History
After successful colonization, S pneumoniae can cause a wide variety of clinical symptoms. By direct extension from the nasopharynx, S pneumoniae infection can spread and then manifest as otitis media, sinusitis, tracheobronchitis, bronchitis, and pneumonia. By invasion and hematogenous spread, S pneumoniae infection can cause primary bacteremia, meningitis, osteomyelitis, pericarditis, endocarditis, myositis, septic arthritis, and peritonitis.
Factors that should prompt consideration of pneumococcal disease in patients with the above conditions are discussed below.
Predisposing factors
Children younger than 5 years, particularly aged 2 years or younger, are at an increased risk of disease. In addition, absence of breastfeeding, exposure to cigarette smoke, daycare attendance, and lack of immunization with the pneumococcal conjugate vaccine further increase the risk of disease. Adults older than 55-65 years are also at an increased risk of disease.
Conditions that cause immune deficits, including HIV infection, malignancy, diabetes mellitus, functional or anatomic asplenia, humoral immunity defects, complement deficiencies, and neutrophil dysfunction, are associated with an increased risk of disease. Conditions associated with decreased pulmonary clearance, such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), viral infections, and active/passive cigarette smoke exposure, also predispose to infection.
Diseases Due to Direct Extension
Conjunctivitis
Bacterial conjunctivitis is more likely to be bilateral and purulent than viral conjunctivitis.
S pneumoniae is found in up to one third of patients with bacterial conjunctivitis; the rate of isolates that are not susceptible to penicillin is increasing.
Otitis media
S pneumoniae is the most commonly isolated bacterial pathogen from children and adults with otitis media. Several early studies demonstrated that otitis media due to S pneumoniae is usually accompanied by fever and pain; the fever associated with pneumococcal otitis media tends to be higher than that caused by other common bacterial pathogens. [30] Pneumococcal disease is less likely to resolve spontaneously.
Increasing antibiotic resistance has led to decreased effectiveness of the antibiotics that were once used most commonly to treat otitis media. S pneumoniae infection is the most common cause of mastoiditis, a complication of otitis media that was more common in the pre-antibiotic era; this complication is now more commonly associated with untreated or improperly treated cases.
Sinusitis
S pneumoniae is the most commonly isolated bacterial organism from patients with acute sinusitis. Acute sinusitis manifestations may vary depending on the age of the patient and the developmental status of individual sinuses. In children younger than 5 years, infection is usually limited to the ethmoid and maxillary sinuses. Acute bacterial sinusitis is usually preceded by a viral upper respiratory infection that leads to mucosal edema, resulting in ostia obstruction. This is followed by the development of a purulent nasal discharge and cough. Halitosis and worsening cough at night due to postnasal drip are often noted.
Acute exacerbations of chronic bronchitis (AECB)
Acute exacerbations of chronic bronchitis manifest as a change from baseline chronic symptoms. Symptoms include shortness of breath, increased production and/or purulence of sputum, increased sputum tenacity, and cough.
An estimated 80% of cases of acute exacerbations of chronic bronchitis are caused by infection, with about one half of those caused by aerobic bacteria, of which S pneumoniae is the most commonly isolated organism.
Symptoms such as sore throat, rhinorrhea, nasal congestion, and dyspnea may indicate a viral cause. [46]
Pneumonia
Classic pneumococcal pneumonia often develops in older children and adults. Sometimes preceded by a viral illness, there is acute onset of high fever, rigors, productive cough, pleuritic chest pain, dyspnea, tachypnea, tachycardia, malaise, and fatigue. Patients typically appear ill and may appear anxious. On physical examination, rales can be heard in most patients. About half of all patients exhibit dullness to percussion, and splinting due to pain may be seen.
In children (particularly school-aged and younger children), the potential manifestations of pneumonia are broad and often nonspecific, including mild respiratory symptoms, with or without a cough on initial presentation; tachypnea, dyspnea, and splinting; high fever; abdominal pain and/or distention; anorexia; emesis (often suggesting a primary gastrointestinal disease); meningeal signs due to meningeal irritation with right upper lobe pneumonias; or chest pain due to pleural irritation.
In elderly patients with pneumococcal pneumonia, tachypnea may be the primary presenting sign. Temperature elevations may be mild or absent.
S pneumoniae is also the most common cause of CAP in HIV-infected patients.
