Antibody Response to Diphtheria-Tetanus-Pertussis Immunization in Preterm Infants Who Receive Dexamethasone for Chronic Lung Disease
* Neonatal Department, Hope Hospital, Salford, United Kingdom
Department of Research and Development, Hope Hospital, Salford, United Kingdom
Neonatal Department, Royal Bolton Hospital, Bolton, United Kingdom
|| Neonatal Department, St Mary’s Hospital, Manchester, United Kingdom
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ABSTRACT |
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Objective. To study the effect of dexamethasone in preterm infants with chronic lung disease (CLD) on antibody response to routine immunization against diphtheria, tetanus, and pertussis (DTP).
Methods. Serum samples were obtained before and after immunization with DTP (Trivax-AD) from an unselected cohort of 93 preterm infants in the United Kingdom. Antibodies to diphtheria and tetanus and to 4 pertussis antigens (pertussis toxin, filamentous hemagglutinin, pertactin, and fimbrial agglutinogens 2 + 3) were measured by an enzyme-linked immunosorbent assay. Linear regression models were fitted to the natural log of antibody titers to compare the dexamethasone-treated and -untreated infants adjusting for potential risk factors.
Results. Sixty-seven (72%) of 93 infants received dexamethasone. Preimmunization geometric mean titers (GMTs) were comparable in both groups for all antibodies. The rise in GMT after immunization was reduced in the dexamethasone-treated group. Final GMT was significantly lower for tetanus, diphtheria, pertussis toxin, and fimbrial agglutinogens 2 + 3 but not for filamentous hemagglutinin or pertactin. Using the minimum protective titer of 0.01 IU/mL, there was no significant reduction in protection for diphtheria and tetanus in the dexamethasone-treated infants. Using the higher reference titer of 0.1 IU/mL, there was a 16% reduction in protection for diphtheria (95% confidence interval: 3%–27%) and a 9% reduction in protection for tetanus (95% confidence interval: –7% to 20%).
Conclusions. The use of dexamethasone for CLD in preterm infants is associated with a reduction in antibody titer to routine immunization against diphtheria and tetanus. Antibody responses to 2 of 4 pertussis antigens are reduced, but the clinical significance of this observation is unclear. Protection against tetanus and diphtheria is not impaired when the lower reference value for protective antibody is used. On the basis of this study of UK preterm infants who were treated with dexamethasone for the management of CLD, we conclude that the current DTP immunization schedule is adequate and do not recommend additional booster protection against tetanus or diphtheria during early infancy. When diphtheria prevalence is increased, however, additional protection should be considered.
Key Words: preterm • dexamethasone • chronic lung disease • diphtheria • tetanus • pertussis • immunization
Abbreviations: DTP, diphtheria, tetanus, and pertussis • Hib, Haemophilus influenzae type b • CLD, chronic lung disease • PT, pertussis toxin • FHA, filamentous hemagglutinin • AGG2+3, fimbrial agglutinogens 2+3 • PRN, pertactin • CI, confidence interval
All infants in the United Kingdom are routinely offered immunization against diphtheria, tetanus, and pertussis (DTP), polio, and Haemophilus influenzae type b (Hib) at 2, 3, and 4 months of age, irrespective of gestational age at delivery.1 Earlier studies have shown that well, preterm infants respond to this schedule, achieving a rise in pertussis antibodies and protective levels of antibody against diphtheria and tetanus.2–8 There is some evidence to suggest that, although still achieving protective levels, preterm infants respond less well than term infants and that sick preterm infants do not respond as well as healthy preterm infants.9
With improved survival, increasing numbers of preterm and very low birth weight infants are at risk of developing chronic lung disease (CLD). Treatment may involve the use of systemic steroids, usually dexamethasone, to reduce the duration of ventilation. Corticosteroids suppress the immune response and may impair vaccine-conferred protection in these infants,10,11 a high-risk group for whom adequate protective immunity is particularly vital. From 1992, infants routinely received Hib immunization in addition to DTP. Dexamethasone has previously been reported to reduce protective Hib antibody levels in preterm infants after immunization.12–14 In this nonrandomized, observational clinical study, we compared antibody responses to DTP immunization in preterm infants who received postnatal dexamethasone with those in non-dexamethasone-treated preterm infants. We examined the hypothesis that postnatal dexamethasone given to preterm infants for the management of CLD impairs immunogenicity and thereby reduces protection against DTP.
