Pneumococcal infection is one of. Epidemiology of Pneumococcal Disease ...PRESENTATIONS... Based on a presentation by Chris Van Beneden, MD, MPH

Transcription

1 ...PRESENTATIONS... Epidemiology of Pneumococcal Disease Based on a presentation by Chris Van Beneden, MD, MPH Presentation Summary Pneumococcus is a leading cause of pneumonia and meningitis in the United States, causing about 3000 cases of meningitis and 100,000 to 135,000 hospitalizations for pneumonia every year. Approximately 61,000 cases of invasive pneumococcal disease were reported in the United States in The incidence of Streptococcus pneumoniae disease is highest before 2 years of age and after 65 years of age. Rates of disease among African American and American Indian children are twice those of the general US population. Resistance of the organism to antibiotics including newer cephalosporins, erythromycin, and the fluoroquinolones has increased in the past decade, and multidrug-resistant strains have been reported from several countries around the world. Important risk factors for pneumococcal disease are immunologic impairment and underlying illnesses. Pneumococcal infection is one of the world s leading causes of pneumonia and meningitis in young children and the elderly. The World Health Organization estimates that 2.6 million deaths among children younger than 5 years of age each year are attributable to acute respiratory infections; of these, more than 1 million are the result of Streptococcus pneumoniae pneumonia. 1 In developing countries, pneumococcal infection is the leading cause of death in children younger than 2 years of age. In the United States, the burden of pneumococcal disease is also relatively high. Recent estimates indicate that pneumococcal disease accounts for 3000 cases of meningitis annually, 61,000 cases of bacteremia, 100,000 to 135,000 cases of pneumonia requiring hospitalization, and about 7 million ear infections. 2-4 As a result, prevention of pneumococcal disease is a high priority. As 7- to 11-valent conjugate vaccines with more efficacy than polysaccharide vaccines become available, many serious pneumococcal infections will become preventable. Estimating the Burden of Invasive Disease, Pneumonia, and Otitis Media The Active Bacterial Core Surveillance (ABCs) system of the Centers for Disease Control and Prevention (CDC) provides one of the best ongoing estimates of the burden of pneumococcal disease in the United States. This audit captures invasive pneumococcal disease from 8 sites across the United States. 2 In 1998, the total surveillance area included approximately 17 million adults and children. VOL. 5, NO. 17, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S991

2 ... PRESENTATIONS... The age distribution of pneumococcal infection seen in these US survey conjugate vaccine has resulted in a more than 95% reduction in Hib disease data parallels that seen in the global in the United States. 5 With this data, with the highest rates of invasive pneumococcal infection observed at the opposite ends of the age spectrum (Figure 1). Although the caseload is highest in the very young, the mortality associated with pneumococcal infections is greatest among those 65 years of age and older. Projections based on the ABCs data indicate that more than 63,000 cases of invasive pneumococcal disease occurred in Approximately half of these cases occurred in individuals younger than 2 years of age or older than 65 years of age. Overall, slightly more than half of these cases (53%) manifested as bacteremic pneumonia, 39% as bacteremia without focus, and 4% as meningitis. Older patients were more likely to develop bacteremic pneumonia, whereas the youngest patients tended to present with bacteremia without focus. An increase in the use of the Haemophilus influenzae type b (Hib) progress, the pneumococcus is the leading cause of bacterial meningitis in the United States, accounting for about 47% of meningitis cases. 4 In 1998, the rate of pneumococcal meningitis in children younger than 1 year of age was 10 per 100,000 per year, about 10 times higher than that in adults. 2 The true incidence of pneumococcal pneumonia in children remains unknown, not only because of the difficulty of obtaining definitive cultures (eg, lung tap) but also because so many children are managed on an outpatient basis and given empiric antibiotic therapy. In prospective studies that attempted to identify the cause of community-acquired pneumonia in children, 17% to 28% of cases were the result of the pneumococcus 6,7 (Diagnosis was confirmed by blood culture, urine antigen, or serology testing.); again, these are probably underestimates. Otitis media, the predominant clinical manifestation of pneumococcal infection in children, causes more pediatric ambulatory care visits than any other condition. From 1993 Figure 1. Invasive Pneumococcal Disease Burden by Age through 1995, there were an average of 20 million annual pediatric visits for U.S. projections, 1998 middle ear infections in the United States, 8 and such infections are the leading indication for antibiotic use in children. At least one third of acute otitis media cases are caused by S. pneumoniae. In 1995, more than 500,000 tympanostomy tubes were placed in children younger than 15 years of age, and most of these procedures were due to otitis media. 9 Ten years ago, the overall socioeconomic cost of otitis media in the United States was Source: CDC s Active Bacterial Core Surveillance/Emerging Infections Program Network. estimated at $3.5 billion. 10 S992 THE AMERICAN JOURNAL OF MANAGED CARE NOVEMBER 1999

