Pneumococcal Vaccine and Patients with Pulmonary Diseases

Abstract

Chronic pulmonary diseases describe chronic diseases that affect the airways and lung parenchyma. Examples of common chronic pulmonary diseases include asthma, bronchiectasis, chronic obstructive lung disease, lung fibrosis, sarcoidosis, pulmonary hypertension and cor pulmonale. Pulmonary infection is considered a significant cause of mortality in patients with chronic pulmonary diseases. Streptococcus pneumoniae is the leading isolated bacteria from adult patients with community-acquired pneumonia, the most common pulmonary infection. Vaccination against S. pneumoniae can reduce the risk of mortality especially from more serious infections in both immunocompetent and immunocompromised patients. Patients with chronic pulmonary diseases who take steroids or immunomodulating therapy (e.g., methotrexate, anti-TNF inhibitors), having concurrent sickle cell disease or other hemoglobinopathies, primary immunodeficiency disorders, human immunodeficiency virus infection / acquired immunodeficiency syndrome (HIV/AIDS), nephrotic syndrome, and hematologic or solid malignancies should be vaccinated with both 13-valent pneumococcal conjugate vaccine (PCV13) and the pneumococcal polysaccharide vaccine 23-valent (PPSV23).

Introduction

Pneumococcal disease describes many infectious processes caused by Streptococcus pneumoniae (S. pneumoniae), including meningitis, pneumonia, bacteremia, bronchitis, sinusitis, and otitis media. Pneumonia is the most common presentation of pneumococcal disease in adults. In the US, pneumococcal pneumonia is responsible for 30% of adult community-acquired pneumonia cases and 400,000 hospitalizations annually. (1) Pneumococcal pneumonia represents a common complication of many disease processes.

Chronic pulmonary diseases, as mainly defined by asthma, bronchiectasis, chronic obstructive lung disease (COPD), interstitial lung disease, sarcoidosis, pulmonary hypertension and cor pulmonale, represent the third leading cause of death and account for more than 140,000 deaths in 2011.(2) Pneumococcal pneumonia is a frequent complication in patients with chronic pulmonary disease. Mortality is a frequent outcome in these cases, regardless of whether the patients have developed invasive disease. (3) For this reason, the management of pneumonia exists as a major contribution to the economic burden of chronic respiratory diseases. The cost of pneumonia treatment for Medicare beneficiaries alone was reported in excess of $13 billion in 2008.(4)

Streptococcus pneumoniae serotypes

Streptococcus pneumoniae (S. pneumoniae) is classified based on the presence of capsular polysaccharides on the organism. More than 90 different serotypes of S. pneumonia have been identified. (5) Each organism has been classified into 46 distinctive subgroups based on immunological similarities. (6) Although invasive pneumococcal disease may occur with all serotypes, almost 60% of cases are caused by the same 23 serotypes. (7, 8) Furthermore, certain serotypes seem to be more commonly isolated from specific organ systems. For instance, serotype 1 and 3 are more frequently isolated in pneumonia and serotypes 6, 10 and 23 are regularly isolated in meningitis.(9, 10) Regional variations also exist in S. pneumoniae serotype disease etiology. A recently published meta-analysis showed that isolated serotypes from young children with invasive pneumococcal disease varied significantly in respect to geography. In addition, serotype 14 was the most common isolate from all over the world and serotypes 1, 5, 6A, 6B, 14, 19F, and 23F were isolated in 50% of individuals.(11, 12)

Pneumococcal disease

Pneumococcal disease can manifest in numerous body systems. Even though S. pneumoniae is the leading isolated bacteria from adult patients with community-acquired pneumonia globally, pneumococcal disease can present in many other forms.(13-15) Acute otitis media is one of the most commonly diagnosed diseases in children less than 5 years old in the US.(16) S. pneumoniae is the most common bacterial cause of AOM acute otitis media.(17) S. pneumoniae is the leading bacterial cause of meningitis, and the mortality rate is especially high. (18) Prompt antibiotic therapy is indicated for pneumococcal infection. However, increasing drug resistant strains and lack of development of new antibiotics are main concerns in the battle against these bacterial infections. (12)