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METHODS |
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After local ethics committee approval and informed parental consent, an unselected cohort of 93 preterm infants of <1501 g birth weight and below 33 weeks’ gestational age were studied between July 1991 and February 1996 at 3 hospitals in the Greater Manchester conurbation in the North West of England. The routine policy of all units followed official guidelines that advised immunization at 2, 3, and 4 months’ postnatal age unless the infant was acutely unwell.1 Immunization was with 0.5 mL of adsorbed DTP vaccine (Trivax-AD; Evans Medical, Leatherhead, United Kingdom). A 1-mL blood sample was taken before the first immunization, and a second sample taken 6 to 8 weeks after the third immunization. Samples were spun and separated, and sera were stored deep-frozen at –70°C. Using an enzyme-linked immunosorbent assay method described previously,15,16 paired samples were analyzed for titers of diphtheria and tetanus antitoxin and antibodies against 4 pertussis antigens (pertussis toxin [PT], filamentous hemagglutinin [FHA], fimbrial agglutinogens 2 + 3 [AGG2+3], and pertactin [PRN]) at the Health Protection Agency (Wiltshire, UK). Antibody titers to tetanus and diphtheria are expressed as IU/mL. Pertussis antibodies are expressed as titers corrected against standard reference sera (National Institute of Biological Standards and Control 89/530). Infants who developed CLD were treated according to uniform unit guidelines with dexamethasone, introduced at a dose of 500 µg/kg/day and tailed according to clinical progress.
Statistics
A least-squares regression model was fitted to the natural log of the postimmunization sample to compare the dexamethasone-treated and -untreated infants with adjustment for preimmunization antibody titer, days between pre- and postimmunization sample, gestational age, days ventilated, days in oxygen, and antenatal steroid use. Results are presented as back-transformed coefficients. These represent the ratio of the effect on postimmunization antibody titer of being treated with dexamethasone compared with being untreated. A result less than unity suggests a negative effect, a result of 1 suggests no effect, and a result of >1 suggests a positive effect. For the purpose of data analysis, sera with antibody concentrations below the laboratory cutoff were assigned a value equal to half the minimum detectable levels. For comparing the proportion of infants who achieved protection, 95% confidence intervals (CIs) for the difference were used.17 Stata V6.0 and StatsDirect were used for statistical analysis. P < .05 was taken to indicate a statistically significant difference.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Baseline characteristics of the 2 groups are shown in Table 1. Infants who received dexamethasone were, as expected, of lower birth weight and younger gestational age. These infants were ventilated and required supplementary oxygen for longer periods. There were no statistical differences in the distribution of age of immunization, the timing of the second blood sample, or corrected age at the second sample between treated and untreated infants. Preimmunization geometric mean titers of antibodies to diphtheria and tetanus and to the 4 pertussis antigens reflected passively acquired immunity and were statistically similar in both groups (Table 2).
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Table 3 shows the back-transformed coefficient of dexamethasone for each antibody, with 95% CIs and P values for the effect of dexamethasone on final antibody titer, after adjusting for other risk factors. For all antibodies, postimmunization levels were lower in the dexamethasone-treated group compared with the untreated group. After adjusting for days between pre- and postimmunization samples, preimmunization antibody titer, gestation, days ventilated, days on oxygen, and antenatal steroid use, postimmunization titers of AGG2+3, PT, diphtheria, and tetanus were significantly lower in the treated compared with the untreated group. When total dexamethasone dose was added, the relationship was significant for PT and tetanus. For each µg/kg/day of dexamethasone, the relative reduction in AGG2+3 was 0.95 (95% CI: 0.9–1.01; P = .096), in PT was 0.91 (0.86–0.97; P = .002), in diphtheria was 0.98 (0.94–1.03; P = .386), and in tetanus was 0.92 (0.87–0.97; P = .002). For all antibody responses, the initial titer had a negative effect on final titer, which was statistically significant for AGG2+3 (P = .030) and diphtheria (P = .025) but not for PT, FHA, PRN, or tetanus (P = .142, .559, .055, and .284, respectively).
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Table 4 shows the proportion of infants who achieved protective levels of 0.01 IU/mL and 0.1 IU/mL for diphtheria and tetanus. The minimum protective level of 0.01 IU/mL is most frequently accepted as conferring group protection.3,6,7,18–20 A higher level of 0.1 IU/mL, considered to correlate with individual protection, is sometimes used.20 All untreated infants reached the minimum protective level. Of treated infants, 100% were protected against tetanus and 98% were protected against diphtheria after immunization. Eighty-seven percent reached the higher titer for tetanus, and 84% did so for diphtheria. There are no reference protective antibody levels for pertussis, but an increase in antibody titer was taken as an immunization response. In dexamethasone-treated infants, there was attenuation of the rise in titers for all of the pertussis antibodies.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Diphtheria and tetanus are rare in the United Kingdom and the United States but common in the developing world. Complications and death occur most commonly in infants younger than 6 months. The recent increase in the incidence of diphtheria in Eastern Europe indicates that a comprehensive, protective immunization program against this disease should remain important.21,22
We have previously shown that dexamethasone used in the treatment of CLD impairs protection against Hib.13 The present study sought to assess whether the protection afforded to preterm infants during routine immunization with DTP is adversely affected by the use of postnatal dexamethasone. The study was necessarily observational as, during the study period, it was not considered ethically acceptable to randomize infants when there seemed to be justifiable clinical respiratory benefit from dexamethasone treatment. With recent concerns of adverse neurodevelopmental outcome associated with dexamethasone, there has been a decline in the use of postnatal steroids in preterm infants. Randomization in this climate would be difficult, particularly as postnatal dexamethasone is generally used as a last resort.23
Although we cannot exclude the possibility that missed cases may have affected the generalizability of the results, there was no systematic exclusion of cases.
