Evaluation of the Impact of a Pertussis Cocooning Program on Infant Pertussis Infection

Original Studies

C. Mary Healy, MD,*†‡ Marcia A. Rench, BSN,* Susan H. Wootton, MD,§ and Luis A. Castagnini, MD*†

(DTaP) vaccine, the United States recorded its highest number of Background: Tetanus, diphtheria and acellular pertussis immunization of pertussis cases (48,277) in over 50 years in 2012.5 Infants who are infant contacts (cocooning) is recommended by the Centers for Disease too young to have received their primary immunization series at 2, Control and Prevention to prevent infant pertussis. We determined whether 4 and 6 months of age consistently have the highest pertussis attack implementing a cocooning program at Ben Taub General Hospital, Hou- rates and complications. Pertussis-related deaths occur predomi- ston, reduced severe pertussis in young infants. nantly in infants less than 3 months of age.5–8 Reducing pertussis Methods: Infants ≤6 months of age, diagnosed with pertussis (determined disease burden in young infants has been the objective of pertussis by International Classification of Diseases, Ninth Revision codes and immunization recommendations from the Centers for Disease Con- microbiology records) at 4 hospitals, and born at times when only postpar- trol and Prevention (CDC) since the tetanus, diphtheria and acel- tum women (January 2008 through May 2009) and all infant contacts (June 2009 through August 2011) were offered tetanus, diphtheria and acellular lular pertussis (Tdap) booster vaccine for adolescents and adults pertussis vaccine at Ben Taub General Hospital were compared with infants was licensed in 2005. born preintervention (May 2004 through December 2007). Targeted immunization of postpartum women and contacts of infants under 1 year of age (cocooning) was first recommended Results: One hundred ninety-six (49%) infants with pertussis were born 9 preintervention, 140 (35%) during maternal postpartum (PP) and 64 (16%) in 2006. This recommendation was based on studies demonstrat- during cocooning (C) periods. Infants were similar in age at diagnosis (81.2 ing that most pertussis-infected infants are infected by a household contact (75%), most commonly (33%) their mother, many of whom vs. 71.3 [PP] vs. 72.5 [C] days; P 0.07), sex (male 59% vs. 51% [PP] vs. 10–12 48% [C]; P 0.17), hospitalization (68% vs. 71% [PP] vs. 78% [C]; P 0.27) are unaware that they are infected. Although data were lacking and outcome (2 deaths in the PP period; P 0.15), but more were admitted as to the efficacy of this intervention, computer simulation modeling predicted that cocooning could reduce pertussis incidence by 70% to intensive care units during cocooning (24% vs. 35% [PP] vs. 68% [C]; 13 P < 0.001). Similar proportions of infants were born at Ben Taub General in infants less than 3 months of age. Successful cocooning programs in hospital, neonatal intensive care unit and pediatric clinic Hospital throughout the study (8% vs. 9% [PP] vs. 5% [C]; P 0.53). 14–16 Conclusions: Postpartum immunization and cocooning did not reduce per- settings have been reported but logistical and financial barriers precluded widespread implementation of cocooning at a national tussis illness in infants ≤6 months of age. Efforts should be directed toward 3 increasing tetanus, diphtheria and acellular pertussis immunization during level. In 2008, a pertussis immunization program was established pregnancy, combined with cocooning, to reduce life-threatening young in a county hospital in Houston, TX. Initially, the program pro- 17 infant pertussis. vided free Tdap to postpartum women, and it later expanded to include all household contacts of newborn infants (cocooning).15 Key Words: pertussis, cocooning, tetanus, diphtheria and acellular pertus- We previously reported that immunizing only postpartum women sis, infant infection with Tdap did not reduce pertussis among infants ≤6 months of age.18 The objective of the current study was to evaluate whether (Pediatr Infect Dis J 2015;34:22–26) expanding access to free Tdap vaccine to other contacts of young infants reduced severe pertussis in infants in the greater Houston metropolitan area. This study preceded the CDC recommendation onsiderable advances have been made in reducing the inci- to provide Tdap vaccine to pregnant women after week 20 of gesta- dence, morbidity and mortality of vaccine-preventable dis- tion,19 and the later recommendation that pregnant women receive C 3 eases, especially in resource-rich nations.1,2 Pertussis is an exception Tdap during the third trimester of every pregnancy. and outbreaks are regularly reported with morbidity and mortality overrepresented in very young infants.3,4 Despite high infant MATERIALS AND METHODS immunization rates with diphtheria, tetanus and acellular pertussis Patient Population Infants with birth dates between May 1, 2004 and August Accepted for publication June 28, 2014. 31, 2011 and diagnosed with pertussis at ≤6 months of age at 4 From the *Department of Pediatrics, Baylor College of Medicine; †Ben Taub General Hospital; ‡Center for Vaccine Awareness and Research, Texas Chil- hospitals in the Texas Medical Center in Houston, TX [Texas Chil- dren’s Hospital; and §University of Texas Health Sciences Center at Hous- dren’s Hospital, Children’s Memorial Hermann Hospital and 2 Har- ton, Houston, TX. ris Health System county hospitals, Ben Taub General Hospital This work was supported by a research grant from Sanofi Pasteur, Inc. The Ben (BTGH) and Lyndon B. Johnson Hospital] were included in the Taub General Hospital cocooning program was supported through grants from the Baylor-Methodist Community Health Fund and the Harris County study. The majority of severe pertussis cases in young infants in Hospital District Foundations and through donated Tdap vaccine from Sanofi the Houston metropolitan area, and a substantial number of cases Pasteur. in infants who do not need hospitalization, are diagnosed in these C.M.H. is the recipient of research grants from Sanofi Pasteur and Novartis Vac- hospitals, most at Texas Children’s Hospital, which is the largest cines and serves on an Advisory Board for Novartis Vaccines and Pfizer Inc. L.A.C. is on a Speaker’s Bureau for Sanofi Pasteur. All other authors have no free-standing pediatric hospital in the United States. These infant conflicts to disclose. All authors have approved the final article. birth dates coincided with a 44-month period when pertussis immu- Address for correspondence: C. Mary Healy, MD, 1102 Bates Street, Suite 1120, nization interventions were being offered at BTGH (postinterven- Houston, TX 77030. E-mail: [email protected]. tion; January 2008 through August 2011) and compared it with a Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0891-3668/15/3401-0022 44-month preintervention period (May 2004 through December DOI: 10.1097/INF.0000000000000486 2007). The postintervention immunization period further consisted

