Pneumococcal Infections 

Streptococcus pneumoniae is a gram-positive, catalase-negative cocci that has remained an extremely important human bacterial pathogen since its initial recognition in the late 1800s. The term pneumococcus gained widespread use by the late 1880s, when it was recognized as the most common cause of bacterial lobar pneumonia.

Worldwide, S pneumoniae remains the most common cause of community-acquired pneumonia (CAP), bacterial meningitis, bacteremia, and otitis media. S pneumoniae infection is also an important cause of sinusitis, septic arthritis, osteomyelitis, peritonitis, and endocarditis and an infrequent cause of other less-common diseases.

An image depicting pneumococcal pneumonia can be seen below.

Pneumococcal vaccination, particularly routine childhood pneumococcal conjugate vaccine (introduced in the United States in 2000), has led to decreased rates of invasive pneumococcal infections (>90%) caused by pneumococcal serotypes covered by the vaccine, as well as overall decreased rates of invasive disease (45% overall; 77% in children < 5 y). In addition, herd immunity has led to decreased rates of disease in older children and adults.^{[1, 2, 3]}

Many subsequent studies have shown increased rates of invasive and noninvasive disease caused by serotypes not covered by the vaccine, including serotypes 15, 19A, and 33F. Serotype 19A has received the most attention, not only because of increased disease rates associated with this serotype but also because of its increased association with drug resistance. Increased rates of invasive disease with such serotypes have caused the overall rates of invasive disease to remain somewhat steady since 2002, although still greatly reduced from rates prior to introduction of the conjugate vaccine.^{[1, 4, 5, 6, 7, 8, 9, 10, 3]}

Data from 2006-2007 revealed that only 2% of invasive pneumococcal disease in children younger than 5 years in the United States was caused by serotypes contained in pneumococcal conjugate vaccine 7 (PCV7), while an additional 6 serotypes accounted for almost two thirds of invasive disease in this age group.^[11] Development of a vaccine containing additional serotypes continued, and pneumococcal conjugate vaccine 13 (PCV13) was approved by the FDA February 24, 2010.^[12]

Despite an overall decreased incidence of otitis media caused by serotypes not covered by vaccination since the introduction of the conjugate pneumococcal vaccine, an increase in rates of disease caused by serotypes not covered by the vaccine has occurred, as well as an increase in rates of diseases caused by vaccine-covered serotypes in incompletely immunized children. The incidence of otitis media caused by serotype 19F has remained steady. Overall health care utilization for otitis media has decreased, as has the incidence of recurrent otitis media in some populations and studies.^{[2, 13, 14, 15]}

Adherence and invasion

S pneumoniae is an example of a typical extracellular bacterial pathogen. Pathogenicity requires adherence to host cells, along with the ability to replicate and to escape clearance and/or phagocytosis. The organism must then gain access to areas where it can manifest infection, either via direct extension or lymphatic or hematogenous spread.

The rates of pneumococcal colonization in healthy children and adults provide information about the success of adherence and replication of the pneumococcus. After colonization, organisms may gain access to areas of the upper and/or lower respiratory tracts (sinuses, bronchi, eustachian tubes) by direct extension. Under normal conditions in a healthy host, anatomic and ciliary clearance mechanisms prevent clinical infection. However, clearance may be inhibited by chronic (smoking, allergies, bronchitis) or acute (viral infection, allergies) factors, which can lead to infection. Alternatively, pneumococci may reach normally sterile areas, such as the blood, peritoneum, cerebrospinal fluid, or joint fluid, by hematogenous spread after mucosal invasion. In the absence of previously acquired serotype-specific antibodies (see below), clinically apparent infection is likely to occur.

Capsule

Other than some isolates associated with conjunctivitis outbreaks, essentially all clinical isolates of S pneumoniae are encapsulated. Repeating oligosaccharides that make up the capsule of an individual bacterial isolate are transported to the cell surface, where they bind tightly with the cell-wall polysaccharides. Based on antigenic differences within these capsular polysaccharides, 91 serotypes of S pneumoniae have been identified.

The virulence of each organism is determined in part by the makeup and amount of capsule present. In a pneumococcus-naive host (or in the absence of antibody to pneumococcal capsule) host-cell phagocytosis is severely limited because of the inhibition of phagocytosis and the inhibition of the activation of the classic complement pathway. In addition, in vitro and in vivo studies of clinical isolates have shown that pneumococci have the ability to obtain DNA from other pneumococci (or other bacteria) via transformation, allowing them to switch to serotypically distinct capsular types.

