Safety and Immunogenicity of a ChAd155-Vectored Respiratory Syncytial Virus Vaccine in Infants 6-7 Months of age: A Phase 1/2 Randomized Trial.

BACKGROUND: Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections in infants. This phase 1/2, observer-blind, randomized, controlled study assessed the safety and immunogenicity of an investigational chimpanzee-derived adenoviral vector RSV vaccine (ChAd155-RSV, expressing RSV F, N, and M2-1) in infants. METHODS: Healthy 6- to 7-month-olds were 1:1:1-randomized to receive 1 low ChAd155-RSV dose (1.5 × 1010 viral particles) followed by placebo (RSV_1D); 2 high ChAd155-RSV doses (5 × 1010 viral particles) (RSV_2D); or active comparator vaccines/placebo (comparator) on days 1 and 31. Follow-up lasted approximately 2 years. RESULTS: Two hundred one infants were vaccinated (RSV_1D: 65; RSV_2D: 71; comparator: 65); 159 were RSV-seronaive at baseline. Most solicited and unsolicited adverse events after ChAd155-RSV occurred at similar or lower rates than after active comparators. In infants who developed RSV infection, there was no evidence of vaccine-associated enhanced respiratory disease (VAERD). RSV-A neutralizing titers and RSV F-binding antibody concentrations were higher post-ChAd155-RSV than postcomparator at days 31, 61, and end of RSV season 1 (mean follow-up, 7 months). High-dose ChAd155-RSV induced stronger responses than low-dose, with further increases post-dose 2. CONCLUSIONS: ChAd155-RSV administered to 6- to 7-month-olds had a reactogenicity/safety profile like other childhood vaccines, showed no evidence of VAERD, and induced a humoral immune response. Clinical Trials Registration. NCT03636906.

Factors associated with intention for revaccination among patients with adverse events following immunization.

OBJECTIVES: Individuals and healthcare providers may be uncertain about the safety of revaccination after an adverse event following immunization (AEFI). We identified factors associated with physician recommendation for revaccination and participant intention to be revaccinated among patients with adverse events following immunization (AEFIs) assessed in the Canadian Special Immunization Clinic (SIC) Network from 2013 to 2019. METHODS: This prospective observational study included patients assessed in the Canadian Special Immunization Clinic Network from 2013 to 2019 for an AEFI who required additional doses of the vaccine temporally associated with their AEFI. Participants underwent standardized assessment and data collection. Physician recommendations regarding revaccination and participant intent for revaccination were recorded. AEFI impact on daily activities and need for medical attention was captured as low, moderate, high impact and serious (e.g., requiring hospitalization). Multivariable logistic regression analysis identified factors associated with physician recommendation and participant intention for revaccination, controlling for province of assessment. RESULTS: Physician recommendation was significantly associated with the type of AEFI and AEFI impact. Compared to large local reaction, physician recommendation for revaccination was reduced for immediate hypersensitivity (aOR: 0.24 [95% CI: 0.08-0.76]) and new onset autoimmune disease (aOR: 0.16; 95% CI: 0.04-0.69). Compared to low impact AEFIs, physician recommendation was reduced for moderate (aOR: 0.22 [95% CI: 0.07-0.65]), high impact (aOR: 0.08 [95% CI: 0.02-0.30]), and serious AEFIs (aOR: 0.11 [95% CI: 0.03-0.37]). Participant intention for revaccination was significantly associated with AEFI impact, with reduced odds for high versus low impact AEFIs (aOR: 0.12 [95% CI: 0.04-0.42]). CONCLUSION: Physicians appear to use AEFI type and impact to guide recommendations while patients use primarily AEFI impact to form intentions for revaccination. The findings may help inform counselling for patients with AEFIs.

Revaccination and Adverse Event Recurrence in Patients with Adverse Events following Immunization.

