SEVERE PERTUSSIS IN CHILDHOOD: UPDATE AND CONTROVERSY - SYSTEMATIC REVIEW

Machado, Márcia Borges; Passos, Saulo Duarte

doi:10.1590/1984-0462/;2019;37;3;00006

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Revista Paulista de Pediatria

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Sumário

Review Articles • Rev. paul. pediatr. 37 (3) • Jul-Sep 2019 • https://doi.org/10.1590/1984-0462/;2019;37;3;00006 copy

SEVERE PERTUSSIS IN CHILDHOOD: UPDATE AND CONTROVERSY - SYSTEMATIC REVIEW

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Objective:

Through a systematic review, this essay aimed at revising the concepts of severe pertussis, updating the epidemiology, pathophysiology, clinical presentation, antibiotic therapy and auxiliary therapeutic options for symptomatology and complications.

Data sources:

This review considered publications from the last 30years in the databases US National Library of Medicine (PubMed), Scientific Electronic Library Online (SciELO), Literatura Latino-americana e do Caribe em Ciências da Saúde (LILACS), Cochrane, Google Scholar, as well as protocols of the Ministry of Health and recommendations of the Centers for Disease Control and Prevention, related to childhood pertussis (whooping cough), with emphasis on its severe form. This research was based on keywords derived from the terms “pertussis”, “azithromycin”, “antitussives”, “leukocyte reduction” in Portuguese and English. Duplicate studies and those with unavailable full-text were excluded.

Data synthesis:

Among 556 records found, 54 were selected for analysis. Pertussis, as a reemerging disease, has affected all age groups, evidencing the transient immunity conferred by infection and vaccination. Severe cases occur in neonates and infants, with secondary viral and bacterial complications and malignant pertussis, a longside hyperleukocytosis, respiratory failure and shock. Macrolides continue to be the chosen antibiotics, while antitussives for coughing remain without efficacy. The prompt treatment in Intensive Care Units improved the prognostic in severe cases, and transfusion was promising among procedures for leukoreduction.

Conclusions:

Approaching severe pertussis in childhood remains a challenge for diagnostic and therapy, as the available therapeutic options are still unsatisfactory. Strategies of prevention are expected to reduce the occurrence of severe cases, while new studies should confirm the role of auxiliary therapies.

Keywords:
pertussis; Whooping cough; Macrolides; Antitussives agents; Leukocytosis; Decision making