There are 2 recognized numbering systems based on pneumococcal serotypes. In the American system, the serotypes were numbered in order of discovery, with lower numbers corresponding to serotypes that more frequently cause clinical disease, meaning that they were identified earlier. The Danish numbering system is based on grouping of serotypes with similar antigenicity and is more widely accepted and used worldwide. Today, serotyping provides important epidemiological information, especially with the increasingly widespread use of vaccination, but rarely provides timely clinical information.

The Quellung reaction is demonstrated by combining sera of previously immunized animals with capsular antigen. Agglutination causes capsule refractility and the ability to observe the capsule microscopically.

Toxins and other virulence factors

Pneumococcal isolates produce few toxins; however, all serotypes produce pneumolysin, which is an important virulence factor that acts as a cytotoxin and activates the complement system. In addition, pneumolysin causes a release of tumor necrosis factor-alpha and interleukin-1.

Other potential virulence factors include cell surface proteins such as surface protein A and surface adhesin A and enzymes such as autolysin, neuraminidase, and hyaluronidase. The contributions of these substances to pneumococcal virulence are being studied extensively, and some are being investigated as potential vaccine constituents.^[16]

Complement activation

Much of the clinical severity of pneumococcal disease is due to the activation of the complement pathways and cytokine release, which induce a significant inflammatory response. S pneumoniae cell wall components, along with the pneumococcal capsule, activate the alternative complement pathway; antibodies to the cell wall polysaccharides activate the classic complement pathway. Cell wall proteins, autolysin, and DNA released from bacterial breakdown all contribute to the production of cytokines, inducing further inflammation.

Frequency

United States

Colonization

S pneumoniae remains an important pathogen in large part because of its ability to first colonize the nasopharynx efficiently. Studies performed in the United States prior to universal vaccination recommendations have shown average carriage rates of 40%-50% in healthy children and 20%-30% in healthy adults. Factors such as age, daycare attendance, composition of household, immune status, antibiotic use, and others obviously affect these numbers.^{[17, 18, 19]} With the implementation of childhood vaccination with the heptavalent conjugate vaccine for S pneumoniae, the colonization rates have decreased in children receiving the vaccine and in adults and other children in their household because of the phenomenon of herd immunity.

Most individuals who are colonized with S pneumoniae carry only a single serotype at any given time; the duration of colonization varies and depends on specific serotype and host characteristics. Invasive disease is usually related to recent acquisition of a new serotype. However, in most healthy hosts, colonization is not associated with symptoms or disease but allows for the continued presence of S pneumoniae within the population, allowing for prolonged low-level transmission among contacts.

S pneumoniae infection is the most common cause of CAP, bacterial meningitis, bacteremia, and otitis media in the United States. There is a clear seasonality, with infections peaking in the fall and winter months.^[20]

Noninvasive disease

Pneumococcal colonization allows for spread of organisms into the adjacent paranasal sinuses, middle ear, and/or tracheobronchial tree down to the lower respiratory tract. This spread results in specific clinical syndromes (sinusitis, otitis media, bronchitis, pneumonia) related to the noninvasive spread of the organisms.

Worldwide, the most common cause of death due to pneumococcal disease is pneumonia. In adults admitted to the hospital in the United States for pneumonia treatment, S pneumoniae remains the most common organism isolated. Until 2000, 100,000-135,000 patients were hospitalized for pneumonia proven to be caused by S pneumoniae infection in the United States annually. These numbers are likely a gross underestimate, as a definite cause is not determined in most cases of pneumonia treated each year. In addition, the actual rates are also likely decreasing owing to implementation of pneumococcal conjugate vaccination.^[21]

S pneumoniae infection is an important cause of bacterial co-infection in patients with influenza and can increase the morbidity and mortality in these patients. This has been emphasized recently by the increased number of cases of invasive pneumococcal disease seen in association with increased rates of hospitalizations for influenza during the 2009 H1N1 influenza A pandemic.^[22] Postmortem lung specimens from patients who died of H1N1 influenza A from May to August of 2009 were examined for evidence of concomitant bacterial infection. Twenty-nine percent of the specimens showed evidence of bacterial co-infection, with almost half of these being S pneumoniae.^[23]

S pneumoniae infection is estimated to cause over 6-7 million cases of otitis media annually in the United States. These numbers have likely decreased somewhat with the advent of universal vaccinations; however, S pneumoniae infection remains the most common cause of otitis media.^{[24, 19]}