The most common complication of pneumococcal pneumonia is pleural effusion. In patients with concomitant parapneumonic effusion or empyema, physical examination may reveal dullness to percussion, decreased breath sounds, and decreased tactile fremitus at the bases. Although up to 40% of patients with pneumococcal pneumonia may have pleural effusion, only an estimated 10% of these patients have enough fluid to aspirate; of these, only 2% meet the diagnostic criteria for empyema. [30, 31, 47]
Invasive Disease
Meningitis
As a cause of meningitis, S pneumoniae usually invades the meninges via the bloodstream. Although there are multiple possible mechanisms by which this pathogen may cross the blood-brain barrier (BBB), it is likely that multiple factors must act in concert to allow for establishment of infection in the CNS. Transcytosis through meningeal vascular endothelial cells, which are key components of the blood brain barrier, is mediated by pneumococcal adherence to platelet-activating factor receptors. Lastly, by directly invading the meninges after basilar skull fracture or other trauma that compromises the dura, S pneumoniae is the most common cause of recurrent bacterial meningitis following such head trauma.
In countries with routine vaccination policies, S pneumoniae infection is the most common cause of sporadic bacterial meningitis in both children and adults.
Most patients with pneumococcal meningitis present with nonspecific signs and symptoms, including fever, irritability, emesis, lethargy, anorexia, and malaise. Neurologic signs and symptoms, including mental status changes, delirium, lethargy, nuchal rigidity with positive Brudzinski and Kernig signs, cranial nerve palsies, and other focal neurological deficits, are usually prominent. A bulging fontanelle and poor feeding may be seen infants. Twenty to 25% of patients of any age with pneumococcal meningitis experience seizures.
Complications of pneumococcal meningitis include hearing loss, seizures, learning disabilities, mental difficulties, and cranial nerve palsies. In a study from Denmark, 240 patients who survived pneumococcal meningitis were examined using audiometry. [48] More than half (54%) had a hearing deficit, with 39% of these not suspected of hearing loss at the time of hospital discharge. Of the 240 study participants, 14% demonstrated profound hearing loss—7% unilateral and 7% bilateral. Significant risk factors for hearing loss included advanced age, the presence of comorbidity, and higher severity of meningitis. Audiometry should be considered in all patients who survive pneumococcal meningitis.
Pneumococcal meningitis carries a greater risk of death and significant neurological sequelae than does meningitis of other bacterial causes (eg, Haemophilus influenzae type B [Hib], Neisseria meningitidis). [30, 31, 47]
Bacteremia
Bacteremia is the most common manifestation of invasive pneumococcal disease. Most cases are primary bacteremia and are found in children younger than 2 years. It is estimated that S pneumoniae infection has been the cause of 90% of occult bacteremia (bacteremia without a source) cases since the widespread use of the Hib vaccine, although the overall incidence has been decreasing since the institution of routine pneumococcal immunization in infants. [49, 50]
In adult patients, pneumococcal bacteremia is much more likely to be associated with another focus of infection, such as pneumonia or meningitis.
Signs, symptoms, and physical examination findings are usually nonspecific in patients with occult pneumococcal bacteremia. In most patients, fever develops within 24 hours of positive culture findings. A peripheral WBC count greater than 15,000 cells/μL is associated with the presence of occult bacteremia.
Complications, which develop in an estimated 10% of patients with occult bacteremia, include meningitis, osteomyelitis, pneumonia, soft tissue and joint infections, and sepsis. Patients with higher WBC counts and fever, those who have not undergone prior antibiotic therapy, and children younger than 20 months are at a higher risk for persistent bacteremia or the development of focal infection. [31, 30]
Joint and bone infections
S pneumoniae infection is an uncommon cause of osteomyelitis and septic arthritis, causing approximately 4% and 20% of cases in children, respectively.
Septic arthritis: Pneumococcal septic arthritis usually manifests as painful, swollen, and hot joints. The ankles and knees are most commonly involved, and one or more joints may be affected. Blood or synovial cultures usually grow S pneumoniae. Up to half of patients with pneumococcal septic arthritis have concomitant osteomyelitis.
Osteomyelitis: The femur and humerus are most often involved in cases of pneumococcal osteomyelitis in children; the vertebral bones are often involved in adult patients. Up to 20% of patients with pneumococcal osteomyelitis develop long-term sequelae, a figure similar to that of rates of osteomyelitis of other causes. One clinical study performed by the Pediatric Multicenter Pneumococcal Surveillance Study Group (PMPSSG) showed that more than 40% of patients with joint and bone pneumococcal infections had associated bacteremia. [51] Patients with joint prostheses or rheumatic fever are at increased risk for joint disease.
Soft tissue infections
Although uncommon, S pneumoniae infection can be a cause of mild-to-serious soft tissue infections, including cellulitis, myositis, periorbital cellulitis, and abscess, particularly in some immunocompromised hosts (eg, those with SLE). Most patients have WBC counts greater than 15,000 cells/μL and elevated temperatures. Physical findings are related to the site of infection and usually include redness, warmth, and tenderness of the involved area. Movement may be limited by pain and/or swelling. The incidence of soft tissue infections is increased in persons with HIV infection or underlying connective tissue disease; however, most affected individuals are otherwise healthy and respond well to antibiotic therapy. [30]
Peritonitis
Overall, primary peritonitis (peritonitis caused by the spread of organisms via blood or lymph to the peritoneal cavity) is rare, accounting for less than 20% of peritonitis cases.
