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Chapter 151 | Pneumococcal Infections

Section 5 Diseases Caused by Gram-Positive Bacteria · Part 5 – Infectious Diseases: Bacterial

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. S. pneumoniae is a gram-positive, alpha-hemolytic, optochin-sensitive, bile-soluble diplococcus.
  2. The polysaccharide capsule is the primary virulence factor and basis for serotyping (100 serotypes).
  3. Invasive pneumococcal disease (IPD) rates are highest in children <2 years and adults ≥65 years.
  4. Pneumococcal pneumonia classically presents as lobar consolidation; 'round pneumonia' is a specific pediatric finding.
  5. Elderly patients may present with confusion or malaise without fever or cough.
  6. Asplenia or splenic dysfunction is a critical risk factor for overwhelming pneumococcal disease.
  7. Urinary antigen testing is confounded by nasopharyngeal colonization and has modest sensitivity in adults.
  8. Empyema is the most common focal complication, occurring in <5% of cases.
  9. Vancomycin resistance has not yet been observed in clinical pneumococcal strains.
  10. PCV introduction has reduced vaccine-serotype IPD but non-vaccine serotypes are emerging.

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🖼 Figure Prevalence of pneumococcal carriage in adults and children resident in the United...
2 🖼 Figure Chest radiograph depicting classic lobar pneumococcal pneumonia in the right lower lobe...
3 🖼 Figure Schematic diagram of the pneumococcal cell surface, with key antigens
4 🖼 Figure CHAPTER 151 FIGURE 151-1 Pneumococci growing on blood agar, illustrating α hemolysis...

1. DEFINITION & OVERVIEW

  • Pneumococci are spherical gram-positive bacteria of the genus Streptococcus.
  • Within this genus, cell division occurs along a single axis, and bacteria grow in chains or pairs—hence the name Streptococcus, from the Greek streptos, meaning 'twisted,' and kokkos, meaning 'berry.'
  • At least 22 streptococcal species are recognized and are divided further into groups based on their hemolytic properties.
  • S. pneumoniae belongs to the α-hemolytic group that characteristically produces a greenish color on blood agar because of the reduction of iron in hemoglobin.
  • The bacteria are fastidious and grow best in 5% CO but require a source of catalase (e.g., blood) for growth on agar plates, where they develop mucoid (smooth/shiny) colonies.
  • Pneumococci without a capsule produce colonies with a rough surface.
  • Unlike that of other α-hemolytic streptococci, their growth is inhibited in the presence of optochin (ethylhydrocupreine hydrochloride), and they are bile soluble.
  • In the late nineteenth century, pairs of micrococci were first recognized in the blood of rabbits injected with human saliva by both Louis Pasteur, working in France, and George Sternberg, an American army physician.
  • By 1886, when the organism was designated 'pneumokokkus' and Diplococcus pneumoniae, its role in the etiology of pneumonia was well known.
  • In 1974, the organism was reclassified as Streptococcus pneumoniae.
  • Harrison's defines this as: 'Pneumococci are divided into serogroups or serotypes based on capsular polysaccharide structure, as distinguished with rabbit polyclonal antisera; capsules swell in the presence of specific antiserum (the Quellung reaction).'
  • The most recently discovered serotypes—6C, 6D, 6F, 6G, 6H, 10D, 11E, 20A, 20B, and 35D—have been identified with monoclonal antibodies and by serologic, genetic, and biochemical means.
  • The currently recognized 100 serotypes fall into 21 serogroups, and each serogroup contains two to eight serotypes with closely related capsules.

1.1 Historical Context

  • In the late nineteenth century, pairs of micrococci were first recognized in the blood of rabbits injected with human saliva by both Louis Pasteur, working in France, and George Sternberg, an American army physician.
  • The important role of these micrococci in human disease was not appreciated at that time.
  • By 1886, when the organism was designated 'pneumokokkus' and Diplococcus pneumoniae, it had been isolated by many independent investigators, and its role in the etiology of pneumonia was well known.
  • In the 1930s, pneumonia was the third leading cause of death in the United States (after heart disease and cancer) and was responsible for ~7% of all deaths both in the United States and in Europe.
  • While pneumonia was caused by a variety of pathogens, lobar pneumonia—a pattern more likely to be caused by the pneumococcus—accounted for approximately one-half of all pneumonia deaths in the United States in 1929.
  • In 1974, the organism was reclassified as Streptococcus pneumoniae.

1.2 Microbiology & Classification

  • Pneumococci are spherical gram-positive bacteria of the genus Streptococcus.
  • Within this genus, cell division occurs along a single axis, and bacteria grow in chains or pairs—hence the name Streptococcus, from the Greek streptos, meaning 'twisted,' and kokkos, meaning 'berry.'
  • At least 22 streptococcal species are recognized and are divided further into groups based on their hemolytic properties.
  • S. pneumoniae belongs to the α-hemolytic group that characteristically produces a greenish color on blood agar because of the reduction of iron in hemoglobin.
  • The bacteria are fastidious and grow best in 5% CO but require a source of catalase (e.g., blood) for growth on agar plates, where they develop mucoid (smooth/shiny) colonies.
  • Pneumococci without a capsule produce colonies with a rough surface.
  • Unlike that of other α-hemolytic streptococci, their growth is inhibited in the presence of optochin (ethylhydrocupreine hydrochloride), and they are bile soluble.
  • Pneumococci are divided into serogroups or serotypes based on capsular polysaccharide structure, as distinguished with rabbit polyclonal antisera; capsules swell in the presence of specific antiserum (the Quellung reaction).
  • The most recently discovered serotypes—6C, 6D, 6F, 6G, 6H, 10D, 11E, 20A, 20B, and 35D—have been identified with monoclonal antibodies and by serologic, genetic, and biochemical means.
  • The currently recognized 100 serotypes fall into 21 serogroups, and each serogroup contains two to eight serotypes with closely related capsules.