3 One study of more than 2200 infants demonstrated that 80% had 1 episode of otitis media (ie, acute otitis media, otitis media with effusion, or tube otorrhea) by age 1 year and 90% by age 2 years. 11 Nearly one half of these infants received antibiotics and about 4% had a tympanostomy tube placed within the first 2 years of life. However, the burden of otitis media continues beyond 2 years of age. One prospective study of 498 Boston-area children showed a second peak of acute otitis media infections occurring during the fourth year of life. By age 7 years, approximately 75% had experienced 3 or more episodes of acute otitis media. 12 Drug Resistance Both high and intermediate levels of S. pneumoniae resistance to antimicrobials have increased over the past decade in the United States. High-level resistance to penicillin (minimum inhibitory concentrations of 2.0 µg/ml), for example, increased from about 1.3% in 1992 to more than 13.6% in ,14 Resistance tends to be higher in those 0 to 17 years of age and in the white population; this latter effect of race may be the result of greater antibiotic prescribing for white versus African American populations. Increasing pneumococcal resistance to newer antibiotics has also been noted (Figure 2). Data from the 1998 ABCs indicate that 25% of pneumococcal strains are now resistant to at least 2 antibiotic classes and 13% are resistant to at least 3 classes. 2 Of particular concern is the increasing resistance to fluoroquinolones, which are recommended by the Infectious Diseases Society of America for empiric treatment of penicillin-resistant pneumococcal pneumonia in adults. In the United States, low levels of resistance in adults have already been noted in 2 of the newest agents in this class: levofloxacin and trovafloxacin. 2 A Canadian study recently showed that resistance to fluoroquinolones in adults increased from 1.5% in 1993 and 1994 to 2.9% in 1997 and 1998; the authors suggest this increase is associated with the 6-fold escalation in fluoroquinolone prescribing seen over the past decade. 15 The significance of antibiotic resistance is evident across the spectrum of pneumococcal disease. For example, in otitis media caused by pneumococcal strains resistant to penicillin, use of oral cephalosporins has been associated with treatment failure. 16 In pneumococcal meningitis, cases of cephalosporin treatment failures have been reported, suggesting that cerebrospinal fluid drug concentrations lower than 2 µg/ml may be inadequate to eradicate the organism. 17,18 Treatment failures in pneumococcal pneumonia have also... EPIDEMIOLOGY OF PNEUMOCOCCAL DISEASE... Figure 2. Trends in Antimicrobial Susceptibility of Pneumococci P=.001 P.001 P.001 P=.004 Source: CDC s Active Bacterial Core Surveillance/Emerging Infections Program Network. VOL. 5, NO. 17, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S993

4 ... PRESENTATIONS... recently been associated with high levels of pneumococcal resistance, and in hospitalized patients with resistant Table 1. Risk Factors for Invasive Pneumococcal Disease Host factors Immunologic impairment or deficiency Infection with human immunodeficiency virus Asplenia Sickle cell disease Immunosuppressive therapy Underlying illness Cirrhosis Diabetes Chronic obstructive pulmonary disease Renal insufficiency Malignancy Behavioral Cigarette smoking, Breastfeeding (protective) Race or genetic factors Environmental factors Daycare attendance Exposure to children Household crowding Passive smoke exposure Concurrent or antecedent respiratory infection Occupational hazards (eg, gold miners) Figure 3. Invasive Pneumococcal Disease by Age and Race, 1998 Source: CDC s Active Bacterial Core Surveillance/Emerging Infections Program Network. pneumococcal pneumonia, late mortality has increased. 3 Risk Factors for Invasive Pneumococcal Disease Several host-related and environmental risk factors for invasive pneumococcal disease have been identified (Table 1). Certainly, the strongest risk factors are those that diminish host defenses. A survey of invasive pneumococcal disease among residents of a Texas county showed that the relative risks of acquiring pneumococcal infection for the following 3 conditions were quite high: patients with sickle cell disease, 52; those with human immunodeficiency virus infection (HIV), 29; and those with chronic lung disease, 27. In contrast, the etiologic fractions (ie, the proportion of the population having the disease as a result of the respective underlying condition) of the 3 conditions were 3% for patients with sickle cell anemia, 8% for those with HIV, and 15% for those with chronic lung disease. 19 Population-based studies have indicated that underlying disease is present in about 8% to 12% of cases of pediatric pneumococcal invasive disease Overall in the United States, there are 24.3 cases of invasive pneumococcal disease per 100,000 population (Figure 3); for those aged 0 to 23 months, the rate is 160 per 100, Rates are about 2 to 3 times higher in African Americans than whites and higher still among American Indian populations. 2 The incidence is extremely high in HIV-infected individuals (587 per 100,000) and in patients with sickle cell disease (1230 per 100,000). 19 Attendance at daycare centers is a well-recognized risk factor for invasive pneumococcal disease among children, although estimates of the degree of risk have varied widely. In a study from Finland, the odds ratio of acquiring invasive pneumococcal S994 THE AMERICAN JOURNAL OF MANAGED CARE NOVEMBER 1999