S pneumoniae is the most commonly isolated organism in patients with primary peritonitis. Primary peritonitis in children is usually associated with underlying conditions such as nephrotic syndrome or other immunocompromising diseases. In adults, primary peritonitis is usually associated with cirrhosis.
Females with severe pelvic inflammatory disease due to S pneumoniae infection may develop peritonitis. In such cases, organisms may gain access to the peritoneum via the fallopian tubes from the female genital tract. This is the only invasive disease caused by S pneumoniae infection that is more common in females. Other persons at risk for peritonitis include persons with gastrointestinal injury, ulcers, or malignancy.
Presenting symptoms of peritonitis include abdominal pain, anorexia, emesis, diarrhea, and fever. Children may present atypically with right lower quadrant abdominal pain that may be mistaken for appendicitis.
Cardiac infections
In the antibiotic era, pneumococcal cardiac infections are rare.
Endocarditis: Involvement of native aortic and mitral valves are most common; infection can lead to valve destruction, heart failure, and embolization. Presenting signs and symptoms are typical of those seen in other causes of endocarditis and include fever, new or changing murmurs, muscle and/or joint pains, sweating, fatigue, anorexia, and skin findings. In alcoholics, may be part of the triad of endocarditis, pneumonia, and meningitis.
Pericarditis: Prior to the widespread use of antibiotics, S pneumoniae infection was the most common cause of purulent pericarditis in children; now, infection in childhood is extremely rare, and nearly all cases of pneumococcal pericarditis occur in adults. Symptoms, signs, and examination findings may include chest and/or pleuritic pain; radiating pain to the neck, abdomen, shoulder, or back; orthopnea; dry cough; extremity swelling; anxiety; fatigue; fever; pericardial rub; and muffled heart sounds.
Causes
S pneumoniae is an encapsulated, gram-positive, catalase-negative cocci that grows as a facultative anaerobe. These organisms often appear on Gram stain as lancet-shaped diplococci that grow in chains (see image below). On blood and chocolate agar plates, a green zone (alpha-hemolysis; due to the breakdown of hemoglobin by pneumolysin) surrounds the colonies. Other identifying properties include sensitivity to optochin (which distinguishes it from other alpha-hemolytic streptococci) and bile solubility.
Sputum Gram stain from a patient with a pneumococcal pneumonia. Note the numerous polymorphonuclear neutrophils and gram-positive, lancet-shaped diplococci. Courtesy of C. Sinave, MD, personal collection.
Predisposing conditions to pneumococcal infection are broad and often overlap; they include the following:
-
Defects in clearance of pneumococci from the blood
Congenital asplenia
Splenectomy
Decreased splenic function due to autosplenectomy due to sickle cell disease
Systemic lupus erythematosus [54]
-
Defects in clearance from sinopulmonary tissue or inflammatory conditions
Asthma
COPD
Cigarette smoking
Influenza and other respiratory viral infections
Ciliary dyskinesia syndromes
-
Defective antibody formation
Primary
Congenital agammaglobulinemia
Common variable hypogammaglobulinemia
Selective immunoglobulin G (IgG) subclass deficiency
Secondary
Lymphoma
Chronic lymphocytic leukemia
Multiple myeloma
HIV infection
-
Defective complement (primary or secondary): Absent or decreased amounts of C1, C2, C3, or C4
-
Abnormalities in polymorphonuclear leukocytes
Decreased levels associated with cyclic neutropenia, drug-induced neutropenia, or aplastic anemia
Impaired function caused by conditions such as alcoholism, cirrhosis, diabetes mellitus, renal insufficiency, and steroid therapy
-
Other
Age (children < 2 y and elderly persons)
Fatigue
Chronic disease
Hospitalization [31]
-
Sputum Gram stain from a patient with a pneumococcal pneumonia. Note the numerous polymorphonuclear neutrophils and gram-positive, lancet-shaped diplococci. Courtesy of C. Sinave, MD, personal collection.
-
Lobar consolidation with pneumococcal pneumonia. Posteroanterior film. Courtesy of R. Duperval, MD.
-
Lobar consolidation with pneumococcal pneumonia. Lateral film. Courtesy of R. Duperval, MD.
-
Empyema caused by Streptococcus pneumoniae. Anteroposterior film. Courtesy of R. Duperval, MD.
-
Purpura due to pneumococcal sepsis in a 39-year-old man who underwent a splenectomy 20 years earlier. Courtesy of Thomas Herchline, MD, Wright State University, Dayton, Ohio.
