Pneumococcal Pneumonia

Julian P. Lichter

Pneumococcal pneumonia is the most common infection leading to hospitalization in the United States. It occurs in all age groups and is responsible for 500,000 cases of pneumonia and approximately 40,000 deaths annually. Pneumococcal pneumonia accounts for more than 50% of community-acquired pneumonias and 10% of nosocomial pneumonias. A resurgence of outbreaks of pneumococcal pneumonia has occurred, especially in chronic-care facilities where the strains are increasingly resistant to antibiotics. Although pneumococcal pneumonia can occur in any season, it is more common in winter and early spring.

The pneumococcus organism inhabits the nasopharynx of 40% to 50% of normal individuals for 4 to 6 weeks at a time. Disease is frequently caused by acquiring a serotype different from the colonizing serotype. The probability and severity of infection are influenced by host factors and by biologic properties of the bacterium itself. Patients who are most susceptible to pneumococcal infection include those with (1) disorders of swallowing and impairment of airway clearance mechanisms and mucociliary defenses, such as advanced age, seizure and other neurologic disorders, asthma, chronic bronchitis, and bronchiectasis; (2) alveolar fluid accumulation, such as congestive heart failure, burns, and acute respiratory distress syndrome; and (3) impaired phagocytosis and compromised humoral immunity, such as surgical or functional asplenia (e.g., sickle cell anemia, thalassemia, total irradiation), hypogammaglobulinemia, diabetes, HIV infection (50–100 times increase in invasive pneumococcal disease in HIV), multiple myeloma, lymphoma, cirrhosis, and transplant recipients (especially bone marrow). Such individuals are also susceptible to protracted or complicated pneumonias. Viral upper respiratory illness also seems to predispose patients to subsequent pneumococcal pneumonia. Viral disruption of respiratory epithelium increases expression of receptors for pneumococcal attachment and, thus, predisposes the patient to pneumococcal invasion. Other more recently described predisposing factors include alcohol abuse, smoking, pregnancy, homelessness, incarceration, and crack-cocaine use.

Of the more than 82 strains of pneumococci, only a few commonly cause pneumonia. The pathogenicity and virulence of particular strains are related to properties of the outer capsules and cell walls, as well as surface and cytoplasmic regulatory mechanisms. They may be identified in the laboratory by a characteristic capsular swelling (Quellung reaction) when incubated with a specific antibody. Current evidence suggests that the pneumococcal capsule protects the organism from phagocytosis and enhances its pathogenicity. Recent studies suggest that the development of type-specific, anticapsular antibody correlates with the resolution of fever and recovery in untreated patients.

Pneumococci are aerosolized from the nasopharynx to the alveolus, and then pass from alveolus to alveolus through the pores of Cohn, resulting in a mostly lobar distribution of consolidation. They invade alveolar type II cells, a process initiated through binding of bacterial surface choline to the receptor for platelet-activating factor (up-regulated on the alveolar cell surface, presumably by viral infection). Pathologically the consolidated lung evolves through well-described stages of alveolar engorgement followed by red hepatization and, after a few days, grey hepatization with alveoli packed with leukocytes. There is, however, little tissue destruction, and resolution occurs with minimal organization or permanent scarring. Dying pneumococci produce a potent cytotoxin, pneumolysin, which binds to cholesterol on the host’s cell membranes, forming pores and killing the cells. Pneumolysin also promotes intra-alveolar bacterial replication, penetration from alveoli to interstitium, and dissemination into the bloodstream. Approximately 25% of cases of pneumococcal pneumonia were associated with bacteremia in the 1960s but recent studies report a much lower occurrence (as low as 1%–6%).

The clinical manifestations of classic pneumococcal pneumonia include high fever (100% in one series, although high fever may be absent in the elderly or in uremic patients), productive cough (98%), pleuritic chest pain (70%), and the abrupt onset of shaking chills (7%). The sputum is blood streaked or rusty (75%). Pleuritic pain may radiate into the abdomen, masquerading as an acute abdomen. Patients characteristically appear acutely ill, tachypneic, and demonstrate signs of consolidation on chest examination. A pleural rub is occasionally present. Herpes labialis is a relatively common finding. Older patients often present with confusion and delirium.

The chest roentgenogram usually reveals a lobar, alveolar-filling process, frequently with an ipsilateral pleural effusion. The roentgenographic presentations, however, are diverse and include a patchy bronchopneumonia, adult respiratory distress syndrome, and an interstitial appearance when occurring in an emphysematous lobe. The prevalence of these radiologic patterns may depend on the infecting serotype.

