Pediatric News. Management of Pediatric Pneumococcal Diseases in the Era of the Pneumococcal Conjugate Vaccine

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1 A SUPPLEMENT TO Pediatric News Management of Pediatric Pneumococcal Diseases in the Era of the Pneumococcal Conjugate Vaccine Sponsored by Boston University School of Medicine Management of Acute Otitis Media in the Era of Drug Resistance Elizabeth Barnett, MD The Febrile Child and Invasive Pneumococcal Disease Larry Culpepper, MD, MPH Pneumonia and Otitis Media: The Northern California Data in Perspective Henry Shinefield, MD Vaccine Efficacy: Where Are the Gaps? Stephen I. Pelton, MD

2 Pediatric News General Manager/ Group Publisher Alan J. Imhoff Vice President, Medical Education & Business Development Sylvia H. Reitman Editor Joanne M. Still Program Manager, Medical Education Sara M. Hagan National Account Manager Rory Flanagan Graphic Design Lehner & Whyte, Inc. Production Specialist Rebecca Slebodnik The articles in this supplement are based on clinical dialogues with the faculty. The supplement was supported by an unrestricted educational grant from Management of Pediatric Pneumococcal Diseases in the Era of the Pneumococcal Conjugate Vaccine 4 Management of Acute Otitis Media in the Era of Drug Resistance Elizabeth Barnett, MD 7 The Febrile Child and Invasive Pneumococcal Disease Larry Culpepper, MD, MPH 9 Pneumonia and Otitis Media: The Northern California Data in Perspective Henry Shinefield, MD 11 Vaccine Efficacy: Where Are the Gaps? Stephen I. Pelton, MD 14 Self-Assessment Examination 15 Activity Evaluation It was produced by the medical education and business development department of International Medical News Group. Neither the Editor of PEDIATRIC NEWS, the Editorial Advisory Board, nor the reporting staff reviewed or contributed to its content. The opinions expressed in this supplement are those of the faculty and do not necessarily reflect the views of the supporter or the Publisher. Copyright 2003 International Medical News Group, an Elsevier company, and Trustees of Boston University. All rights reserved. No part of this publication may be reproduced or transmitted in any form, by any means, without prior written permission of the Publisher. International Medical News Group and Boston University School of Medicine will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. Faculty Jerome O. Klein, MD (Co-Chair) Professor of Pediatrics Vice Chairman for Academic Affairs Boston University School of Medicine Boston Medical Center Elizabeth Barnett, MD Associate Professor of Pediatrics Boston University School of Medicine Larry Culpepper, MD, MPH Professor and Chairman Department of Family Medicine Boston University School of Medicine Stephen I. Pelton, MD (Co-Chair) Professor of Pediatrics Boston University School of Medicine Director, Pediatric Infectious Diseases Boston Medical Center Henry Shinefield, MD Co-Director Kaiser Permanente Vaccine Study Oakland, Calif.

3 Accreditation Boston University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Boston University School of Medicine designates this educational activity for a maximum of 1 category 1 credit toward the AMA Physician s Recognition Award. Each physician should claim only those credits that he/she actually spent on the activity. In order to successfully complete this activity, you are required to read the entire monograph and complete and submit the completed test answer sheet by October 31, CME credit will be awarded provided a score of 70% or better is achieved. A certificate of credit will be sent within six weeks of receipt of the test answers to those who successfully complete the examination. Term of Approval: November 2003-October Estimated time to complete this educational activity: 1 hour. Target Audience This activity has been developed for pediatricians, primary care physicians, and other health care professionals involved in the treatment of infectious diseases in children. Educational Needs Since the introduction of the heptavalent pneumococcal conjugate vaccine (PCV-7) in the United States in 2000, the number of cases of invasive pneumococcal disease has declined significantly. This decline has been documented by three large studies, including the Active Bacterial Core Surveillance program, part of the U.S. Centers for Disease Control and Prevention s Emerging Infections Program Network. These studies show that vaccination confers protection on vaccinated children, but they also support the theory of herd immunity in that the rate of pneumococcal infections has dropped in whole study populations, not just among vaccinated groups. Along with the good news about declining rates of pneumococcal disease, the epidemiologic evidence that has accumulated prior to and since the introduction of the vaccine presents clinicians with practical challenges in managing those pediatric patients who may have pneumococcal disease despite vaccination. This supplement focuses on treatment issues within the context of widespread use of the PCV-7. Learning Objectives By reading and studying the articles in this supplement, participants should be able to discuss: The rational use of antibiotics for patients with otitis media, given the changing trends and emerging geographic variations in resistance patterns of pneumococci and other causative organisms; Evidence-based management of the febrile child who may have invasive pneumococcal disease; The most recent data on the effect of the PCV-7 on pneumonia and otitis media from the large database accumulated by the Northern California Kaiser Permanente investigators; Which children are still at increased risk for pneumococcal disease. Faculty Disclosure Statement It is the policy of Boston University School of Medicine, Department of Continuing Medical Education, that faculty disclose to program participants any real or apparent conflict of interest. In addition, faculty are asked to disclose any discussion pertaining to the unapproved use of products. Dr. Barnett has received grant/research support from GlaxoSmithKline and is on the speaker s bureaus at Pfizer Inc. and Wyeth. Dr. Culpepper is a consultant to Abbott Laboratories, Eli Lilly and Company, Forest Laboratories, Janssen Pharmaceutica, Pfizer, and Wyeth. Dr. Klein has received grant/research support from Wyeth and is a consultant to Abbott, Bristol-Myers Squibb, Pfizer, and Wyeth. Dr. Pelton has received grant/research support from Apovia, Aventis, GlaxoSmithKline, and Wyeth. He is also a consultant to Wyeth and serves on the speaker s bureaus of Wyeth and GlaxoSmithKline. Dr. Shinefield has received grant/research support from and is on the speaker s bureaus of Aventis, Chiron, GlaxoSmithKline, Merck, and Wyeth. He is also a consultant to Wyeth. The faculty members do not discuss unlabeled/investigational uses of a commercial product.