Author Country Year	Type of study Number	Relevance for inclusion	Results and conclusions
Torres SL¹1. Torres SL, Santos TZ, Torres RA, Pereira VV, Fávero LA, Filho OR, et al. Resurgence of pertussis at the age of vaccination: clinical, epidemiological, and molecular aspects. J Pediatr (Rio J). 2015;91:333-8. Brazil 2015	Descriptive, cross-sectional study 1.209	Epidemiological, clinical, death and vaccination aspects	Increased incidence of pertussis and its complications
Lynfield R²2. Lynfield R, Schaffner W. Can we conquer coqueluche? J Infect Dis. 2014;209 (Suppl 1):S1-3. USA 2014	Editorial -	Review of clinical, microbiological and epidemiological aspects	Important disease in public health and reemergence in the 21st century
Cherry JD³3. Cherry JD. Pertussis: challenges today and for the future. PLoS Pathog. 2013;9:e1003418. USA 2013	Editorial -	Review of clinical aspects, prevention and control	Epidemiological changes in infection and new prevention strategies
Matoo S⁴4. Mattoo S, Cherry JD. Molecular pathogenesis, epidemiology, and clinical manifestations of respiratory infections due to Bordetella pertussis and other Bordetella subspecies. Clin Microbiol Rev. 2005;18:326-82. USA 2005	Review -	Review of epidemiological, clinical and molecular biology aspects	Broad subject review, including other species of Bordetella
Belletini CV⁵5. Bellettini CV, Oliveira AW, Tusset C, Baethgen LF, Amantéa SL, Motta F, et al. Preditores clínicos, laboratoriais e radiográficos para infecção por Bordetella pertussis. Rev Paul Pediatr. 2014;32:292-8. Brazil 2014	Retrospective study of case series 222	Clinical, laboratory and radiological predictors for pertussis	Cyanosis and lymphocytosis were independent predictors of pertussis in children up to six months of age
Zlamy M⁶6. Zlamy M. Rediscovering Pertussis. Front Pediatr. 2016;4:52. Austria 2016	Review -	Virulence factors and prevention strategies	Host-toxin interaction defines immunological vaccine modulation by natural infection
Korppi M⁹9. Korppi M. Whooping cough - still a challenge. J Pediatr (Rio J). 2013;9:89:520-2. Finland 2013	Editorial -	Review of clinical picture and prevention	Approach to disease improved over the past 50 years
SVS, MS¹⁰10. Brasil. Ministério da Saúde. Coqueluche. Guia de vigilância em saúde. Brasília: Ministério da Saúde; 2014. p.87-104. Brazil 2014	Surveillance Protocol by Ministry of Health, Brazil -	Official protocol, with changes in definitions and criteria	Redefines case criteria and recommends preferential use of azithromycin
SVS, MS¹²12. Brasil. Ministério da Saúde. Guia de Vigilância em Saúde. Brasília: Ministério da Saúde; 2016. Brazil 2016	Surveillance Protocol by Ministry of Health, Brazil -	Official protocol, in use in Brazil	Update of concepts, case criteria and therapeutic recommendations
Munoz FM¹³13. Munoz FM. Pertussis in infants, children, and adolescents: diagnosis, treatment, and prevention. Semin Pediatr Infect Dis. 2006:17:14-9. 2016	Review -	Pertussis in children and adolescents: diagnosis, treatment and prevention	Adolescents and adults and their importance in the chain of transmission. Recommends their immunization
McGirr A¹⁴14. McGirr A, Fisman DN. Duration of pertussis immunity after DTaP immunization: a meta-analysis. Pediatrics. 2015;135:331-43. Canada 2015	Review -	Duration of vaccine immunity	Immunity conferred by DTP is longer lasting than DTPa
CGPNI, MS¹⁵15. Brasil. Ministério da Saúde. Informe técnico. Implantação da vacina adsorvida difteria, tétano e coqueluche (pertussis acelular) tipo adulto - dTpa. Brasília: Ministério da Saúde; 2014. Brazil 2014	Technical report -	Implantation of the dTpa vaccine	Criteria and recommendations for use of the dTpa vaccine in adults
CDC¹⁶16. Centers for Diseases Control and Prevention. [homepage on the Internet]. Pertussis (Whooping Cough) [cited 2016 Dec 20]. Available from: http://www.cdc.gov/vaccines/vpd-vac/pertussis. http://www.cdc.gov/vaccines/vpd-vac/pert... 2016	CDC recommendation -	Prevention strategies	Recommendation of vaccination of the pregnant woman with dTpa
SVS, MS¹⁷17. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Boletim Epidemiológico. Coqueluche no Brasil: análise da situação epidemiológica 2015. Brasília: Ministério da Saúde; 2015. Brazil 2016	Epidemiological Bulletin Descriptive study 10.487	Analysis of the epidemiological situation of pertussis in Brazil, 2015	Epidemiological standard would not have changed in Brazil, continuing to undertake preferentially infants under the age of one.
SVS, MS¹⁸18. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Boletim Epidemiológico. Coqueluche no Brasil: análise da situação epidemiológica de 2010 a 2014. Brasília: Ministério da Saúde; 2015. Brazil 2015	Epidemiological Bulletin Descriptive study 72.901	Analysis of the epidemiological situation of pertussis in Brazil, 2010-2014	Increased number of cases in Brazil due to cyclical behavior of the disease
Smith AM¹⁹19. Smith AM, Guzmán CA, Walker MJ. The virulence factors of Bordetella pertussis: a matter of control. FEMS Microbiol Rev. 2001;25:309-33. Australia 2001	Review -	Virulence Factors	Detailed description of the virulence mechanisms
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Author Country Year	Type of study Number	Relevance for inclusion	Results and conclusions
Heininger U²²22. Heininger U, Klich K, Stehr K, Cherry JD. Clinical findings in Bordetella pertussis infections: results of a prospective multicenter surveillance study. Pediatrics. 1997;100:E10. Germany 1997	Cohort 20.972	Clinical and laboratory aspects	Classical and laboratory clinical picture in non-vaccinated patients. Pneumonia was the most frequent complication.
