Adequate pneumococcal prophylaxis continues to be a moving target.1,2 Introduction of Prevnar (PCV7, Wyeth Lederle Vaccines, Madison, NJ), a 7-serotype pneumococcal conjugated vaccine, in 2000 significantly decreased the incidence of invasive pneumococcal infections and increased herd protection worldwide.3–5 However, increasing prevalence of non-PCV7 pneumococcal serotypes6,7 and drug-resistant serotypes6,8 led to the development and recent introduction of Prevnar13 (PCV13, Wyeth Lederle Vaccines) that includes 6 additional pathogenic pneumococcal serotypes.9,10 The long-term effects of PCV13 on pneumococcal disease incidence and herd protection are unknown. Pneumovax (PPV23, Merck Vaccines, Whitehouse, NJ), another pneumococcal vaccine available since 1977, consists of a mixture of purified capsular polysaccharides from the 23 most prevalent and invasive types of Streptococcus pneumoniae including the serotypes present in PCV13.11 Currently, PPV23 is indicated in children aged 2–18 years with underlying medical conditions such as asplenia or HIV that increase their risk for contracting pneumococcal disease or who may experience complications of pneumococcal disease if infected.11 PPV23 is also indicated for pneumococcal prophylaxis in adults. The clinical and serological responses to PPV23 in patients with recurrent upper respiratory tract infections and pneumococcal antibody deficiency have been known for the last 30 years.12 However, there is no information concerning the use of PPV23 in children and adolescent with recurrent respiratory infections and pneumococcal antibody deficiency despite appropriate immunization with PCV7.
In this retrospective, descriptive study, we report the clinical and serological response to PPV23 in 72 patients older than 2 years, 62 percent of which (45 of 72) had received PCV7. These patients were seen in our clinic with recurrent upper respiratory tract infections, mainly otitis media and rhinosinusitis, and had evidence of deficiency of pneumococcal antibodies with data over a follow-up period of at least 6 months.
MATERIALS AND METHODS
We did a retrospective analysis of 72 patients between 2 and 25 years of age, referred to our subspecialty clinic for evaluation of recurrent respiratory infections between December 2002 and January 2011. The following data were gathered: sex, age, ethnicity, type and frequency of respiratory infections, medical and surgical history, family medical history and immunization record to PCV7. Blood was drawn for IgG and IgG subclasses: IgA, IgM and IgE levels; pneumococcal, Haemophilus influenzae type b, tetanus and diphtheria antibody titers. Institutional review board approval was obtained before the review of the patient data.
Assessment of Clinical Response
Frequency and type of respiratory infections were documented at first visit. Patients with 4 or more upper respiratory tract infections treated with antibiotics per year, 4 or more acute otitis media episodes treated with antibiotics per year or 2 or more episodes of sinusitis per year fulfilled the criteria for recurrent upper respiratory infections and were included in the study.13,14 Most patients had a combination of recurrent otitis media and rhinosinusitis. The changes in frequency, type and severity of infections were recorded at first and subsequent visits for 6 months after administration of PPV23. A clinical response was considered positive if the parents reported complete resolution of the infections or more than 50% decrease in the frequency according to the aforementioned criteria.
Pneumococcal Antibody Testing and Response
All patients had a 12–14 serotype pneumococcal antibody panel drawn to assess their pneumococcal antibody status as part of the initial evaluation. The pneumococcal antibody titers for each of the serotypes were analyzed by a reference laboratory using the Multi-Analyte Immunodetection panel based on the Luminex flow cytometric system. The procedure included absorption of sera with cross-reactive polysaccharide C and serotype polysaccharide 22F.15 The antibody levels were considered protective if the specific IgG titer was ≥1.3 μg/mL in at least 50% of the serotypes in children aged 2–5 years and in >70% of children aged 6 years and older.16–18 On the basis of these criteria, patients with nonprotective pneumococcal antibodies levels were given a dose of PPV23. A positive IgG antibody response to a given serotype was defined as a postimmunization antibody concentration of ≥1.3 μg/mL in at least 50% of the serotypes tested in children from 24 months through 5 years of age with at least a 2-fold increase in the titers.16,17,19 For subjects 6 years of age and older, a normal response is defined as conversion of 70% of the serotypes tested with at least a 2-fold increase in the titers.16,17,19 The vaccine (0.5 mL) was applied intramuscularly in the anterolateral thigh for toddlers aged 24–35 months and in the deltoid muscle of the arm for children aged 3 years and older. Written parental consent for treatment was obtained before PPV23 administration. To assess the serological response, pneumococcal antibody levels were drawn at approximately 1, 3 and 6 months after immunization.
Clinical and serological responses to PPV23 were recorded in the 1- to 6-month interval after immunization. Patients were additionally divided according to age (2–5 years and 6 years and older) and according to previous administration of PCV7.