4 Management of Acute Otitis Media in the Era of Drug Resistance Elizabeth Barnett, MD cute otitis media (AOM) is defined as signs and symptoms of acute illness (fever; A otalgia, or pulling on the ear; otorrhea, or recent onset of irritability; anorexia; vomiting; or diarrhea) plus the presence of middle ear effusion (MEE). Documentation of MEE is made by examination of the tympanic membrane with a pneumatic otoscope. The diagnosis of AOM is challenging because, with the exception of otorrhea, the associated signs and symptoms are not specific to middle ear infection and because examination of the middle ear is not always straightforward. Judicious use of antibiotics for AOM depends on accurate diagnosis, understanding of treatment options, awareness of local patterns of antibiotic susceptibility, and knowledge of the natural history of the disease. Recommendations for Definitive Diagnosis MEE is usually diagnosed by the use of pneumatic otoscopy. The examiner employs the insufflator bulb to assess the mobility of the tympanic membrane. Because of availability, ease of use, and balance of sensitivity and specificity when compared with other methods, pneumatic otoscopy is the best option for most clinicians for diagnosing MEE. 1 Other techniques available to identify the presence of MEE include tympanometry and acoustic reflectometry, which allow objective assessment for the presence of middle ear fluid. Although the equipment for these techniques may not be available in all clinical settings and practices, it is important for clinicians to be aware of how and under what circumstances they may be most useful. Tympanometry measures pressure changes within the ear canal by obtaining a seal between the instrument and the ear canal; a maneuver that may be difficult to perform on very young infants or those who are not cooperative. Acoustic reflectometry, based on reflected sound waves, does not require a seal within the ear canal but may be difficult to use in small infants because of the shape of their ear canals. 2 Judicious use of antibiotics for [acute otitis media] depends on accurate diagnosis, understanding of treatment options, awareness of local patterns of antibiotic susceptibility, and knowledge of the natural history of the disease. Middle ear fluid clears gradually following resolution of AOM but may persist for as long as 4 weeks in up to 40% of children. 1 Identification of additional episodes of AOM during this time is challenging and may require special attention to signs of inflammation of the tympanic membrane when pneumatic otoscopy is performed. Antibiotic Resistance in AOM: An Overview AOM is most commonly caused by Streptococcus pneumoniae, nontypeable Haemophilus influenzae, and Moraxella catarrhalis. Middle ear infection caused by S. pneumoniae is the least likely to resolve without antibacterial therapy. 3 H. influenzae and M. catarrhalis may be identified in the middle ear fluid of children who have failed initial therapy. 4 Between 1994 and 2000 the proportion of strains of S. pneumoniae that are resistant to the antibiotics commonly used for the treatment of AOM has increased. In the United States, between and , the proportion of isolates from children with reduced susceptibility to penicillin increased from 31% to 42.5%. 5,6 The proportion of strains resistant to macrolide antibiotics increased from 10.6% in to 20.4% in ,6 Rates of resistance of pneumococci to penicillin vary geographically within the United States. These rates are monitored by the Active Bacterial Core Surveillance (ABCs) Program at selected sites throughout the United States. 7 In New York State, the proportion of resistant strains was lowest, at 14.7%, in The site with the highest reported proportion of resistant strains was Tennessee, with 35.1%. Rates of resistance of H. influenzae and M. catarrhalis have remained more stable, with about 50% of H. influenzae isolates and almost 100% of M. catarrhalis strains exhibiting resistance to penicillins. 4 It is therefore helpful and important for clinicians to have a good understanding of, and to follow the resistance trends of pneumococci in their practice locations. Mechanisms of resistance have an effect on selection of therapy. Resistance in pneumococci arises from alterations in the penicillin-binding protein on the 4 Management of Pediatric Pneumococcal Diseases

5 Table. Acute Otitis Media (AOM) Treatment Recommendations* for Children Who Either Have Not or Have Received Antimicrobial Therapy During the Prior Month Antibiotics in Clinically Defined Clinically Defined Treatment Prior Month Day 0 Treatment Failure on Day 3 Failure on Days 10 to 28 No High-dose amoxicillin, High-dose amoxicillin/clavulanate, Same as day 3 usual-dose amoxicillin cefuroxime axetil, IM ceftriaxone Yes High-dose amoxicillin, IM ceftriaxone, clindamycin, High-dose amoxicillin/clavulanate, high-dose amoxicillin/ or tympanocentesis cefuroxime axetil, IM ceftriaxone, clavulanate, cefuroxime axetil or tympanocentesis * Recommended drugs are those for which strong evidence for efficacy currently exists. Other drugs may prove efficacious. High-dose amoxicillin, 80 to 90 mg/kg/day. High-dose amoxicillin/clavulanate, 80 to 90 mg/kg/day of the amoxicillin component, with 6.4 mg/kg/day of clavulanate (requires newer formulations, or combination with amoxicillin). Documented efficacy in AOM treatment failures if three daily doses are used. Clindamycin is not effective against Haemophilus influenzae or Moraxella catarrhalis. Adapted from Dowell SF et al. Pediatr Infect Dis J. 1999;18:1-9. cell wall of the organism. A minor alteration in these penicillin-binding proteins results in slightly more resistant bacteria, and major alterations can result in highly resistant organisms. Infections caused by strains of pneumococci with minor alterations of penicillin-binding proteins can still be treated with penicillin, but require higher doses. In contrast, resistance in both H. influenzae and M. catarrhalis occurs through production of the enzyme beta-lactamase, which can deactivate antibiotics in the penicillin family. Infections due to organisms that produce beta-lactamase cannot be treated with increased doses of antibiotics in the penicillin family. Either a beta-lactamase stabilizer must be added (such as in the amoxicillin/clavulanic acid combination) or a drug stable against beta-lactamase must be used. Treatment for AOM Amoxicillin remains the best initial therapy for the treatment of AOM. This recommendation is discussed in a report prepared by the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group. 