5 ... EPIDEMIOLOGY OF PNEUMOCOCCAL DISEASE... infections was 36 when daycare attendees were compared with those who were not in daycare. In a recently published populationbased, case-control study of risk factors for invasive pneumococcal disease in children in North America, children younger than 5 years of age who had pneumococcal infections were approximately 3 times as likely to have attended daycare in the past 3 months as children who were not ill. 22 This same North American study showed that breastfeeding was highly protective against invasive disease in infants 2 to 11 months of age (odds ratio = 0.21). Children who attended daycare were also less likely to be currently breastfed and more likely to have had a recent ear infection. Therefore, some of the risk of invasive pneumococcal infection associated with recent daycare attendance may be the result of decreased breastfeeding in younger children and an increased risk of otitis media. 22 Multivariate analysis of risk factors for penicillin-resistant infections among children in this study showed that recent daycare attendance, antibiotic use, and ear infections were all independently associated with penicillin-resistant pneumococcal infections. 22 Distribution of Serotypes As vaccination becomes a more widespread preventive tool in the control of pneumococcal disease, knowledge of the epidemiology of pneumococcal serotypes will become increasingly important. The 7-valent pneumococcal conjugate vaccine and the 23-valent pneumococcal polysaccharide vaccine cover different percentages of invasive pneumococcal diseases occurring among people in the United States. This is because of the different serotypes included in the 2 vaccines. In 1998, more than 3300 invasive pneumococcal isolates were obtained from the CDC s ABCs of the Emerging Infections Program Network. An estimated 82% of the isolates obtained from children younger than 2 years of age and 54% of isolates As vaccination becomes a more widespread preventive tool in the control of pneumococcal disease, knowledge of the epidemiology of pneumococcal serotypes will become increasingly important. recovered from infected patients age 65 years and older will be covered by the 7-valent conjugate vaccine. In contrast, 91% of isolates from children younger than 2 years of age and 86% of those from people older than 65 years of age would be covered by the 23-valent polysaccharide vaccine, a difference that emphasizes the variations in serotype distribution by age group. Analysis of 3000 isolates from this national surveillance system showed that 77.5% of the pneumococcal isolates found to be penicillin resistant would be covered by the 7-valent pneumococcal conjugate vaccine. 2 As conjugate pneumococcal vaccines are introduced and as treatment and vaccination guidelines change, clinicians and healthcare administrators will need to monitor the evolving epidemiologic and demographic patterns of pneumococcal disease. As recognized more than a decade before the phase III testing of these conjugate vaccines, 23 ongoing surveillance of serotypes and antimicrobial resistance will remain an important element of any national pneumococcal preventive effort. VOL. 5, NO. 17, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S995

