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January - March 2017: 
Volume 30, Issue 1

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Pneumon 2017, 30(1):32-40
Prevention of Invasive Pneumococcal Disease (IPD)
Authors Information

1: 2nd Pulmonary Department, “ATTIKON” University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
2: Pulmonary Medicine Department, General Hospital of Pireaus, Pireaus , Greece
3: Associate Professor, Department of Critical Care, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

Abstract
Streptococcus pneumoniae consists of a major cause of community-acquired pneumonia in the elderly, resulting in considerable morbidity and mortality worldwide. Although pneumococcal community-acquired pneumonia presents usually as non-bacteremic disease, invasive pneumococcal disease (IPD) concerns infection of normally sterile sites, such as blood or cerebral fluid. The risk for Invasive Pneumococcal Disease increases in particular groups of patients, including hematologic malignancies, infection with human immu-nodeficiency virus (HIV), asplenia - functional or anatomic, chronic diseases and extreme ages (65 years old). The prevention against IPD is achieved by vaccines against Streptococcus pneumoniae. Today, there are two available types of vaccines, the polysaccharide pneumonococcus vaccine (PPSV23 and the pneumonococcus con-jugated vaccine (PCV13).
Full text

INTRODUCTION

Streptococcus pneumoniae consists of a major cause of community-acquired pneumonia in the elderly, resulting in considerable morbidity and mortality worldwide1,4,5. It is estimated that among all age groups, pneumococcal disease caused 1.6 million deaths annually6. While pneumococcal disease occurring in childhood is well understood, its burden among adults remains a clinical challenge impeding policy formulation for prevention and treatment7.

Streptococcus pneumoniae is a lancet-shaped, gram-positive, facultative anaerobic organism. It was first isolated by Pasteur in 1881 from the saliva of a patient with rabies. Typically, it is observed in pairs (diplococcus) but may also be found as singular or in short chains (Figure 1). Some pneumococci are encapsulated, with surfaces composed of polysaccharides. Encapsulated organisms are pathogenic for humans as capsular antigenic polysaccharides are the primary basis for the pathogenicity of the organism. The classification of pneumococci to serotypes is based on their capsular  polysaccharides. Pneumococci express over 90 capsular serotypes, which have different potential to cause disease8- 11 . Although pneumococcal community-acquired pneumonia occurs usually as non-bacteremic disease, invasive pneumococcal disease (IPD) concerns infection of normally sterile sites, such as blood or cerebral fluid, occurring in approximately 25% of cases4,7  (Table 1). The majority of IPD cases (80%) present with bacteremic  pneumonia whilst 25-30% of patients with pneumococcal pneumonia experience pneumococcal bacteremia2 .

FIGURE 1. Streptococcus pneumoniae (diplococci)and the polysaccharide capsule.
 

TABLE 1. Classification of pneumococcal disease
 

The aim of this article is to underline the importance of prevention of IPD through vaccination, as well as to elucidate the main differences of the two available vaccines regarding their efficacy and immunogenicity.

IPD: INCIDENCE AND RISK FACTORS

More than 12,000 cases of pneumococcal bacteremia without pneumonia occur each year. The overall case mortality for bacteremia is about 20% but may be as high as 60% among elderly patients10 . The incidence of pneumococcal disease is estimated to more than 35,000 cases and more than 4,200 deaths from invasive pneumococcal disease (bacteremia and meningitis) in the United States in 20112,12 . In Europe, the overall annual incidence of community acquired pneumonia (CAP) in adults ranged between 1.07 to 1.2 per 1000 person-years24  (Figure 2). Interestingly, the majority of these cases concern adults with indication for vaccination against Str. pneumoniae . A number of clinical conditions have been identified to increase the risk for IPD development12-15 . Patients with decreased immune function, including hematologic cancer and HIV infection or asplenia - functional or anatomic present a higher risk. More specifically, the rate of IPD for adults aged 18-64 years with hematologic cancer in 2010 was 186 per 100,000, and for individuals with human immunodeficiency virus (HIV) the rate was 173 per 100,00012 . Furthermore, it has been shown that patients with asplenia developing bacteremia experience a fulminant clinical course. Chronic diseases, such as heart failure, pulmonary diseases, including asthma and COPD, liver or renal disease consist of risk factors for IPD development. Cigarette smoking, cerebrospinal fluid (CSF) leak and cochlear implant increase as well the risk of IPD2  (Figure 3).

