Pneumococcal Infections

Sandra R. Arnold and P. Joan Chesney

Streptococcus pneumoniae, Staphylococcus aureus, and group A Streptococcus pyogenes are the three most important bacterial pathogens causing infections in otherwise well children. In 2005 it was estimated that S pneumoniae caused 700,000 to 1 million deaths in children younger than 5 years of age. Most of these children lived in developing countries.¹

There are 90 immunologically and chemically distinct capsular polysaccharides that determine virulence. Based on antigenic similarities, the 90 types have been grouped into 45 serotypes. Relatively few serotypes cause most disease, which has lead to development of polyvalent vaccines.²

S pneumoniae can cause infection in almost any tissue or organ. The vast majority of infections in children occur in the middle ear, sinuses, lungs, meninges, and bloodstream. In 2000, the Food and Drug Administration approved and the Advisory Committee on Immunization Practices recommended the heptavalent pneumococcal conjugate vaccine (PCV7) for routine use in infants and young children as a primary series at 2, 4, and 6 months of age and a booster dose at 12 to 15 months of age.³ This vaccine has had an impressive effect on the incidence of invasive pneumococcal disease in vaccine recipients and the general population (see Chapter 244).

EPIDEMIOLOGY

Recent nasopharyngeal colonization with a new serotype almost always precedes infection.^4,5 Colonization rates are highest in infants and preschool children, where they may be as high as 35%.⁴ PCV7 includes the 7 most common serotypes causing colonization and infection in children (4, 6B, 9V, 14, 18C, 19F, and 23F). These serotypes and the cross-reactive serotypes (6A, 9A, 9L, 18B, 18F) caused 86% of cases of bacteremia, 83% of cases of meningitis, and 65% of cases of acute otitis media in children younger than 6 years.³

PCV7 was licensed for use in the prevention of invasive pneumococcal disease (a positive culture from a normally sterile body site, eg, meningitis and bacteremia) in infants and toddlers. In the Northern California Kaiser Permanente Vaccine Study among 37,686 infants, vaccine efficacy was 97.4% compared with placebo for vaccine serotype invasive pneumococcal disease.⁹

Based upon active surveillance by the Centers for Disease Control and Prevention, overall invasive pneumococcal disease rate among children aged 5 years or younger was 77% lower in 2005 (approximately 13,000 fewer cases) compared with 1998 to 1999.¹⁷ In addition, secondary to indirect effects of PCV7 herd immunity,¹⁸ disease incidence dropped by 18% in the 65 years or older age group^19,20; however, clinically important, nonvaccine serotypes have emerged in this time period (eg, serotype 19A, which is multidrug resistant).

Prior to the release of PVC7, the incidence of penicillin-resistant and multidrug-resistant strains had increased dramatically through the late 1990s and was as high as 35% in many parts of the United States.⁸ Between 1999 and 2004, the incidence of resistant strains in invasive pneumococcal disease fell by 81% in children under 2 years of age and by approximately 50% across all age groups due to a reduction in disease caused by antibiotic-resistant vaccine serotypes^30,31

PATHOPHYSIOLOGY AND GENETICS

Virulence of the Organism

Invasive pneumococcal disease is preceded by colonization of the nasopharynx, the organism having been acquired through respiratory droplet spread from a colonized individual. Infection can occur by bacterial aspiration into the lower respiratory tract or spread to the middle ear or sinuses.³⁶ Adherence at these sites may be enhanced by the presence of viral respiratory pathogens resulting in exposed muscosal receptors.^37,38 Bacteremia and meningitis occur when colonizing bacteria gain access to the bloodstream, penetrating the epithelial barrier of the nasopharynx.

Host Immunity

Local and circulating antibody and an intact complement pathway are the most important factors mediating the outcome of S pneumoniae invasive pneumococcal disease. Serotype specific or cross-reactive antibody adheres to the capsule, which results in capsular swelling and “stickiness” enhancing opsonization and phagocytosis by neutrophils. Without antibody attached to the organism, these cells are unable to phagocytose the organisms, which can reproduce unhindered. Infants under 2 years of age are unable to produce anticapsular antibody after infection or following immunization with polysaccharide vaccine.

