RESEARCH Azithromycin to Prevent Pertussis in Household Contacts, Catalonia and Navarre, Spain, 2012–2013 Josep Alvarez, Pere Godoy, Pedro Plans-Rubio, Neus Camps, Monica Carol, Gloria Carmona, Ruben Solano, Cristina Rius, Sofia Minguell, Irene Barrabeig, Maria R. Sala-Farré, Raquel Rodriguez, Manuel Garcia-Cenoz, Carmen Muñoz-Almagro, Angela Dominguez, Transmission of Pertussis in Households Working Group1 We retrospectively assessed the effectiveness of Many researchers attribute this pattern to an increas- azithromycin in preventing transmission of pertussis to ingly waning immunity in persons vaccinated with a patient’s household contacts. We also considered the the acellular vaccines currently used in most coun- duration between symptom onset in the primary patient tries instead of the whole-cell vaccines used until the and azithromycin administration. We categorized con- late 1990s (7–11). tacts into 4 groups: those treated within <7 days, 8–14 The causative agent of pertussis, Bordatella per- days, 15–21 days, and >21 days after illness onset in the tussis, is mainly spread through household contacts primary patient. We studied 476 primary index patients (12,13). However, guidelines contain few measures and their 1,975 household contacts, of whom 4.5% were to prevent intrahousehold transmission. Most guide- later identified as having pertussis. When contacts start- lines recommend patient isolation, vaccination of ed chemoprophylaxis within <21 days after the primary patient’s symptom onset, the treatment was 43.9% effec- children <7 years of age, and chemoprophylaxis tive. Chemoprophylaxis started >14 days after primary for household members and other frequent con- patient’s symptom onset was less effective. We recom- tacts (14,15). Generally, guidelines recommend that mend that contacts of persons with pertussis begin che- household contacts begin chemoprophylaxis with a moprophylaxis within <14 days after primary patient’s macrolide within 21 days after symptom onset in the symptom onset. index patient. However, evidence of its effectiveness in preventing transmission is limited (16,17). In addi- A fter decades of decline (1,2) and despite high vaccination coverage, the incidence of pertussis has increased substantially in Catalonia, Spain (3,4); tion, there is a lack of studies on the effectiveness of azithromycin, because studies on chemoprophylaxis for pertussis usually use erythromycin (18,19). Spain (5); and other regions and countries with well- A study of pertussis patients in Catalonia and established epidemiologic surveillance systems (6). Navarre, 2 autonomous communities in Spain, as- sessed the overall effectiveness of azithromycin in Author affiliations: Agència de Salut Pública de Catalunya, preventing transmission among household contacts Barcelona, Spain (J. Alvarez, P. Godoy, P. Plans-Rubio, (20). After adjustment for age, sex, vaccination his- N. Camps, M. Carol, G. Carmona, S. Minguell, I. Barrabeig, tory, and relationship to the primary patient, chemo- M.R. Sala-Farré, R. Rodriguez); Institut de Recerca Biomédica prophylaxis had an adjusted effectiveness of 62.1% in de Lleida, Leida, Spain (P. Godoy); Consorcio de Investigación this study, consistent with the results of other stud- Biomédica en Red de Epidemiología y Salud Pública (CIBERSP), ies (21). However, this study cohort (20) included 164 Madrid, Spain (P. Godoy, P. Plans-Rubio, R. Solano, C. Rius, nonprimary index patients (i.e. patients with the first I. Barrabeig, M. García Cenoz, C. Muñoz-Almagro, A. Domínguez) reported case of pertussis in a household, but not the Agència de Salut Pública de Barcelona, Barcelona (R. Solano, first chronological case) and their 877 contacts, did C. Rius); Instituto de Salud Pública de Navarra, Pamplona, Spain not consider the duration between symptom onset in (M. Garcia-Cenoz); Hospital de Sant Joan de Deu, Barcelona the primary patient and start of treatment, and did (C. Muñoz-Almagro); Universitat de Barcelona, Barcelona (A. Dominguez) Members of the Transmission of Pertussis in Households Working 1 DOI: https://doi.org/10.3201/eid2611.181418 Group who contributed data are listed at the end of this article. 