FIGURE 2. Incidence of Community Acquired Pneumonia (CAP) in Europe in patients >15 years old and major risk factors. Data fromanalysis of 60 studies.
 

FIGURE 3. Main Risk factors for the appearance of Community Acquired Pneumonia (CAP)
 

IPD: CLINICAL FEATURES AND SYMPTOMS

Pneumococcal pneumonia is the most common clinical presentation of pneumococcal disease among adults. The incubation period is short, about 1 to 3 days. The nasopharynx consists of the reservoir of pneumococci, while they are transmitted by direct person-to-person contact via respiratory droplets. Infections by Str. pneumoniae are more commonly observed during the winter and in early spring. Symptoms generally include an abrupt onset of fever and chills or rigors. Classically chills or rigors are common. Other not specific symptoms of pneumonia could be present, including pleuritic chest pain, productive cough, dyspnea, tachypnea,hypoxia, tachycardia, malaise, and weakness. Nausea, vomiting, and headaches occur less frequently. The definitive diagnosis of IPD is based on isolation of Str. pneumoniae from blood or other normally sterile body sites. So far, a variety of tests have been developed, including tests that are available to detect capsular polysaccharide antigen in body fluids. A positive Gram stain with predominance of gram-positive diplococci could be suggestive of infection by Str. pneumoniae, however the interpretation of the stained sputum specimens may need special attention due to the presence of normal nasopharyngeal bacteria. Thus, there have been introduced suggested criteria for obtaining a diagnosis of pneumococcal pneumonia using gram-stained sputum, including more than 25 white blood cells and less than 10 epithelial cells per high-power field10. The urinary antigen test based on an immunochromatographic membrane technique has been widely used lately for the detection of the C-polysaccharide antigen of Streptococcus pneumoniae (Pneumococcus C-polysaccharide- PnC) as a cause of community-acquired pneumonia. Rapid and simple in use, it presents a coherent specificity in adults. Importantly, it is available for detecting pneumococcal pneumonia even after antibiotic therapy has been initiated10.

IPD: PREVENTION

The prevention against IPD is achieved by vaccines against Streptococcus pneumoniae. The initial efforts for effective pneumococcal vaccines began as early as 1911. However, the introduction of penicillin in the 1940s resulted in a reduced interest in pneumococcal vaccination. However, the observation that many patients died despite antibiotic treatment emerged the issue and by the late 1960s, the idea of a polyvalent pneumococcal vaccine emerged again. In 1977, the first pneumococcal vaccine was licensed in the United States and in 2000 was the turn of the first conjugate pneumococcal vaccine. Two types of vaccines are available today the Pneumococcal Polysaccharide Vaccine (PPSV23) and the Conjugate Vaccine (PCV13) which replaced the previous pneumonococcus conjugated vaccine (PCV7) (Figure 4). The first one contains purified capsular polysaccharide antigen from pneumococcal bacteria,and 23 types of pneumococcal bacteria, accounting for 90% of serotypes provoking IPD. PPSV23stimulates B cells to produce antibodies resulting in a T cell independent immune response16,17  (Figure 5). However, it has been shown from different studies that PPSV23 provides a short-lasting immune response, with no booster effect and has limited efficacy in immunocompromised patients (Table 1)2 .

FIGURE 4. Comparison of contained serotypes of in PCV7 and PCV13.
 

FIGURE 5. Differences betweenPPSV23 and PCV13.
 