2. EPIDEMIOLOGY

  • Pneumococcal infections remain a significant global cause of morbidity and death, particularly among children and the elderly.
  • Rapid and dramatic changes in the epidemiology of this disease during the past 20 years in several developed countries followed the licensure and routine childhood administration of pneumococcal polysaccharide–protein conjugate vaccine (PCV).
  • With PCV introduction in low- and middle-income countries (LMIC), additional profound changes in pneumococcal ecology and disease epidemiology are occurring.
  • The disease burden and serotype distribution in the PCV era are influenced not only by the reduction in disease caused by serotypes included in PCV but also by serotype replacement as a result of reductions in vaccine serotypes, concomitant secular trends in pneumococcal strains unrelated to vaccine use, the impact of antibiotic use on pneumococcal strain ecology, and surveillance system attributes that can themselves affect analysis of epidemiologic features of pneumococcal strains and disease.
  • Not all pneumococcal serotypes are equally likely to cause disease; observed serotype distributions vary by age category, disease syndrome, and geography.
  • Geographic differences may be driven by variations in the relative prevalence of syndromes causing disease rather than by true serotype distribution differences, as certain serotypes are more common causes of some syndromes than others (e.g., pneumonia and meningitis).
  • Most data on serotype distribution come from pediatric invasive pneumococcal disease (IPD, defined as infection of a normally sterile site); much less information on global or regional serotype distributions is available for disease in adults.
  • In the era before PCV use, five to seven serotypes caused >60% of IPD cases among children 75%, a decrease driven by the near elimination of vaccine-serotype IPD.
  • A similar impact of PCV on vaccine-serotype IPD rates has been consistently observed in countries where PCV has been introduced into the routine pediatric vaccination schedule.
  • However, the magnitudes of change in the non-vaccine-serotype IPD rate in various countries have been heterogeneous; the interpretation of this heterogeneity is a complex issue.
  • In the United States, Canada, and Australia, rates of non-vaccine-serotype IPD have increased but the magnitude of the increase is generally small relative to the substantial reductions in vaccine-serotype IPD.
  • In contrast, in other settings (e.g., Alaska Native communities and adults in the United Kingdom), the reduction in vaccine-serotype IPD has been offset by notable increases in rates of disease caused by non-vaccine serotypes.
  • Explanations for the heterogeneity of findings include replacement disease resulting from vaccine pressure, changes in clinical case investigation, secular trends unrelated to PCV use, antibiotic pressure selecting for resistant organisms, changes in surveillance or reporting systems, rapidity of PCV introduction, and inclusion of a catch-up campaign.
  • Serotype replacement in IPD follows the use of PCV7, PCV10, and PCV13, but the magnitude of this phenomenon may be small relative to the reduction in disease from vaccine serotypes in vaccinated populations.
  • In adults in the UK, however, where rates of IPD due to vaccine serotypes fell following PCV introduction, the increase in IPD secondary to non-vaccine serotypes is eroding the original impact of PCV.
  • Furthermore, not all vaccine serotypes have declined and persistent disease due to serotypes 3 and 19A in particular has been noted in many settings.
  • Pneumonia is the most common of the serious pneumococcal disease syndromes and poses special challenges from a clinical and public health perspective.
  • Most cases of pneumococcal pneumonia are not associated with bacteremia, and in these cases a definitive etiologic diagnosis is difficult or impossible.
  • As a result, estimates of disease burden focus primarily on IPD rates and fail to include the major portion of the burden of serious pneumococcal disease.
  • Among children, PCV trials designed to collect efficacy data on syndrome-based outcomes (e.g., radiographically confirmed pneumonia, clinically diagnosed pneumonia) have revealed the burden of culture-negative pneumococcal pneumonia.
  • These trials have provided the means to infer that only ~5–20% of pneumococcal pneumonia cases result in bacteremia.
  • An important randomized controlled trial of PCV among the elderly in the Netherlands (the CAPiTA trial) has revealed the small fraction of adult pneumococcal pneumonia patients who also have bacteremia.
  • Use of high-quality sputum specimens and, in the case of adults with a low likelihood of colonization absent disease, urine antigen detection both contribute to the diagnosis of nonbacteremic pneumococcal pneumonia.
  • Furthermore, accruing evidence continues to indicate that pneumococcal pneumonia events are often the result of co-infection with viral or other bacterial pathogens.
  • Thus a pneumonia case resulting from a pulmonary infection with a single pathogen is probably an uncommon event; rather, most cases of pneumonia likely result from the sequential or contemporaneous co-infection of a host with multiple pathogens, often both viruses and bacteria.
  • The case–fatality ratios (CFRs) for pneumococcal pneumonia and IPD vary by age, underlying medical condition, and access to care.
  • In addition, the CFR for pneumococcal pneumonia varies with the severity of disease at presentation (rather than according to whether the pneumonia episode is associated with bacteremia) and with the patient’s age (from 12% among those >65 years old, even when appropriate and timely management is available).
  • Notably, the likelihood of death in the first 24 h of hospitalization did not change substantially with the introduction of antibiotics; this surprising observation highlights the fact that the pathophysiology of severe pneumococcal pneumonia among adults reflects a rapidly progressive cascade of events that often unfolds irrespective of antibiotic administration.
  • Management in an intensive care unit can provide critical support for the patient through the acute period, with lower CFRs, while antibiotics address the underlying infection.
  • Rates of pneumococcal disease vary by season, with higher rates in colder than in warmer months in temperate climates; by sex, with males more often affected than females; and by risk group, with risk factors including underlying medical conditions, behavioral issues (e.g., smoking), and ethnic group.
  • In the United States, some Native American populations (including Alaska Natives) and African Americans have higher rates of disease than the general population; the increased risk is probably attributable to socioeconomic conditions and the prevalence of underlying risk factors for pneumococcal disease.
  • Medical conditions that increase the risk of pneumococcal infection are listed in Table 151-1.
  • Outbreaks of disease are well recognized in crowded settings with susceptible individuals, such as infant day-care facilities, military barracks, and nursing homes.
  • Furthermore, there is a clear association between preceding viral respiratory disease (especially but not exclusively influenza) and risk of secondary pneumococcal infections.
  • The significant role of pneumococcal pneumonia in the morbidity and mortality associated with seasonal and pandemic influenza is increasingly well recognized.
  • Nasopharyngeal Carriage Pneumococci are intermittent inhabitants of the healthy human nasopharynx and are transmitted by respiratory droplets.
  • In children, pneumococcal nasopharyngeal ecology varies by geographic region, socioeconomic status, climate, degree of crowding, and particularly intensity of exposure to other children, with children in day-care settings having higher rates of colonization.
  • In developed-world settings, children serve as the major vectors of pneumococcal transmission.
  • By 1 year of age, ~50% of children have had at least one episode of pneumococcal colonization.
  • Cross-sectional prevalence data show rates of pneumococcal carriage ranging from 20% to 50% among children 40%) also are colonized.
  • Their high rates of colonization make adults an important source of transmission and may affect community transmission dynamics.