Pneumococcal disease is commonly categorized as invasive or noninvasive pneumococcal disease. Invasive pneumococcal disease is defined as a serious condition with major organ involvement or bacteremia, in which S. pneumoniae isolates from normally sterile biofluids such as blood, cerebrospinal fluids, pleural fluid, and peritoneal fluid. The case fatality of invasive pneumococcal disease is reported at least 10%. However, it is higher in elderly and immunocompromised patients.(19) An estimated 5,000 adults died due to invasive S. pneumoniae infections nationwide in 2009.(20) NIPD Noninvasive pneumococcal disease addresses less serious conditions such as otitis media and nonbacteremic pneumococcal pneumonia.(21, 22)

Conditions predisposing to pneumococcal disease

Pneumococcal infection is common in patients with immunocompromising conditions (23), central nervous system and spleen anatomical abnormalities (24), hemoglobinopathies (25), chronic pulmonary diseases (26), heart failure (27), chronic kidney disease (28), smokers (29), and elderly (30). Patients who have low antibody level and ineffective serum opsonizing against S. pneumonia are at a higher risk as well.(31)

Pneumococcal vaccines

Pneumococcal vaccination targeting common serotypes is the current recommended standard of prevention. Pneumococcal vaccines work by stimulating the humoral immune system that facilitates anticapsular antibody. The first large trial assessing the efficacy of pneumococcal vaccine goes back to 1911 in South Africa.(32) The first advanced pneumococcal vaccine was approved in the US by the Food and Drug Administration (FDA) in 1977. This vaccine included coverage of 14 serotypes. Invasive pneumococcal disease in immunocompetent children and adults has been declining after introduction of pneumococcal vaccines in the US. The rate of the disease declined 32% in 20-39 years old group, 8% for 40-64 years old, and 18% for individuals 65 years and older.(33) Although vaccines are the only current proven method for acquired pneumococcal resistance, emerging research indicates that cell-mediated immunity may also be achieved by CD4+ T cells regardless of antibody status or capsular type as observed in laboratory mice.(34)

PPSV23 vaccine

In 1983, additional serotypes were added to the original pneumococcal vaccine in order to form the pneumococcal polysaccharide vaccine 23-valent (PPSV23).(35) PPSV23 covers serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F.(36, 37) (Table 2)

Table 2.

Streptococcus pneumoniae strains that are covered by PPSV23 and PCV13 vaccines

Vaccine name	Serotypes covered by
PPSV23	1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F
PCV13	1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F
Both PPSV 23 and PCV13	1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F

PPSV23 (23-valent pneumococcal polysaccharide vaccine; Pneumovax23, marketed by Merck & Company, Inc.)

PCV13 (Pneumococcal 13-valent Conjugate Vaccine; Prevnar 13, Manufactured by Wyeth Pharmaceuticals Inc. Marketed by Pfizer Inc.)

In a study evaluating PPSV23 against invasive pneumococcal disease, Butler et al. demonstrated an efficacy of 75% for the immunocompetent elderly (age>65 years old), 84% for patients with diabetes mellitus (DM), 77% for patients with anatomic asplenia, and 65% for patients with chronic pulmonary disease. (38) The Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP) recommended PPSV23 immunization for all individuals who are in significant risk of invasive pneumococcal disease such as patients with diabetes mellititus, chronic respiratory diseases (e.g., COPD, asthma, and bronchiectasis), congestive heart failure, chronic renal failure, and chronic liver disease.(20) Table 1 shows current recommendation for administration of PPSV23 and revaccination at 5 years after the first dose for adults aged ≥19 years.

Table 1.

Indications for administration of PPSV23 and re-vaccination 5 years after the first dose in adults aged ≥19 years*

Vaccine responder	Underlying medical condition	PPSV23	PPV23 re- vaccination
Good responders	Chronic pulmonary diseases**	⋆
	Chronic heart disease***	⋆
	Chronic liver disease	⋆
	CSF leaks	⋆
	Cochlear implants	⋆
	Alcoholism	⋆
	Diabetes mellitus	⋆
	Tobacco smoking	⋆
Poor responder	Sickle cell disease and other hemoglobinopathies	⋆	⋆
	Congenital or acquired asplenia	⋆	⋆
	Primary immunodeficiencies§	⋆	⋆
	Iatrogenic immunodeficiency §§	⋆	⋆
	HIV infection	⋆	⋆
	Hematologic malignancies	⋆	⋆
	Generalized malignancy	⋆	⋆
	Solid organ transplant	⋆	⋆
	Chronic renal failure	⋆	⋆
	Nephrotic syndrome	⋆	⋆

Note: adapted from Advisory Committee on Immunization Practices, United States, 2012 with authors’ comments. All adults≥65 years should be revaccinated with PPSV23 without consideration of previous pneumococcal vaccination

^**Such as COPD, asthma, bronchiectasis, sarcoidosis

^***including congestive heart failure (CHF) and cardiomyopathies

^§All type of B and T cell lymphocyte deficiencies, complement specially early complements (C1, C2, C3, C4), and phagocyte disorders except chronic granulomatous disease.