2678 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 26, No. 11, November 2020 Azithromycin to Prevent Pertussis not exclude co-primary and tertiary patients (who might differ from the index patient, who had the first might not have been infected by the primary patient) reported case); co-primary patient, symptom onset (20). We assessed whether delays in chemoprophy- within <6 days of the primary patient; secondary laxis reduce its effectiveness. patient, symptom onset within 7–28 days after the primary patient; and tertiary patient, symptom on- Materials and Methods set within >28 days after the primary patient. Before The study cohort comprised the household contacts of administering treatment, ESU staff took nasopharyn- primary index patients with pertussis detected by the geal samples of each patient and their contacts with Epidemiologic Surveillance Units (ESU) of Catalonia possible pertussis symptoms. We considered symp- and Navarre from January 1, 2012, through December tomatic contacts as patients when we confirmed their 31, 2013. We followed up on the household contacts diagnosis by culture or real-time PCR or found an ep- 28 days after symptom onset in the index patient. idemiologic link (onset of symptoms ≤28 days later) The index patient was the first patient with per- with a laboratory-confirmed case. tussis reported to the ESU in each household and the We evaluated the characteristics of persons who primary patient was the first patient with pertussis in did or did not receive chemoprophylaxis using χ2 (for each household, regardless of whether or when his categorical variables) and Student t-test (for continu- or her case had been reported. In most situations, the ous variables). We then studied the effectiveness of index and primary patients were the same person; for chemoprophylaxis in preventing pertussis in persons our study, we excluded instances when the index and classified as healthy contacts or secondary patients primary patients were different persons. The ESU after 28 days of follow-up. We excluded co-primary prescribed the postexposure intervention for every and tertiary patients from the analysis because they index patient and their contacts. Our study included might not have been infected by primary patients. only patients with B. pertussis infection confirmed by We calculated the effectiveness of azithromycin culture or real-time PCR of nasopharyngeal samples. for 5 days using the formula effectiveness = (1 − rela- We categorized household contacts as persons regu- tive risk) × 100. We considered effectiveness accord- larly living in the same household or persons in the ing to the duration between symptom onset in the home for >2 hours during the transmission period primary patient and start of chemoprophylaxis. We (<21 days after symptom onset in the primary patient classified this duration into 4 categories: 1–7 days, or <5 days after the patient’s start of treatment). 8–14 days, 15–21 days, and >21 days after illness on- ESU staff conducted telephone interviews to set in the primary patient. gather information about each contact’s age, sex, re- We used unconditional logistic regression to es- lationship to the index or primary patient, receipt of timate effectiveness adjusted by vaccination status. chemoprophylaxis and start date, vaccination history, We also assessed effectiveness according to the age and presence of pertussis symptoms (cough lasting of contacts (<1 year, 1 year, 2–3 years, 4–6 years, 7–10 >2 weeks, paroxysmal cough, posttussive vomiting, years, 11–18 years, 19–40 years, and >40 years of age), inspiratory stridor, and apnea). Staff collected vac- degree of relationship (cohabitants vs. persons in the cination statuses and laboratory results (i.e., culture home >2 hours), and type of relationship with the pri- assay, PCR) from the contacts’ medical records and mary index patient (mother, father, sibling, grandpar- determined a person’s vaccination status