OBJECTIVES: To estimate the risk of recurrence of adverse events following immunization (AEFIs) upon revaccination and to determine among patients with suspected vaccine allergy whether allergy skin test positivity was associated with AEFI recurrence. STUDY DESIGN: This prospective observational study included patients assessed in the Canadian Special Immunization Clinic Network from 2013 to 2019 with AEFIs who required revaccination with the vaccine temporally associated with their AEFI. Participants underwent standardized assessment and data collection. Special Immunization Clinic physicians used guidelines to inform their recommendations. Participants were followed up after revaccination to capture AEFI recurrences. Data were transferred to a central database for descriptive analysis. RESULTS: Overall, 588 participants were assessed for 627 AEFIs; 570 (91%) AEFIs occurred in children <18 years of age. AEFIs included immediate hypersensitivity (130/627; 21%), large local reactions (110/627; 18%), nonurticarial rash (51/627; 8%), seizures (26/627; 4%), and thrombocytopenia (11/627; 2%). Revaccination was recommended to 513 of 588 (87%) participants. Among participants recommended and due for revaccination during the study period, 63% (299/477) were revaccinated. AEFI recurrence was 10% (31/299) overall, 31% (15/49) for large local reactions, and 7% (5/66) for immediate hypersensitivity. No recurrence was serious. Among 92 participants with suspected vaccine allergy who underwent skin testing and were revaccinated, the negative predictive value of skin testing for AEFI recurrence was 96% (95% CI 92.5%-99.5%). CONCLUSIONS: Most individuals with AEFIs were safely revaccinated. Among those with suspected vaccine allergy, skin testing may help determine the safety of revaccination.

Effectiveness of palivizumab immunoprophylaxis to prevent respiratory syncytial virus hospitalizations in healthy full-term <6-month-old infants from the circumpolar region of Nunavik, Quebec, Canada.

In Quebec, Canada, eligibility for palivizumab (PVZ) immunoprophylaxis was expanded in fall 2016 to include healthy-full-term (HFT) infants residing in the circumpolar region of Nunavik and aged <3 months at the start of the RSV season or born during the season. This study assessed the effectiveness of PVZ to prevent RSV hospitalizations in these infants during the 3 seasons following its implementation. Medical and laboratory records of <1-year-old infants (375 average annual birth cohort) admitted to regional and tertiary hospitals with respiratory infection during 6 years were reviewed. Individual pharmacy data and birth registries were used to estimate adherence to PVZ and direct PVZ effectiveness in 0-5-month-old HFT infants by comparing the incidence of RSV hospitalizations 1) in protected and unprotected infants, and 2) during PVZ-protected and unprotected days. Over six seasons, the RSV hospitalization rate was 50.2/1000 (72.6/1000 adjusted for underdetection) in <1-year-old infants. PVZ was administered to 73% (469) of eligible HFT infants; 37% (237) received all recommended doses. Overall for the three RSV seasons the incidence of RSV hospitalization in PVZ-protected infants was similar to PVZ-unprotected infants, resulting in PVZ direct effectiveness of -6.7% (95% CI -174.8%, 85.6%). The incidence of RSV hospitalization during PVZ-protected and during PVZ-unprotected days was also similar, resulting in PVZ direct effectiveness of -3.8% (CI -167.6%, 64.9%). Over three RSV seasons, there was no evidence that PVZ reduced RSV hospitalizations in HFT Nunavik infants. In addition, the sub-optimal adherence to the recommended PVZ administration schedule suggests feasibility and acceptability issues.

Promoting vaccination in maternity wards ─ motivational interview technique reduces hesitancy and enhances intention to vaccinate, results from a multicentre non-controlled pre- and post-intervention RCT-nested study, Quebec, March 2014 to February 2015.

BackgroundMany countries are grappling with growing numbers of parents who delay or refuse recommended vaccinations for their children. This has created a need for strategies to address vaccine hesitancy (VH) and better support parental decision-making regarding vaccination.AimTo assess vaccination intention (VI) and VH among parents who received an individual motivational-interview (MI) based intervention on infant immunisation during post-partum stay at a maternity ward between March 2014 and February 2015.MethodsThis non-controlled pre-/post-intervention study was conducted using the results from parents enrolled in the intervention arm of the PromoVaQ randomised control trial (RCT), which was conducted in four maternity wards across the Province of Quebec. Participants (n = 1,223) completed pre- and post-intervention questionnaires on VI and VH using Opel's score. Pre-/post-intervention measures were compared using McNemar's test for categorical variables and Wilcoxon signed-rank test for continuous variables.ResultsPre-intervention: overall VI was 78% and significantly differed across maternity wards (74%, 77%, 84%, 79%, p = 0.02). Post-intervention: VI rose significantly across maternity wards (89%, 85%, 95%, 93%) and the overall increase in VI was 12% (78% vs 90%, p < 0.0001). VH corroborated these observations, pre- vs post-intervention, for each maternity ward (28% vs 16%, 29% vs 21%, 27% vs 17%, 24% vs 13%). Overall, VH was curbed post-intervention by 40% (27% vs 16%; p < 0.0001).ConclusionsCompared with pre-intervention status, participants who received the MI-based intervention on immunisation displayed lower hesitancy and greater intention to vaccinate their infant at 2 months of age.