Concerning the pneumococcal conjugate vaccine, the first (PCV7) was licensed in the United States in 2000, containing purified capsular polysaccharide of seven serotypes of S. pneumoniae  (4, 9V, 14, 19F, 23F, 18C, and  6B) conjugated to a nontoxic variant of diphtheria toxin known as CRM197. PCV type stimulated T cells to allow B cells to produce antibodies and to generate immune memory with a T cell-dependent immune response16,17 . It has been generally shown that PCV type transform T-cell independent antigens into T-cell dependent antigens, providing higher affinity to IgG antibodies2 . In 2010 a 13-valent pneumococcal conjugate vaccine (PCV13) was introduced in the United States. It contains the 7 serotypes of S. pneumoniae  as PCV7 plus serotypes 1, 3, 5, 6A, 7F and 19A, also conjugated to CRM197.The use of PCV7 had a great impact on the reduction of the incidence of IPD in children, as it was observed a 99% decrease caused by the vaccine serotypes, as well as by serotype 6A due to cross-reaction2,12 . Beforethe introduction of PCV13 had suggested that approximately 61% of invasive pneumococcal disease cases among children younger than 5 years were attributable to the serotypes included in PCV13, with serotype 19A accounting for 43% of cases, while the PCV7 serotypes had caused less than 2% of cases12 .

In December 2011 the Food and Drug Administration (FDA), based on non-inferior immunogenicity compared to PPSV23, approved PCV13 as a single dose for the prevention of CAP and IPD caused by vaccine serotypes of S. pneumoniae in persons 50 years of age and older. More specifically, in a randomized, modified double-blindtrial which compared a single dose of (PCV13) with (PPSV23) in 831 pneumococcal vaccine naive adults 60-64 years of age, PCV13 met the primary endpoint of non-inferior immune response for all shared serotypes and concerning the secondary endpoint PCV13 was demonstrated to result in statistically significantly greater immune responses for 8 of 12 shared serotypes20 . Similar results were also described for adults aged more than 70 years old21 . During 2008- 2013, a randomized placebo-controlled trial (CAPiTA trial) in the Netherlands enrolled 85,000 adults older than 65 years in order to evaluate PCV13 in preventing pneumococcal pneumonia4 . Interestingly, it was shown that the efficacy of PCV 13 against vaccinetype non- bacteremic pneumococcal pneumonia in adults older than 65 years was approximately 45.6%, while against vaccine-type pneumonia caused by Str. pneumoniae  around 45.6% and against vaccine-type invasive pneumococcal disease (IPD) 75%. Moreover, in an observational cohort study, conducted in England and Wales 4 years after the introduction of PCV13 observed 32% decrease in incidence of IPD compared with the pre-PCV13 baseline18 . The aforementioned results were attributed to a 86% reduction of the serotypes covered by  PCV7 and a 69% reduction of the additional six serotypes covered by PCV1318 .

VACCINATION PROGRAMS

PNEUMOCOCCAL CONJUGATE VACCINE (PCV13)

In December 2011, PCV13 was licensed for use in adults older than 50 years old for the prevention of IPD. However, the recommendations for routine use among all adults aged more than 50 years old will be reevaluated in 2018 and revised as needed. Until now, the recommendations of Advisory Committee Practices (ACIP)of USA are as followed. Adults 65 years of age or older who have not previously received pneumococcal vaccine or whose previous vaccination history is unknown should receive initially a dose of PCV13. In high risk adults for the appearance of IPD, aged more than 65 years old (chronic diseases, malignancies etc) one dose of PPSV23 should be given 6-12 months after the dose of PCV13. Regarding PCV13-naïve adults aged more than 65 years, who have previously received one or more doses of PPSV23 a dose of PCV13 should be received 6 to 12 months after PPSV23 (Table 2). Immunogenicity and safety of the sequential vaccination protocols was studied by Greenberg RN and colleagues and concluded that an initial use of PPSV diminished the response to a subsequent dose of PCV13 compared to PCV13 alone, whilst an initial use of PCV13 enhanced the response to a subsequent dose of PPSV compared to PPSV alone23. The two vaccines should not be administered simultaneously on the same day and the minimum suggested acceptable interval between PCV13 and PPSV23 is 8 weeks. Generally, PPSV23 should be given 6-12 months after the dose of PCV13.

TABLE 2. Differences between the two available vaccines against Str. pneumoniae
 

TABLE 3. ACIP recommendations for vaccination against IPD in adults ≥65 years old.
 