22 | www.pidj.com The Pediatric Infectious Disease Journal • Volume 34, Number 1, January 2015 The Pediatric Infectious Disease Journal • Volume 34, Number 1, January 2015 Cocooning and Pertussis

of 2 phases, phase 1 when Tdap vaccine was offered to postpar- the preintervention period were compared first with infants diag- tum women only at BTGH (January 2008 through May 2009) and nosed in the entire postintervention period, and then infants born phase 2 when Tdap was offered to postpartum women and all infant during the preintervention, postpartum and family cocooning peri- contacts (June 2009 through August 2011), and ended when the ods were compared. Where possible, the completeness of an indi- recommendation to immunize pregnant women was posted on the vidual infant’s cocoon was calculated by assessing the proportion CDC website in August 2011. The study was approved by the insti- of their contacts who were vaccinated. The proportions of infants tutional review boards of participating hospitals and institutions. born at BTGH during different intervention periods were compared. Multiple logistic regression analysis accounted for potential Pertussis Diagnosis demographic confounders such as age, sex and Hispanic ethnicity. Infants with a diagnosis of pertussis were identified from 2 sources: those with a primary or secondary diagnosis of pertus- RESULTS sis using International Classification of Diseases, Ninth Revision codes (033.0, 033.1, 033.8, 033.9 and 484.3) and those identified Patient Population through microbiology laboratory records. Laboratory diagnosis was Four hundred eight infants ≤6 months of age with a birth defined as the detection of Bordetella pertussis by culture, direct date during the 88-month study period were identified as possible fluorescence assay or polymerase chain reaction (PCR). PCR was pertussis cases. Eight cases were excluded after review of the elec- performed using standard techniques to amplify the IS481 insertion tronic medical record because only B. parapertussis was identified sequence in B. pertussis (GenBank accession no. M28220), and the leaving 400 infants meeting criteria for analysis, 196 in the pre- same methods and reagents from Roche Diagnostics (Indianapolis, intervention period and 204 postintervention (Table 1). Between IN) were used in each of the hospitals. the preintervention and postintervention periods, cases of pertussis in infants ≤6 months of age increased by 70% in counties served Intervention Hospital by study hospitals. The mean age at pertussis diagnosis was 76.5 The BTGH pertussis immunization program has been pre- days (median 68) with a range of 14–207 days; 292 (73%) were <3 viously described.15,17 Briefly, free Tdap vaccine was provided to months of age. Two hundred eighteen (54.5%) infants were male postpartum women through a standing-order protocol and later to and the majority (270 [67.5%]) were of Hispanic ethnicity. Three other infant contacts. BTGH is 1 of 2 tax-supported hospitals in the hundred thirty-nine (84.8%) infants were diagnosed at Texas Chil- Harris Health System and serves a largely underinsured, medically dren’s Hospital, the only free-standing children’s hospital. Microbi- underserved population. Approximately 4000 live-born infants, ological diagnosis was most often made by PCR (92.8%) followed predominantly of Hispanic ethnicity (>90%), are delivered there by direct fluorescence assay (4.8%) and culture (2.6%). Overall, annually. The program’s success was driven by targeted education 284 (71%) infants were admitted to hospital, 102 (36%) of whom of healthcare personnel and families, and by providing Tdap vac- needed intensive care. Two infants (0.5%) died. cination on-site daily at convenient times for families. More than 90% of eligible postpartum women received Tdap vaccine15,17 