Nephrotic syndrome following four-component meningococcal B vaccination: Epidemiologic investigation of a surveillance signal.

BACKGROUND: In May 2014, a mass vaccination campaign with four-component meningococcal serogroup B (4CMenB) vaccine was launched in a localized region of Quebec, Canada experiencing high invasive meningococcal B disease endemicity. Active post-marketing surveillance identified several cases of nephrotic syndrome (NS) among ∼49,000 vaccinated individuals aged 2 months to 20 years. We report the epidemiologic investigation of this potential vaccine safety signal. METHODS: Active vaccine safety surveillance was conducted electronically, with participants completing an online questionnaire prompted at 7 days after each dose and 6 months following the last dose. Additional NS cases were sought from provincial hospitalization and emergency room databases. RESULTS: In the year following the first dose of 4CMenB vaccination, four confirmed NS cases (three hospitalized) were identified among vaccinated children 2-5-years-old with onset several months post-vaccination. None had renal biopsy but given their age, and positive response to steroids, idiopathic NS was presumptively diagnosed. Among vaccinated children 1-9-years-old, the NS incidence in the year post-vaccination was 17.7 per 100,000 (1 per 5650 vaccinees) with an NS hospitalization rate (i.e. excluding the outpatient case) that was 3.6-fold higher (95%CI = 0.7-11.8; p = 0.12) than the rest of the province for the same period, and 8.3-fold greater (95%CI = 1.1-62.0; p = 0.039) than during the eight years preceding the immunization campaign in the affected region. CONCLUSION: Active safety surveillance identified an unexpected increase in NS incidence following 4CMenB vaccination. Further epidemiological investigation identified four vaccinated cases in total over a 12 month period of follow up. The greater risk in vaccinees had wide confidence intervals with he lower limit including or just above the nul value, an observation with no or marginal statistical significance. The temporal association with vaccination may be explained by other causes and/or chance clustering of a rare event unrelated to vaccination. To confirm or refute a potential link to vaccination, surveillance in other jurisdictions administering 4CMenB to children 1-9-years-old is needed.

Respiratory syncytial virus contributes to more severe respiratory morbidity than influenza in children < 2 years during seasonal influenza peaks.

PURPOSE: To compare the frequency and the severity of influenza and respiratory syncytial viruses (RSV) infections among children < 24 months hospitalized with respiratory symptoms. METHODS: Data from a prospective study conducted during the peak of five influenza seasons in the Province of Quebec, Canada were used. RESULTS: We detected higher frequency of RSV compared to influenza viruses (55.3% vs. 16.3%). Radiologically confirmed pneumonia was significantly more frequent in children with RSV (39%) than those with influenza (18%) and the clinical course was more severe in RSV than influenza-infected children, especially among infants < 3 months. CONCLUSION: Even during peak weeks of influenza season, we found a higher burden and severity of RSV compared with influenza virus disease in hospitalized children < 24 months.

Promoting vaccination in the province of Québec: the PromoVaQ randomized controlled trial protocol.

BACKGROUND: Vaccination has a huge public health impact. Maintaining vaccine coverage is key to avoid the devastating consequences of resurgence. In the Province of Québec, vaccine coverage in young children are sub-optimal, mostly due to ambivalence toward vaccine safety and efficacy. We previously conducted a regional study in the Québec's Eastern Townships region, the PromoVac Study, to test a new educational intervention, based on motivational interviewing techniques, aimed at promoting infant vaccination. This first study evidenced that the intervention led to a marked increase in mothers' intention to vaccinate, and vaccine coverage in their infants. The current study protocol aims at scaling up these results at a provincial level using a randomized controlled trial design. METHODS: This pragmatic, randomized, controlled, parallel-group clinical trial will compare the effectiveness of the motivational interviewing to an educational intervention, including the distribution of an information flyer as standard of care on vaccination coverage in four maternity wards across the Province of Québec (PromovaQ). Adult mothers of children born in participating maternity wards were recruited between March 2014 and February 2015. Vaccination coverage will be assessed at 3-years of age, thus the trial is expected to be completed in March 2019. Statistical analyses will be conducted under the intention-to-treat principle. Vaccine coverage will be analyzed using Chi-squared distribution testing and logistic regression to identify determinant factors. Secondary outcomes will include vaccine hesitation and intention scores, mother's knowledge, attitudes and beliefs about immunization, and psychosocial determinants of intention to vaccinate. DISCUSSION: In the case results of this Provincial RCT be confirmed, serious consideration should then be given by Ministry of Health authorities to the possible implementation of MI-based strategies across provincial maternity wards. To ensure adequate input and secure implementation, study design and results will be reviewed with relevant stakeholders, including the children's families, and provincial and regional decision-makers. Results will be adapted and shared with all stakeholders. TRIAL REGISTRATION: ClinicalTrials.gov NCT02666872 (Retrospectively registered as January 28, 2016).

