus (RSV); rapid antigen detection assays are now the standard of care for influenza, SARS-CoV-2, and RSV.

These techniques should be reserved for patients in whom specific diagnosis is being considered. They are not recommended as a part of a routine workup for CAP. The 2018 joint American Thoracic Society (ATS) and IDSA guideline does recommend that blood cultures, Gram’s staining, and cultures of expectorated sputum be done in hospitalized patients, if any of the following conditions are met:

• CAP is classified as severe (Table 4-4)
• Patient is being empirically treated for MRSA or P aeruginosa
• Patient was previously infected with MRSA or P aeruginosa
• Patient was hospitalized and received parenteral antibiotics (whether during hospitalization or not) in the last 90 days.

Both C-reactive protein (CRP) and procalcitonin levels may assist in the decision to use antibacterial agents.

Management

Most patients with CAP present with signs and symptoms of an acute respiratory illness. However, the rigorous definition of pneumonia includes a finding of pulmonary infiltrate on chest radiograph. Further, no individual or group of clinical findings rule in the diagnosis of CAP. Differentiating pneumonia from sinusitis or bronchitis can sometimes be done by physical examination. Therefore, a chest radiograph should be obtained in all patients suspected of having pneumonia. Once an infiltrate is observed, the diagnosis of pneumonia can be made if other clinical signs and symptoms are present. In the absence of other clinical signs and symptoms that point to pneumonia, it is important to recognize that certain radiologic findings may be confounded with pneumonia (i.e., pulmonary embolism (PE), heart failure). CT scanning will often confirm the diagnosis when initial chest radiograph is inconclusive or negative. In some cases, lung ultrasound can supplement uncertain radiographic findings (see, Diagnosis of Pneumonia).

The most important initial question is whether the patient will need to be admitted to the hospital or can be managed as an outpatient. The Patient Pneumonia Outcomes Research Team has developed a scoring system that allows the severity of illness to be quantitatively measured (PSI). While both PSI and the alternative CURB-65 are recommended, actual clinical use has been limited in real world practice due to the perception and reality that they are cumbersome and time consuming.

Using an algorithm (Figure 4-1), the patient can be classified according to 30-day mortality risk. The total number of points assigned to the patient increases risk of poor outcome. Patients in risk classes I, II and III have an expected mortality <5% and potentially could be managed as outpatients. Patients in risk class IV and V have mortality rates of 8% to 29% and should be admitted to the hospital. Admission should be considered for:

• Those with underlying immunosuppression secondary to chemotherapy
• Elderly patients
• Patients with mental status change from baseline
• Those with impending hemodynamic or respiratory compromise
• Patients with poor social support or without ability to self-supervise.

The risk table also documents the high mortality associated with CAP in some groups. Patients in risk class V often require intensive care. A caveat is that the risk schema is heavily age-weighted and thus some older patients in good health will have a high score without attendant true risk. Patients with the following characteristics should be considered for admission to an intensive-care unit (ICU) and are classified as having severe pneumonia:

• Hypotension (systolic BP <90 mm Hg)
• Impending respiratory failure that may require mechanical ventilation
• Hypoxemia (PO₂ <60 mm Hg)
• Hemodynamic instability
• Organ failure
• Deteriorating comorbid illness
• Heart failure, diabetes, COPD.

Another, simpler risk assessment system called CURB-65 devised by the British Thoracic Society (BTS), has come into use (see Diagnosis of Pneumonia).

In addition to the history and physical exam, particular attention should be given to determining whether the patient has any epidemiologic risk factors that may influence the initial selection of antimicrobials and diagnostic tests that need to be done. These are presented in Table 4-2, but the most common include:

• Chronic obstructive pulmonary disease (COPD): S pneumoniae, H influenzae, Moraxella catarrhalis, Pseudomonas
• Influenza outbreak: S pneumoniae, S aureus, H influenzae
• Poor dental hygiene, seizures: anaerobes (necrotizing pneumonia, empyema, abscess)
• Rodent droppings: Hantavirus
• Travel to the southwestern United States: coccidioidomycosis, Hantavirus
• Severe structural lung disease: P aeruginosa or Acinetobacter, methicillin-resistant Staphylococcus aureus (MRSA)
• Recent antibiotic therapy: enteric gram-negatives, MRSA.