8 Amoxicillin has a long track record, has good efficacy against the major pathogens that cause AOM, is associated with few adverse events, has a good safety profile, and has a good costbenefit ratio. Recall that pneumococci exhibit a range of resistance patterns. Thus, infections caused by pneumococcal strains that are not highly resistant to an antibiotic can be treated by increasing the dose of the antimicrobial agent. The panel recommended use of a higher dose of amoxicillin in areas where resistance rates are high or in situations in which an individual child may be more likely to be infected with a resistant Infections caused by strains of pneumococci with minor alterations of penicillin-binding proteins can still be treated with penicillin, but require higher doses. organism. An acceptable alternative treatment would be the use of amoxicillin with clavulanic acid, although this combination may be associated with an increased incidence of diarrhea. The panel considered whether empiric treatment should vary by geographic regions. The recommendation was that, in general, it should not, unless good data are available that suggest that the resistance rates in a specific area are very high. Recommendations for children who fail initial antibiotic therapy are summarized in the Table. 8 A child who is treated with an antibiotic and who remains ill if symptoms of ear pain and/or fever do not resolve or if the clinical condition worsens has experienced antibiotic failure. In cases of amoxicillin treatment failure in which children have had no antibiotic exposure in the prior month, the recommendation is either to increase the dose of amoxicillin or to switch to amoxicillin/clavulanate (or, alternatively, cefuroxime axetil or intramuscular ceftriaxone). The rationale behind this recommendation is that if amoxicillin is used initially, failure may occur because the infection may be caused by a beta-lactamase producing strain of H. influenzae or M. catarrhalis. For patients who fail initial therapy and who have been exposed to antibiotics within the previous month, intramuscular ceftriaxone, clindamycin, or tympanocentesis (for fluid culture and sensitivity to identify the organism and its susceptibility to the available agents) are recommended. Management of the child with AOM also should include appropriate treatment for pain or discomfort. Acetaminophen, ibuprofen, or another analgesic medication are reasonable choices. Management of Pediatric Pneumococcal Diseases 5

6 New Guidelines Under Development Evidence-based guidelines on the diagnosis and management of AOM by primary care clinicians are being developed by the American Academy of Pediatrics and the American Academy of Family Physicians. Topics to be included in this document include the definition of AOM, the assessment and treatment of pain associated with AOM, and guidelines for initial management by observation only, without the use of antibiotics. The major criteria to be addressed when considering the option of watchful waiting include illness severity, age of the child (usually 2 years of age or older), diagnostic certainty, and assurance of follow-up. The option to observe is available in cases of borderline results on examination of the ear in an older child who appears well, as long as follow-up is certain. The panel continues to recommend amoxicillin as first-line therapy for AOM when the decision to treat with antibiotics is made. Duration of therapy is addressed by affirming that the standard 10-day course of antibiotics remains appropriate for most children. A shortened course (5 to 7 days) of oral antibiotics may be appropriate for older children with mild to moderate disease. Good communication between the clinician and the parents is essential in the management of AOM, especially for children who have multiple episodes. It is helpful for parents to understand the risk factors for AOM. Some of these are unalterable, such as sibling history of ear disease or the child s genetic makeup or ear canal anatomy. Parents may, however, be able to make changes that could alter their child s or subsequent children s experience with AOM. These include longer duration of breast-feeding, enrollment in family-based day care or home care rather than a large day care center, reducing exposure to tobacco smoke, and obtaining all vaccines, including pneumococcal conjugate vaccine and influenza vaccines, that could prevent infections associated with middle ear infections. Good communication between the clinician and the parents is essential in the management of [acute otitis media], especially for children who have multiple episodes. Conclusion The management of AOM in the era of antibiotic resistance includes attention to accuracy of diagnosis and judicious use of antibiotics that is based on a knowledge of local resistance patterns and an individual child s risk for infection due to resistant organisms. In addition, vaccines should be administered to prevent infections associated with middle ear disease. Finally, parents can be empowered to consider lifestyle changes that could alter their children s experience with ear disease. References 1. Marcy M, Takata G, Shekelle P, et al. Management of acute otitis media. Evidence Report/Technology Assessment No. 15 (Prepared by the Southern California Evidence-Based Practice Center under Contract No ). Rockville, Md.; Agency for Healthcare Research and Quality; May AHRQ Publication No 01-E010. Available at: Accessed September 26, Carlson LH, Carlson RD. Clinical management: Diagnosis. In: Rosenfeld RM, Bluestone CD, eds. Evidence-Based Otitis Media. Hamilton, Ontario: BC Decker; 2003, pp Klein JO. Microbiologic efficacy of antibacterial drugs for acute otitis media. Pediatr Infect Dis J. 1993;12: Doern GV, Jones RN, Pfaller MA, Kugler K. Haemophilus influenzae and Moraxella catarrhalis from patients with communityacquired respiratory tract infections: Antibacterial susceptibility patterns from the SENTRY antibacterial surveillance program (United States and Canada, 1997). Antimicrob Agents Chemother. 1999; 43: Doern GV, Brueggemann AB, Holley HP, Rauch A. Antimicrobial resistance of Streptococcus pneumoniae recovered from outpatients in the US during the winter months of 1994 to 1995: Results of a 30- center national surveillance study. Antimicrob Agents Chemother. 1996;40: Doern GV, Heilman KP, Huynh HK, Rhomberg PR, Coffman SL, Brueggemann AB. Antimicrobial resistance among clinical isolates of Streptococcus pneumoniae in the US during , including a comparison of resistance rates since Antimicrob Agents Chemother. 2001;45: Whitney CG, Farley MM, Hadler J, et al. Increasing prevalence of multidrugresistant Streptococcus pneumoniae in the United States. N Engl J Med. 2000; 343: Dowell SF, Butler BC, Giebink GS, et al. Acute otitis media: Management and surveillance in an era of pneumococcal resistance A report from the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group. Pediatr Infect Dis J. 1999;18: Management of Pediatric Pneumococcal Diseases