Yildirim I²³23. Yildirim I, Ceyhan M, Kalayci O, Cengiz AB, Secmeer G, Gur D, et al. Frequency of pertussis in children with prolongued cough. Scand J Infect Dis. 2008;40:314-9. Turkey 2008	Cohort 148	Clinical and laboratory aspects	Clinical presentation was not always typical
SVS, MS²⁴24. Brasil. Ministério da Saúde. Coqueluche. In: Ministério da Saúde. Secretaria de Vigilância em Saúde. Guia de vigilância epidemiológica. 7ª ed. Brasília: Ministério da Saúde; 2009. p.200-2. Brazil 2009	Surveillance Protocol by Ministry of Health, Brazil	Official protocol, with pre-updated definitions and criteria	Case criteria and therapeutic recommendations
Elliot E²⁷27. Elliott E, McIntyre P, Ridley G, Morris A, Massie J, McEniery J, et al. National study of infants hospitalized with pertussis in the acellular vaccine era. Pediatr Infect Dis J. 2004;23:246-52. Australia 2004	Descriptive study 140	Severe pertussis	Pertussis as an important cause of morbidity and mortality
Kazantzi M²⁸28. Kazantzi MS, Prezerakou A, Kalamitsou SN, Ilia S, Kalabalikis PK, Papadatos J, et al. Characteristics ofBordetella pertussisinfection among infants and children admitted to paediatric intensive care units in Greece: a multicentre, 11-year study. J Paediatr Child Health. 2017;53:257-62. Greece 2017	Multicenter descriptive study	Characteristics and Complications of pertussis	Higher mortality in young infants Hyperleukocytosis, mechanical ventilation and hyponatremia are associated with higher lethality
Bouziri A²⁹29. Bouziri A, Hamdi A, Khaldi A, Smaoui H, Kechrid A, Menif K, et al. Malignant pertussis: an underdiagnosed illness. Med Trop (Mars). 2010;70:245-8. Tunisia 2010	Descriptive study 10	Malignant pertussis	Malignant pertussis is often underdiagnosed and fatal in infants less than three months old
Paddock CD³⁰30. Paddock CD, Sanden GN, Cherry JD, Gal AA, Langston C, Tatti KM, et al. Pathology and pathogenesis of fatal Bordetella pertussis infection in infants. Clin Infect Dis. 2008;47:328-38. USA 2008	Observational anatomopathological study 15	Severe pertussis	Necropsy in pulmonary tissue with hypertension and presence of B. pertussis in the lung
Palvo F³¹31. Palvo F, Fabro AT, Cervi MC, Aragon DC, Ramalho FS, Carlotti AP. Severe pertussis infection: A clinicopathological study. Medicine (Baltimore). 2017;96:e8823. Brazil 2017	Observational anatomopathological study 6	Severe pertussis	Necropsy in lung tissue with pulmonary hypertension, respiratory syncytial virus and B. pertussis in lungs and kidneys
Milekova³²32. Mikelova LK, Halperin SA, Scheifele D, Smith B, Ford-Jones E, Vaudry W, et al. Predictors of death in infants hospitalized with pertussis: a case-control study of 16 pertussis deaths in Canada. J Pediatr. 2003;143:576-81. Canada 2003	Case-control study 48	Severe pertussis	Leukocytosis and pneumonia were death predictors in infants less than two months old
Marshall H³³33. Marshall H, Clarke M, Rasiah K, Richmond P, Buttery J, Reynolds G, et al. Predictors of disease severity in children hospitalized for pertussis during an epidemic. Pediatr Infect Dis J. 2015;34:339-45. Australia 2015	Cohort 120	Severe pertussis	Presence of co-infections, prematurity and high fever require rigorous monitoring
Vaz de Lima³⁴34. Vaz-de-Lima LR, Martin MD, Pawloski LC, Leite D, Rocha KC, de Brito CA, et al. Serodiagnosis as adjunct assay for pertussis infection in São Paulo, Brazil. Clin Vaccine Immunol. 2014;21:636-40. Brazil 2014	Experimental study 503	Laboratory diagnosis	Serology as an auxiliary method in late diagnosis
Regan J³⁵35. Regan J, Lowe F. Enrichment medium for the isolation of Bordetella. J Clin Microbiol. 1977;6:303-9. Canada 1977	Experimental study 3.237	Laboratory diagnosis	Description of gold-standard method for B. pertussis culture
Gilligan PH³⁶36. Gilligan PH, Fisher MC. Importance of culture in laboratory diagnosis of Bordetella pertussis infections. J Clin Microbiol. 1984;20:891-3. USA 1984	Experimental study 223	Laboratory diagnosis	Culture was more sensitive than serology for diagnosis of B. pertussis
Müller FM³⁷37. Müller FM, Hoppe JE, Wirsing von König CH. Laboratory diagnosis of pertussis: state of the art in 1997. J Clin Microbiol. 1997;35:2435-43. Germany 1997	Review	Laboratory diagnosis	Review of the laboratory diagnostic method. Introduction of the PCR exam in the laboratory routine
Inst. Ad. Lutz³⁸38. Vaz TM, Leite D, Kinue I. Coqueluche: Manual de diagnóstico laboratorial do Instituto Adolfo Lutz. São Paulo: Instituto Adolfo Lutz, Centro de Bacteriologia, Laboratório de Referência Nacional para Coqueluche; 2010. Brazil 2010	Manual of laboratory diagnosis	Laboratory diagnosis	Describes standards, routines and recommendations by the national reference laboratory
Reish U³⁹39. Reischl U, Lehn N, Sanden GN, Loeffelholz MJ. Real-time PCR assay targeting IS481 of Bordetella pertussis and molecular basis for detecting Bordetella holmesii. J Clin Microbiol. 2001;39:1963-6. Germany 2001	Experimental study 113	Laboratory diagnosis	RT-PCR technique showed high specificity and high predictive value
Lopez MA⁴⁸48. Lopez MA, Cruz AT, Kowalkowski MA, Raphael JL. Trends in hospitalizations and resource utilization for pediatric pertussis. Hosp Pediatr. 2014;4:269-75. USA 2014	Cohort 1.012	Severe pertussis	Neonates and children with chronic diseases are the most vulnerable groups, requiring hospitalization