and Comparison of Intervention Periods approximately 60% of infants for whom detailed information was When the preintervention period was compared with the available had one or more contacts, other than a mother, immunized postintervention period (maternal postpartum only and cocoon- with Tdap.15 ing periods combined), age at diagnosis was younger (mean 71.9 vs. 81.2 days, P 0.024), and a higher proportion of infants were Data Collected <3 months of age at diagnosis (77.4% vs. 68.4%, P 0.043) during The electronic medical record of infants with a diagnosis of the postintervention period. There was no difference in the propor- pertussis through hospital microbiology records and International tions of infants requiring hospitalization (67.8% preintervention vs. Classification of Diseases, Ninth Revision codes were reviewed to 73.5% postintervention; P 0.188) or in their duration of hospitali- ensure they met the following criteria: birth date from May 1, 2004 zation (mean 8.8 days [range 1–92] preintervention vs. mean 9.1 through August 31, 2011, ≤6 months of age at the time of pertussis days [range 1–77]). Those born in the postintervention period were diagnosis and microbiologically confirmed infection with B. pertus- more likely to be admitted to an ICU (24% preintervention vs. 46% sis. Infants with B. parapertussis infection only were excluded from postintervention; P 0.01) and to be diagnosed by PCR (88.7% vs. further analysis. Additional data collected included demographics, 96.6%; P 0.003). There was no difference in the mortality (0 vs. hospital of diagnosis, need for hospitalization and admission to an 1%; P 0.499) or in the proportion of infants born at BTGH (8.2% intensive care unit (ICU), duration of hospitalization and outcome. vs. 7.8%; P 0.99) between the intervention periods. These find- It was determined whether infants had been born at the intervention ings were confirmed when tested in a multiple logistic regression hospital (BTGH) using their date of birth and electronic database. model accounting for age, sex and Hispanic ethnicity (P < 0.001 Infants born at BTGH were then cross-referenced with the BTGH for increased admission to the ICU in the postintervention period). pertussis immunization program database to determine whether There was no difference in age at diagnosis, need for or their mothers and/or infant contacts had received Tdap vaccine. duration of hospitalization, or eventual outcome when the preintervention, postpartum only or cocooning time periods were com- Statistical Analysis pared (Table 1) but more infants were admitted to the ICU during Statistical analysis was performed using SPSS version 22.0 the cocooning period. Similar proportions of infected infants were (SPSS, Chicago, IL). Descriptive characteristics were assessed. born at the intervention hospital in each period, although the pro- Statistical significance for dichotomous outcomes was determined portion was lowest during the time of cocooning. by χ2 and Fisher exact tests. Normally distributed data were evalu- ated by means and the Student’s t test or one-way analysis of vari- Infants Born at the Intervention Hospital ance; where positive or negative skewing of data occurred, statisti- Thirty-two infants were born at BTGH, 16 each in the pre- cal significance was calculated by medians and the Mann–Whitney intervention and postintervention periods. Infants born at BTGH U test. A number of analyses were performed. Characteristics of were more likely to be of Hispanic ethnicity than the remainder infants diagnosed with pertussis and the severity of illness during of the study cohort (93.8% vs. 65.4%; P 0.001) but were similar

TABLE 1. Characteristics of Infants ≤6 Months of Age Diagnosed With Pertussis During Preintervention, Postpartum and Family Cocooning Intervention Periods