^§§any condition that patient takes chronic systemic corticosteroids (such as prednisone 15 mg per day for more than 6 months) or immunosuppressant agents such as methotrexate, or radiation therapy

PPSV23 and immunocompromised patients

Despite the proven effectiveness of PPSV23 to reduce invasive and noninvasive pneumococcal diseases in immunocompetent populations, the data suggest this vaccine does not deliver the same benefits to immunocompromised patients.(39-41) A meta-analysis analyzing 64,852 individuals from 18 randomized clinical trials showed PPSV23 might prevent invasive pneumococcal disease in adults, but evidence did not support the efficacy of PPSV23 in patients with significant underlying diseases such as malignancy, end-stage renal disease and acquired immunodeficiency syndrome.(42) Blumberg et al. showed that IgG antibody responses to 5 representative vaccine capsular polysaccharides of PPSV23 in immunocompromised patients with a heart transplant were significantly impaired.(43) Tobudic et al. confirmed these findings in renal transplant recipients.(44) A randomized clinical trial in adult patients with stem cell transplants in Canada showed poor immunogenicity to PPSV23 in this population.(45) This poor antibody response to PPSV23 was also seen in patients Human Immunosuppressive Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS). Rodriguez et al. investigated the immunogenicity of PPSV23 in patients with HIV/AIDS, noting that individuals with lower CD4+ T cell counts had a lower antibody levels against capsular polysaccharide.(46) A 5-year lonigitudal study confirmed these results.(47) All of the above studies support the idea that immunocompromised patients have an inferior immunogenic response to PPSV23. Therefore, this vaccine is not an effective preventative tool for invasive pneumococcal disease in this population.

PPSV23 and pediatric patients

PPSV23 has also proven ineffective in the pediatric population, particularly in children under the age of 2 years. (48) This is an important limitation given the prevalence and potential severity of pneumococcal disease in this population. Several explanations exist for the lack of protection provided of PPSV23 in young children. (49) First, the 23 most common serotypes in adult populations covered by the vaccine are not congruent with the most common serotypes in pediatrics. Also, serotypes covered by the PPSV23 commonly found in this population are more likely to be drug resistant. This undermines the effectiveness of the vaccine by failing to induce immunologic memory and facilitate response in the event of exposure. PPSV23 also fails to protect the nasopharyngeal pathway, thus, failing to prevent infections of the mucosa, which leaves young children susceptible to the one of the most common pneumococcal diseases in this population: acute otitis media. Also, pneumococcal diseases are transmissible to others through exposures from the mucosa, which leaves children both unprotected and contagious.(50)

7-valent pneumococcal conjugate vaccine

Given the limitations of PPSV23 particularly in pediatric populations, PCV7 was developed as a means of preventing pneumococcal disease in children by covering the common serotypes unique to pediatric populations. These serotypes include 4, 6B, 9V, 14, 18C, 19F, and 23F.(51) Invasive pneumococcal disease was reported in an estimated 68,000 individuals annually before PCV7 was introduced in the US in 2000s. Following the use of PCV7 in children, the numbers of invasive pneumococcal disease identified cases were drastically decreased to around 38,000 annually with an overall incidence reduction of 45% after 7 years. (52) However, infection with non PCV7-serotypes still increased in this population. (53) Also, PCV7 was not proven for immunocompromised adults or for use in children with HIV, sickle cell disease or other specific risk groups for invasive pneumococcal disease.(51)

13-valent pneumococcal conjugate vaccine

According to the CDC, more than half of the serotypes isolated in immunocompromised patients with invasive pneumococcal disease were not serotypes included in the PPSV23 coverage profile. The CDC reports that S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F were isolated in half of immunocompromised adults with invasive pneumococcal disease in 2010.(54) Among the total number of invasive pneumococcal disease cases in the immunocompromised, less than a quarter were caused by serotypes 8, 9N, 10A, 11A, 12F, 15B, 17F, 18C, 19A, 20, 22F, and 33F, which are included in PPSV23.(55) This data offered an explanation for the well-proven mixed results of PPSV23 vaccine studies. Also, this report illuminated the need for a vaccine with coverage of S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. As a result, the 13-valent pneumococcal conjugate vaccine was introduced (PCV13). In February 2010, the FDA licensed PCV13 for prevention of invasive pneumococcal disease and otitis media in infants and young children. In December 2011, FDA licensed this vaccine for prevention of pneumonia and invasive pneumococcal disease in adults aged ≥50 years.(55) In the same year, a large randomized, double blind clinical trial study in Europe demonstrated that PCV 13 (manufactured by Pfizer) is a safe and immunogenic vaccine in the adults aged ≥65 years old.(56)