S pneumoniae continues to be the most common bacterial pathogen, and the so-called “atypical pathogens” M pneumoniae and C pneumoniae are also frequent causes of pneumonia, especially among patients who can be treated safely in an outpatient setting. Patients who have recently been hospitalized or transferred from chronic-care facilities need to be approached as if they have HAP pneumonia (see Management of Hospital-Acquired Pneumonia). Although there continues to be controversy regarding the extent of the diagnostic workup that is necessary prior to initiating therapy, the approach should be individualized. In younger patients with an acute illness, a history, physical examination and chest radiograph are often all that is necessary prior to the initiation of empiric therapy. In patients with a specific epidemiologic risk factor or those with severe pneumonia, additional workup should be performed.

Blood cultures have been recommended for certain patients who are hospitalized for CAP, but are not necessary in those who are being treated empirically as outpatients. Blood cultures are positive in <5% of patients with pneumonia. This test has a low sensitivity but a high specificity in CAP but not HAP. Several studies have suggested that patients can be stratified according to risk of a positive blood culture. Eight independent predictors of bacteremia (recent antibiotic therapy, liver disease, systolic blood pressure (BP), pulse, temperature, serum blood urea nitrogen (BUN), sodium and white blood cell (WBC) count) were used in combination to formulate a “decision-support tool” for obtaining blood cultures in patients at low (2%), moderate (5%) and high (11%) risk of bacteremia. No blood cultures were recommended for low-risk patients, one culture for moderate risk and two cultures for high-risk patients. The clinical tool, validated in a cohort of 12,771 Medicare patients, resulted in 38% fewer blood cultures and identification of bacteremia in nearly 90% of patients. A simplified version of this tool identified 87% of the bacteremias with 44% fewer cultures.

Sputum cultures also are of variable value, depending upon the quality of the sample and the proper handling of the specimen. The sputum should be obtained by deep cough, and the Gram’s stain must demonstrate an adequate number of polymorphonuclear (PMN) neutrophils prior to proceeding with the cultures. Sputum must be transported and plated within hours of collection. Although transtracheal aspiration has been recommended in the past, it is rarely done. Sputum analysis (using both Gram’s stain and culture) has 50% sensitivity and 80% specificity for pneumococcal pneumonia. Sputum analysis is also useful in the diagnosis of gram-negative and staphylococcal infection. When many PMNs are seen without organisms, the likelihood of an atypical pneumonia is high. Administration of antibiotics should not be delayed while awaiting procurement of a sputum sample. Extensive diagnostic testing is recommended for critically ill CAP patients.

In addition to the blood and sputum cultures, a variety of other serologic and microbiologic tests are available. More invasive tests (pleural fluid analysis and bronchoscopy) should be used depending upon:

• Epidemiologic factors present
• Severity of disease
• Response to initial antibiotic therapy.

In general, bronchoscopy to collect sputum samples is reserved for those patients unresponsive to conventional therapy or those who are critically ill or immunocompromised at the time of presentation.

In hospitalized patients with CAP, empiric treatment with antibiotic should continue until a bacterial cause is ruled out.

In addition to antibiotic therapy, adjuvant therapy with corticosteroids to limit excessive systemic inflammation may help prevent complications and improve outcomes. This therapy, however, remains controversial. One randomized trial in 785 Swiss patients with CAP found that prednisone significantly reduced mean time to clinical stability compared to the placebo (3.0 vs 4.4 days), but had no effect on pneumonia-associated complications. This is in concordance with the findings of meta-analysis of 6 trials (with a total of 1506 individual patients), which found a 1-day reduction in the time to clinical stability and length of hospitalization in patients who received corticosteroids, but no significant effect on mortality. However, other studies did not find a consistent benefit for adjunctive corticosteroid use in patients with CAP, and neither the 2019 ATS-IDSA nor the 2023 European Respiratory Society (ERS) guidelines for the treatment of CAP recommend the routine use of corticosteroids in patients with CAP. For patients with CAP in septic shock, the ATS-IDSA guidelines state that corticosteroids may be considered, while the ERS guidelines recommend them conditionally.

Specific Types of Pneumonia

S pneumoniae (or pneumococcus) is a gram-positive coccus that grows as single cells, pairs and chains in culture. It is a classic example of an encapsulated organism, which resists phagocytosis in the absence of type-specific antibody. More than 80 serotypes exist based on specific antigens in the capsule. Immunity after infection is limited to the specific serotype. Therefore, reinfection can occur multiple times. The bacteria produce disease by direct invasion of tissue, which produces an inflammatory reaction.