In addition, in 2012, ACIP recommended vaccination of adults 19 years and older with specific risk factors, including functional or anatomic asplenia - sickle cell disease, splenectomy, HIV infection, leukemia, lymphoma, Hodgkin disease, multiple myeloma, generalized malignancy, chronic renal failure, nephrotic syndrome, other conditions associated with immunosuppression, such as organ or bone marrow transplantation, or immunosuppressive chemotherapy and long-term corticosteroids, CSF leak or cochlear implants (Table 3, 4). Adults with these specific risk factors should initially receive a dose of PCV13, followed by a dose of PPSV23 after 6 to 12 months. Revaccination with PPSV23 is recommended 5 years after the first PPSV23 dose (Table 3)2. Minor solicited adverse events there have been observed, including local  reactions, such as pain, redness, swelling and limitation of the arm movement, as well as systemic events - fever, diarrhea, fatigue, headache, vomiting, decreased appetite, rash and muscle/joint pain (Table 6) while any serious adverse events and deaths did not differ significantly between the vaccine and the control group (Table 6)4 .

TABLE 4. ACIP recommendations for IPD vaccination in immunosuppressed adults >19 years old
 

TABLE 5. PCV13 vaccination in highrisk adults >19 years old
 

TABLE 6. PPSV23 Recommendations
 

PNEUMOCOCCAL POLYSACCHARIDE VACCINE (PPSV23)

PPSV23 recommendations suggest the routine vaccination of all adults 65 years of age and older and their revaccination after 5 years, as well as persons more than 2 years old with chronic diseases (cardiovascular disease, pulmonary disease, diabetes, alcoholism, chronic liver disease, cirrhosis, splenic dysfunction or absence, Hodgkin disease, lymphoma, multiple myeloma, chronic renal failure, nephrotic syndrome, cerebrospinal fluid leak, or a cochlear implant asymptomatic or symptomatic HIV infection, organ transplantation, chemotherapy or highdose corticosteroid therapy for longer than 14 days) (Table 3)2. Pneumococcal vaccine is also suggested for persons living in specific environments or social settings with an identified increased risk of pneumococcal disease, such as certain Native American (i.e., Alaska Native, Navajo, and Apache) populations (Table 5). Moreover, in 2010 ACIP added asthma and cigarette smoking to the list of indications for PPSV23 vaccination due to increasepd risk of IPD2.

Regarding the suggested revaccination with PPSV23, immunocompetent adults aged 19 through 64 years old  with chronic heart disease, pulmonary disease -including asthma, liver disease, alcoholism, CSF leaks, cochlear implants, or those who smoke cigarettes should receive one dose of PPSV23 before the age of 65 years. A second PPSV23 dose is recommended 5 years after the first PPSV23 dose for those aged 19-64 years with functional or anatomic asplenia – including sickle cell disease or splenectomy, as well as immunocompromised adults with medical conditions, such as HIV infection, leukemia, lymphoma, Hodgkin disease, multiple myeloma, generalized malignancy, chronic renal failure, nephrotic syndrome, or other conditions associated with immunosuppression, such as organ or bone marrow transplantation and those receiving immunosuppressive treatment, including chemotherapy and long-term corticosteroids2 . The 30%–50% of vaccinated individuals report local reactions, such as pain, swelling, or erythema at the site of injection, symptoms that usually persist for less than 48 hours (Table 7). These aforementioned local reactions are reported more frequently following the second dose of PPSV23 than following the first dose. Moderate systemic reactions, including fever and myalgia have been reported in less than 1% of the vaccinees, while more severe systemic adverse reactions are generally rare.2

TABLE 7. Adverse Events of Pneumococcal Vaccines
 

Regarding daily clinical practice, in cases where elective  splenectomy or cochlear implant is being considered, the vaccine should be given at least 2 weeks before2 . In the same way, a 2-week interval is recommended between vaccination and initiation of chemotherapy or other immunosuppressive therapy, if possible. Both, pneumococcal and influenza vaccines can be given at the same time but at different anatomical sites. PCV13 should never be performed during the same visit with PPSV23. There are no guidelines supporting the vaccination with PCV13 or PPSV23 in pregnant women.

In conclusion, prevention against IPD is achieved by the use of the two available vaccines against Streptococcus pneumoniae , the polysaccharide pneumonococcus vaccine (PPSV23) one and the pneumonococcus conjugated vaccine (PCV13). The knowledge of immunogenicity and vaccine efficacy, as well as the minor adverse effects and the recommended vaccination programs constitute a critical issue for modern pulmonologists.

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