Given the fact that young children (<2 years old) and immunocompromised patients have a poor response to polysaccharide vaccine, pneumococcal antigens are conjugated to a nontoxic diphtheria carrier protein to improve immunogenicity and inducing T-cells response.(57) For this reason, PCV7 was commonly used in this population instead of PPSV23. PCV13 that is an updated version of PCV7, which improved antibody response with longer coverage against invasive pneumococcal disease in immunocompetent and immunocompromised persons.(58) PCV13 (Prevnar 13, Wyeth Pharmaceuticals, Inc., a subsidiary of Pfizer, Inc.) was approved by the FDA for adult based on immunogenicity studies. (59) PCV13 is a safe and effective strategy to prevent invasive pneumococcal disease and induces higher immune response as compared to PPSV23 in pneumococcal vaccine-naive adults.(60) The cost analysis of PVC13 immunization showed that one dose of PCV13 is more cost effective than PPSV23 in immunocompromised persons.(61, 62) While PCV13 covers numerous serotypes that are prevalent in immunocompromised individuals, other non-covered serotypes remain a serious concern in this group of patients.(63)

Recommendations for PCV13

ACIP published new recommendations for PCV13 on 2012.(55) These recommendations include the use of PCV13 in adults 19 years old and older with an underlying immunocompromised disorder. The Infectious Diseases Society of America (IDSA) recently recommended PCV13 vaccination for immunocompromised patients.(64)

PCV13 for patients with pulmonary diseases

Chronic pulmonary diseases are a group of chronic diseases that affect the airways and lung parenchyma. Asthma, bronchiectasis, chronic obstructive lung disease, interstitial lung disease, sarcoidosis, pulmonary hypertension and cor pulmonale are some of the most common chronic pulmonary diseases. All patients with chronic pulmonary diseases should receive PCV13 if they meet any of the risk factors listed in table 3.

Table 3.

Indications for 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged ≥19 years

Immune status	Underlying medical condition	PCV13
Immunocompetent	CSF leaks	⋆
	Cochlear implants	⋆
Immunocompromised	Sickle cell disease and other hemoglobinopathies	⋆
	Congenital or acquired asplenia	⋆
	Primary immunodeficiencies*	⋆
	Iatrogenic immunodeficiency**	⋆
	HIV infection	⋆
	Hematologic malignancies	⋆
	Generalized malignancy	⋆
	Solid organ transplant	⋆
	Chronic renal failure	⋆
	Nephrotic syndrome	⋆

Note: adapted from Advisory Committee on Immunization Practices, United States, 2012 with authors’ comments

^*All type of B and T cell lymphocyte deficiencies, complement specially early complements (C1, C2, C3, C4), and phagocyte disorders except chronic granulomatous disease

^**Any condition that patient takes chronic systemic corticosteroids (such as prednisone 15 mg per day for more than 6 months) or immunosuppressant agents such as methotrexate, or radiation therapy

Concurrent Sickle cell disease or other hemoglobinopathies

The incidence of invasive pneumococcal disease in sickle cell disease cases is higher as compared to normal healthy population.(65) Pneumococcal immunization with PPSV23 and PCV13 have reduced the incidence of invasive pneumococcal disease in patients with sickle cell disease.(66) Lungs may be affected in patients with sickle cell disease and other forms of hemoglobinopathies. Acute chest syndrome, pulmonary hypertension, airway disease, and interstitial lung disease are common respiratory complications in these patients.(67) Pulmonary underlying diseases such as pulmonary hypertension may not meet the indication for PCV13, but physicians should consider PCV13 for patients with pulmonary hypertension associated with hemoglobinopathies.