7 The Febrile Child and Invasive Pneumococcal Disease Larry Culpepper, MD, MPH ccording to a recent report, 1 the rate of invasive disease A caused by Streptococcus pneumoniae has dropped significantly since the introduction of the heptavalent pneumococcal conjugate vaccine (PCV-7) in Population-based data from the Active Bacterial Core Surveillance of the U.S. Centers for Disease Control and Prevention show that the largest decline in invasive disease occurred in children less than 2 years of age in whom the rate of disease caused by pneumococcal serotypes contained in the vaccine dropped by 78% (P < 0.001) between 1998 and In this same age group and for the same time period, the rate of disease caused by vaccine serotypes dropped by 50% (P < 0.001). In addition, the rate of invasive pneumococcal disease (IPD) also has dropped in adults and nonvaccinated older siblings of vaccinated children, presumably as a result of the phenomenon of herd immunity. Prior to the introduction of the PCV-7, serotypes contained in the vaccine were responsible for 90% of cases of IPD. The PCV-7 has been shown to be 97.4% effective in reducing invasive disease due to the serotypes included in the vaccine, 89.1% effective when all serotypes (including nonvaccine types) are considered, and 73% effective in reducing radiologically confirmed pneumonia with consolidation. 2 This most welcome news is accompanied by a new challenge for clinicians. Some children, even the occasional child who has been fully immunized with the PCV-7, will still develop IPD. Among these, some will have a compromised immune system, either already recognized or previously not diagnosed. In this era of PCV-7, what is the appropriate evaluation and management of a child who presents with a febrile illness? Perhaps the clearest way to approach this question is to consider patients according to their age group. Infants Less Than 1 Month of Age Among infants less than 1 month of age, herd immunity may reduce the incidence of IPD. However, no new recommendations for evaluation and treatment have been proposed for children in this age group who present with a febrile illness. Most febrile infants less Some children, even the occasional child who has been fully immunized with the PCV-7, will still develop [invasive pneumococcal disease]. than 1 month of age should be admitted to the hospital for a complete evaluation, including complete blood count, urine culture, and lumbar puncture and culture of cerebrospinal fluid (CSF). Infants 1 to 3 Months of Age As with infants less than 1 month of age, the PCV-7 also has no direct effect on the management of the infant between 1 and 3 months of age who has a febrile illness. (As with infants less than 1 month of age, widespread immunization programs ultimately may lead to herd immunity and decreased carriage by parent and older siblings, thereby reducing the incidence of pneumococcal disease in this age group.) In infants between 1 and 3 months of age, consideration is given to whether individuals are at low or high risk for IPD. In infants who appear to be nontoxic, this assessment can be made on the basis of presence of fever, white blood cell (WBC) count, and urinalysis. An infant who has a WBC count of 5,000 to 15,000 cells/ L with fewer than 1,500 bands is at low risk. A normal urinalysis and, if an infant has diarrhea, a stool examination that shows fewer than five WBCs per high-power field confirms that low risk. With such reassurance, neither blood culture nor CSF culture is required. Baraff and colleagues 3 reported that infants who meet these criteria have a risk for serious bacterial infection of 1.4%. According to these same data, infants who are nontoxic but in whom these criteria have not been applied have a risk for invasive disease of 8.6%. The febrile infant who appears toxic and/or who has a WBC count of 15,000 cells/ L or greater has a risk for serious bacterial infection of 17.6%. Admission to the hospital for parenteral antibiotic therapy is indicated, and blood, urine, and CSF cultures should be performed. Infants and Children 3 to 36 Months of Age In the era of the PCV-7, a viral infection is the most frequent cause of illness in patients with a temperature less than 39 C who do not appear to be toxic; under these circumstances, no diagnostic testing is required. If the fever persists, if the temperature increases to 39 C or higher, or if the child s condition worsens, further evaluation is required. The diagnostic workup in such children should include WBC count, blood culture, urine culture, and chest x-ray. If the chest x-ray is positive or WBC count is 15,000 cells/ L or greater, immediate Management of Pediatric Pneumococcal Diseases 7

8 antibiotic administration is indicated. If the child is nontoxic, the chest x-ray is normal, and the WBC count is less than 15,000 cells/ L, no antibiotic therapy is needed, pending the urine and blood culture results. A child who appears toxic despite a WBC count less than 15,000 cells/ L and a normal chest x- ray should be admitted to the hospital for immediate antibiotic therapy, even if blood and urine culture results are still pending. Management of Children With Positive Blood Cultures Children whose blood culture results are positive for S. pneumoniae must be reevaluated. The guidelines for patients with pneumococcal bacteremia proposed by Bachur and Harper 4 provide a logical and prudent approach reflecting our current understanding of the risks and benefits involved (Figure). If the child appears toxic, admission to the hospital for a repeat blood culture, CSF culture, and intravenous antibiotics is indicated whether or not the child has previously been started on outpatient antibiotics. If the child does not appear toxic, the degree of fever determines the course of action. Those with a temperature of less than 38 C who have been started on antibiotics previously should have them continued for a complete 7- to 10-day course. Those with a temperature of less than 38 C who did not receive a course of antibiotics previously should have a repeat blood culture at the time of reevaluation and should begin a 7- to 10-day course of antibiotics. For nontoxic children with bacteremia and a temperature of 38 C or higher (a lower cutoff temperature than for children without bacteremia), a repeat blood culture should be done whether or not they have received antibiotics previously, and, depending