Overview of knowledge, attitudes, beliefs, vaccine hesitancy and vaccine acceptance among mothers of infants in Quebec, Canada.

BACKGROUND: Vaccine hesitancy (VH) is a growing problem. The first step in addressing VH is to have an understanding of who are the hesitant individuals and what are their specific concerns. The aim of this survey was to assess mothers' level of vaccine hesitancy and vaccination knowledge, attitudes, and beliefs. METHODS: Mothers of newly-born infants in four maternity wards in Quebec (Canada) completed a self-administered questionnaire. The questionnaire included items to assess VH and intention to vaccinate. VH scores were calculated using the Parents Attitudes about Childhood Vaccines (PACV) survey. Multivariate logistic regression was performed to determine variables associated with intention to vaccinate (OR; 95% CI). RESULTS: Overall, 2645 questionnaires were included in this analysis and 77.5% of respondents certainly intended to vaccinate their infant at 2 months of age. Based on the PACV 100-point scale, 56.4% of mothers had a 0 to ˂30 score (low level of VH); 28.6% had a 30 to ˂50 and 15.0% had a score of 50 and higher (high level of VH).The main determinants of mothers' intention to vaccinate were the perceived importance of vaccinating infants at 2 months of age (OR = 9.2; 5.9-14.5) and a low score of VH (OR = 7.4; 5.3-10.3). DISCUSSION: Although the majority of mothers held positive attitudes toward vaccination, a large proportion were moderately or highly vaccine hesitant. Mothers' level of VH was strongly associated with their intention to vaccinate their infants, showing the potential detrimental impact of VH on vaccine uptake rates and the importance of addressing this phenomenon.

Thalidomide in Refractory Tuberculomas and Pseudoabscesses.

Paradoxical immune reconstitution inflammatory syndrome is a well-described entity even in immunocompetent children, principally in association with Mycobacterium tuberculosis infections. Central nervous system involvement is a potential life-threatening form, sometimes refractory to standard treatment. We report the case of an HIV-negative refugee teenager, who presented with brain tuberculomas and pseudoabscesses responsive only to thalidomide.

Immunizing Patients With Adverse Events After Immunization and Potential Contraindications to Immunization: A Report From the Special Immunization Clinics Network.

BACKGROUND: For patients who have experienced adverse events following immunization (AEFI) or who have specific medical conditions, there is limited evidence regarding the best approach to immunization. The Special Immunization Clinics (SICs) Network was established to standardize patient management and assess outcomes after reimmunization. The study objective was to describe the first 2 years of the network's implementation. METHODS: Twelve SICs were established across Canada by infectious diseases specialists and allergists. Inclusion criteria were as follows: local reaction ≥ 10 cm, allergic symptoms < 24 hours postimmunization, neurologic symptoms and other AEFI or medical conditions of concern. Eligible patients underwent a standardized evaluation, causality assessment was performed, immunization recommendations were made by expert physicians and patients were followed up to capture AEFI. After individual consent, data were transferred to a central database for analysis. RESULTS: From June 2013 to May 2015, 151 patients were enrolled. Most were referred for prior AEFI (132/151, 87%): 42 (32%) for allergic-like reactions, 31 (23%) for injection-site reactions, 20 (15%) for neurologic symptoms and 39 (30%) for other systemic symptoms. Nineteen patients (13%) were seen for underlying conditions that complicated immunization. Reimmunization was recommended for 109 patients, 60 of whom (55%) were immunized and followed up. Eleven patients (18%) experienced recurrence of their AEFI; none were serious (eg, resulting in hospitalization, permanent disability or death). CONCLUSIONS: The most frequent reasons for referral to a SIC were allergic-like events and injection site reactions. Reimmunization was safe in most patients. Larger studies are needed to determine outcomes for specific types of AEFI.