using the ent, spouse, child, and other). We analyzed the data vaccination records of each autonomous community. using SPSS Statistics 18.0 (IBM, https://www.ibm. We categorized each contact as fully vaccinated (>4 com), and Epi Info (Centers for Disease Control and doses of vaccine), incompletely vaccinated (<4 dos- Prevention, https://www.cdc.gov). es), unvaccinated (no dose), incompletely vaccinated The Ethics Committee of the Hospital Sant Joan because of age (i.e. children <18 months of age who de Deu approved the study (code: PIC-79–11). All had received recommended doses), and unvaccinated contacts and family members gave informed written because of age (i.e. children <2 months of age). Be- consent to participate. cause few contacts >18 years of age had vaccination records, we analyzed this variable only in contacts Results <18 years of age. From January 1, 2012, through December 31, 2013, At 28 days after symptom onset in the primary the ESU detected 688 cases of pertussis, of which patient, we categorized contacts as follows: healthy 524 (76.2%) were primary index cases. Of these, 476 contact, no clinical symptoms of pertussis; primary (90.8%) case-patients had reported data on the ad- patient, the first patient at a specific address (this ministration and outcome of chemoprophylaxis for Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 26, No. 11, November 2020 2679 RESEARCH 2,051 contacts. We excluded 76 contacts because they vaccinated (65.7% had received >4 doses and 6.1% were co-primary patients (65 persons) or tertiary pa- were completely vaccinated in accordance with rec- tients (11 persons). Therefore, our final study consist- ommendations for their age). ed of 1,975 household contacts of 476 primary index Of the 1,720 (87.1%) contacts who received che- patients (hereafter primary patients). moprophylaxis, 1,266 (73.6%) were treated within Of the 1,975 contacts we analyzed, 53.5% were <21 days after symptom onset of the primary patient: female. The mean age was 33.9 (SD ± 20.5) years; 309 (18%) were treated within <7 days, 544 (31.6%) 2.2% of contacts were <1 year of age (the most vul- within 8–14 days, 413 (24%) within 15–21 days, and nerable group), 34.7% were 19–40 years of age, and 393 (22.8%) in >21 days. At 28 days after symptom 35.4% were >40 years of age. A total of 76.5% of con- onset in the primary patient, pertussis had developed tacts lived with the primary patient; 23.4% of con- in 4.5% of contacts, including 1% of those who had re- tacts were mothers, 21.5% were fathers, and 19.6% ceived chemoprophylaxis <7 days and 7.6% of those were siblings of the primary patient (Table 1). Most who received it >21 days after symptom onset in the of the 591 contacts <18 years of age were completely primary patient (Figure). The 1,720 (87.1%) contacts Table 1. Characteristics of household contacts of primary patients with pertussis, Catalonia and Navarre, Spain, 2012–2013 Received chemoprophylaxis* Characteristic Contacts* Yes No p value† Total 1,975 (100) 1,720 (87.1) 255 (12.9) Sex M 919 (46.5) 797 (46.3) 122 (47.8) 0.64 F 1,056 (53.5) 923 (53.7) 133 (52.2) Age, y <1 44 (2.2) 41 (2.4) 3 (1.2) 0.67 1 33 (1.7) 33 (1.9) 0 (0.0) 2–3 79 (4.0) 67 (3.9) 12 (4.7) 4–6 132 (6.7) 120 (7.0) 12 (4.7) 7–10 154 (7.8) 135 (7.8) 19 (7.5) 11–18 149 (7.5) 131 (7.6) 18 (7.1) 19–40 685 (34.7) 595 (34.6) 90 (35.3) >40 699 (35.4) 598 (34.8) 101 (39.6) Mean age, y (± SD) 33.9 (20.5) 33.4 (20.5) 37.3 (20.6) 0.005‡ Median age, y 36 36 39 Type of household contact Household cohabitant 1,511 (76.5) 1,311 (76.2) 200 (78.4) 0.44 Other >2 h 464 (23.5) 409 (23.8) 55 (21.6) Relationship to primary patient Mother 463 (23.4) 400 (23.3) 63 (24.7) 0.69 Father 424 (21.5) 366 (21.3) 58 (22.7) Sibling 388 (19.6) 352 (20.5) 36 (14.1) Grandparent 281 (14.2) 248 (14.4) 33 (12.9) Child 19 (1.0) 15 (0.9) 4 (1.6) Spouse 26 (1.3) 20 (1.2) 6 (2.4) Other 374 (18.9) 319 (18.5) 55 (21.6) Vaccination status <18 y 591 527 64 Fully vaccinated (>4 doses) 388 (65.7) 349 (66.2) 39 (60.9) 0.36 Incomplete for age 36 (6.1) 35 (6.6) 1 (1.6) Incomplete 16 (2.7) 15 (2.8) 1 (1.6) Not vaccinated 24 (4.1) 21 (4.0) 3 (4.7) Too young for vaccination 5 (0.8) 4 (0.8) 1 (1.6) Not stated 122 (20.6) 103 (19.5) 19 (29.7) Chemoprophylaxis initiation, d§ 1–7 309 (15.6) 309 (18.0) 0 8–14 544 (27.5) 544 (31.6) 0 15–21 413 (20.9) 413 (24.0) 0 >21 393 (19.9) 393 (22.8) 0 Unknown 61 (3.1) 61 (3.5) 0 No chemoprophylaxis 255 (12.9) 255 (14.8) 0 Type of contact Healthy contact 1,886 (95.5) 1,645 (95.6) 241 (94.5) 0.44 Secondary case 89 (4.5) 75 (4.4) 14 (5.5) *Values are no. (%) except as indicated. †p value for χ2 test. ‡p value for Student t-test. §Days after symptom onset of the primary patient. 2680 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 26, No. 11, November 2020 Azithromycin to Prevent Pertussis Figure. Flowchart of study of effectiveness of chemoprophylaxis in preventing pertussis transmission among household contacts of primary index patients, Catalonia and Navarre, Spain, 2012–2013. *Pooled data. who received and 255 (12.9%) who did not receive Overall, in comparison with results for contacts chemoprophylaxis differed significantly only by who did not receive chemoprophylaxis, the treatment mean age (33.4 vs. 37.3 years) and being a sibling of had an effectiveness of 82.3% (95% CI 39.1%–94.9%) the primary patient (20.5% vs. 14.1%) (Table 1). for contacts who received it within <7 days, 46.4% Chemoprophylaxis was 43.9% (95% CI –1.8% to (95% CI –8.1% to 73.4%) for those who received it 69.1%) effective when administered <21 days after within 8–14 days, and 11.8% (95% CI –71.5% to 54.6%) symptom onset in the primary patient. Chemopro- for those who received it within 15–21 days. When we phylaxis was ineffective (–39.0% [95% CI –157.0% to adjusted the results by vaccination history, we found 25.0%]) when administered after >21 days (Table 2). the reduction over time resembled the declining ef- Of contacts <18 years of age, 87.6% (298/340) fectiveness (Table 3). received chemoprophylaxis, which was 44.1% (95% CI –42.2% to 77.7%) effective. Comparison of con- Discussion tacts <18 years of age who did and did not receive Most guidelines recommend that contacts take che- chemoprophylaxis within <21 days showed that che- moprophylaxis with azithromycin <21 days after moprophylaxis was 44.1% (95% CI –59.5% to 80.4%) symptom onset in the index patient (14,22–24). By effective in completely vaccinated persons (e4 doses) only including primary index cases, our study more and 50% (95% CI –248.0% to 92.8%) effective in in- precisely assessed the effectiveness of chemoprophy- completely vaccinated persons. This difference was laxis in preventing household transmission. not significant, although the statistical power was Chemoprophylaxis had an overall effectiveness very low (16% for completely vaccinated and 8% for of 43.9% (95% CI –1.8% to 69.1%), lower than the unvaccinated persons) (Table 2). 62.1% found in the previous study in Catalonia and Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 26, No. 11, November 2020 2681 RESEARCH Table 2. Effectiveness of chemoprophylaxis to prevent pertussis transmission among 1,975 household contacts, Catalonia and Navarre, Spain, 2012–2013 Type of contact Healthy contact, Secondary case- Chemoprophylaxis timing for contacts* No. contacts no. (%) patient, no. (%) Effectiveness, % (95% CI) All 1,914 1831 (95.7) 64 (3.3) 1–21 d 1,266 1,227 (96.9) 39 (3.1) 43.9 (−1.8 to 69.1) >21 d 393 363 (92.4) 30 (7.6) −39.0 (−157.0 to 25.0) No chemoprophylaxis 255 241 (94.5) 14 (5.5) Reference Completely vaccinated 1–21 d 248 233 (94.0) 15 (6.0) 44.1 (−59.5 to 80.4) No chemoprophylaxis 37 33 (89.2) 4 (10.8) Reference Incompletely vaccinated 1–21 d 50 45 (90.0) 5 (10.0) 50.0 (−248.0, 92.8) No chemoprophylaxis 5 4 (80.0) 1 (20.0) Reference *No. days after symptom onset in primary patient whose contacts received chemoprophylaxis. Includes vaccination status of contacts <18 years of age. Navarre (20). The effectiveness was highest when giv- be more closely investigated in children <1 year of en during the first 7 days after symptom onset in the age, in whom pertussis