Invasive disease

Statistics regarding invasive pneumococcal disease in the United States are based on active surveillance using the Centers for Disease Control and Prevention (CDC) Active Bacterial Core Surveillance (ABC) system. Calculations for 2008 estimated 43,000 (14.3 per 100,000 population) cases of invasive disease nationally, with 4,400 (1.5 cases per 100,000 population) deaths. Children younger than 5 years and adults older than 65 years are two identified age groups in whom rates of disease and death are increased. In 2008, rates of pneumococcal invasive disease in these groups were 20 per 100,000 population and 40.8 per 100,000 population, respectively. This compares with rates of 21.8 and 39.2 in 2007 and 23.2 and 43.3 in 2002, respectively. More than half of deaths due to invasive pneumococcal disease occur in adults with specific risk factors (age, immunosuppression) for severe disease. Such risk factors are an indication for vaccination.^[25]

International

Despite the worldwide importance of disease due to S pneumoniae infection, very little information is available on the extent of pneumococcal disease, particularly in developing countries.

Children

In developing countries, pneumococcus remains the most common and important disease-causing organism in infants. Although exact numbers are difficult to obtain, it is estimated that pneumococcus infection is responsible for more than one million of the 2.6 million annual deaths due to acute respiratory infection in children younger than 5 years. Case fatality rates associated with invasive disease vary widely but can approach 50% and are greatest in patients with meningitis.^{[24, 26]}

Estimates of pneumococcal disease in Gambian children show high rates of infection in the first year of life (≥500 per 100,000 children).^[27] Latin American studies also show a particularly high risk in infants younger than 6 months, and children in southern India have higher rates of colonization at younger ages compared with US children, according to US clinical studies. Some particular populations, such as indigenous Australians and minority Israeli persons, also have disproportionately higher rates of disease, similar to the native Alaskan and native Indian populations in the United States, although determining the role of socioeconomic factors in the higher incidence of disease in these populations is difficult.^[27]

In Europe, children younger than 2 years constitute the population most at risk for pneumococcal infection, with rates decreasing as persons age. The overall incidence of invasive disease is estimated to be somewhat lower in Europe (14 per 100,000 persons in Germany vs 35.8 per 100,000 persons in England vs 45.3 per 100,000 persons in Finland vs 90 per 100,000 persons in Spain vs 235 per 100,000 persons in the United States), although many have postulated that this may be due in part to the more liberal blood-culture collection practices in the American health care system.^{[27, 24]}

Adults

Even fewer data are available on the worldwide incidence of pneumococcal disease in adults. As in the United States, the most common cause of CAP in Europe is S pneumoniae infection, affecting approximately 100 per 100,000 adults each year. Overall rates of febrile bacteremia and meningitis are also similar, (15–19 per 100,000 adults and 1–2 per 100,000 adults, respectively), with the risk for these diseases increased in elderly and infant populations.^[28]

Because no population-based data on pneumococcal disease in adults in developing countries are available, estimates of disease burden are based on small clinical studies, vaccine trials, extrapolation from data in developed countries, and studies of persons at high risk for disease. The information gleaned from these sources suggests that the incidence of and mortality rates associated with pneumococcal disease are high, with HIV-positive populations exhibiting particularly high rates of infection. Further studies are greatly needed.^{[29, 24]}

Mortality/Morbidity

Although exact rates are difficult to determine, the World Health Organization (WHO) estimates that, worldwide, 1.6 million deaths were caused by pneumococcal disease in 2005, with 700,000 to 1 million of these occurring in children younger than 5 years.^[30] Even in patients in developed countries, invasive pneumococcal disease carries a high mortality rate—an average of 10-20% in adults with pneumococcal pneumonia, with much higher rates in those with risk factors for disease.^{[31, 32]}

Race

In the United States, invasive pneumococcal disease is more common in native Alaskans, Navajo and Apache Indians, and African Americans than in other ethnic groups. Some studies have shown this difference persists even when the results are controlled for socioeconomic factors, and the reasons for this discrepancy among certain populations are unclear.^[18]

Sex

Most clinical studies of pneumococcal disease show a slight male predilection for disease; the reason for this is unclear.

Age

Children younger than 2 years carry the highest burden of S pneumoniae disease worldwide. In developed countries, the incidence is highest in those aged 6 months to 1 year, while, in developing countries, the disease is particularly common in children younger than 6 months.

Adults older than 55-65 years are the next most commonly affected age group worldwide.

Immunosuppressed persons of any age are at a higher risk for pneumococcal disease.