2.1 Risk Groups

  • Medical conditions that increase the risk of pneumococcal infection are listed in Table 151-1.
  • Asplenia or splenic dysfunction: Sickle cell disease and other hemoglobinopathies, celiac disease.
  • Chronic respiratory disease: Chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, interstitial lung fibrosis, pneumoconiosis, bronchopulmonary dysplasia, aspiration risk, neuromuscular disease (e.g., cerebral palsy), severe asthma.
  • Chronic heart disease: Ischemic heart disease, congenital heart disease, hypertension with cardiac complications, chronic heart failure.
  • Chronic kidney disease: Nephrotic syndrome, chronic renal failure, renal transplantation.
  • Chronic liver disease: Cirrhosis, biliary atresia, chronic hepatitis.
  • Diabetes mellitus: Diabetes mellitus requiring insulin or oral hypoglycemic drugs.
  • Immunocompromise: HIV infection, primary immunodeficiency (including agammaglobulinemia) [B cell, T cell, complement, and some phagocytic disorders], leukemia, lymphoma, Hodgkin's disease, multiple myeloma, generalized malignancy, chemotherapy, organ or bone marrow transplantation, systemic glucocorticoid treatment for >1 month at a dose equivalent to ≥20 mg/d (children, ≥1 mg/kg per day).
  • Cochlear implants.
  • Cerebrospinal fluid leaks.
  • Miscellaneous: Infancy and old age; prior hospitalization; alcoholism; malnutrition; cigarette smoking; day-care center attendance; residence in military training camps, prisons, homeless shelters.
  • Note: Groups for whom pneumococcal vaccines are recommended by the Advisory Committee on Immunization Practices can be found at www.cdc.gov/vaccines/schedules/.