Seventy-two individuals with recurrent respiratory tract infections and pneumococcal antibody deficiency were studied. As seen in Table 1, 41 patients (57%) were 2–5 years old, 31 patients (43%) were 6 years and older. There were 26 females (36%) and 46 males (64%). Patient population ethnicities included 31 Caucasians (43%), 36 Hispanics (50%) and 5 African Americans (7%). Forty-eight patients had recurrent acute otitis media (67%); 71 had recurrent rhinosinusitis (98%); 18 had recurrent streptococcal pharyngitis (25%); 5 had bronchitis (7%) and 3 had pneumonia (4%). Twenty-two patients had asthma (30%); 8 had allergies (11%) and 2 patients had atopic dermatitis (3%). Fourteen patients had a family history of recurrent respiratory infections (19%). Thirty-four patients (47%) had undergone surgical procedures; 18 patients (25%) had ear tubes placed, 11 (15%) had tonsillectomy and adenoidectomy and 5 (7%) had sinus surgery. Forty-five patients (62%) received 3–4 doses of PCV7. Twenty-seven patients (37%) were not given PCV7; of these, 21 (77%) were born before this vaccine became available (Table 1).
Clinical response to PPV23 was assessed at approximately 1, 3 and 6 months after immunization. Overall, 69 patients (96%) had a positive clinical response to PPV23 with resolution of the upper respiratory infections in most cases, whereas only 3 patients (4%) had no clinical response (Table 2). Pneumococcal immunization was well tolerated by most patients; a mild febrile reaction was reported in 1 individual and mild local pain at the injection site in another.
Preimmunization, 64 patients (89%) had nonprotective antibody levels according to the aforementioned criteria, whereas 8 (11%) had low-range protective levels. These were patients with at least 50% of antibody levels between 1.3 and 2.0 μg/mL. Seven (10%) of these patients had received PCV7. Most patients had normal serum immunoglobulins, IgG subclasses and normal antibody titers to H. influenzae type b, tetanus and diphtheria. Sixty patients (83%) developed a protective serological response after immunization, whereas 12 patients (17%) showed a partial response, because they generated protective titers to fewer than the expected numbers of serotypes for their age group (Table 2).
Clinical and Serologic Response
Sixty-nine individuals (96%) showed positive clinical responses despite partially protective serology in 12 (17%), whereas 3 individuals (4%) had no clinical response despite protective serology. No patients had negative clinical and nonprotective serology (Table 2).
Patients were subdivided according to age: 2–5 years (41 patients) and 6 years and older (31 patients). In the 2–5 years of age group, 36 individuals (88%) developed both positive clinical and protective serology, whereas 2 patients (5%) in this age group had a positive clinical response despite nonprotective serology. Three patients (7%) had no clinical response despite protective antibody levels (Table 2). In the 6 years of age and older group (31 patients), 21 (68%) had both positive clinical and serological responses and 10 patients (32%) had a positive clinical response despite nonprotective serology. All patients in this age group had a positive clinical response to PPV23 despite nonprotective serology in 10 (32%) (Table 2).
Patients were further subdivided into PCV7 (45 patients) and non-PCV7 (27 patients) administration groups. In the PCV7 group, 37 (82%) of patients had positive clinical and protective serology, 5 (11%) had positive clinical response despite nonprotective serology and 3 (7%) patients had no clinical response despite protective serology. No patients in this group had negative clinical and nonprotective serology. In the group with no previous PCV7 history, 20 (74%) had both positive clinical and serological response, whereas 7 (26%) patients had a positive clinical response despite nonprotective serology (Table 2).
Four (5%) patients were given a booster of PPV23: 3 (4%) because of recurrence of the upper respiratory infections and loss of antibodies over time and 1 (1%) because of lack of clinical response with partial serology. Two patients (3%) were given intravenous IgG for 6 months because of lack of clinical and serological response to the PPV23 booster. Three (4%) other patients were given intravenous IgG after no clinical or serological responses to the first dose of PPV23 were observed (Table 3).
In this retrospective, descriptive study, we report the clinical and serological response to PPV23 in 72 children and teens seen in our clinic for evaluation of recurrent upper respiratory tract infections, who had evidence of pneumococcal antibody deficiency and normal immunoglobulins levels, IgG subclasses and responses to protein antigens. Forty-five (63%) of these patients had received PCV7 as part of their immunization schedule. Administration of PPV23 benefited 69 of the 72 patients (96%) with resolution of the infections in most cases including the 27 patients (37%) who did not receive PCV7. The positive clinical effect was most evident during the first 6 months after administration of PPV23. In 60 patients (83%), the clinical response was associated with a protective antibody response according to the criteria outlined earlier,17,19 whereas 12 patients had a positive clinical response despite nonprotective serology (Table 2).