The pneumococcus colonizes the respiratory tract of both children and adults. It can cause a wide variety of illnesses, but the most common include otitis media, sinusitis, bronchitis, pneumonia, sepsis and meningitis. About 5% to 10% of healthy adults are colonized, especially during winter. The organism is spread through close contact and therefore is more common in closed and crowded areas. Host immunity is important in determining the risk of invasive disease. Although immunity to pneumococci is complex, anticapsular antibody is the most important determinant of disease. This is the major reason that vaccination is effective.

Defective antibodies (in quality and/or quantity) dramatically increases the risk of invasive pneumococcal disease. A number of clinical conditions exist that produce defective or insufficient antibody. The more common include:

• HIV infection
• Multiple myeloma
• Lupus erythematosus
• Chronic leukemia
• Nephrotic syndrome
• Splenectomy.

Other factors that predispose to infection include:

• Smoking
• Influenza infection
• Chronic disease states, including diabetes, respiratory disease, cardiopulmonary disease, and neurologic disease.

The constellation of pneumonia symptoms varies with age. Typically, the onset of pneumonia is acute, with high fever, chills, cough, sputum production and other symptoms of respiratory infection. In very elderly patients, the onset may be more indolent, specifically, fever and leukocytosis decrease with age. Moreover, older patients sometimes present with confusion due to hypoxia and gastrointestinal (GI) disturbances (e.g., anorexia, nausea). Physical examination and radiographs may suggest lobar consolidation. Although pleural effusions develop in about 20% of cases, empyema is rare. Most patients will have leukocytosis, but 10% will have leukopenia, which is considered a poor prognostic sign. A carefully obtained and examined sputum will be diagnostic by either Gram’s stain or culture in about one half of the patients. Blood cultures demonstrate bacteremia in a minority of cases.

For many years, penicillin was the mainstay of antimicrobial treatment of this infection. However, over the past decade, resistance to penicillin has grown dramatically. Pneumococcal resistance is classified as sensitive (minimum inhibitory concentration [MIC] <0.1 g/mL), intermediate (MIC 0.1 to 1.0 g/mL) and resistant (MIC >1 g/mL). Most intermediate and resistant pneumonia-causing strains will respond to high doses of a penicillin or cephalosporin, but failure in the treatment of meningitis is common.

In addition, high-level resistance to the oral cephalosporins is increasing. Equally important is the fact that penicillin-resistant strains are more likely to be resistant to other unrelated antibiotics, including the macrolides, clindamycin and trimethoprim/sulfamethoxazole (TMP/SMX). While resistance to vancomycin has not been reported in the United States and resistance to the newer fluoroquinolones is extremely rare, resistance to the macrolide antibiotics is increasing and may limit the efficacy of these drugs in the treatment of patients with pneumonia (Table 4-5). There is a paucity of data linking in vitro bacterial resistance and clinical failures although clinical failures do occur in the presence of high-level macrolide and quinolone resistance. It appears that high-level penicillin resistance can be overcome when very high doses of penicillin are used.

Legionnaires’ Disease

Legionella spp cause a variable number of cases of CAP (Table 4-6). Risk factors include:

• Smoking
• Advanced age
• Organ transplantation.

Person-to-person transmission has not been reported. Transmission occurs through potable water in both hospital-acquired and community-acquired cases. Legionnaires’ disease typically presents with:

• High fever
• Hyponatremia
• Systemic toxicity.

The sputum demonstrates polymorphonuclears (PMNs) but no organisms, which is also seen in other atypical pneumonias. The chest roentgenogram often demonstrates bilateral alveolar infiltrates but can mimic lobar or interstitial pneumonias. The diagnosis can be made by serology, with a 4-fold rise between acute and convalescence titers (after 4 to 6 weeks), but this is of value only in retrospect. Urinary antigen is a sensitive and specific test, but can only detect L pneumophila serogroup 1, which accounts for about 75% of cases. The urinary antigen will not pick up other Legionella spp or the other serotypes. Most mPCR platforms test for L pneumophila DNA. Selective media can be used to culture Legionella from sputum and other respiratory specimens. DFA testing of sputum can also be used but has a low sensitivity. Often, therapy for Legionnaires’ disease must be initiated prior to microbiologic confirmation.