3. ETIOLOGY & PATHOPHYSIOLOGY

  • Within the cytoplasm, cell membrane, and cell wall, many molecules that may play a role in pneumococcal pathogenesis and virulence have been identified (Fig. 151-2).
  • These proteins are often involved in direct interactions with host tissues or in concealment of the bacterial surface from host defense mechanisms.
  • Pneumolysin (PLY) is a secreted cytotoxin thought to result in cytolysis of cells and tissues, and LytA enhances pathogenesis.
  • A number of cell wall proteins interfere with the complement pathway, thus inhibiting complement deposition and preventing lysis and/or opsonophagocytosis.
  • The pneumococcal H inhibitor (Hic) impedes the formation of C3 convertase, while pneumococcal surface protein C (PspC), also known as choline-binding protein A (CbpA), binds factor H and is thought to accelerate the breakdown of C3.
  • PspA and CbpA inhibit the deposition of or degrade C3b.
  • To avoid clearance by the mucus, pneumococci utilize the matrix metalloprotease ZmpA, which cleaves mucosal IgA to evade complement activation, preventing agglutination and thus clearance by the mucociliary flow.
  • The numerous pneumococcal proteins thought to be involved in adhesion include pneumococcal surface adhesin A (PsaA) and the exoglycosidases such as neuraminidase (NanA), β-galactosidase (BgaA), and β-N-Acetylglucosaminidase (StrH), which deglycosylate host glycoproteins releasing sugars as a nutrient source and exposing hidden receptors for adhesion.
  • Once through the epithelial barrier, pneumococci utilize PLY and mannose receptor C type lectin 1 (MRC-1/CD206) on the surface of dendritic cells and macrophages to enter cells, where they may survive intracellularly in vacuoles thus facilitating spread.
  • To outcompete the other co-colonizing bacteria, the pneumococcus produces bacteriocins called pneumocins that mediate intraspecific competition.
  • Some of the antigens mentioned above are potential vaccine candidates (see 'Prevention,' below).
  • Biofilm production by pneumococci is now well recognized and is likely to be an important mechanism aiding survival of pneumococci in the upper respiratory tract and contributing to local disease manifestations such as otitis media.
  • Although the capsule surrounding the cell wall of S. pneumoniae is the basis for categorization by serotype, the disease potential of a serotype is also related to the genetic composition of the strain.
  • Molecular genotyping and epidemiology are therefore essential.
  • Conventionally, multilocus sequence typing (MLST) was the gold-standard technique for epidemiologic analyses due to its simplicity and effectiveness.
  • Alleles at seven loci are sequenced, compared with all of the known alleles at that locus and a unique sequence type (ST) assigned using the pneumococcal MLST website (pubmlst.org/organisms/streptococcus-pneumoniae/).
  • With the advent of high-throughput and relatively inexpensive sequencing techniques, whole-genome sequencing has facilitated even more precise molecular epidemiology: enhanced genomic epidemiology can be performed using ribosomal MLST (rMLST; >50 ribosomal genes) or core genome MLST (cgMLST; >1300 core genes) with assignment via the PubMLST website, while k-mer–based methods fully exploit core and accessory genomic variation (PopPUNK, github.com/bacpop/PopPUNK) to assign Global Pneumococcal Sequence Clusters (GPSCs) via the Global Pneumococcal Sequencing project website (pneumogen.net).
  • Twenty-three years after the first pneumococcal genome was sequenced, >50,000 pneumococcal genomes are now available on public nucleotide sequence databases.
  • There are two curated pneumococcal genome databases: the PubMLST Pneumococcal Genome Library contains ~33,000 curated, published, assembled genomes and isolate provenance data (pubmlst.org/organisms/streptococcus-pneumoniae/pgl/), and the GPS Database Monocle Dataviewer, which contains ~21,000 high-quality genomes with epidemiologic data (www.pneumogen.net/gps/gps-database-overview/).
  • These databases are publicly available and free to access.
  • Over the past decade, web applications such as Pathogenwatch (pathogen.watch/) have provided a user-friendly platform to enable fast and reliable analysis of pneumococcal genome data without the requirement for bioinformatic expertise.
  • Users can simply drag and drop genome data into a browser to obtain details such as serotype, genotype (including GPSC and MLST), and antimicrobial resistance profiles.
  • In recent years, genome sequence analyses have made major contributions to the understanding of pneumococcal molecular epidemiology, biology, diversity, pathogenicity, and vaccine impact.

3.1 Virulence Factors

  • Within the cytoplasm, cell membrane, and cell wall, many molecules that may play a role in pneumococcal pathogenesis and virulence have been identified (Fig. 151-2).
  • These proteins are often involved in direct interactions with host tissues or in concealment of the bacterial surface from host defense mechanisms.
  • Pneumolysin (PLY) is a secreted cytotoxin thought to result in cytolysis of cells and tissues, and LytA enhances pathogenesis.
  • A number of cell wall proteins interfere with the complement pathway, thus inhibiting complement deposition and preventing lysis and/or opsonophagocytosis.
  • The pneumococcal H inhibitor (Hic) impedes the formation of C3 convertase, while pneumococcal surface protein C (PspC), also known as choline-binding protein A (CbpA), binds factor H and is thought to accelerate the breakdown of C3.
  • PspA and CbpA inhibit the deposition of or degrade C3b.
  • To avoid clearance by the mucus, pneumococci utilize the matrix metalloprotease ZmpA, which cleaves mucosal IgA to evade complement activation, preventing agglutination and thus clearance by the mucociliary flow.
  • The numerous pneumococcal proteins thought to be involved in adhesion include pneumococcal surface adhesin A (PsaA) and the exoglycosidases such as neuraminidase (NanA), β-galactosidase (BgaA), and β-N-Acetylglucosaminidase (StrH), which deglycosylate host glycoproteins releasing sugars as a nutrient source and exposing hidden receptors for adhesion.
  • Once through the epithelial barrier, pneumococci utilize PLY and mannose receptor C type lectin 1 (MRC-1/CD206) on the surface of dendritic cells and macrophages to enter cells, where they may survive intracellularly in vacuoles thus facilitating spread.
  • To outcompete the other co-colonizing bacteria, the pneumococcus produces bacteriocins called pneumocins that mediate intraspecific competition.
  • Some of the antigens mentioned above are potential vaccine candidates (see 'Prevention,' below).
  • Biofilm production by pneumococci is now well recognized and is likely to be an important mechanism aiding survival of pneumococci in the upper respiratory tract and contributing to local disease manifestations such as otitis media.