Populations at Risk

Children in daycare centers who are not breastfed and children who are American Indians, Alaskan natives, and African American have an increased risk of invasive pneumococcal disease.^27,39-41 Increased risk for invasive pneumococcal disease also occurs among children with immunodeficiency,⁴⁴ including defects in humoral immunity; HIV infection⁴⁴; asplenia or splenic dysfunction,⁴⁵ including sickle hemoglobinopathies⁴⁶; and recently described defects of the innate immune system (see Chapters 187 and 188). Other populations at risk include children with cancer, central nervous system disorders or craniofacial anomalies, congenital heart disease, asthma,⁵⁰ chronic kidney disease (especially nephrotic syndrome), liver disease, recent trauma, and children who have received cochlear implants.^51,52

CLINICAL MANIFESTATIONS

In the pre-PCV7 era, S pneumoniae was the predominant organism causing occult bacteremia (92% of cases).⁵³ In the postvaccine era, this entity has virtually disappeared.^54,55

In children beyond the neonatal period, S pneumoniae is the leading bacterial cause of pneumonia in the United States, causing 70% of cases that involve respiratory bacteria (see Chapter 240).⁵⁶ In infants and young children, bronchopneumonia with scattered distribution of parenchymal consolidation is commonly seen on x-rays. In older children and adults, lobar consolidation is more common. Other radiographic findings can include pleural fluid, lung abscess(es) resulting from necrosis, and, infrequently, pneumatoceles. Symptoms may range from mild fever and non-specific respiratory symptoms with or without cough to high fever with toxicity and severe respiratory impairment. In infants and toddlers, fever, vomiting, abdominal distension, and pain may suggest appendicitis. The classic clinical presentation in older children and adults, following a viral prodrome, is the abrupt onset of high fever with chills, dyspnea, and cough with rust-colored sputum. Patients with right upper lobe pneumonia can have nuchal rigidity suggestive of meningitis. Forty percent of cases of bacterial pneumonia are associated with parapneumonic effusions, (inflammatory fluid collection adjacent to a pneumonic process). Pneumonia rates have declined in the PCV7 era,^57,58 but reports of complicated parapneumonic effusion or empyema (fibrinopurulent exudate) increased before and after PCV7 with nonvaccine serotype 1 S pneumoniae as the predominant pathogen.^27,59-62

Local spread from the colonized nasopharynx may result in acute otitis media, sinusitis, conjunctivitis, and periorbital or buccal cellulitis. Other important but uncommon infections resulting from metastatic seeding following S pneumoniae bacteremia are meningitis, acute bacterial endocarditis, pericarditis, pyogenic arthritis, osteomyelitis, and cellulitis. All of these infections are covered in more detail in other chapters. In children with defective humoral immunity, functional, or anatomic asplenia, and/or complement defects, fulminant septicemia occurs with S pneumoniae.⁴⁵ Pneumococcal peritonitis may be uniquely seen in children with nephrotic syndrome.⁶⁴

DIAGNOSTIC EVALUATION

Pneumococcal infections can only be diagnosed with certainty if the organism is isolated from a normally sterile site, such as blood; cerebrospinal fluid; joint, pleural, pericardial, or middle ear fluid; or a bone or abscess aspirate. Every attempt should be made to obtain these cultures before starting antibiotics in order to document the etiology and perform antimicrobial susceptibility testing.

Nasopharngeal cultures are of no value as almost all young children are colonized with S pneumoniae at some time. Lower respiratory tract secretions obtained by tracheal aspirate or bronchoalveolar lavage or needle aspirate of infected lung tissue are valuable but rarely justified.