Although diarrhea and hyponatremia are common, they are not at all specific for Legionella infections and can be seen with other pneumonias. The newer quinolones have excellent activity and can also be used as primary therapy. Intravenous (IV) azithromycin is highly effective and does not have the problems of fluid overload and phlebitis associated with IV erythromycin. Macrolides may also be synergistically combined with quinolones, with clarithromycin-levofloxacin and azithromycin-levofloxacin showing the best results. Rifampin has been used as adjuvant therapy but is not used alone because of the rapid acquisition of resistance. Newer antibiotics, including lefamulin, omadacycline, and delafloxacin, all have activity against Legionella. Unlike other bacterial pneumonias, those caused by Legionella should be treated for 2 to 3 weeks to decrease the risk of relapse.

Other Atypical Pneumonias

Most pneumonias in young adults are due to either C pneumoniae or M pneumoniae (Table 4-7). Mycoplasma infection is the most common etiologic source of outpatient pneumonia, and has been observed to increase during epidemics, which occur approximately every 3 to 4 years. These organisms can cause bronchitis, pharyngitis, or pneumonia. Usually, most patients are not critically ill and can be treated as outpatients. Respiratory failure rarely occurs. Patients usually have cough, fever, sore throat and headache. Although there are clinical differences between C pneumoniae and M pneumoniae, there is so much overlap that it is impossible to tell the two apart. In addition, both organisms are difficult to culture and the diagnosis is often not easy. Acute and convalescent titers are useful in retrospect only. Cold agglutinin titers are often positive (>1:64) with positive Mycoplasma, but this test is not specific. Other uncommon causes of CAP are listed in Table 4-8.

H influenzae

H influenzae is a small, gram-negative rod (coccobacillus) that colonizes the nasopharynx like pneumococcus. There are both encapsulated and unencapsulated forms of the organism. Usually, invasive disease (i.e., meningitis) is caused by the encapsulated strain type B. The unencapsulated strains can cause a variety of respiratory infections, including:

• Sinusitis
• Otitis media
• Conjunctivitis
• Bronchopneumonia.

This organism remains an important cause of respiratory infection in both adults and children although childhood conjugate vaccination may have altered the incidence and recent epidemiologic surveys are few. In addition, it can cause bronchitis without pneumonia, especially in smokers and those with chronic pulmonary disease. Like the pneumococcus, any impairment in immunoglobulin production predisposes one to H influenzae infection. Invasive type B H influenzae in children has virtually disappeared with the introduction of a species-specific vaccine. There appears to be herd immunity since invasive type B H influenzae infections in adults has also decreased.

Approximately 25% of nonencapsulated strains produce β-lactamase and therefore need to be treated with antibiotics that resist inactivation by these enzymes. Quinolones, second- and third-generation cephalosporins, amoxicillin-clavulanate, tetracyclines, trimethoprim/sulfamethoxazole (TMP/SMX), and the newer macrolides all have activity against these strains. Newer antibiotics and antibiotic combinations, including ceftobiprole, ceftolozane-tazobactam, ceftazidime-avibactam, cefiderocol, meropenem-vaborbactam, imipenem-relebactam, aztreonam-avibactam, and eravacycline, are also effective against H influenzae.

Anaerobic Pulmonary Disease

Anaerobic bacteria are normally present in the mouth. Infection of the lung follows aspiration that may be either overt or occult. Often this is due to:

• Altered consciousness related to alcoholism
• Anesthesia
• Seizures
• Drug overdose
• Neurologic disease.

Poor dental hygiene and periodontal disease allow for the overgrowth of bacteria in the mouth and increase the risk of infection following aspiration. Clinically, the infection presents as an isolated lung abscess, necrotizing pneumonia, or empyema. In the absence of these clinical findings, the role of anaerobes and antianaerobic therapy is unclear.

Lung abscess presents with fever, malaise, foul-smelling sputum, and cough. The abscess appears as a cavitary lesion on the chest radiograph, often with an air-fluid level. The air-fluid level is not usually seen with tuberculosis (TB), which is also a well-known cause of cavitary pulmonary disease. The diagnosis usually is made clinically, as culture of sputum for anaerobic organisms is not practical due to contamination from oral flora. A wide variety of anaerobic organisms can cause this infection, but β-lactamase–producing strains of Bacteroides are included. Empyema may occur as a primary problem or as a complication of pneumonia.