Safety of live-attenuated influenza vaccination in cystic fibrosis.

OBJECTIVES: Given the improved efficacy of the nasal live-attenuated influenza virus vaccine (LAIV) compared with the injectable vaccine in children, we aimed to determine its safety in individuals with cystic fibrosis (CF). METHODS: A cohort of 168 study participants, aged 2 to 18 years with CF, vaccinated with LAIV between October 1, 2012, and January 30, 2013, was followed prospectively for 56 days after initial vaccination in 3 pediatric CF clinics across the province of Quebec. Days 0 to 28 post-LAIV were considered the at-risk period for all outcomes of interest, and days 29 to 56 post-LAIV were considered the non-at-risk period. Incident respiratory deteriorations were defined as an unscheduled medical visit, hospitalization, or a new course of oral antibiotics for respiratory complaints. Using a self-controlled design, incidence rate ratios (IRR) were used to compare at-risk and non-at-risk periods. RESULTS: Comparing at-risk to non-at-risk periods, there was no significant increase in the rate of incident respiratory deteriorations (IRR, 0.72; 95% confidence interval, 0.11-4.27) or all-cause hospitalizations (IRR, 1.16; 95% confidence interval, 0.30-4.81). A greater proportion of participants reported experiencing at least 1 minor respiratory and/or systemic adverse event after immunization during the at-risk period compared with the non-at-risk period (77% vs 54%, respectively). During the first week after LAIV, 13 of 168 (8%) children reported some wheezing, with the vast majority, 9 of 13 (69%), on the day of vaccination. CONCLUSIONS: There was no increased risk of respiratory deterioration or all-cause hospitalization associated with LAIV in our study population. LAIV seems well tolerated in children and adolescents with CF.

Effectiveness of pandemic H1N1 vaccine against influenza-related hospitalization in children.

OBJECTIVE: Young children are generally considered immunologically naive with respect to influenza exposure opportunities; thus, a 2-dose schedule is recommended when a child is first immunized with conventional influenza vaccine lacking adjuvant. We estimated the effectiveness of a single pediatric dose of AS03-adjuvanted vaccine against hospitalization for confirmed pandemic influenza A/H1N1 (pH1N1) infection in children aged 6 months to 9 years during the fall 2009 vaccination campaign. METHODS: In a matched case-control design, case subjects were children hospitalized for pH1N1 infection in the Fall of 2009, in Quebec, Canada. Controls were nonhospitalized children, matched by age and region of residence. Vaccination status in case subjects and controls was ascertained in relation to the case subject's date of illness onset. Vaccine effectiveness was estimated through conditional logistic regression. RESULTS: The overall effectiveness of a single pediatric dose of vaccine administered ≥14 days before illness onset was 85% (95% confidence interval [CI]: 61% to 94%), varying according to age category but with wide and overlapping CIs: 92% (95% CI: 51% to 99%) in 6-23 month-old children, 89% (95% CI: 34% to 98%) in 2-4 year-olds, and 79% (95% CI: -31% to 96%) in 5-9 year-olds. Overall vaccine effectiveness for immunization ≥10 days before illness onset was slightly lower at 80% (95% CI: 60% to 90%), with similar variation according to age. CONCLUSION: In children aged 6 months to 9 years, a single pediatric dose of the AS03-adjuvanted pH1N1 vaccine was highly protective against hospitalization beginning at 10 and 14 days after vaccination.

Acute otitis media and its prevention by immunization: a survey of Canadian pediatricians' knowledge, attitudes and beliefs.