3.2 Colonization & Invasion

  • Although the capsule surrounding the cell wall of S. pneumoniae is the basis for categorization by serotype, the disease potential of a serotype is also related to the genetic composition of the strain.
  • Molecular genotyping and epidemiology are therefore essential.
  • Conventionally, multilocus sequence typing (MLST) was the gold-standard technique for epidemiologic analyses due to its simplicity and effectiveness.
  • Alleles at seven loci are sequenced, compared with all of the known alleles at that locus and a unique sequence type (ST) assigned using the pneumococcal MLST website (pubmlst.org/organisms/streptococcus-pneumoniae/).
  • With the advent of high-throughput and relatively inexpensive sequencing techniques, whole-genome sequencing has facilitated even more precise molecular epidemiology: enhanced genomic epidemiology can be performed using ribosomal MLST (rMLST; >50 ribosomal genes) or core genome MLST (cgMLST; >1300 core genes) with assignment via the PubMLST website, while k-mer–based methods fully exploit core and accessory genomic variation (PopPUNK, github.com/bacpop/PopPUNK) to assign Global Pneumococcal Sequence Clusters (GPSCs) via the Global Pneumococcal Sequencing project website (pneumogen.net).
  • Twenty-three years after the first pneumococcal genome was sequenced, >50,000 pneumococcal genomes are now available on public nucleotide sequence databases.
  • There are two curated pneumococcal genome databases: the PubMLST Pneumococcal Genome Library contains ~33,000 curated, published, assembled genomes and isolate provenance data (pubmlst.org/organisms/streptococcus-pneumoniae/pgl/), and the GPS Database Monocle Dataviewer, which contains ~21,000 high-quality genomes with epidemiologic data (www.pneumogen.net/gps/gps-database-overview/).
  • These databases are publicly available and free to access.
  • Over the past decade, web applications such as Pathogenwatch (pathogen.watch/) have provided a user-friendly platform to enable fast and reliable analysis of pneumococcal genome data without the requirement for bioinformatic expertise.
  • Users can simply drag and drop genome data into a browser to obtain details such as serotype, genotype (including GPSC and MLST), and antimicrobial resistance profiles.
  • In recent years, genome sequence analyses have made major contributions to the understanding of pneumococcal molecular epidemiology, biology, diversity, pathogenicity, and vaccine impact.

4. CLINICAL FEATURES

  • There is no pathognomonic presentation of pneumococcal disease; patients may present with one or more clinical syndromes (e.g., pneumonia, meningitis, sepsis).
  • S. pneumoniae can infect nearly any body tissue, manifesting as disease ranging in severity from mild and self-limited to life-threatening.
  • The differential diagnosis of common clinical syndromes such as pneumonia, otitis media, fever of unknown origin, and meningitis should always include pneumococcal infection.
  • A microbiologically confirmed diagnosis is made in only a minority of pneumococcal cases since, in most circumstances (and especially in pneumonia and otitis media), fluid from the site of infection is not available for etiologic determination, and infection of body fluids distant from the site of infection (e.g., blood in the case of pneumonia) occurs in only a minority of true pneumococcal cases.
  • Empirical therapy that includes appropriate treatment for S. pneumoniae is often indicated.
  • Pneumonia Pneumonia is the most common serious pneumococcal syndrome and is considered invasive when associated with a positive blood culture.
  • Whether to categorize nonbacteremic pneumococcal pneumonia as invasive or noninvasive remains debatable.
  • Pneumococcal pneumonia can present as a mild community-acquired infection at one extreme and as a life-threatening disease requiring intubation and intensive support at the other.
  • The presentation of pneumococcal pneumonia does not reliably distinguish it from pneumonia of other etiologies.
  • In a subset of cases, pneumococcal pneumonia is recognized at the outset as associated with a viral upper respiratory infection and is characterized by the abrupt onset of cough and dyspnea accompanied by fever, shaking chills, and myalgias.
  • The cough evolves from nonpurulent to productive of sputum that is purulent and sometimes tinged with blood.
  • Patients may describe stabbing pleuritic chest pain and significant dyspnea indicating involvement of the parietal pleura.
  • Among the elderly, the presenting clinical symptoms may be less specific, with confusion or malaise but without fever or cough.
  • In such cases, a high index of suspicion is required because failure to treat pneumococcal pneumonia promptly in an elderly patient is likely to result in rapid evolution of the infection, with increased severity, morbidity, and risk of death.
  • The clinical signs associated with pneumococcal pneumonia among adults include tachypnea (defined as >20 breaths/min) and tachycardia, hypotension in severe cases, and fever in most cases (although not in all elderly patients).
  • Respiratory signs are varied, including dullness to percussion in areas of the chest with significant consolidation, crackles on auscultation, reduced expansion of the chest in some cases as a result of splinting to reduce pain, bronchial breathing in a minority of cases, pleural rub in occasional cases, and cyanosis in cases with significant hypoxemia.
  • Among infants with severe pneumonia, chest wall indrawing and nasal flaring are common.
  • Nonrespiratory findings can include upper abdominal pain if the diaphragmatic pleura is involved as well as mental status changes, particularly confusion in elderly patients.
  • Meningitis Pneumococcal meningitis usually presents as a pyogenic condition that is clinically indistinguishable from meningitis of other bacterial etiologies.
  • Meningitis can be the primary presenting pneumococcal syndrome or a complication of other conditions such as skull fracture, otitis media, bacteremia, or mastoiditis.
  • Now that H. influenzae type b vaccine is routinely used in children, S. pneumoniae and Neisseria meningitidis are the most common bacterial causes of meningitis.