is particularly serious. primary patient and fell significantly with increased Our finding that azithromycin was ineffective treatment delays. when administered >14 days after symptom onset in Our results reinforce the ineffectiveness (14,24) the primary patient suggests that physicians should (–39.0% [95% CI –157.0% to 25.0%]) of administering not initiate chemoprophylaxis after that time. This chemoprophylaxis >21 days after symptom onset in strategy might reduce costs, potential adverse effects, the primary patient. Chemoprophylaxis also had a and risk for azithromycin resistance (26–28). low effectiveness when administered after 14 days. The limited effectiveness of chemoprophylaxis Our results indicate that chemoprophylaxis should be in reducing pertussis transmission highlights the im- started <14 days after symptom onset in the primary portance of patient isolation until 21 days after symp- patient; however, this recommendation conflicts with tom onset, or 5 days after treatment initiation (22,24). the established clinical definition of pertussis, which Furthermore, communities should strive for high describes a cough lasting >2 weeks (22,25). Therefore, vaccination coverage; physicians should review the we recommend that chemoprophylaxis should start vaccination status of contacts; and physicians should immediately after the ESU is alerted to the possibil- regularly update the vaccination schedule, as recom- ity of pertussis, without waiting for a laboratory-con- mended by some guidelines (22). These measures are firmed diagnosis. especially important when a patient with pertussis Perhaps because of the small number of persons has contact with children <1 year of age; pregnant in each category, effectiveness was not associated women; immunosuppressed persons; and persons with age, vaccination status, degree of home contact, with chronic diseases, such as asthma, cystic fibrosis, or relationship with the primary patient. However, or congenital heart disease (6). confounding variables might influence the (lack of) Our study was subject to several limitations. It association between vaccination status and chemo- lacked the statistical power to estimate the effective- prophylaxis effectiveness; for example, vaccine ef- ness of chemoprophylaxis in terms of contact age, fectiveness might wane in some age groups or be degree of home contact, and relationship with the bolstered in persons not cohabiting (i.e., point contact primary patient. We used self-reported data on treat- instead of prolonged contact) with the primary pa- ment, so we cannot verify whether contacts complied tient. The effectiveness of chemoprophylaxis should with treatment. We also cannot rule out the possibility Table 3. Effect of delay in chemoprophylaxis on preventing pertussis transmission among 1,975 household contacts, Catalonia and Navarre, Spain, 2012–2013 Type of contact Chemoprophylaxis for contacts, No. Healthy contact, Secondary case- Effectiveness, % Adjusted effectiveness, d* contacts no. (%) patient, no. (%) (95% CI) %† (95% CI) 1–7 309 306 (99.0) 3 (1.0) 82.3 (39.1, 94.9) 89.0 (6.7, 98.7) 8–14 544 528 (97.1) 16 (2.9) 46.4 (−8.1 to 73.4) 37.2 (−114.9 to 75.4) 15–21 413 393 (95.2) 20 (4.8) 11.8 (−71.5 to 54.6) 2.8 (−171.3 to 65.2) No chemoprophylaxis 255 241 (94.5) 14 (5.5) Referent *No. days after symptom onset in primary patient whose contacts received chemoprophylaxis. †Adjusted by vaccination status. 2682 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 26, No. 11, November 2020 Azithromycin to Prevent Pertussis that undetected infected persons could have altered epidemic despite high levels of vaccination coverage with transmission dynamics. Finally, confirmatory labora- acellular pertussis vaccine. Enferm Infecc Microbiol Clin. 2015;33:27–31. https://doi.org/10.1016/j.eimc.2013.09.013 tory testing was not conducted for 40.4% of second- 5. Sizaire V, Garrido-Estepa M, Masa-Calles J, Martinez de ary patients. However, we believe the probability of Aragon MV. Increase of pertussis incidence in 2010 to 2012 misclassification is very low. after 12 years of low circulation in Spain. Euro In conclusion, our results show azithromycin Surveill. 