Postintervention

Preintervention Postpartum Family Cocooning N = 196 N = 140 N = 64 P Value*

Age (days) at diagnosis Mean (range) 81.2 (14–207) 71.3 (16–181) 72.5 (15–199) 0.07 Male 116 (59%) 71 (51%) 31 (48%) 0.17 Ethnicity 0.22 White 25 (12.7%) 19 (13.6%) 14 (21.9%) — Hispanic 128 (65.3%) 98 (70%) 44 (68.7%) — Black 33 (16.8%) 17 (12.1%) 3 (4.7%) — Asian 1 (0.5%) 1 (0.7%) 0 — Other or unknown 9 (4.7%) 5 (3.6%) 3 (4.7%) — Diagnostic test 0.02 PCR 174 (88.8%) 135 (96.4%) 62 (96.9%) — DFA† 16 (8.2) 3 (2.1%) 0 — Culture 6 (3%) 2 (1.5%) 2 (3.1%) — Hospitalized 133 (68%) 100 (71%) 50 (78%) 0.27 Length of stay‡ (days) Mean (range) 8.9 (1–92) 10.3 (1–77) 6.7 (1–27) 0.19 Intensive care 32 (24%) 35 (35%) 34 (68%) <0.001 Died 0 2 (1.4%) 0 0.15 Born at BTGH 16 (8%) 13 (9%) 3 (5%) 0.53

*Comparison of preintervention, postpartum women only and postpartum women plus family cocooning periods. †DFA, direct fluorescence assay. ‡N = 133, N = 100, N = 50 for preintervention, postpartum and family cocooning, respectively. by gender, age at diagnosis, need for hospitalization and outcome. hospitalization. Many contacts may not visit the mother and infant Infants born at BTGH were also similar regarding their demo- while in the hospital due to time and financial constraints second- graphic and clinical characteristics and outcome regardless of their ary to employment. In addition, part of the study period coincided birth intervention period. Of the infants born during the postinter- with the H1N1 influenza pandemic of 2009. During the latter time vention period, 15 of 16 mothers (93.7%) had received Tdap vac- period, strict visiting restrictions were enforced at the hospital, and cine postpartum. Three mothers and family contacts of 2 of the 3 even though infant contacts could attend to receive Tdap vaccine, infants born during the cocooning period also received Tdap after they were not able to visit either mother or baby, which inevitably the infant’s birth. For these 2 infants their individual cocoon was decreased the numbers availing themselves of this service. Second, 30% and 80% complete, respectively. current recommendations stress the desirability of immunizing contacts a minimum of 2 weeks before infant contact is antici- DISCUSSION pated, but implementation of cocooning in the antenatal setting has The critical evaluation of cocooning and determination of not been reported. This likely reflects the lack of infrastructure to its relative impact on severe pertussis illness in young infants is provide immunizations combined with the difficulty of accessing difficult because implementation is suboptimal, and immunization contacts who do not attend scheduled antenatal visits with the preg- recommendations have changed frequently since cocooning was nant woman. All programs reported to date have provided Tdap in 14–16,20 first recommended.3,19 This study is one of the first, to our knowl- the postpartum period. Since the optimal antibody response edge, to attempt this evaluation in a “real world” setting rather than following administration of Tdap takes 10–14 days, this means using theoretical modeling or cost-effectiveness estimates. This that contacts, and by extension infants, remain at risk for acquir- 21 study did not show a beneficial effect from a postpartum cocooning ing infection for some weeks after the infant’s birth. Third, not program. The age at diagnosis of pertussis actually decreased after all Tdap vaccine recipients demonstrate a robust immune response; maternal postpartum immunization and cocooning was introduced, recent estimates range between 65% and 71%.22 Fourth, immunity and more infants were admitted to the ICU during the interven- from acellular pertussis vaccines wanes more quickly than was tion periods. These latter findings likely reflect increased awareness previously thought,23,24 and a baboon model suggests that acellu- of the need for monitoring for potential pertussis complications in lar pertussis vaccines do not reduce carriage.25 Tdap is currently this age group because duration of hospitalization and outcome did recommended as a once in a lifetime dose (except for pregnant not change, but should be studied prospectively in the future. Our women),3 resulting in a replenishing reservoir of pertussis-suscepti- results, while disappointing, are not unexpected and lend further ble individuals for whom further Tdap doses are not recommended support to recent changes in recommendations to prevent pertussis but who may become transmitters of pertussis to infants. Finally, in very young infants through maternal immunization. Tdap uptake in the adult population is extremely low, reaching only The reasons that cocooning is inherently limited as a stand- 12.5% in 2011, further contributing to this pool of potential trans- alone intervention that is unlikely to significantly impact disease mitters of pertussis to young infants.26 are multifactorial. First, on a practical level cocooning is difficult The recommendation to administer Tdap during weeks 27 to implement.3,14–16 Even in the BTGH program that provided free through 36 of every pregnancy brings some prospect of reducing Tdap vaccine and a 7-day clinic research nurse service at conveni- pertussis in young infants.26 Immunization during the third trimes- ent hours for contacts, some family contacts inevitably remained ter should result in high pertussis-specific antibodies in mothers unimmunized. It is extremely difficult to provide Tdap to every prior to delivery that will not only protect mothers from acquir- potential contact of a newborn infant during a short postpartum ing pertussis, but should also be transported to the infant across