4.1 Physical Examination

  • The clinical signs associated with pneumococcal pneumonia among adults include tachypnea (defined as >20 breaths/min) and tachycardia, hypotension in severe cases, and fever in most cases (although not in all elderly patients).
  • Respiratory signs are varied, including dullness to percussion in areas of the chest with significant consolidation, crackles on auscultation, reduced expansion of the chest in some cases as a result of splinting to reduce pain, bronchial breathing in a minority of cases, pleural rub in occasional cases, and cyanosis in cases with significant hypoxemia.
  • Among infants with severe pneumonia, chest wall indrawing and nasal flaring are common.
  • Nonrespiratory findings can include upper abdominal pain if the diaphragmatic pleura is involved as well as mental status changes, particularly confusion in elderly patients.

4.2 Radiographic Findings

  • The radiographic appearance of pneumococcal pneumonia is varied; it classically consists of lobar or segmental consolidation (Fig. 151-5) but in some cases is patchy.
  • More than one lobe is involved in ~30% of cases.
  • Consolidation may be associated with a small pleural effusion or empyema in complicated cases.
  • In children, 'round pneumonia,' a distinctly spherical consolidation on chest radiography, is associated with a pneumococcal etiology.
  • Round pneumonia is uncommon in adults.
  • S. pneumoniae is not the only cause of such lesions; other causes, especially cancer, should be considered.

5. DIFFERENTIAL DIAGNOSIS

  • The differential diagnosis of pneumococcal pneumonia includes cardiac conditions such as myocardial infarction and heart failure with atypical pulmonary edema; pulmonary conditions such as atelectasis; and pneumonia caused by viral pathogens, mycoplasmas, Haemophilus influenzae, Klebsiella pneumoniae, Staphylococcus aureus, Legionella, or (in HIV-infected and otherwise immunocompromised hosts) Pneumocystis jirovecii.
  • In cases with abdominal symptoms, the differential diagnosis includes cholecystitis, appendicitis, perforated peptic ulcer disease, and subphrenic abscesses.
  • The challenge in cases with abdominal symptoms is to remember to include pneumococcal pneumonia—a nonabdominal process—in the differential diagnosis.

6. INVESTIGATIONS & DIAGNOSIS

  • Some authorities advocate treating uncomplicated, nonsevere, community-acquired pneumonia without determining the microbiologic etiology, given that this information is unlikely to alter clinical management.
  • However, efforts to identify the cause of pneumonia are important when the disease is more severe and when the diagnosis of pneumonia is not clearly established.
  • The gold standard for etiologic diagnosis of pneumococcal pneumonia is pathologic examination of lung tissue.
  • In lieu of that procedure, evidence of an infiltrate on chest radiography warrants a diagnosis of pneumonia.
  • However, cases of pneumonia without radiographic evidence do occur.
  • An infiltrate can be absent either early in the course of the illness or with dehydration; upon rehydration, an infiltrate usually appears.
  • The radiographic appearance of pneumococcal pneumonia is varied; it classically consists of lobar or segmental consolidation (Fig. 151-5) but in some cases is patchy.
  • More than one lobe is involved in ~30% of cases.
  • Consolidation may be associated with a small pleural effusion or empyema in complicated cases.
  • In children, 'round pneumonia,' a distinctly spherical consolidation on chest radiography, is associated with a pneumococcal etiology.
  • Round pneumonia is uncommon in adults.
  • S. pneumoniae is not the only cause of such lesions; other causes, especially cancer, should be considered.
  • Blood drawn from patients with suspected pneumococcal pneumonia can be used for supportive or definitive diagnostic tests.
  • Blood cultures are positive for pneumococci in a minority (15,000/μL in most cases and upward of 40,000/μL in some), leukopenia in <10% of cases (a poor prognostic sign associated with a fatal outcome), and elevated values in liver function tests (e.g., both conjugated and unconjugated hyperbilirubinemia).
  • Anemia, low serum albumin levels, hyponatremia, and elevated serum creatinine levels are all found in ~20–30% of patients.
  • Urinary pneumococcal antigen assays, based on identifying a ubiquitous common cell wall polysaccharide, have facilitated etiologic diagnosis, but the application of the results is confounded by the fact that nasopharyngeal colonization with the pneumococcus, in the absence of disease, also results in a positive test.
  • In adults, therefore, a positive pneumococcal urinary antigen test has a predictive value for etiologic attribution of pneumonia because the prevalence of pneumococcal nasopharyngeal colonization is relatively low, although the sensitivity of the assay is modest.
  • In communities, particularly those in low-income countries, where colonization rates among adults are high, urine antigen assays may be less useful.
  • The same issue holds for children, in whom a positive urinary antigen test is usually uninformative for etiologic attribution of their pneumonia illness because colonization rates are generally high.
  • A recent advance is the development of quantitative serotype-specific urinary antigen detection assays for up to 24 pneumococcal antigens; their application for adults and children holds promise, especially in detecting serotypes that are rarely identified in asymptomatic carriage (e.g., serotype 1), even among children.
  • Most cases of pneumococcal pneumonia in adults are diagnosed by Gram’s staining and culture of sputum.
  • The utility of a sputum specimen is directly related to its quality and the patient’s antibiotic treatment status.