Treatment consists of drainage, usually with a chest tube and/or surgically. All anaerobic pulmonary infections are treated with a prolonged course of antibiotics
(2 to 3 weeks) (Table 4-9). A wide variety of antimicrobial agents, either alone or in combination, can be used but must have activity against these organisms. The usual agents chosen are penicillin or clindamycin. The morbidity and mortality associated with anaerobic infections is significant. In addition, bronchoscopy is then necessary to make sure that there is not an associated foreign body or tumor.

Gram-Negative Pneumonia

Gram-negative aerobic pneumonia is usually a hospital-acquired infection. Colonization of the upper airway rapidly occurs in the elderly who are hospitalized or in chronic-care facilities, and patients are often admitted to the intensive care unit (ICU). Aspiration of colonized bacteria can lead to pneumonia in already ill patients. Community-acquired, gram-negative pneumonia is unusual but is well described. It is more likely to occur in patients who have chronic obstructive pulmonary disease (COPD), have been recently hospitalized, or are on steroids or immunosuppressive drugs. Klebsiella and P aeruginosa can occur in the alcoholic or debilitated elderly patient without additional risk factors. These infections are associated with a high mortality and require aggressive antimicrobial therapy.

Viral Pneumonia

Many atypical pneumonias are falsely labeled viral pneumonia. However, true viral pneumonia is increasingly recognized as a common etiology and likely represents about half of all pneumonias. In etiological studies since 2010, viral pathogens have been found in up to 56% of pneumonia cases in which a pathogen is identified at all. Viral mPCR panels are now routinely performed on almost all patients with pneumonia. Several respiratory viruses can cause pneumonia (Table 4-10), including epidemic and episodic adenovirus. Usually, adenovirus causes pharyngitis, adenitis and conjunctivitis more often than pneumonia. The diagnosis is made by viral culture of respiratory secretions and therapy is supportive.

In the winter months, influenza is a cause of primary viral pneumonia and predisposes to secondary bacterial pneumonia. In 2009, a worldwide pandemic of “swine flu” H1N1 was identified in late spring. Typically, influenza has an abrupt onset after a 1- to 2-day incubation period. The illness is characterized by fever, chills, myalgia, headache and respiratory symptoms. Often the myalgia is severe and the most bothersome of the symptoms. This is due to direct viral infection of the muscles and can be complicated by myositis and myoglobinuria. Patients often appear to be toxic and may have hypoxia in the presence of a normal chest radiograph. Pneumonia occurs as a progressive interstitial process with negative bacterial sputum cultures.

Influenza pneumonia can occur at any age but is more common in the elderly and is associated with a high mortality. Influenza is caused by two major antigenic types (A and B). Type A tends to cause more severe disease and is associated with most cases of viral pneumonia. In addition, influenza predisposes to bacterial pneumonia with S pneumoniae, H influenzae and S aureus. The latter is an uncommon cause of CAP in the absence of preceding influenza. The secondary bacterial pneumonias are more likely to present as biphasic illness that follows the initial disease by 3 to 5 days. Rapid viral antigen methods and viral cultures are available to make the diagnosis. Influenza A can be treated with amantadine and rimantadine, though resistance to these agents has been increasing (Table 4-11). The neuraminidase inhibitors (NAIs), zanamivir (inhaled for 5 days) and oseltamivir (oral for 5 days), are effective when introduced within 36 hours of onset of symptoms. Resistance to oseltamivir has also been reported. The newest antivirals against influenza are the NAI peramivir (administered as a single IV infusion within 2 days of the onset of influenza symptoms) and the polymerase acidic endonuclease inhibitor baloxavir (taken as a single oral dose [tablets or oral suspension] within 28 hours of influenza symptom onset). During an epidemic, it is reasonable to initiate therapy against influenza even without microbiologic confirmation.

Vaccination of all individuals over 6 months of age is recommended. Target groups include patients with comorbid illness likely to increase severity of influenza, health care personnel, and migrant and refugee children. The vaccine is revised each year based on the most recent circulating viral isolates as antigenic shift and drift occur, making long-lasting immunity impossible.

The novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is another major cause of pneumonia worldwide. This virus, a relative of SARS-CoV (see below), first emerged in late 2019 in the city of Wuhan in China. It spread rapidly, infecting at least 118,000 people in 114 countries by March 2020, when the World Health Organization (WHO) declared it a pandemic and hundreds of millions thereafter. During the pandemic, the virus rapidly evolved from into several strains which sequentially predominated in the population (alpha, delta and omicron); descendants of the omicron strain predominate at present (August 2024). By the time the WHO declared the end of the SARS-CoV-2 public health emergency in May 2023, the virus had caused more than 760 million infections and nearly 7 million deaths worldwide. Most experts now agree that SARS-CoV-2 has become an endemic virus, and possibly in a seasonal pattern.

The disease caused by SARS-CoV-2 has been designated Coronavirus Disease 19 (COVID-19). When it initially emerged, it caused systemic inflammation in multiple organs, including the heart, lung, kidney, liver and lymph nodes and therefore had a heterogenous presentation. Common symptoms include fever, fatigue, chills, headache, nasal congestion, sore throat, dry cough, dyspnea, nausea, diarrhea and myalgia. Anosmia and ageusia are common. The risk of micro- and macrovascular thrombotic events was also increased initially. Disease severity ranges from asymptomatic through mild (various symptoms but no pneumonia), moderate (pneumonia but no hypoxia) and severe (pneumonia and hypoxia). The probability of severe and life-threatening disease is highest in persons ≥65 years of age and those living in nursing homes or long-term care facilities. Early in the SARS-CoV-2 pandemic, pneumonia was more commonly reported (with an abnormal chest radiograph in up to 75% of patients), but the rate appears to have decreased with the emergence of the omicron strain. Data from Japanese hospitalized patients suggest a drop in pneumonia prevalence from 77% with earlier strains to 34% with omicron. Similarly, data from the United States show that, among persons who died from COVID-19, pneumonia was present in 83% of those infected with an earlier variant and 53% of those who died in the omicron era.

Infection with SARS-CoV-2 can be confirmed with rapid antigen tests (most common in outpatient settings) or with molecular testing. All major mPCR platforms include SARS-CoV-2 in their testing panel.

In 2021, the IDSA has issued a set of guidelines on the treatment and management of COVID-19, and continues to regularly update them as new data become available. The recommendations cover pre- and post-exposure prophylaxis, outpatient treatment and inpatient treatment. The IDSA classifies patients with COVID-19 into four categories of increasing disease severity: patients with mild-to-moderate disease, who have oxygen saturation >94% and do not require supplemental oxygen; patients with severe illness, whose oxygen saturation is ≤94% on room air, or who require supplemental oxygen; patients with critical illness who require mechanical ventilation; and patients with critical illness who require extracorporeal mechanical oxygenation (ECMO).

For out-patient treatment, the treatment options include nirmatrelvir/ritonavir, a 3-day course of remdesivir, molnupiravir and neutralizing monoclonal antibodies (mAbs). Selected recommendations from IDSA are presented in Table 4-12. The choice of therapy should consider patient-specific factors such as symptom duration, renal insufficiency, contraindications, drug interactions, as well as logistical challenges, infusion capacity, and product availability.

The IDSA guidelines suggest starting nirmatrelvir/ritonavir within five days of symptom onset in patients with mild-to-moderate COVID-19 who are at high risk of severe disease progression. Nirmatrelvir, a peptidomimetic inhibitor of the SARS-CoV-2 main protease, antagonizes viral replication. By contrast, ritonavir, an HIV-1 protease inhibitor, has no direct activity against SARS-CoV-2 but inhibits the CYP3A-mediated metabolism of nirmatrelvir, increasing its plasma concentration. Nirmatrelvir/ritonavir should be taken every 12 hours during a 5-day course. The dosing depends on renal function, i.e., on the estimated glomerular filtration rate (eGFR). For patients with eGFR >60 mL/min, the recommended dose is 300 mg nirmatrelvir/100 mg ritonavir; for patients with eGFR ≤60 and ≥30 mL/min, 150 mg nirmatrelvir/100 mg ritonavir; the use of nirmatrelvir/ritonavir is not recommended for patients with eGFR <30 mL/min. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance or those that are potent CYP3A inducers. It may also cause clinically significant interactions with other medications, including immunosuppressive agents (eg, tacrolimus, cyclosporine, or sirolimus) and hormonal contraceptives containing ethinyl estradiol. Therefore, women of childbearing potential should use a non-hormonal backup method of contraception during treatment.