on age, a CSF culture is strongly recommended. A lumbar puncture in these circumstances is indicated in all children less than 12 months of age and in most children from 12 to 24 months of age. In older children, examination for signs of meningismus should determine the need for a lumbar puncture. The ability of the family to recognize and obtain follow-up if the child s condition worsens or does not improve following treatment should also be considered in determining the need for a lumbar puncture. In addition, these children should receive ceftriaxone on an outpatient basis or be admitted to the hospital for intravenous antibiotic treatment. The choice of outpatient or inpatient antimicrobial treatment should be based on the clinician s assessment of the reliability of the family to closely monitor the child, recognize any important changes in the child s condition, and follow instructions about obtaining further evaluation and treatment. IPD in Vaccinated Children The issue of how to manage a child who has received a partial or full series of vaccination with the PCV-7 has been addressed thoroughly by Pelton and Klein. 5 Children who have not received the full series should complete the course Continued on top of page 13 Figure. Guidelines for the Reevaluation of Outpatients With Proven Pneumococcal Bacteremia Positive blood culture for Streptococcus pneumoniae Clinical evaluation Well appearing Ill appearing BC and LP Admit for IV antibodies Fever (T 38ºC) Yes Received antibiotic at the first visit No No Yes Received antibiotic at the first visit BC, strongly consider LP, and either ceftriaxone as outpatient or admit for IV antibiotic Age No Yes <12 mo >12mo BC + oral antibiotic for 7-10 days Oral antibiotic for 7-10 days BC, LP, and either ceftriaxone as outpatient or admit for IV antibiotic BC, strongly consider LP, and either ceftriaxone as outpatient or admit for IV antibiotic BC = blood culture; LP = lumbar puncture; IV = intravenous; T = temperature Adapted with permission from Bachur R, Harper MB. Pediatrics. 2000;105: Management of Pediatric Pneumococcal Diseases

9 Pneumonia and Otitis Media: The Northern California Data in Perspective Henry Shinefield, MD treptococcus pneumoniae has been the cause of significant S morbidity and mortality among children, causing 3,000 cases of meningitis, 50,000 cases of bacteremia, 500,000 cases of pneumonia, and 7 million cases of otitis media annually. 1 Among the bacterial causes of pneumonia, several studies have shown that S. pneumoniae is the most common etiologic agent. 2-4 This organism is the most common cause of pediatric otitis media. 5 When the heptavalent pneumococcal conjugate vaccine (PCV-7) was introduced in 2000, the hope was that its use would result in a reduction in the incidence of invasive pneumococcal disease, pneumonia, and otitis media. In Northern California, the Kaiser Permanente Vaccine Study Group was involved in the clinical trials of the PCV-7 prior to its introduction in We have continued to monitor the incidence of pneumococcal diseases since the PCV-7 was licensed. In this article, our data on the incidence of pneumococcal pneumonia and otitis media will be reviewed. Pneumococcal Pneumonia Outcomes In Northern California, we conducted a randomized, double-blind, controlled trial 6 comparing the PCV-7 with a meningococcal conjugate vaccine (MCV) in 37,868 infants. These children were immunized at 2, 4, and 6 months of age, with a booster dose given at 12 to 15 months of age. The PCV-7 was given concomitantly with routine childhood vaccines. The study was unblinded in April To study pneumonia, we reviewed both inpatient and outpatient databases for all diagnoses in the clinical trial. Pneumonia cases were grouped into four categories. The first of these was clinical diagnosis by either a physician or a nurse practitioner. The second category comprised clinical cases in which the clinician ordered a chest x-ray. This subgroup of cases was divided into two groups forming the third and fourth categories: perihilar pneumonia and pneumonia...[t]he hazard ratios for white children differed from those of Asian, African-American, Hispanic, and other minority children... with infiltrates outside the perihilar area, or with consolidation and effusion (ie, positive x-rays). The x-rays were read by clinical radiologists within the Kaiser Permanente health maintenance organization network. There was no attempt to establish the etiology of the disease. Clinical pneumonia was diagnosed in 7.3% of children (n = 2,764) less than 24 months of age and in 2.5% of children 24 months of age or older. Clinical cases of pneumonia with positive film were observed in 1.5% of children less than 24 months of age (n = 569) and in 0.4% of children 24 months of age or more (n = 168). Intent-to-Treat Analysis According to the intent-to-treat analysis for the first episode of pneumonia in children up to 3.5 years of age, the overall efficacy outcome of the PCV-7 vaccine for all clinical cases of pneumonia was 6% (P = 0.13). The efficacy of the vaccine among the second group that is, those children in whom an x-ray was obtained was significant, 8.9% (P < 0.03). With clinical pneumonia and perihilar findings only, efficacy was not significant, but with clinical pneumonia and a positive x-ray, the efficacy rate was 17.7% (P < 0.01). Breaking down the intent-to-treat analysis according to age groups, efficacy rates are low and not statistically significant. However, in children less than 12 months of age who had clinical pneumonia and a positive x-ray, vaccine efficacy was statistically significant, 24.3% (P < 0.02). Among all children less than 24 months of age, the efficacy was 22.7% (P < 0.02). In older children 24 months of age or greater with clinical pneumonia and a positive film, the vaccine had an efficacy of 6.1% (P = 0.70). Thus, for pneumonia, the PCV-7 demonstrated efficacy only in children younger than 24 months of age. Racial and Ethnic Differences When the data were analyzed for race- and ethnicity-specific first cases of pneumonia in the children in our study, the hazard ratios for white children differed from those of Asian, African-American, Hispanic, and other minority children in the categories of clinical cases of pneumonia, clinical pneumonia and x-ray obtained, and clinical pneumonia with a positive film. For these three categories, the hazard ratios for the minority children ranged between 1.3 and 1.9. Management of Pediatric Pneumococcal Diseases 9