6.1 Diagnostic Criteria & Tests

  • The gold standard for etiologic diagnosis of pneumococcal pneumonia is pathologic examination of lung tissue.
  • In lieu of that procedure, evidence of an infiltrate on chest radiography warrants a diagnosis of pneumonia.
  • However, cases of pneumonia without radiographic evidence do occur.
  • An infiltrate can be absent either early in the course of the illness or with dehydration; upon rehydration, an infiltrate usually appears.
  • Blood drawn from patients with suspected pneumococcal pneumonia can be used for supportive or definitive diagnostic tests.
  • Blood cultures are positive for pneumococci in a minority (15,000/μL in most cases and upward of 40,000/μL in some), leukopenia in <10% of cases (a poor prognostic sign associated with a fatal outcome), and elevated values in liver function tests (e.g., both conjugated and unconjugated hyperbilirubinemia).
  • Anemia, low serum albumin levels, hyponatremia, and elevated serum creatinine levels are all found in ~20–30% of patients.
  • Urinary pneumococcal antigen assays, based on identifying a ubiquitous common cell wall polysaccharide, have facilitated etiologic diagnosis, but the application of the results is confounded by the fact that nasopharyngeal colonization with the pneumococcus, in the absence of disease, also results in a positive test.
  • In adults, therefore, a positive pneumococcal urinary antigen test has a predictive value for etiologic attribution of pneumonia because the prevalence of pneumococcal nasopharyngeal colonization is relatively low, although the sensitivity of the assay is modest.
  • In communities, particularly those in low-income countries, where colonization rates among adults are high, urine antigen assays may be less useful.
  • The same issue holds for children, in whom a positive urinary antigen test is usually uninformative for etiologic attribution of their pneumonia illness because colonization rates are generally high.
  • A recent advance is the development of quantitative serotype-specific urinary antigen detection assays for up to 24 pneumococcal antigens; their application for adults and children holds promise, especially in detecting serotypes that are rarely identified in asymptomatic carriage (e.g., serotype 1), even among children.
  • Most cases of pneumococcal pneumonia in adults are diagnosed by Gram’s staining and culture of sputum.
  • The utility of a sputum specimen is directly related to its quality and the patient’s antibiotic treatment status.

7. MANAGEMENT & TREATMENT

  • Today, parenteral β-lactam drugs such as ampicillin, cefotaxime, ceftriaxone, and cefuroxime are often used as first-line agents for community-acquired infections.
  • Macrolides and cephalosporins are alternatives for penicillin-allergic patients.
  • While agents such as clindamycin, tetracycline, and trimethoprim-sulfamethoxazole exhibit some activity against pneumococci, resistance to these agents is common.
  • Empyema is the most common focal complication of pneumococcal pneumonia, occurring in <5% of cases.
  • When fluid in the pleural space is accompanied by fever and leukocytosis (even low-grade) after 4–5 days of appropriate antibiotic treatment for pneumococcal pneumonia, empyema should be considered.
  • Parapneumonic effusions are more common than empyema, representing a self-limited inflammatory response to pneumonia.
  • Pleural fluid with clinical frank pus, bacteria (detected by microscopic examination), or a pH of ≤7.1 indicates empyema and demands aggressive and complete drainage, usually through chest tube insertion.
  • Meningitis Now that H. influenzae type b vaccine is routinely used in children, S. pneumoniae and Neisseria meningitidis are the most common bacterial causes of meningitis.

7.1 Antibiotic Therapy

  • Today, parenteral β-lactam drugs such as ampicillin, cefotaxime, ceftriaxone, and cefuroxime are often used as first-line agents for community-acquired infections.
  • Macrolides and cephalosporins are alternatives for penicillin-allergic patients.
  • While agents such as clindamycin, tetracycline, and trimethoprim-sulfamethoxazole exhibit some activity against pneumococci, resistance to these agents is common.

7.2 Complication Management

  • Empyema is the most common focal complication of pneumococcal pneumonia, occurring in <5% of cases.
  • When fluid in the pleural space is accompanied by fever and leukocytosis (even low-grade) after 4–5 days of appropriate antibiotic treatment for pneumococcal pneumonia, empyema should be considered.
  • Parapneumonic effusions are more common than empyema, representing a self-limited inflammatory response to pneumonia.
  • Pleural fluid with clinical frank pus, bacteria (detected by microscopic examination), or a pH of ≤7.1 indicates empyema and demands aggressive and complete drainage, usually through chest tube insertion.

8. PROGNOSIS & COMPLICATIONS

  • The case–fatality ratios (CFRs) for pneumococcal pneumonia and IPD vary by age, underlying medical condition, and access to care.
  • In addition, the CFR for pneumococcal pneumonia varies with the severity of disease at presentation (rather than according to whether the pneumonia episode is associated with bacteremia) and with the patient’s age (from 12% among those >65 years old, even when appropriate and timely management is available).
  • Notably, the likelihood of death in the first 24 h of hospitalization did not change substantially with the introduction of antibiotics; this surprising observation highlights the fact that the pathophysiology of severe pneumococcal pneumonia among adults reflects a rapidly progressive cascade of events that often unfolds irrespective of antibiotic administration.
  • Management in an intensive care unit can provide critical support for the patient through the acute period, with lower CFRs, while antibiotics address the underlying infection.
  • Empyema is the most common focal complication of pneumococcal pneumonia, occurring in <5% of cases.
  • When fluid in the pleural space is accompanied by fever and leukocytosis (even low-grade) after 4–5 days of appropriate antibiotic treatment for pneumococcal pneumonia, empyema should be considered.
  • Parapneumonic effusions are more common than empyema, representing a self-limited inflammatory response to pneumonia.
  • Pleural fluid with clinical frank pus, bacteria (detected by microscopic examination), or a pH of ≤7.1 indicates empyema and demands aggressive and complete drainage, usually through chest tube insertion.