Remdesivir is an inhibitor the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), and thus antagonizes viral replication. It has documented efficacy for improving outcomes in both hospitalized and non-hospitalized patients with mild-to-moderate and severe COVID-19. In a study of non-hospitalized patients with mild-to-moderate disease at high risk of disease progression, remdesivir treatment resulted in significantly fewer hospitalizations (0.7%) compared to the placebo (5.3%; P=0.008). Based on this result, the IDSA suggests initiating remdesivir within 7 days of symptom onset in patients with mild-to-moderate COVID-19 who are at high risk of progression (e.g., those with obesity, diabetes mellitus, hypertension, immune compromise etc.). In these patients, remdesivir has also demonstrated a decrease in medically-attended visits related to COVID-19. For mild-to-moderate COVID-19, the recommended dosing regimen is 200 mg on the first day, followed by 100 mg on days two and three. For pediatric patients, the recommended dosing is 5 mg/kg on the first day and 2.5 mg/kg on subsequent days.

Molnupiravir is a prodrug of β-D-N4-hydroxycyti­dine, a nucleoside analog that introduces mutations into the SARS-CoV-2 genome when incorporated by the viral RdRp, reducing the viability of the virus. The IDSA suggests molnupiravir for ambulatory patients 18 year of age and older with mild-to-moderate COVID-19 who are at high risk of progression to severe disease and who have no other treatment options. Molnupiravir should be initiated within five days of symptom onset. Studies have shown it has the greatest benefit in patients with risk factors for progression to severe disease, such as advanced age, high-risk comorbidities, incomplete vaccination status, or immunocompromised conditions. It is important to note that molnupiravir is not authorized by the FDA for use in patients under 18 years of age due to potential effects on bone and cartilage growth. Additionally, it is not recommended for use during pregnancy because of concerns about fetal harm, as indicated by animal reproduction studies. Women of childbearing potential should be counseled to use reliable contraception during treatment and for four days after the last dose of molnupiravir. Men of reproductive potential who are sexually active with women of childbearing potential should also use reliable contraception during treatment and for at least three months after the final dose. Finally, breastfeeding is not recommended during molnupiravir treatment, and lactating individuals may consider interrupting breastfeeding and discarding breast milk during treatment and for four days after the last dose to ensure safety.

For ambulatory patients who have no other options for the treatment mild-to-moderate COVID-19 with high risk for progression to severe disease, the IDSA guidelines suggest FDA-qualified high-titer COVID-19 convalescent plasma within 8 days of symptom onset.

The inpatient treatment options include glucocorticoids such as dexamethasone, or methylprednisolone or prednisone when dexamethasone is not available; IL-6 inhibitors such as tocilizumab (in addition to standard care) or sarilumab when tocilizumab is not available; remdesivir; and JAK inhibitors such as baricitinib (administered with corticosteroids or remdesivir if corticosteroids are contraindicated) and tofacitinib. Molnupiravir may also be administered to patients with mild-to-moderate COVID-19 who are hospitalized for reasons unrelated to the virus and are at a high risk of developing a severe illness. Selected IDSA recommendations for inpatient treatment are shown in Table 4-13.

For prevention of COVID-19 by vaccination, please see, Switch Therapy, Step-Down Therapy and Prevention.

Respiratory syncytial virus (RSV), a member of the Paramyxoviridae family, is one of the most important seasonal respiratory viruses and the leading cause of lower respiratory tract illness (LRTI), including pneumonia, in infants and children. Although virtually everyone is infected with RSV by three years of age, its immunomodulatory properties prevent the formation of effective long-term immunity, making reinfection common in older children and adults. While generally asymptomatic or productive of mild disease, RSV reinfection can cause serious disease in older adults (a problem that has been significantly increasing in recent years), immunocompromised individuals and persons with cardiopulmonary comorbidities. Before the COVID-19 pandemic, RSV exhibited a seasonal pattern of activity, peaking in the autumn and winter (October to March in the Northern hemisphere); while the pandemic disrupted this pattern, RSV dynamics appear to have largely returned to the pre-pandemic patterns by the 2023/24 season.