10 Summary of Observations on Pneumonia The PCV-7 was shown to be effective in reducing the risk of pneumonia in children. The effect was most marked in children less than 2 years of age with positive x-rays. Asian, African- American, and Hispanic children seemed to be at increased risk for developing pneumonia, and this elevated risk was highest in Asians in our study population. The cases of pneumonia seen in our study were not identified specifically as pneumococcal pneumonia, or even as a bacterial pneumonia. This should broaden the perspective of clinical pneumonia in children. Many cases of pneumonia in the past that had been presumed to be of viral etiology are likely to have been, in fact, pneumococcal pneumonia. The incidence of pneumonia, therefore, should decline with the use of the PCV-7. Otitis Media The follow-up data on the effect of the PCV-7 on otitis media were published recently. 7 The main outcome measures for this study were visits for otitis media, frequency of visits, and tympanostomy tube procedures. Recall that these data were collected as part of a double-blind study in 37,868 children comparing PCV-7 with MCV. The children received a primary series of the PCV-7 vaccine at 2, 4, and 6 months of age and a booster dose at 12 to 15 months of age. The study period was 1995 to The data also were analyzed according to variables of age, season, and year. In terms of age, the reduction in visits in children less than 12 months of age was 8.2% (95% confidence interval [CI], 5.1%-11.1%). Between 12 and 24 months of age, the reduction in visits was 8.7% (CI, 5.8%-11.6%). In children more than 24 months of age, there was a falloff of 3.7% (CI, 1.8%-8.8%). Thus, efficacy was established for the first 2 years of life. The vaccine also proved to be as effective in the noninfluenza season as in the influenza season. No significant differences were found from year to year during the 3 years of the study. We found that by dose 3 plus 14 days, the children who received the PCV-7 had 7.8% fewer visits for otitis media than did the controls (CI, 5.4%- 10.1%). Between dose 3 and the booster dose, the difference was 7.9%, and between the booster dose and the end of the study, the difference was 7.5%. In addition, antibiotic prescriptions were reduced by 5.7% (CI, 4.2%- 7.2%). From the standpoint of managing pneumonia in the era of PCV-7, the possible causative organisms now must carefully be considered in a broader context. By 3.5 years of age, the percentage of children in the control group who had ever had 3, 5, or 10 visits for otitis media within 6 months was 28%, 12%, and 1.4%, respectively. Of these three levels of frequency of otitis media visits, the risk for tube placement by 3.5 years of age rose to 14%, 26%, and 66%, respectively. Thus, as visits for otitis media increased, tympanostomy tube placements increased markedly. Among the children in the PCV-7 group, the placement of tympanostomy tubes was reduced by 24% (CI, 12%-35%). Summary of Observations Regarding Otitis Media These data demonstrate that the vaccine prevented 43 visits by 3.5 years of age for every 100 children vaccinated as recommended. On a national level, this would amount to 1.7 million preventable visits for otitis media in a U.S. birth cohort of 4 million children. The qualitative burden of otitis media is apparent, including the suffering of infected children, the parental stress and lost time from work and other activities, the hearing loss and language impairment that may be associated with persistent and recurrent infections, the cost of medical care, and the emergence of drugresistant pneumococci from the selective pressure of the antibiotic medications. The magnitude of burden is difficult to quantify, but the high incidence of otitis media suggests that a 5% to 10% reduction is noteworthy, and it is important for the benefit of preventing invasive pneumococcal disease. We can conclude that administration of the PCV-7 to infants and preschool children affords a moderate amount of protection against ear infections and a greater amount of protection against frequent otitis. After the three-dose primary series, children given the vaccine had fewer visits for otitis media than control children in every subgroup and time period examined by sex, race, clinic, season, calendar year, and age to 3.5 years. Conclusion From the standpoint of managing pneumonia in the era of PCV-7, the possible causative organisms now must carefully be considered in a broader context. When given to children older than 24 months of age, the vaccine does not appear to be effective in reducing the incidence of pneumonia. In dealing with children who have been vaccinated before 24 months of age, clinicians are likely to see a greatly reduced incidence of infections caused by S. pneumoniae. In addition, clinicians must consider that pneumonia in vaccinated children may be caused by vaccine or nonvaccine serotypes of S. pneumoniae, or by Continued on bottom of page Management of Pediatric Pneumococcal Diseases

11 Vaccine Efficacy: Where Are the Gaps? Stephen I. Pelton, MD ince the introduction of the heptavalent pneumococcal S conjugate vaccine (PCV-7) in 2000, three postlicensure studies have examined the efficacy of the vaccine in preventing invasive pneumococcal disease (IPD) in children or in both children and adults. IPD is defined as isolation of Streptococcus pneumoniae from a normally sterile body fluid most commonly, blood or cerebrospinal fluid or, occasionally, pleural, abscess, or joint fluid. Evidence from those three large studies indicates that the rate of IPD has substantially decreased, but the evidence also shows that gaps still exist in protection for certain groups. Evidence That the PCV-7 Works Recently, Whitney and colleagues, 1 investigators with the Active Bacterial Core Surveillance (ABCs) program, which is part of the U.S. Centers for Disease Control and Prevention s (CDC) Emerging Infection Program Network, reported a substantial decline in IPD beginning in 2000 and falling further in 2001, presumably as a result of increasingly widespread use of the PCV-7. For children less than 5 years of age, the CDC investigators reported a 59% decline, from an average of 96 cases per 100,000 children to 39.7 cases per 100,000 children. The ABCs program tracks data on adults as well as children, and the investigators report that IPD rates also have declined in adults since the introduction of the PCV-7 for children. Compared with the baseline years of 1988 and 1989, IPD rates in adults between 20 and 39 years of age declined by 32% by In adults 65 years of age or older, the IPD rate dropped by 18% for that same time period. These data strongly suggest a herd effect in adults as a result of immunization of children with PCV-7. The second large study, from Black and colleagues, 2 looked at IPD in the