Tables
- Table 1. Routine Vaccination With Pneumococcal Vaccines [86, 89, 90]
- Table 2. Vaccination of High-Risk Children Aged 2-18 Years With Pneumococcal Polyvalent Vaccine 23-Valent [91]
- Table 3. Vaccination of High-Risk Adults Aged 19 Years and Older With Pneumococcal Vaccines [89, 88]
- Table 4. Recommended Schedule for Doses of PCV13 or PCV15, Including Catch-up Immunizations in Previously Unimmunized and Partially Immunized Children [90]
Population |
Vaccine |
|
Children aged 6 weeks through 5 years: 0.5 mL IM |
Pneumococcal conjugate vaccine 13-valent (Prevnar 13) or 15-valent (Vaxneuvance) Series of 4 doses at ages 2, 4, 6, and 12-15 months (catch-up schedule through age 5 y) |
|
Adults aged 65 years and older*†: 0.5 mL IM |
Adults who have not previously received a pneumococcal conjugate vaccine or whose previous immunization history is unknown should receive either PCV20 or PCV15 If PCV15 is used, follow with a dose of pneumococcal polyvalent vaccine 23-valent (PPSV23) after 1 year (or at least 8 weeks if immunocompromised) |
|
†Those who received PPSV23 before age 65 years for any indication should receive another dose of the vaccine at age 65 years or later if at least 5 years have passed since their previous dose. |
||
Pediatric Risk Group |
High-Risk Condition |
Chronic medical conditions |
Chronic heart disease (particularly cyanotic congenital heart disease and cardiac failure) Chronic lung disease (including asthma if treated with high-dose corticosteroids) Diabetes mellitus Cerebrospinal fluid leaks Cochlear implant Sickle cell disease and other hemoglobinopathies Anatomic or functional asplenia |
Hepatic disease |
Chronic liver disease, alcoholism |
Immunocompromising conditions |
HIV infection Chronic renal failure and nephrotic syndrome Immunosuppressive drugs or radiation therapy, malignant neoplasms, leukemias, lymphomas, Hodgkin disease, solid organ transplantation Congenital or acquired immunodeficiency |
Risk Group |
Condition |
Immunocompetent individuals |
Chronic heart disease* |
Chronic lung disease† |
|
Diabetes mellitus |
|
Cerebrospinal fluid leaks |
|
Cochlear implant |
|
Alcoholism |
|
Chronic liver disease, cirrhosis |
|
Functional or anatomic asplenia |
Sickle cell disease and other hemoglobinopathies |
Congenital or acquired asplenia |
|
Immunocompromised individuals |
Congenital or acquired immunodeficiency |
HIV infection |
|
Chronic renal failure |
|
Nephrotic syndrome |
|
Leukemia |
|
Lymphoma |
|
Hodgkin disease |
|
Generalized malignancy |
|
Iatrogenic immunosuppression‡ |
|
Solid organ transplant |
|
Multiple myeloma |
|
*Congestive heart failure and cardiomyopathies, excluding hypertension. †Including chronic obstructive pulmonary disease, emphysema, and asthma. ‡Diseases requiring treatment with immunosuppressive drugs, including long-term systemic corticosteroids and radiation therapy. |
|
Age at Examination (mo) |
Immunization History |
Recommended Regimen* |
2-6 |
0 doses |
3 doses, 2 mo apart; fourth dose at age 12-15 mo |
|
1 dose |
2 doses, 2 mo apart; fourth dose at age 12-15 mo |
|
2 doses |
1 dose, 2 mo after the most recent dose; fourth dose at age 12-15 mo |
7-11 |
0 doses |
2 doses, 2 mo apart; third dose at age 12 mo |
|
1 or 2 doses before age 7 mo |
1 dose at age 7-11 mo, with another dose at age 12-15 mo (≥2 mo later) |
12-23 |
0 doses |
2 doses, ≥2 mo apart |
|
1 dose at < 12 mo |
2 doses, ≥2 mo apart |
|
1 dose at ≥12 mo |
1 dose, ≥2 mo after the most recent dose |
|
2 or 3 doses at < 12 mo |
1 dose, ≥2 mo after the most recent dose |
24-71 |
|
|
Healthy children (24-59mo) |
Any incomplete schedule |
1 dose, ≥2 mo after the most recent dose† |
Children at high risk‡ (24-71 mo) |
Any incomplete schedule of < 3 doses |
2 doses, one ≥2 mo after the most recent dose and another dose ≥2 mo later |
|
Any incomplete schedule of 3 doses |
1 dose, ≥2 mo after the most recent dose |
*In children immunized before age 12 mo, the minimum interval between doses is 4 weeks. Doses administered at age 12 months or later should be administered at least 8 weeks apart. † Providers should administer a single dose to all healthy children aged 24-59 mo with any incomplete schedule. ‡Children with sickle cell disease, asplenia, chronic heart or lung disease, diabetes mellitus, CSF leak, cochlear implant, HIV infection, or another immunocompromising condition. PPV23 is also indicated (see below). |
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