6 ... PRESENTATIONS DISCUSSION HIGHLIGHTS... Dr. Santosham: Much of this epidemiologic data is from the CDC s ABCs [Active Bacterial Core Surveillance] program. How does that program work? Dr. Van Beneden: Currently, we actively identify cases and collect bacterial isolates from invasive disease caused by pathogens of public health importance, including invasive disease caused by Streptococcus pneumoniae. Surveillance is conducted in 8 Emerging Infections Program sites from diverse geographic areas of the United States. The surveillance areas represent approximately 17 million people and include San Francisco County, Connecticut, and select counties in Georgia, Maryland, Minnesota, New York, Oregon, and Tennessee. Dr. Block: Do current data show either daycare attendance or lack of breastfeeding to be more important as a risk factor? Dr. Van Beneden: In the case-control study conducted in North America, the protective effect of breastfeeding was limited to children ages 2 to 11 months. However, the association between daycare attendance and an increased risk for invasive pneumococcal disease was found for all age groups ages 2 to 59 months. Dr. Black: Most studies say daycare attendance is the greatest factor. Dr. Van Beneden: Yes, I suspect the overall risks of daycare probably overwhelm the risk related to lack of breastfeeding, but I don t have data on that. Dr. Santosham: What effect does the trend toward greater antibiotic resistance have on physician prescribing practices? Dr. Van Beneden: Some physicians do consider the MIC [minimum inhibitory concentration] and adjust their prescribing accordingly. Dr. Pelton: The main effect I see is a rising dose of amoxicillin. I don t know whether this will lead to higher levels of resistance, but I do know that in other parts of the world where they use higher than traditional doses they also have pneumococci with a higher MIC. I m not sure whether that s a direct relationship. Dr. Black: What about the larger picture of physician perceptions? Do providers have a realistic picture of pneumococcal disease burden and resistance? My impression is that pediatricians are already quite aware that the pneumococcus is a major cause of bacterial meningitis and pneumonia. Dr. Cogen: For the geriatric population, the polysaccharide pneumococcal vaccine has been available for years, but vaccine use is only around 20% to 30% nationally. We recently tried encouraging vaccine use in one state s Medicare population. The internists and family physicians all understood the disease burden in the elderly, but they didn t employ the vaccine. Why? One reason is that primary care physicians are worried that their patients have already been vaccinated in community centers or in pharmacies and they are afraid to revaccinate and get local injection site or more serious reactions. Dr. Austrian: Another reason for limited use is that the pneumococcal vaccine got some bad press shortly after it was licensed. The initial paper from the CDC estimated its efficacy to be 36%, and several papers in the ensuing 5 to 6 years denigrated the vaccine. Another problem relates to the polyvalency of the pneumococcal vac- S996 THE AMERICAN JOURNAL OF MANAGED CARE NOVEMBER 1999

7 ... EPIDEMIOLOGY OF PNEUMOCOCCAL DISEASE... cines. They will never be as effective as a monovalent vaccine because one is actually giving 7 to 23 distinct vaccines simultaneously, and their aggregate efficacy is unlikely ever to equal that of a monovalent vaccine. Nevertheless, many physicians and recipients of a pneumococcal vaccine expect it to be as effective as tetanus toxoid, for example. This is an important educational problem that needs to be addressed. Dr. Block: What is the efficacy of the 23-valent pneumococcal vaccine in adults? Dr. Austrian: The best current estimate is 60% to 70%. If you assume a monovalent component has an efficacy of 90% and exposure to 4 new pneumococcal types over 2 to 3 years, then the calculated efficacy works out to 0.94 or 64%, which is about the rate seen in practice. Pneumococcal Conjugate Vaccines Dr. Block: In our practice, which is nonmetropolitan and includes a 15% African American population, we only see 2% or 3% positive blood cultures per year for pneumococcus, and that is in children with fever and high white counts. In acute otitis media, of course, the pneumococcal conjugate vaccine may not make a huge dent in preventing the usual strains in all ages, but it will probably prevent most of the drug-resistant strains, the ones that require 3 to 6 courses of antibiotics and result in tube placements. That s how this vaccine should be positioned for pediatricians. Dr. Santosham: That s true. I think in otitis media the serotypes that persist are those that are drug resistant. Alternatively, we may just be unmasking strains that were there the whole time. Serotypes Dr. Austrian: We haven t had a meaningful study of pneumococcal carrier state in the past quarter century. The Many physicians and recipients of a pneumococcal vaccine expect it to be as effective as tetanus toxoid, for example. This is an important educational problem that needs to be addressed. best studies, which were done in the 1930s in Germany, showed that half of the children studied simultaneously carried at least 2 capsular types and a few carried as many as 4. However, accurate studies require mouse inoculation of respiratory secretions and are expensive. The techniques used today are insensitive. Dr. Black: Well, if our current techniques are just picking up 1 strain in the typical child s ear even though a better mouse model might pick up 2 or 3 is this isolated strain still the most clinically important, either because of its high quantity or high invasiveness? Dr. Austrian: We don t know. Pneumococcus type 1, for example, infrequently is carried by healthy people but it is highly invasive. The situation is similar for types 2 and 14. The degree of invasiveness may be influenced by the timing of antibody development, which is related to age. The paradigm is complex. Dr. Santosham: In the Navajo population, type 1 is actually common. One hypothesis is that a less robust immune response in the host will allow invasiveness of certain Robert Austrian, MD VOL. 5, NO. 17, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S997