Northern California Kaiser Permanente health maintenance organization (HMO) system subsequent to the licensure of the vaccine. These investigators also reported significant declines in IPD rates in the pediatric population. For The ABCs program... investigators report that [invasive pneumococcal disease] rates also have declined in adults since the introduction of the PCV-7 for children. children less than 5 years of age, the rate of IPD prior to 2000 was between 40 and 60 cases per 100,000 children. The current rate is fewer than 10 cases per 100,000 children, adding further evidence for an efficacy rate of PCV-7 as high as 80% to 85%. The greater decline in IPD in this population compared with what was found in the CDC study may be explained by the fact that the Kaiser data are from a group of children who receive their health care from an HMO, and the rate of vaccination is likely higher than it is for the population included in the CDC s ABCs program (the general population in the states of California, Connecticut, Georgia, Maryland, Minnesota, New York, and Oregon). In addition, patients in an HMO population are, presumably, more likely to be from families who receive health insurance through employers. Thus, the distribution of the HMO-population children is likely to differ from that in the ABCs study. The Northern California Kaiser Permanente Vaccine Study Center Group has provided details about the effect of the PCV-7 on invasive disease due to both vaccine-serotype and nonvaccine-serotype pneumococci. The rate of IPD due to vaccine serotypes has declined dramatically. In contrast, IPD due to nonvaccine serotypes continues to occur at the rate observed prior to introduction of the PCV-7 but does not appear to have increased significantly. As with the CDC data, reductions in IPD among adults has been documented. Significant declines have been reported in adults between 20 and 39 years of age and among individuals 60 years of age or older. The overall decline in IPD for individuals 5 years of age or older was 18%. In Massachusetts, our group 3 has conducted a statewide surveillance for IPD in all children less than 18 years of age. When we compared the rate of disease in children less than 5 years of age with the rate from a similar surveillance study reported a decade ago, 4 we noted a 70% decline in IPD in that group of children. Defining the Populations Still at Higher Risk Data from the ABCs surveillance program of the CDC demonstrate a decline in IPD disease in African- American children less than 2 years of age. The rate of IPD in African- American children has declined by 73% since the introduction of the PCV-7 in 2000, compared with a 62% decline in white children less than 2 years of age. Management of Pediatric Pneumococcal Diseases 11

12 However, these figures must be viewed in perspective. The data from the Massachusetts Surveillance Study show that African-American children (and, it seems Hispanic children in Massachusetts, as well) have a higher relative risk for IPD than do white children. This observation is supported by data from the CDC that also demonstrate that the relative risk for African-American children compared with white children is approximately 2. Further study is required to determine whether this difference can be attributed to sociodemographic or economic disadvantages, behaviors such as smoking in the household, or genetic predisposition. The Massachusetts Surveillance Study also shows that children in the first year of life continue to be at greatest risk for IPD. According to our study, about 30% of cases still occur in infants from birth to 12 months of age. According to data from the Massachusetts study, a substantial number of children with IPD also have comorbid conditions. Some of these conditions for example, nephrotic syndrome, malignancy, chemotherapy, or sickle-cell disease are commonly recognized to increase the risk for IPD. However, preliminary evidence suggests that other conditions also may be associated with an increased risk for IPD. These latter include chronic lung disease, asthma, gastroesophageal reflux, heart disease, heart murmurs, diabetes, and seizure disorders. Such an association has not yet been firmly established, but if further study confirms that children with these conditions truly are at increased risk for IPD, they may be candidates for PCV-7 immunization even if they are older than 2 years of age. Vaccine Failures Some children develop IPD despite immunization. Those who have completed a primary series of immunization and have IPD that is due to one of the seven pneumococcal serotypes contained in the vaccine are considered true vaccine failures. (Completion of the primary series is defined as three doses of the PCV-7 if the child was first immunized before 12 months of age, two doses if he or she was first immunized between 12 and 23 months of age, and one dose if he or she was first immunized at 24 months of age or older.) In 18 months of surveillance in Massachusetts, we have seen more than 100 cases of IPD in children. However, we have identified only five meeting the definition of true vaccine failure. Of these five, three had IPD due to serotype 19F, a serotype against which the PCV-7 is likely to be less effective than it is against the other six serotypes. Current evidence demonstrates a dramatic decline in [invasive pneumococcal disease] in both immunized children and adults (herd effect). In addition, we have seen 11 cases of disease due to the vaccine-related serotypes in children who were considered to be completely immunized. Most of the cases in these children were due to serotype 19A, against which the PCV-7 probably has lower efficacy. An important observation from these cases is that very few of the children who either were true vaccine failures or acquired IPD due to a vaccinerelated serotype became ill at a point in time when they would have been expected to have received a booster dose. Thus, it does not appear that the shortage of vaccine that occurred in January 2002 and the deferral of the booster dose is a likely explanation for the cases of IPD that we have seen in fully immunized children. Serotype Replacement The evidence to date demonstrates that the overall benefit of the PCV-7 in preventing IPD is clear. The accumulated data from the CDC, the Kaiser Permanente group, and the Massachusetts Surveillance Study show a decline in IPD approaching 70%. Within that context, is there a small increase in disease due to nonvaccine serotypes? It is too early to be able to answer that question decisively. However, all three of these studies have demonstrated a small increase in disease due to nonvaccine