INTRODUCTION: Acute otitis media (AOM) is one of the most common bacterial infectious diseases among children and is a leading cause of child healthcare visits and antibiotic prescriptions. Few vaccines have the potential to prevent AOM. The newer pneumococcal conjugate vaccines (PCV) offer a larger spectrum of protection against AOM, as well as preventing severe diseases. The main aim of this study was to assess pediatricians' opinions regarding AOM and its prevention by immunization. RESULTS: Response rate was 50%. Around 60% of respondents estimated that more than 50% of their patients under the age of 3 years would suffer from at least one episode of AOM in the following year. Most respondents (79%) rated consequences of AOM as moderate. Almost all physicians (99%) considered the newer PCV as safe and effective. Most respondents considered their knowledge of the new vaccines was sufficient. More than 90% had a firm intention to recommend newer PCV to their patients. Perceived benefits of AOM prevention by immunization were: reduction of antibiotic administration and reduction of post-AOM complications. More than half of respondents (53%) considered the risk of adverse events as a barrier to AOM prevention by immunization. In multivariate analysis, the main determinant of pediatricians' intention to recommend newer PCV was perceived safety and efficacy of the vaccines (partial R2 = 0.40, p < 0.0001). DISCUSSION: Results of this survey show that AOM is perceived as an important health problem by paediatricians. Information about the increased protection against AOM offered by newer PCV should be disseminated to physicians. MATERIALS AND METHODS: A self-administered, anonymous, mail-based questionnaire based upon the Health Belief Model and the Analytical framework for immunization programs was sent to all 1,852 Canadian pediatricians.

Canadian family physicians' and paediatricians' knowledge, attitudes and practices regarding A(H1N1) pandemic vaccine.

BACKGROUND: One of the main determinants of public immunization success is health professionals' support and recommendations. Little is known about the physicians' level of support and intentions regarding A(H1N1) pandemic influenza vaccination. The aim of this survey was to document Canadian family physicians' and paediatricians' knowledge, attitudes and practices (KAP) as well as their intentions regarding A(H1N1) pandemic influenza vaccines right before the beginning of the largest immunization campaign in Canadian history. FINDINGS: A self-administered, anonymous, mail-based questionnaire was sent to a random sample of family physicians and to all paediatricians practicing in Canada. All 921 questionnaires received by October 29 2009 were included in the analysis. Between 72% and 92% of respondents agreed with the statements regarding vaccine safety, effectiveness and acceptability. More than 75% of respondents intended to recommend the A(H1N1) pandemic influenza vaccine to their patients and to get vaccinated themselves. The most significant factors associated with the intention to recommend A(H1N1) pandemic vaccines were physicians' intention to be vaccinated against influenza themselves and the perceived acceptability of the vaccine by the vaccinators. CONCLUSIONS: Most Canadian family physicians and paediatricians surveyed were supportive of the A(H1N1) pandemic influenza vaccination before its implementation and large media coverage.

Is pertussis immune globulin efficacious for the treatment of hospitalized infants with pertussis? No answer yet.

In a multicenter, randomized, placebo-controlled clinical trial of pertussis immune globulin, intravenous (P-IGIV), 25 infants hospitalized with pertussis were enrolled in 24 months (15% of the target sample size) before the study was prematurely terminated because of expiration of the P-IGIV lots and unavailability of additional study product. Although well tolerated, there was no difference in the number or rate of improvement of symptoms (paroxysmal cough, whoop, apnea, bradycardia, oxygen desaturations) in P-IGIV recipients compared with placebo.

Human parechovirus 3 and neonatal infections.

A third serotype of human parechovirus (HPeV) has been recently isolated from stool specimens of a young Japanese child with transient paralysis. We report 3 additional cases of neonatal sepsis caused by HPeV-3 in the fall of 2001 in Canadian infants 7-27 days old. All children were hospitalized with high fever, erythematous rash, and tachypnea for a median of 5 days. The viruses isolated from nasopharyngeal aspirates grew slowly on tertiary monkey kidney cells and were successfully passaged on Vero cells. The predicted amino acid identity of the VP0-VP3-VP1 region of the three viruses was 74.6%-74.8%, 73.4%-73.6%, and 97.0%-97.1% when compared to HPeV-1, -2, and -3 prototype strains, respectively. Although different, our isolates were closely related; amino acid identity was 99.6%-100% for the last 3 proteins.

Azithromycin is as effective as and better tolerated than erythromycin estolate for the treatment of pertussis.

