Pneumococcal Conjugate Vaccine in Children
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《新英格兰医药杂志》
To the Editor: In their trial of a 9-valent pneumococcal conjugate vaccine in children with human immunodeficiency virus infection and those without infection, Klugman and colleagues (Oct. 2 issue)1 found an increased risk of asthma among vaccinees. We assessed this risk in a randomized, controlled trial of the 7-valent pneumococcal conjugate vaccine in northern California.2
From 1995 to 1998, a total of 37,868 children at Kaiser Permanente received pneumococcal conjugate vaccine or control meningococcal C conjugate vaccine. The risk of a first hospitalization or emergency department visit for asthma (International Classification of Diseases, code 493.xx) was assessed with the use of Cox regression analysis. We conducted an intention-to-treat analysis of follow-up data through 2002 (keeping in the control group the 23 percent of controls who received pneumococcal conjugate vaccine after the completion of the trial). A total of 359 children were hospitalized for asthma, and 1210 were seen in the emergency department for asthma. The risk of asthma that required hospitalization did not differ significantly between the two groups (relative risk in the pneumococcal-vaccine group, 1.03; 95 percent confidence interval, 0.84 to 1.27), nor did the risk of asthma that required a visit to the emergency department (relative risk, 1.09; 95 percent confidence interval, 0.97 to 1.22). Intention-to-treat and per-protocol analyses that ended at the completion of the trial (in April 1999) also showed no significant difference between the groups with respect to hospitalization or an emergency department visit for asthma. In contrast to the findings reported by Klugman et al., we found no association between conjugate pneumococcal vaccination and severe asthma.
Editor's note: Drs. Davis and Shinefield and Mr. Fireman report having received research grants from Wyeth–Ayerst, maker of the referenced pneumococcal conjugate vaccine.
Robert L. Davis, M.D., M.P.H.
Kaiser Permanente Vaccine Studies Center
Oakland, CA 94612
rdavis@u.washington.edu
Bruce Fireman, M.A.
Kaiser Permanente Division of Research
Oakland, CA 94612
Henry R. Shinefield, M.D.
Kaiser Permanente Vaccine Studies Center
Oakland, CA 94612
References
Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. N Engl J Med 2003;349:1341-1348.
Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000;19:187-195.
The authors reply: We are gratified to learn that there was only a small, statistically nonsignificant excess of asthma episodes among recipients of the 7-valent conjugate pneumococcal vaccine in the northern California study.1 Differences in study design, follow-up, and detection of cases make direct comparisons of rates difficult to interpret. The administration of meningococcal conjugate in controls and the continued inclusion in the control group of the 23 percent of controls who received pneumococcal vaccine after the completion of the trial may have reduced the strength of the association between vaccination and asthma in that study. On the assumption of a follow-up time per group of 107,000 person-years in the California study,1 the intention-to-treat rates of asthma episodes in that study were 760 per 100,000 person-years among vaccinees and 707 per 100,000 person-years among controls (an excess of 53 episodes per 100,000 person-years). In Soweto, South Africa, there were 128 episodes per 100,000 person-years in vaccinees and 71 per 100,000 in controls (an excess of 57 episodes per 100,000 person-years). The higher rates in California may be due to increased identification of outpatient diagnoses of asthma (the Soweto data include only patients in whom asthma was diagnosed at the hospital) and higher rates of asthma among older children included in the California follow-up study. Attack rates of asthma continue to be monitored in our trial, and these data suggest that they should continue to be monitored in post-marketing surveillance and in ongoing trials of pneumococcal conjugate vaccine in the Czech and Slovak Republics, the Gambia, and the Philippines.
Keith P. Klugman, M.B., B.Ch., Ph.D.
Emory University
Atlanta, GA 30322
kklugma@sph.emory.edu
Shabir A. Madhi, M.B., B.Ch.
Respiratory and Meningeal Pathogens Research Unit
Bertsham, Gauteng 2013, South Africa
Robert Kohberger, Ph.D.
Wyeth
Pearl River, NY 10965
References
Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000;19:187-195.
From 1995 to 1998, a total of 37,868 children at Kaiser Permanente received pneumococcal conjugate vaccine or control meningococcal C conjugate vaccine. The risk of a first hospitalization or emergency department visit for asthma (International Classification of Diseases, code 493.xx) was assessed with the use of Cox regression analysis. We conducted an intention-to-treat analysis of follow-up data through 2002 (keeping in the control group the 23 percent of controls who received pneumococcal conjugate vaccine after the completion of the trial). A total of 359 children were hospitalized for asthma, and 1210 were seen in the emergency department for asthma. The risk of asthma that required hospitalization did not differ significantly between the two groups (relative risk in the pneumococcal-vaccine group, 1.03; 95 percent confidence interval, 0.84 to 1.27), nor did the risk of asthma that required a visit to the emergency department (relative risk, 1.09; 95 percent confidence interval, 0.97 to 1.22). Intention-to-treat and per-protocol analyses that ended at the completion of the trial (in April 1999) also showed no significant difference between the groups with respect to hospitalization or an emergency department visit for asthma. In contrast to the findings reported by Klugman et al., we found no association between conjugate pneumococcal vaccination and severe asthma.
Editor's note: Drs. Davis and Shinefield and Mr. Fireman report having received research grants from Wyeth–Ayerst, maker of the referenced pneumococcal conjugate vaccine.
Robert L. Davis, M.D., M.P.H.
Kaiser Permanente Vaccine Studies Center
Oakland, CA 94612
rdavis@u.washington.edu
Bruce Fireman, M.A.
Kaiser Permanente Division of Research
Oakland, CA 94612
Henry R. Shinefield, M.D.
Kaiser Permanente Vaccine Studies Center
Oakland, CA 94612
References
Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. N Engl J Med 2003;349:1341-1348.
Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000;19:187-195.
The authors reply: We are gratified to learn that there was only a small, statistically nonsignificant excess of asthma episodes among recipients of the 7-valent conjugate pneumococcal vaccine in the northern California study.1 Differences in study design, follow-up, and detection of cases make direct comparisons of rates difficult to interpret. The administration of meningococcal conjugate in controls and the continued inclusion in the control group of the 23 percent of controls who received pneumococcal vaccine after the completion of the trial may have reduced the strength of the association between vaccination and asthma in that study. On the assumption of a follow-up time per group of 107,000 person-years in the California study,1 the intention-to-treat rates of asthma episodes in that study were 760 per 100,000 person-years among vaccinees and 707 per 100,000 person-years among controls (an excess of 53 episodes per 100,000 person-years). In Soweto, South Africa, there were 128 episodes per 100,000 person-years in vaccinees and 71 per 100,000 in controls (an excess of 57 episodes per 100,000 person-years). The higher rates in California may be due to increased identification of outpatient diagnoses of asthma (the Soweto data include only patients in whom asthma was diagnosed at the hospital) and higher rates of asthma among older children included in the California follow-up study. Attack rates of asthma continue to be monitored in our trial, and these data suggest that they should continue to be monitored in post-marketing surveillance and in ongoing trials of pneumococcal conjugate vaccine in the Czech and Slovak Republics, the Gambia, and the Philippines.
Keith P. Klugman, M.B., B.Ch., Ph.D.
Emory University
Atlanta, GA 30322
kklugma@sph.emory.edu
Shabir A. Madhi, M.B., B.Ch.
Respiratory and Meningeal Pathogens Research Unit
Bertsham, Gauteng 2013, South Africa
Robert Kohberger, Ph.D.
Wyeth
Pearl River, NY 10965
References
Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000;19:187-195.