8 ... PRESENTATIONS... serotypes. We have evidence that American Indians don t respond as well to the Hib polysaccharide vaccines, so their immune response to pneumococcal vaccines may also be different. Dr. Block: We only see type 1 in our young patients as they get older. Our data for acute otitis media show that serotypes 1, 3, and 4 become much more common after age 24 months. 24 Dr. Austrian: The serotypes vary from country to country, seemingly with some relationship to industrialization. China and Southern Europe in the 1980s had serotypes similar to those found in the United States in the 1950s. Serotypes in Northern Europe and Japan have paralleled the United States more closely. Half a century ago, type 2 was important; today, it s rare. The bases for these patterns are not understood.... REFERENCES Pneumococcal vaccines. Weekly Epidemiological Record 1999;74: Active Bacterial Core Surveillance (ABCs)/Emerging Infections Program Network Surveillance Report: Streptococcus pneumoniae, cdc.gov/ncidod/dbmd/abcs/spneu98.pdf. 3. Feikin D, Schuchat A, Kolczak M, et al. Mortality for invasive pneumococcal pneumonia in the era of antibiotic resistance, Am J Public Health. In press. 4. Schuchat A, Robinson K, Wenger JD, et al. Bacterial meningitis in the United States in N Engl J Med 1997;337: Centers for Disease Control and Prevention. Progress toward elimination of Haemophilus influenzae type b disease among infants and children-united States, Morb Mortal Wkly Rep 1994;43: Turner RB, Lande AE, Chase P, et al. Pneumonia in pediatric outpatients: Cause and clinical manifestations. J Pediatr 1987;111: 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: Freid VM, Makuc DM, Rooks RN. Ambulatory health care visits by children: Principal diagnosis and place of visit. National Center for Health Statistics. Vital Health Stat 1998; Series Hall MJ, Lawrence L. Ambulatory surgery in the United States, Advance data. Vital Health Stat Stool SE, Field MJ. The impact of otitis media. Pediatr Infect Dis J 1989;8(suppl): S11-S Paradise JL, Rockette HE, Colborn DK, et al. Otitis media in 2253 Pittsburgh-area infants: Prevalence and risk factors during the first two years of life. Pediatrics 1997;99: Teele D, Klein JO, Roaner B, et al. Epidemiology of otitis media during the first seven years of life in children in greater Boston: A prospective cohort study. J Infect Dis 1989;160: Breiman RF, Butler JC, Tenover FC, et al. Emergence of drug-resistant pneumococcal infections in the United States. JAMA 1994;271: Centers for Disease Control and Prevention. Geographic variation in penicillin resistance in Streptococcus pneumoniae selected sites, United States, Morb Mortal Wkly Rep 1999;48: Chen DK, McGeer A, De Azavedo JC, et al. Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. N Engl J Med 1999;341: Dagan R, Abramson O, Leibovitz E, et al. Impaired bacteriologic response to oral cephalosporins in acute otitis media caused by pneumococci with intermediate resistance to penicillin. Pediatr Infect Dis J 1996;15: Catalan MJ, Fernandez JM, Vazquez A, et al. Failure of cefotaxime in the treatment of meningitis due to relatively resistant Streptococcus pneumoniae. Clin Infect Dis 1994;18: Sloas MM, Barrett FF, Chesney PJ, et al. Cephalosporin treatment failure in penicillinand cephalosporin-resistant Streptococcus pneumoniae meningitis. Pediatr Infect Dis J 1992;11: Pastor P, Medley F, Murphy TV. Invasive pneumococcal disease in Dallas County, Texas. S998 THE AMERICAN JOURNAL OF MANAGED CARE NOVEMBER 1999

9 ... EPIDEMIOLOGY OF PNEUMOCOCCAL DISEASE... Results from population-based surveillance in Clin Infect Dis 1998;26: Takala AK, Jero J, Kela E, et al. Risk factors for primary invasive pneumococcal disease among children in Finland. JAMA 1995;273: Zangwill KM, Vadheim CM, Vannier AM, et al. Epidemiology of invasive pneumococcal disease in Southern California: Implications for the design and conduct of a pneumococcal conjugate vaccine efficacy trial. J Infect Dis 1996;174: Levine OS, Farley M, Harrison LH, et al. Risk factors for invasive pneumococcal disease in children: A population-based case control study in North America. Pediatrics 1999;103:E Austrian R. Epidemiology of pneumococcal capsular types causing pediatric infections. Pediatr Infect Dis J 1989;8:S21-S Block SL, Hedrick JA, Harrison CJ. Pneumococcal serotypes from acute otitis media in rural Kentucky. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, CA; September VOL. 5, NO. 17, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S999