OBJECTIVE: Although universal immunization against Bordetella pertussis (whooping cough) infection has resulted in dramatic reductions in the incidence of pertussis, outbreaks continue to occur in countries with excellent vaccine coverage. Treatment of infection may ameliorate symptom severity during the catarrhal phase of pertussis but has no effect on established paroxysms, emesis, or apnea if given during the paroxysmal or convalescent phases. Erythromycin, recommended for treatment of pertussis to prevent transmission of infection, is poorly tolerated because of gastrointestinal side effects. We compared the safety and efficacy of erythromycin with azithromycin for treatment of pertussis in a large, randomized, controlled trial that enrolled children from primary care practices in 1 American and 11 Canadian urban centers. METHODS: Children who were 6 months to 16 years of age and had cough illness that was suspected to be or was culture confirmed as pertussis were randomized to azithromycin (10 mg/kg on day 1 and 5 mg/kg on days 2-5 as a single dose) or erythromycin estolate (40 mg/kg/day in 3 divided doses for 10 days) with stratification by center. The primary outcome measure was bacteriologic cure of infection as determined by cultures of nasopharyngeal aspirates. Culture-positive participants had a second aspirate collected at the end of therapy (days 5-7 for azithromycin, days 10-12 for erythromycin) and 1 week after therapy. Bacteriologic cure was defined as negative cultures at the end of therapy. Bacteriologic relapse was defined as a positive culture 1 week after completion of therapy and after a negative end-of-therapy culture. Secondary outcomes were pertussis diagnosed by serology and polymerase chain reaction (PCR), treatment-associated adverse events, compliance, and presence of clinical symptoms at the end of the treatment course. Serology was performed using standard enzyme-linked immunosorbent assay methods. A participant was considered to have pertussis when the PCR was positive or a 4-fold increase in pertussis toxin antibody between baseline and follow-up visits was observed. PCR was performed using a 1046-bp ClaI DNA fragment from B pertussis. Adverse events (nausea, vomiting, diarrhea, any gastrointestinal complaint, or other) were determined by a parent-completed diary that was reviewed with study personnel during study visits. Compliance was measured by review of the parent medication diary during study visits and observation of medication containers by the pharmacist at study completion. Symptoms were determined by history collected by study personnel at enrollment and subsequently from the diary. The design of the study was an equivalence trial, aimed at demonstrating that the bacteriologic failure rates with the 2 therapies did not differ by >8%. For the safety analysis, all participants who received at least 1 dose of study drug were included. In the per-protocol efficacy analysis, all culture-positive participants with end-of-treatment cultures were considered. RESULTS: A total of 477 children were enrolled and randomly assigned to either azithromycin (n = 239) or erythromycin (n = 238). Of these children, 114 (24%) grew B pertussis from nasopharyngeal specimens (azithromycin group: 58 of 239 [24%]; erythromycin group: 56 of 238 [23%]); these children composed the efficacy cohort for the per-protocol and intention-to-treat analyses. Serology and PCR added 52 children to the number considered to have pertussis for a total of 35% (166 of 477) of all children who presented with cough illness. In the safety analysis (antibiotic side effects, compliance) and comparison of cough symptoms after treatment, all randomized children are reported in their assigned treatment group. At end of therapy, bacterial eradication was demonstrated in all 53 patients in the azithromycin group and all 53 patients in the erythromycin group with follow-up cultures available (eradication 100%; 95% confidence interval [CI]: 93.3-100). No bacterial recurrence was demonstrated in children with 1 week posttreatment nasopharyngeal cultures available (51 and 53 participants in the azithromycin and erythromycin arms, respectively [0%, 95% CI: 0-7.0; and 0%, 95% CI: 0-6.7]). No serious adverse events attributable to study drug were observed. Gastrointestinal adverse events were reported less frequently in azithromycin (18.8%; 45 of 239) than in erythromycin estolate (41.2%; 98 of 238) recipients (90% CI on difference: -29.0% to -15.7%) as a result of less nausea (2.9% vs 8.4%; 95% CI: -8.9% to -2.0%), less vomiting (5.0% vs 13.0%; 95% CI: -4.9% to -1.4%), and less diarrhea (7.1% vs 11.8%; 95% CI: -9.0% to -0.3%). Children who were randomized to azithromycin were much more likely to have complied with antimicrobial therapy over the treatment period. In the azithromycin group, 90% of children took 100% of prescribed doses, whereas only 55% of children in the erythromycin group took 100% of prescribed doses. CONCLUSIONS: In this large, multicenter, randomized trial, we found that azithromycin is as effective as erythromycin estolate for the treatment of pertussis in children. Gastrointestinal adverse events were much more common with erythromycin treatment than azithromycin. Compliance with therapy was markedly better with azithromycin than with erythromycin in this study.