2014;19:20875. https://doi.org/10.2807/1560-7917. ES2014.19.32.20875 chemoprophylaxis for pertussis had low effective- 6. Hartzell JD, Blaylock JM. Whooping cough in 2014 and ness when initiated >14 days after symptom onset in beyond: an update and review. Chest. 2014;146:205–14. the primary patient. Therefore, public health services https://doi.org/10.1378/chest.13-2942 should expedite chemoprophylaxis in homes where 7. Witt MA, Katz PH, Witt DJ. Unexpectedly limited durability of immunity following acellular pertussis contacts of suspected patients have risk factors for vaccination in preadolescents in a North American outbreak. this disease. Clin Infect Dis. 2012;54:1730–5. https://doi.org/10.1093/ cid/cis287 Members of the Transmission of Pertussis in Households 8. Clark TA. Changing pertussis epidemiology: everything old is new again. J Infect Dis. 2014;209:978–81. https://doi.org/ Working Group who contributed data are Miquel Alsedà, 10.1093/infdis/jiu001 Josep Alvarez, Cesar Arias, Irene Barrabeig, Neus Camps, 9. Clark TA, Messonnier NE, Hadler SC. Pertussis control: Glòria Carmona, Mónica Carol, Maria Company, time for something new? Trends Microbiol. 2012;20:211–3. Joaquim Ferràs, Glòria Ferrús, Pere Godoy, Mireia Jané, https://doi.org/10.1016/j.tim.2012.03.003 10. Klein NP, Bartlett J, Fireman B, Rowhani-Rahbar A, Sofia Minguell, Pedro Plans, Raquel Rodríguez, Baxter R. Comparative effectiveness of acellular versus María-Rosa Sala, Roser Torra, Inma Crespo, Diana Toledo, whole-cell pertussis vaccines in teenagers. Pediatrics. Àngela Domínguez, Rubén Solano, Joan Caylà, 2013;131:e1716–22. https://doi.org/10.1542/peds.2012-3836 Sara Lafuente, Cristina Rius, Manuel García Cenoz, Rosana 11. Klein NP, Bartlett J, Rowhani-Rahbar A, Fireman B, Baxter R. Waning protection after fifth dose of acellular pertussis Burgui, Jesús Castilla, Pedro Brotons, Iolanda Jordan, and vaccine in children. N Engl J Med. 2012;367:1012–9. Carmen Muñoz-Almagro. https://doi.org/10.1056/NEJMoa1200850 12. Wendelboe AM, Njamkepo E, Bourillon A, Floret DD, This study was funded by the Carlos III Health Institute Gaudelus J, Gerber M, et al.; Infant Pertussis Study Group. through project nos. PI11/02557 and PI15/01348 Transmission of Bordetella pertussis to young infants. Pediatr (cofunded by European Regional Development Fund Infect Dis J. 2007;26:293–9. https://doi.org/10.1097/ 01.inf.0000258699.64164.6d “Investing in your future” program) and the Catalan 13. Kowalzik F, Barbosa AP, Fernandes VR, Carvalho PR, Agency for the Management of University Grants (grant Avila-Aguero ML, Goh DYT, et al. Prospective multinational no. 2017/SGR 1342). study of pertussis infection in hospitalized infants and their household contacts. 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Antimicrob Agents Chemother. 2013;57:5193–4. https://www.gov.uk/government/uploads/system/ https://doi.org/10.1128/AAC.01081-13 uploads/attachment_data/file/541694/Guidelines_for_ the_Public_Health_management_of_Pertussis_in_ Address for correspondence: Pere Godoy, Departament de Salut, England.pdf Epidemiología Alcalde Rovira Roure 2 Lleida, Lleida 25006 Spain; 24. Britton PH, Jones CA. Pertussis prophylaxis. Aust Prescr. 2012;35:82–4. https://doi.org/10.18773/austprescr.2012.036 email: pere.godoy@gencat.cat The Public Health Image Library (PHIL) The Public Health Image Library (PHIL), Centers for Disease Control and Prevention, contains thousands of public health–related images, including high-resolution (print quality) photographs, illustrations, and videos. PHIL collections illustrate current events and articles, supply visual content for health promotion brochures, document the effects of disease, and enhance instructional media. PHIL images, accessible to PC and Macintosh users, are in the public domain and available without charge. Visit PHIL at http://phil.cdc.gov/phil 2684 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 26, No. 11, November 2020