Primary immunodeficiency disorders

More than 150 distinct syndromes have been categorized as primary immunodeficiency.(68) Patients with primary immunodeficiency may experience a broad range of pulmonary complications.(69) Bronchiectasis, obstructive airway disease, and interstitial lung disease are common pulmonary complications in patients with primary immunodeficiency.(70, 71) Invasive pneumococcal disease is particularly common in patients with most forms of primary immunodeficiency.(72) For example, patients with any humoral, cellular, complement deficiencies and phagocytic disorder types excluding chronic granulomatous disease are considered high-risk groups for invasive pneumococcal disease.(73) Interestingly, research has shown that patients with chronic granulomatous disease, even with neutropenia, are an exception and rarely develop invasive pneumococcal disease.(72, 74) Although there is no clinical trial to show PCV13 may improve immune response in these individuals, conjugated protein may enhance immunity response with involving T cell lymphocytes.

HIV/AIDS patients with pulmonary complications

Pulmonary hypertension is a rare but serious complication of HIV infection. However, given the number of patients who live with chronic HIV infection globally (approximately 30 million), HIV associated pulmonary hypertension will become an important issue in the coming years.(75, 76) Pulmonary malignancies (77), interstitial lung disease (78), obstructive airway disease and emphysema (79), and bronchiectasis (80) are other pulmonary disorders which are frequently seen in HIV infected population. Immunogenicity and safety of conjugated pneumococcal vaccine have been demonstrated.(81) All pulmonary patients with HIV/AIDS should receive PCV13 and PPSV23 per recommendation.

Immunosuppressive therapy

invasive pneumococcal disease is a serious infection in patients with hematologic and solid malignancies. For example, a population-based retrospective study in Canada showed an increased risk for invasive pneumococcal disease in patients with lung cancer (Odds ratio = 13.4).(82) Leukemia is the most common malignancy in children, which increases the risk for invasive pneumococcal disease 10 fold as compared to children in the general population.(83) PCV13 alone covers 84% of the serotypes that were isolated from invasive pneumococcal disease patients with a hematologic malignancy in a French study. French researchers found when PPSV23 was added, 92% of serotypes were covered. (84) Patients on steroid or immunomodulating drugs (e.g., methotrexate, anti-tumor necrosis factor (TNF) inhibitors) have higher risk for invasive pneumococcal disease and poorer response to vaccines.(85, 86) Although there is little information about sarcoidosis and invasive pneumococcal disease, we recommend PCV13 in all patients on steroid and nonsteroidal treatment. Nonsteroidal therapy for sarcoidosis has been discussed elsewhere.(87)

Vaccination protocol per ACIP recommendation (55)

Pneumococcal vaccine-naive persons

Patients who have never been vaccinated with pneumococcal vaccine should receive a single dose of PCV13 first, followed by a dose of PPSV23 at least 8 weeks later. For patients with any of the above listed indications, a follow up dose of PPSV23 is recommended five years following initial vaccination (Table 1 and 3). For patients who do not meet criteria to receive a second dose of PPSV23 per medical indications listed on Tables 1 and 3 should still receive this dose if they were first vaccinated before the age of 65. Please note that the follow up vaccine of PPSV23 is not due in these patients until more than 5 years have elapsed since first immunization with PPSV23.

Previous vaccination with PPSV23

Among patients who have previously received PPSV23, those who meet indication criteria for PCV13 immunization should receive a single dose of PCV13 at least a year after receiving the last dose of PPSV23. In those who meet criteria for repeating PPSV23, the vaccine should be given 8 weeks after receiving PCV13.

Interaction with other vaccines

In healthy adults, it was shown that the concomitant administration of PCV13 and trivalent inactivated influenza vaccine might diminish the antibody response to PCV13.(88) Therefore, it would be recommended to administer these vaccines in different visits.

This review concludes that patients with chronic pulmonary diseases who take steroids or immunomodulating therapy (e.g., methotrexate, anti-TNF inhibitors), having concurrent sickle cell disease or other hemoglobinopathies, primary immunodeficiency disorders, human immunodeficiency virus infection / acquired immunodeficiency syndrome (HIV/AIDS), nephrotic syndrome, and hematologic or solid malignancies should be vaccinated with both 13-valent pneumococcal conjugate vaccine and the pneumococcal polysaccharide vaccine 23-valent.

Clinical Significance.

• Immunocompromised patients have a poor response to pneumococcal polysaccharide vaccine 23-valent (PPSV23).

• 13-valent pneumococcal conjugate vaccine (PCV13) is a safe and effective strategy to prevent invasive pneumococcal disease.

• Patients with chronic pulmonary diseases who take steroids or immunomodulating therapy or having some certain risk factors should be vaccinated with both PCV13 and the PPSV23.