Pneumococci frequently causing otitis media include serotypes 6B, 14, 19A and 23F, which are the same serotypes found to have developed resistance to antibiotics in the United States and elsewhere.6,8 These serotypes are included in the PPV23, which may explain the positive clinical and serological responses seen in our patients. Eleven percent (5 of 72) of our patients had clinical improvement after PPV23 despite nonprotective serology, whereas 3 patients (7%) had no apparent clinical response to PPV23 despite protective serology (Table 2). The infections in these patients may have been because of pneumococcal serotypes other than the 14 that we were able to measure.
Despite vaccination with PCV7, many children still suffer from recurrent acute otitis media, rhinosinusitis, bronchitis and pneumonia because of Streptococcus pneumoniae. Increasing prevalence of non-PCV7 pneumococcal serotypes6,7 and drug resistant serotypes6,8 have been implicated. It is expected that the new vaccine PCV13 will overcome these issues. However, there is a group of patients who are unable to develop a normal response to pneumococcal and other polysaccharides.12,13 Before the introduction of PCV7, it has been estimated that approximately 5%–10% of patients older than 2 years who present with recurrent respiratory infections belong to this group.12,20
The terms impaired polysaccharide responsiveness and polysaccharide nonresponsiveness were first used to characterize children and adults with recurrent bacterial respiratory infections, normal or increased immunoglobulins and IgG subclasses, intact antibody responses to protein antigens and absent or subnormal response to polysaccharide antigens.21,22 Because polysaccharide nonresponsiveness may be a feature of a variety of systemic illnesses and other immunodeficiency disorders, the term selective antibody deficiency (SAD) is currently used to characterize patients older than 2 years with recurrent upper respiratory infections in which polysaccharide nonresponsiveness is the only identifiable immunological abnormality.11,16,18 Before the introduction of PCV7, SAD was the most frequently identified immunodeficiency in patients with recurrent upper respiratory infections.23 The syndrome of specific antibody deficiency is defined using the combined response to all the serotypes tested. Normal children between 2 and 5 years of age are expected to have an adequate response to at least 50% of serotypes tested, whereas older patients should respond to at least 70% of serotypes tested.16,18
Only 17% of our patients (12 of 72) can be characterized as having SAD because they generated protective antibody titers to fewer than the expected numbers of serotypes for their age group after administration of PPV23; 2 patients in the 2–5 years of age group and 10 in the 6 years and older age group were poor responders. Notwithstanding, the 2 patients in the 2–5 years of age group and the 31 patients in the 6 years and older age group had positive clinical responses including the 10 patients who were poor serological responders (Table 2).
Clinical and serologic responses to PPV23 in children older than 3 years with recurrent upper tract respiratory infections and low or absent pneumococcal antibodies were reported by Epstein and Gruskay in 1995.12 In their study, 87 of 100 children generated protective antibody responses to 8–12 of the serotypes in PPV23 measured by radioimmunoassay. Eighty-three percent (72 of 87) had improvement in the frequency of the respiratory infections in the following 2–4 years. Thirteen of the original cohort of 100 patients did not respond to PPV23 even on repeated vaccination. All the children in their study had normal immunoglobulins, subclass levels and normal responses to protein antigens.
Our study showed that despite appropriate immunization schedules with PCV7, there is still a population of children who are seen frequently in the pediatrician’s office for recurrent otitis media and sinopulmonary infections. They receive multiple courses of antibiotics per year, and many of them undergo surgical procedures including placement of ear tubes, tonsillectomies and adenoidectomies and sinus surgery with little or no relief (Table 1). The poor responders to PCV7 can be identified by measuring their pneumococcal antibody titers, preferably the 23-serotype panel, which is now commercially available. The immune laboratory evaluation should include serum immunoglobulins, IgG subclasses and antibody titers to the usual vaccinations such as diphtheria, tetanus toxoid and H. influenzae type b, to assess their T-cell–dependent antibody responses. Children and teens with evidence of impaired pneumococcal responsiveness and otherwise normal antibody responses should receive a dose of PPV23. Clinical and serological responses should be evaluated 4–6 weeks from immunization. Children who fail to respond to PPV23 may have the immunodeficiency known as SAD and may benefit from other treatment options such as monthly infusions of gamma globulin (Table 3).
Our data are relevant because of the increasing cost of providing pneumococcal prophylaxis in children using the new conjugated pneumococcal vaccines in the United States and the low reimbursement rates for the primary care providers who administer them. Based on the evidence demonstrating that children as young as 6 months of age can mount pneumococcal antibody responses,19,24 inclusion of PPV23, a much more affordable vaccine in the routine pneumococcal immunization schedule of children, and its use in the treatment of children with recurrent upper respiratory tract infections despite PCV7 and PCV13, should be reconsidered.