Rapid antigen tests for S pneumoniae have been of limited value for rapid diagnosis, but with better sensitivity hold promise for the future. Latex agglutination, enzyme immunoassay, immunochromatic, and polymerase chain reaction assays in general are as effective as Gram stains.^65,66

TREATMENT

Penicillin and all β-lactam drugs act on S pneumoniae by inhibiting the activity of transpeptidase enzymes (also called penicillin-binding proteins), which build the peptidoglycan lattice or scaffolding of the cell wall. Through the process of transformation, S pneumoniae acquired mutated penicillin-binding proteins from other resistant streptococcal species (see Chapter 222). These changes in penicillin-binding proteins have resulted in a slow but steady increase the minimal inhibitory concentrations for β-lactam antibiotics.⁶⁷ Multidrug resistance occurs in penicillin-resistant pneumococci as well.^8,68,69 Vancomycin is the only drug to which no strains have yet become resistant.

The definition of antimicrobial susceptibility is based upon achievable levels of the antibiotic at the site of infection and varies by antibiotic. Recently, changes have been made to the susceptibility break points for penicillin and cefotaxime (eTable 280.1 ).

All patients with suspected bacterial meningitis should be treated initially with vancomycin and cefotaxime (or ceftriaxone) until susceptibilities of the organism are available. After susceptibilities are available, antibiotic modifications can be made. Therapy is usually continued for 10 days, but may extend for longer periods. The use of dexamethasone as adjunctive therapy for bacterial meningitis remains unresolved (see Chapter 231).^70,71

For nonmeningeal invasive pneumococcal disease in the immunocompetent host, empiric use of vancomycin is not generally indicated because treatment failures are rare with penicillins and cephalosporins for bacteremia and pneumonia. In patients with fulminant and potentially life-threatening invasive infections, particularly in immunocompromised hosts, the addition of vancomycin to the usual regimen for an invasive, nonmeningeal infection may be justified, providing the vancomycin is discontinued after susceptibilities reveal that therapy with β-lactam agents should be successful. Treatment failures with the use of newer macrolides and fluoroquinolones (the latter in adults) to treat bacteremia and pneumonia due to nonsusceptible strains have been reported^75,76; thus, empiric monotherapy with these agents for community-acquired pneumonia should take into account the antibiotic-resistance patterns and the severity of illness. Linezolid was licensed for the treatment of gram-positive community-acquired and nosocomial pneumonia in children in 2002 and is a treatment option for suspected or confirmed multidrug-resistant pneumococcal pneumonia; it may be most useful when infection (either primary or coinfection) with methicillin-resistant S aureus cannot be excluded (see Chapter 240).⁷⁷

High doses of amoxicillin (80–90 mg/kg/day) remains the drug of choice for otitis media caused by S pneumoniae,^78,79 although recent guidelines suggest holding initial therapy in children with nonsevere or questionable infection (see Chapter 243).

COMPLICATIONS

Pneumococcal meningitis has a case fatality rate of 5% to 10% in developed countries.^71,80,81 Hearing loss is the most common neurologic sequela occurring in up to 10% of infections; other neurologic sequelae occur with less frequency, ranging from mild to severe.^72,80,82 Fulminant pneumococcal sepsis is unusual but can occur, especially among immunocompromised or asplenic individuals. Pneumococcal pneumonia may be complicated by pleural effusion or empyema necessitating a chest tube or surgical procedure to hasten resolution. Mastoiditis is an uncommon complication of otitis media that may be complicated by meningitis or brain abscess. Invasive pneumococcal infections may be rarely be complicated by hemolytic uremic syndrome.⁸⁵

PREVENTION

The 23-valent pneumococcal capsular polysaccharide vaccine licensed in 1977 covers 90% of the serotypes causing invasive pneumococcal disease in the United States. This vaccine elicits type-specific antibody responses in children older than 5 years of age and adults, but not for children younger than 2 years of age (see Chapter 244).^3,86 New pneumococcal conjugate vaccines containing capsular polysaccharide from additional serotypes (1, 3, 5, and 7F) currently being studied should expand coverage for both invasive and noninvasive pneumococcal disease and improve coverage for invasive pneumococcal disease in developing countries where these serotypes cause more invasive disease.^87,88 The development of novel pneumococcal vaccines are based on pneumococcal proteins that contribute to virulence and are common to all serotypes (eFig. 280.1 ).³⁵

REFERENCES

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