serotypes, but to date this increase has not reached the level of statistical significance. In addition, in Massachusetts, investigators at Boston City Hospital 5 noted a trend toward increasing disease due to nonvaccine serotypes between 1981 and 1998, before the vaccine was introduced. Thus, it is not clear whether the small increase in nonvaccine serotypes that has been observed is a continuing trend that began before the vaccine was introduced or, indeed, has been accelerated by the introduction of the vaccine. Conclusion Current evidence demonstrates a dramatic decline in IPD in both immunized children and adults (herd effect). Vaccine failure, as defined above, is an uncommon event most often associated with serogroup 19. The rate of disease due to nonvaccine serotypes has increased, but the increase to date is not clinically or statistically significant. Among the nonvaccine serotypes that are identified most frequently are types 7F, 3, 1, and 5. A nine-valent vaccine, currently being studied, includes serotypes 1 and 5. Both serotypes 7F and 3 are recognized as invasive serotypes that are especially important in other parts of the world. If an 11-valent PCV currently under development should reach the market, both of those serotypes would be contained in that formulation. Data from Massachusetts demonstrate that serotypes 7F and 3 account for between 10% and 12% of IPD in children and therefore would be valuable for the U.S. population. Continued on bottom of page Management of Pediatric Pneumococcal Diseases

13 The Febrile Child Continued from page 8 of vaccination on schedule. Children more than 24 months of age who have completed the PCV-7 series may receive the 23-valent pneumococcal polysaccharide vaccine as a booster. Pelton and Klein 5 advise that the reason for the development of IPD in an immunized child should be determined. First, the causative pneumococcal isolate should be serotyped to determine whether it is one of the seven serotypes included in the vaccine, a vaccine-related serotype, or a nonvaccine serotype. Infection with a vaccine or vaccine-related serotype may indicate a previously undiagnosed immunodeficiency. Children with such IPD who have been adequately immunized should be evaluated for this possibility. Studies in such an evaluation include measurement of total immunoglobulins, immunoglobu- lin G subclasses, complement, determination of subsets of T and B cells, a smear to detect Howell-Jolly bodies, and a human immunodeficiency virus test. Conclusion The introduction of the PCV-7 has led to dramatic declines in the occurrence of IPD, even prior to its availability in sufficient quantities to fully immunize the U.S. population. Now that vaccine shortages have been eliminated, even greater reductions can be expected. In spite of such reductions, the evaluation and management of febrile infants and children will still need to be guided by the potential occurrence of IPD. At the present time, the evaluation and treatment of the febrile child should continue to be managed similarly, whether or not the child has been vaccinated. However, in addition, the clinician should determine the child s current vaccination status, need for additional References 1. Dagan R. Immunisation with a pneumovaccine doses, and, if pneumococcal disease is confirmed, need for assessment of immunocompetency. References 1. Whitney DG, Farley MM, Hadler J, et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med. 2003;348: Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J. 2000;19: Baraff LJ, Oslund S, Prather M. Effect of antibiotic therapy and etiologic microorganism on the risk of bacterial meningitis in children with occult bacteremia. Pediatrics. 1993;92: Bachur R, Harper MB. Reevaluation of outpatients with Streptococcus pneumoniae bacteremia. Pediatrics. 2000;105: Pelton SI, Klein JO. The future of pneumococcal conjugate vaccines for prevention of pneumococcal diseases in infants and children. Pediatrics. 2002; 110: Pneumonia and Otitis Media Continued from page 10 organisms other than pneumococci. Thus, appropriate management may depend on a panoply of factors. As more follow-up data become available, the approach to treatment of otitis media in the era of the PCV-7 will become clarified. However, at this time, it seems likely that the widespread use of the PCV-7 will contribute to fewer clinic and office visits, which, in turn, is likely to result in less administration of antibiotics. Reduced use of antibiotics can be expected to lead to less antibiotic resistance among pneumococci, so that the antibiotics that are used will be more effective. In time, it is also likely that fewer procedures will be performed for tympanostomy tube placement and that clinicians will see fewer children with frequent episodes of acute otitis media. coccal 7-valent conjugate vaccine. Int J Clin Pract. 2002;56: Juven T, Mertsola J, Waris M, et al. Etiology of community-acquired pneumonia in 254 hospitalized children. Pediatr Infect Dis J. 2000;19: Wubbel L, Muniz L, Ahmed A, et al. Etiology and treatment of communityacquired pneumonia in ambulatory children. Pediatr Infect Dis J. 1999; 18: Heiskanen-Kosma T, Korppi M, Jokinen C, et al. Etiology of childhood pneumonia: Serologic results of a prospective population-based study. Pediatr Infect Dis J. 1998;17: Bluestone CD, Klein JO. Otitis Media in Infants and Children. 2nd ed. Philadelphia; WB Saunders; Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J. 2000;19: Fireman B, Black SB, Shinefield HR, Lee J, Lewis E, Ray P. Impact of the pneumococcal conjugate vaccine on otitis media. Pediatr Infect Dis J. 2003;22: Vaccine Efficacy: Where Are the Gaps? Continued from page 12 References 1. Whitney CG, Farley MM, Hadler J, et al. Decline in invasive pneumococcal disease after the introduction of protein polysaccharide conjugate vaccine. N Engl J Med. 2003;348: Black SB, Shinefield HR, Hansen J, Elvin L, Laufer D, Malinoski F. Postlicensure evaluation of the effectiveness of seven valent pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2001;20: Hsu KK, Pelton SI, Heisey-Grove DM, Hashemi S, Klein JO, Members of the Massachusetts Department of Health. Risk factors for childhood invasive pneumococcal disease in the PCV-7 era. Pediatr Res. 2003;53:308A. Abstract Loughlin AM, Marchant CD, Lett SM. The changing epidemiology of invasive bacterial infections in Massachusetts children, 1984 through Am J Public Health. 1995;85: Babl FE, Pelton SI, Theodore S, Klein JO. Constancy of distribution of serogroups of invasive pneumococcal isolates among children: Experience during 4 decades. Clin Infect Dis. 2001;32: Management of Pediatric Pneumococcal Diseases 13