the placenta.27–29 It is hoped that these maternally derived antibod- not yet completed their primary, 3-dose immunization series with ies will passively protect the infant through the first months of life DTaP vaccine. For those women who receive and respond to Tdap until active infant immunization results in protection. Small stud- in pregnancy, there is the prospect of additional time for cocoon- ies from several decades ago using whole-cell pertussis vaccines ing to occur postpartum, allowing the development of programs demonstrated that this approach was safe and resulted in higher that are hospital, clinic or pharmacy based. Further, establishing antibody levels in mothers and infants.4,30 Further, high levels of a robust cocooning platform that would provide Tdap, and other maternally derived pertussis-specific antibodies did not interfere vaccines, is one potential method of targeting an adult popula- with immune response to acellular pertussis vaccines in infants.31 A tion that is hard to access and whose vaccination uptake for many recent phase 1 study also demonstrated high pertussis-specific anti- recommended vaccines lags considerably behind Healthy People bodies in infants whose mothers received Tdap in the third trimes- 2020 targets.26,37,38 ter and did not show significant interference with infant immune In conclusion, this study adds to evidence that postpartum response to DTaP vaccine.32 Studies are ongoing to confirm the effi- immunization and cocooning are not effective stand-alone policies cacy of maternal immunization in reducing infant disease. Wide- to control pertussis in young infants.18,36 In the longer term, effec- spread implementation of this strategy as a standard of care will tive control of pertussis in all age groups will require improved vac- likely take some time, as evidenced by the experience with mater- cines capable of inducing robust and durable immune responses, nal influenza vaccination, although there are increasing data that but the development and licensure of such vaccines will require pregnant women are willing to receive vaccines when accompanied time. In the interim, pertussis prevention efforts will likely continue by strong healthcare provider recommendations.33,34 to target infants ≤6 months of age who have the highest risk of life- There are several limitations to our findings. First, Tdap threatening illness. Immunization during pregnancy shows con- vaccine could have been administered to mothers and other family siderable promise in this regard, but cocooning of infant contacts, contacts of infants born at hospitals other than BTGH, limiting our while ineffective as a single strategy, remains an adjunct that may ability to assess the impact of our program. We think this is unlikely reduce the reservoir of infection among those who infect infants. because, to our knowledge, no hospital in our area offered a similar cocooning program during the intervals described, public awareness of the need for cocooning was not widespread in Houston and ACKNOWLEDGMENTS national data do not support widespread uptake of Tdap.26 Second, We thank Nancy Ng, BSN, RN, and Betsy H. Mayes, BSN, pertussis may have been diagnosed in infants attending hospitals RN (Center for Vaccine Awareness and Research, Texas Children’s other than those included in our study. However, in general, the Hospital, Houston, TX) and Elizabeth Aguilera (University of Texas majority of infants in the Houston area with moderate or severe Health Sciences Center at Houston) for assistance with data col- pertussis illness, those targeted specifically by the cocooning rec- lection, Rachel Wiseman, MPH (Texas Department of State Health ommendation, are transferred to 1 of these 4 tertiary care facili- Services) for epidemiological data, Robin Schroeder (Baylor Col- ties. Third, we only included laboratory-confirmed pertussis cases, lege of Medicine, Houston, TX) for assistance with manuscript thereby excluding infants in whom the clinician did not order a preparation and Carol J. Baker, MD (Baylor College of Medicine) pertussis diagnostic test. Fourth, although we chose a shorter pre- for her thoughtful review of the manuscript. We thank the staff of intervention period than our previous analysis18 to ensure greater Ben Taub General Hospital, Houston, TX for their cooperation and consistency in diagnostic methods over time, the increased avail- assistance with performing this study. ability of PCR in postintervention periods may mean that clinicians were more likely to test for pertussis than previously. Fifth, our REFERENCES sequential study design did not allow contemporaneous compari- 1. Roush SW, Murphy TV; Vaccine-Preventable Disease Table Working Group. son of cases and controls, thus limiting our ability to account for Historical comparisons of morbidity and mortality for vaccine-preventable the cyclical incidence of pertussis in the community. Epidemiologi- diseases in the United States. JAMA. 2007;298:2155–2163. cal data from the Texas Department of State Health Services, how- 2. van Panhuis WG, Grefenstette J, Jung SY, et al. Contagious diseases in the United States from 1888 to the present. 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