As with other bacterial pneumonias, the methods and criteria for establishing a diagnosis are controversial. Gram stain of expectorated sputum typically reveals numerous polymorphonuclear granulocytes and lancet-shaped Gram-positive diplococci. However, the predominant organism may not be obvious on some specimens because of heavy smear contamination with oropharyngeal flora. Sputum Gram stain and culture also can be misleading in patients who have received prior antibiotics and in patients with chronic obstructive pulmonary disease. Isolation of the organism in the sputum is not sensitive for the presence of infection; in fact, only 45% of patients with pneumonia and blood cultures positive for pneumococci grow the organism on sputum culture. For this reason, many culture-negative cases of pneumonia may be caused by the pneumococcus. Isolation of the organism from blood, pleural fluid, or other involved closed tissue space (e.g., joint, cerebrospinal fluid, pericardium) may be required for a firm diagnosis. A rapid urinary antigen test (Binax NOW) is available to detect pneumococcal pneumonia earlier in its course. The sensitivity is 60% to 70% (higher for bacteremic patients), whereas the specificity approaches 100%. Two recent studies have reported immunochromatographic tests capable of rapidly detecting streptococcus pneumonia antigen in sputum and pleural fluid. In the sputum study, the sensitivity was greater than the urinary antigen test and just as specific.

Much of our understanding of the natural history of pneumococcal pneumonia comes from experience during the preantibiotic era, when three clinical patterns were observed: (1) a 5- to 10-day course characterized by high fevers with defervescence and recovery occurring either gradually (lysis) or dramatically (crisis); (2) a protracted or recrudescent febrile course indicative of complications such as empyema, meningitis, endocarditis, and pericarditis; or (3) rapid respiratory deterioration and death. An initial leukocytosis exceeding 20,000 correlated with a good prognosis, whereas a normal or low leukocyte count implied a grave prognosis. An abrupt fall in leukocyte count often preceded resolution by crisis, but persistent leukocytosis frequently was a harbinger of complications such as empyema.

Although antibiotics have improved survival, pneumococcal pneumonia remains a serious disease. In the preantibiotic era, the overall mortality rate was 25% to 35%. In bacteremic patients, it exceeded 80%. Antibiotics have reduced the mortality rate to 5% and 20%, respectively most within the first week of illness. Of patients who die despite antibiotic therapy, 35% die within the first 24 hours of antibiotic treatment, underscoring the fulminant course this disease can pursue. Mortality in those who require mechanical ventilation remains high. Advanced age, presence of asthma or chronic obstructive pulmonary disease, and high acute physiology and chronic health evaluation (APACHE) scores are independent predictors of poor outcome in bacteremic pneumococcal disease. Inability to mount a fever and nosocomially-acquired pneumococcal pneumonia are additional risk factors for respiratory failure or death.

Penicillin G continues to be the drug of choice for sensitive pneumococcal pneumonia. It is effective either orally or intramuscularly in moderately to severely ill patients but should be administered intravenously in the critically ill and in those with empyema or extrapulmonary foci of infection. Penicillin-sensitive strains can also be treated with penicillin derivatives, and second and third-generation cephalosporins. First generation cephalosporins should not be used because poor penetration into the cerebrospinal fluid increases the risk of developing pneumococcal meningitis. Administration of at least one active antibiotic within 4 hours has been associated with reduced mortality and shortened length of stay especially in bacteremic patients. Therapy of uncomplicated pneumonia should be continued for 5 to 7 days or at least 3 to 5 days after defervescence of fever in more severe cases. Although monotherapy with a single effective antibiotic for pneumococcal pneumonia is standard, recent studies have shown a significant survival benefit for combination therapy in patients with bacteremic pneumococcal pneumonia who required intensive care unit admission. In one large study, mortality rate at 14 days was reduced from 55% to 14% with combination therapy.

Worldwide it is becoming more common to find pneumococcal strains that have developed intermediate or full resistance to penicillin, probably through alteration of cellular penicillin-binding proteins. Approximately 20% of pneumococcal strains in the United States show an intermediate resistance, indicated by a mean inhibitory concentration of 0.1 to 1.0 g/μL. In this setting, increasing the penicillin dose to 12 to 18 million units per day may be effective, as would administration of cefotaxime, ceftriaxone, imipenem, or fluoroquinolones once sensitivities have been confirmed. Twenty percent of pneumococcal isolates are highly resistant (types 6, 9, 14, 19, and 23), with a mean inhibitory concentration of at least 2 μg/mL. Multiresistant strains (resistant to penicillin, trimethoprim–sulfamethoxazole, chloramphenicol, tetracycline, macrolides, and even second- and third-generation cephalosporins) have been isolated in the United States. Resistance to levofloxacin and moxifloxacin has been reported as well but rates remain low (<1%). Vancomycin, fluoroquinolones, or an alternative agent based on in vitro sensitivities should be used for strains with high-level penicillin resistance or resistance to multiple antibiotics. Drug-resistant infections have been observed in certain institutional settings, particularly daycare centers, hospitals, and nursing homes.

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