9. SPECIAL CONSIDERATIONS

  • Medical conditions that increase the risk of pneumococcal infection are listed in Table 151-1.
  • Asplenia or splenic dysfunction: Sickle cell disease and other hemoglobinopathies, celiac disease.
  • Chronic respiratory disease: Chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, interstitial lung fibrosis, pneumoconiosis, bronchopulmonary dysplasia, aspiration risk, neuromuscular disease (e.g., cerebral palsy), severe asthma.
  • Chronic heart disease: Ischemic heart disease, congenital heart disease, hypertension with cardiac complications, chronic heart failure.
  • Chronic kidney disease: Nephrotic syndrome, chronic renal failure, renal transplantation.
  • Chronic liver disease: Cirrhosis, biliary atresia, chronic hepatitis.
  • Diabetes mellitus: Diabetes mellitus requiring insulin or oral hypoglycemic drugs.
  • Immunocompromise: HIV infection, primary immunodeficiency (including agammaglobulinemia) [B cell, T cell, complement, and some phagocytic disorders], leukemia, lymphoma, Hodgkin's disease, multiple myeloma, generalized malignancy, chemotherapy, organ or bone marrow transplantation, systemic glucocorticoid treatment for >1 month at a dose equivalent to ≥20 mg/d (children, ≥1 mg/kg per day).
  • Cochlear implants.
  • Cerebrospinal fluid leaks.
  • Miscellaneous: Infancy and old age; prior hospitalization; alcoholism; malnutrition; cigarette smoking; day-care center attendance; residence in military training camps, prisons, homeless shelters.
  • Note: Groups for whom pneumococcal vaccines are recommended by the Advisory Committee on Immunization Practices can be found at www.cdc.gov/vaccines/schedules/.

10. KEY PEARLS & CLINICAL TRAPS

  • Optochin sensitivity distinguishes S. pneumoniae from other alpha-hemolytic streptococci.
  • Bile solubility is a key characteristic.
  • Round pneumonia is a distinct radiographic finding in children associated with pneumococcal etiology.
  • Elderly patients may present with confusion or malaise without fever or cough.
  • Asplenia or splenic dysfunction is a critical risk factor for overwhelming pneumococcal disease.
  • PCV introduction has reduced vaccine-serotype IPD but non-vaccine serotypes are emerging.
  • Vancomycin resistance has not yet been observed in clinical pneumococcal strains.
  • Urinary antigen testing is confounded by nasopharyngeal colonization and has modest sensitivity in adults.
  • Most cases of pneumococcal pneumonia are not associated with bacteremia.
  • Pneumococcal pneumonia events are often the result of co-infection with viral or other bacterial pathogens.

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

Prevalence of pneumococcal carriage in adults and children resident in...

Caption: FIGURE 151-3 Prevalence of pneumococcal carriage in adults and children resident in the United Kingdom who had nasopharyngeal swabs collected monthly for 10 months (no seasonal trend; t test trend, >.05). (Data adapted from D Goldblatt et al: J Infect Dis 192:387, 2005.) pneumonia) have revealed the burden of culture-negative pneumococ- cal pneumonia. These trials have provided the means to infer that only ~5–20% of pneumococcal pneumonia cases result in bacteremia. An important randomized controlled trial of PCV among the elderly in — Figure 151-1: Pneumococci growing on blood agar, illustrating α hemolysis and optochin sensitivity (zone around optochin disk). Inset: Gram’s stain, illustrating gram-positive diplococci.

Figure 2

Chest radiograph depicting classic lobar pneumococcal pneumonia in the right...

Caption: FIGURE 151-5 Chest radiograph depicting classic lobar pneumococcal pneumonia in the right lower lobe of an elderly patient’s lung. — Figure 151-2: Schematic diagram of the pneumococcal cell surface, with key antigens and their roles highlighted (e.g., Polysaccharide capsule, Pneumolysin, PspA, PspC, IgA1 protease, Neuraminidase).

Figure 3

Schematic diagram of the pneumococcal cell surface, with key antigens...

Caption: FIGURE 151-2 Schematic diagram of the pneumococcal cell surface, with key antigens — Figure 151-3: Prevalence of pneumococcal carriage in adults and children resident in the United Kingdom who had nasopharyngeal swabs collected monthly for 10 months (no seasonal trend).

Figure 4

CHAPTER 151 FIGURE 151-1 Pneumococci growing on blood agar, illustrating...

Caption: CHAPTER 151 FIGURE 151-1 Pneumococci growing on blood agar, illustrating α hemolysis and optochin sensitivity (zone around optochin disk). Inset: Gram’s stain, illustrating gram-positive diplococci. (Photographs courtesy of Paul Turner, University of Oxford, United Kingdom.) into 21 serogroups, and each serogroup contains two to eight serotypes with closely related capsules. Detailed genetic analysis of the locus cod- ing for the polysaccharide capsule, the cps locus, continues to reveal — Figure 151-5: Chest radiograph depicting classic lobar pneumococcal pneumonia in the right lower lobe of an elderly patient’s lung.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.