Postnatal dexamethasone was a rescue intervention given on clinical grounds, so treated infants were necessarily sicker, smaller, and less mature. Numbers of infants with CLD as clinically defined by oxygen dependence at 28 days, 36 corrected weeks, and 40 corrected weeks are shown in Table 1. After accounting for baseline factors, comparison with non-steroid-treated infants showed that those who received dexamethasone produced approximately half the antibody titers to diphtheria, one third the levels to tetanus, and between 27% and 84% to the 4 pertussis antigens. Previous studies suggested that preterm and chronically ill infants mount a lower response to immunization.2–14 These data confirm that although antibody titers to diphtheria and tetanus are significantly impaired, protection remains adequate. Adjustment was made for potential confounding factors, but we are unable to exclude the possibility that the reduction in antibody titers was influenced by demographic differences.24 The overall negative effect of initial antibody titer confirmed earlier observations13 and may have contributed to the reduced antibody response in dexamethasone-treated infants.
No consistent dose-dependent steroid effect was found. Although all antibody titers in the dexamethasone-treated group were reduced, only those to PT and tetanus were found to be affected in a dose-related manner.
There is some controversy regarding appropriate reference protective antibody levels. A minimum protective titer of 0.01 IU/mL for both diphtheria and tetanus is usually acceptable, although some support the use of the higher level of 0.1 IU/mL.25 Protection against diphtheria improves as antibody titer rises above 0.01 IU/mL, suggesting that the higher level is a safer protective target.26 Cases of tetanus have been reported in which the preinfective antibody titer was >0.01 IU/mL.27 The World Health Organization suggests that the higher protective level for diphtheria indicates individual protection,25 although in the developed world, where herd immunity is high, this view may be less justifiable. CIs for protection against tetanus using both the higher and the lower titers straddled 0, suggesting that the differences in protection were not statistically significant. For diphtheria, using the lower accepted titer, CIs also straddled 0. Using the higher level 16% (95% CI: 3%–27%), fewer dexamethasone-treated than -untreated infants were unprotected.
Postnatal dexamethasone reduced the titers of all 4 pertussis antibodies. The differences in titers to PT and AGG2+3 between treated and nontreated infants were statistically significant. These differences may have been confounded, in part, by the elevated baseline titers, which we are unable to explain. None of the infants received immunoglobulin. Any effect relating to the increased requirement for packed red blood cell transfusion in the treated group would have influenced all baseline titers. Because there are no accepted protective pertussis antibody levels, the effect of dexamethasone on protection against pertussis cannot be discerned. Preterm infants respond less robustly to primary immunization, and some antibody titers show a continuing reduction relative to term infants over time.24 It is possible that this effect is exaggerated in dexamethasone-treated infants, placing them at a disadvantage compared with full-term infants during the preschool period.
Qualitative antibody response as measured by avidity was not assessed yet may be a key variable.28,29 Preterm infants are not overrepresented in reported cases of Hib disease.30 This may reflect herd immunity or the irrelevance of antibody titers as long as immunologic memory has been primed. There are currently no comparable epidemiologic data for DPT. Despite the more rapid fall of protective antibody titers to Hib, tetanus, and diphtheria in preterm infants, it is reassuring that, in relation to Hib, avidity remains as high as that of term infants.24 It is not known whether infants with lower antibody titers are more vulnerable or whether the presence of any primed memory of competent antibodies is able to ensure an appropriate response to wild antigen.
The study identifies reductions in some specific antibody titers. The effect on protection rates to pertussis cannot be known. Protection against diphtheria and tetanus is not reduced when the lower reference range is chosen, although it may be attenuated to diphtheria if the higher reference level is used. There is insufficient evidence from this study to recommend alteration to the current immunization schedule for preterm infants who have received postnatal dexamethasone.
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CONCLUSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Dexamethasone-treated preterm infants show significantly reduced antibody levels to diphtheria, tetanus, and to 2 of 4 pertussis antigens after primary immunization. Nevertheless, these infants seem to be adequately protected against tetanus. There may be, however, some increased vulnerability to diphtheria, and additional protection may be required for susceptible infants who travel to areas of increased prevalence. Because the level of protection to pertussis is uncertain, it is not known whether infants are compromised by the reduction in antibody titers. This study suggests that no alteration to the existing primary DTP immunization schedule is currently required for preterm infants who receive treatment with dexamethasone.
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ACKNOWLEDGMENTS |
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Appreciation is warmly acknowledged to the Microbiology Department at Hope Hospital for storage of specimens; to Carol Thornton, who performed the assays; and to Dr Paul Clarke for valuable critical comments and suggestions.
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FOOTNOTES |
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Received for publication Aug 19, 2002; Accepted Aug 14, 2003.
Reprint requests to (M.J.R.) Neonatal Department, Hope Hospital, Salford M6 8HD, UK. E-mail: mrobinso{at}fs1.ho.man.ac.uk
Ms Heal is currently affiliated with Stepping Hill Hospital, Stockport, United Kingdom.
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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics
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