The authors thank their nursing staff, in particular Sue Vazquez, RN, who made it possible to follow-up these patients and collect their samples; Edgar Munoz, MS, for helpful review of the manuscript and suggestions concerning presentation of patient data and Nicole Gonzalez, for expert secretarial assistance.
1. Peters TR, Poehling KA. Invasive pneumococcal disease: the target is moving. JAMA. 2007;297:1825–1826
2. Rodgers GL, Klugman KP. The future of pneumococcal disease prevention. Vaccine. 2011;29(suppl 3):C43–C48
3. Hennessy TW, Singleton RJ, Bulkow LR, et al. Impact of heptavalent pneumococcal conjugate vaccine on invasive disease, antimicrobial resistance and colonization in Alaska Natives: progress towards elimination of a health disparity. Vaccine. 2005;23:5464–5473
4. Poehling KA, Szilagyi PG, Grijalva CG, et al. Reduction of frequent otitis media and pressure-equalizing tube insertions in children
after introduction of pneumococcal conjugate vaccine. Pediatrics. 2007;119:707–715
5. Whitney CG, Farley MM, Hadler J, et al.Active Bacterial Core Surveillance of the Emerging Infections Program Network. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med. 2003;348:1737–1746
6. Pichichero ME, Casey JR. Evolving microbiology and molecular epidemiology of acute otitis media in the pneumococcal conjugate vaccine era. Pediatr Infect Dis J. 2007;26(10 suppl):S12–S16
7. Pilishvili T, Lexau C, Farley MM, et al.Active Bacterial Core Surveillance/Emerging Infections Program Network. Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine. J Infect Dis. 2010;201:32–41
8. Pichichero ME, Casey JR. Emergence of a multiresistant serotype 19A pneumococcal strain not included in the 7-valent conjugate vaccine as an otopathogen in children
. JAMA. 2007;298:1772–1778
9. Bryant KA, Block SL, Baker SA, et al. Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine. Pediatrics. 2010;125:866–875
10. Yeh SH, Gurtman A, Hurley DC, et al.004 Study Group. Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine in infants and toddlers. Pediatrics. 2010;126:e493–e505
11. Sorensen RU, Paris K. Selective antibody deficiency with normal immunoglobulins. 2013:1–14 UpToDate
. Available at: htpp://wwwuptodatecom
. Accessed July 17, 2015
12. Epstein MM, Gruskay F. Selective deficiency in pneumococcal antibody response in children
with recurrent infections. Ann Allergy Asthma Immunol. 1995;75:125–131
13. Sorensen RU, Leiva LE, Javier FC III, et al. Influence of age on the response to Streptococcus pneumoniae vaccine in patients with recurrent infections and normal immunoglobulin concentrations. J Allergy Clin Immunol. 1998;102:215–221
14. Sorensen RU, Moore C. Antibody deficiency syndromes. Pediatr Clin North Am. 2000;47:1225–1252
15. Pickering JW, Martins TB, Greer RW, et al. A multiplexed fluorescent microsphere immunoassay for antibodies to pneumococcal capsular polysaccharides. Am J Clin Pathol. 2002;117:589–596
16. Orange JS, Ballow M, Stiehm ER, et al. Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2012;130(3 suppl):S1–S24
17. Sorensen RU, Leiva LE, Giangrosso PA, et al. Response to a heptavalent conjugate Streptococcus pneumoniae vaccine in children
with recurrent infections who are unresponsive to the polysaccharide vaccine. Pediatr Infect Dis J. 1998;17:685–691
18. Wasserman RL, Sorensen RU. Evaluating children
with respiratory tract infections: the role of immunization with bacterial polysaccharide vaccine. Pediatr Infect Dis J. 1999;18:157–163
19. Paris K, Sorensen RU. Assessment and clinical interpretation of polysaccharide antibody responses. Ann Allergy Asthma Immunol. 2007;99:462–464
20. Hidalgo H, Moore C, Leiva LE, et al. Preimmunization and postimmunization pneumococcal antibody titers in children
with recurrent infections. Ann Allergy Asthma Immunol. 1996;76:341–346
21. Ambrosino DM, Siber GR, Chilmonczyk BA, et al. An immunodeficiency characterized by impaired antibody responses to polysaccharides. N Engl J Med. 1987;316:790–793
22. Stiehm ER. The four most common pediatric immunodeficiencies. J Immunotoxicol. 2008;5:227–234
23. Javier FC III, Moore CM, Sorensen RU. Distribution of primary immunodeficiency diseases diagnosed in a pediatric tertiary hospital. Ann Allergy Asthma Immunol. 2000;84:25–30
24. Balloch A, Licciardi PV, Russell FM, et al. Infants aged 12 months can mount adequate serotype-specific IgG responses to pneumococcal polysaccharide vaccine. J Allergy Clin Immunol. 2010;126:395–397