While the most common form of RSV-associated LRTI in infants is bronchiolitis, pneumonia is also commonly seen. An estimated 15-50% of infants and young children with their first RSV infection develop LRTI, and hospitalization is required in 1-3% of the annual birth cohort. In a small proportion (5-10%) of hospitalized children, admission to the ICU is required. Among older adults, RSV is an increasing cause of pneumonia hospitalization, with a rate comparable to that of influenza. RSV also accounts for a significant proportion of pneumonia-related deaths among older adults, which is again similar to influenza. Although the rate of bacterial superinfection or coinfection is believed to be low, RSV infection may create an environment for commensal pneumococcus to become invasive.

There is at present no safe and effective treatment known for RSV infection; in both children and adults, management is symptomatic. The first immune therapy for RSV disease, the mAb palivizumab, received FDA approval in 1998. Another mAb, nirsevimab, was approved in 2023. These agents confer passive immunity by targeting the F (fusion) protein of RSV, preventing its entry into the host cell. The first vaccines against RSV disease, Arexvy (GSK) and Abrysvo (Pfizer), which contain the F protein as the active ingredient, were also approved in 2023. They were followed in 2024 by mRESVIA (Moderna), an mRNA-based vaccine. Arexvy is currently approved for vaccination of older adults (≥60 years of age or 50-59 years of age if at increased risk of RSV-associated LRTI), while Abrysvo is approved for vaccination of older adults (≥60 years of age) and pregnant individuals (at 32-36 weeks of gestational age, for immunization of infants), and mRESVIA is approved for vaccination of adults ≥60 years of age only. The Centers for Disease Control (CDC) recommends that infants or young children be immunized through mAbs or maternal vaccination (most infants will not require both). For older adults, the CDC recommends that individuals ≥75 years of age or those ≥60 years of age who are at increased risk of severe RSV disease receive one dose of an RSV vaccine, ideally just before the regular RSV season, i.e., in the late summer or early fall (see Switch Therapy, Step-Down Therapy and Prevention for more information).

Hantaviruses (or orthohantaviruses) are another, albeit rare, cause of viral pneumonia Hantaviruses are a genus of viruses that asymptomatically infect rodents, in whose urine and stool the virions are shed. Once aerosolization of the virus occurs, humans may be infected by inhaling the droplets; a rapidly progressive disease characterized by fever, chills, headache, nausea, and vomiting develops. This prodrome is followed by the development of hypoxemia secondary to diffuse pulmonary injury. Circulating immunoblasts and thrombocytopenia may be seen. The diagnosis can be made by serology as high titers of IgM and IgG antibodies are present in the blood at the time of presentation. The history of rodent exposure is important in diagnosis. Although the disease has been reported throughout the United States, most cases have originated in the southwestern part of the country.

Varicella is also a well-recognized cause of potentially fatal pneumonia. Varicella usually presents as a self-limited disease in children. However, in adults it tends to be more severe and is more often associated with pneumonia. Pregnant women in the third trimester and immunosuppressed hosts tend to be at higher risk for this complication. The diagnosis should be suspected in the presence of typical vesicular lesions plus pulmonary infiltrates. Treatment with an antiviral agent such as acyclovir should be initiated as soon as possible, as it is more likely to be successful if given early (Table 4-11).

SARS is a febrile severe lower respiratory illness that is caused by infection with a coronavirus, SARS-CoV, related to the 2019 pandemic coronavirus SARS-CoV-2. During the winter of 2002 through the spring of 2003, the WHO received reports of >8000 SARS cases and nearly 800 deaths. The vast majority of patients with SARS-CoV disease have a clear history of exposure, either to a SARS patient(s) or to a setting in which SARS-CoV transmission is occurring, and develop pneumonia. Laboratory tests are helpful but do not reliably detect infection early in the illness. SARS-CoV can be detected by PCR-based methods, but given its apparent extinction in human hosts after 2004, most mPCR platforms do not include tests for it.

Therapy

Therapy for pneumonia will be either empiric or, where possible, organism-specific. A suggested treatment decision tree for the treatment of hospitalized patients with CAP is shown in Figure 4-2. Even when empiric therapy is to be used, it can be individualized. The presence of epidemiologic risk factors and the severity of the disease will also influence the medications selected. Table 4-14 lists antimicrobial therapy for both ambulatory and hospitalized patients with CAP. Recommended antimicrobial therapies for specific pathogens are shown in Table 4-15.

All patients should be reevaluated within 48 to 72 hours of therapy to make certain there has not been a clinical deterioration requiring hospitalization (Table 4-16).

Guideline-directed therapy has been demonstrated to produce improved outcomes including reduced mortality and shortened length of hospital stay.