Author Country Year	Type of study Number	Relevance for inclusion	Results and conclusions
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Kilgore PE⁸8. Kilgore PE, Salim AM, Zervos MJ, Schmitt HJ. Pertussis: microbiology, disease, treatment, and prevention. Clin Microbiol Rev. 2016;29:449-86. USA 2016	Review -	Review of microbiology, clinical aspects, treatment and prevention	Comprehensive review on pertussis
Dierig A¹¹11. Dierig A, Beckmann C, Heininger U. Antibiotic treatment of pertussis: are 7 days really sufficient? Pediatr Infect Dis J. 2015;34:444-5. Switzerland 2015	Case report 2	Duration of treatment with clarithromycin	Positive PCR tests after seven days of clarithromycin
Wood N²⁰20. Wood N, McIntyre P. Pertussis: review of epidemiology, diagnosis, management and prevention. Paediatr Respir Rev. 2008;9:201-11. Australia 2008	Review -	Review of epidemiology, diagnosis, treatment and prevention	Broad review
Berger JT²⁵25. Berger JT, Carcillo JA, Shanley TP, Wessel DL, Clark A, Holubkov R, et al. Critical pertussis illness in children: a multicenter prospective cohort study. Pediatr Crit Care Med. 2013;14:356-65. USA 2013	Cohort 127	Severe pertussis: supportive treatment	Hyperleukocytosis reduced by Nitric oxide Exchange transfusion indicated for pulmonary hypertension
Halperin SA²⁶26. Halperin SA, Bortolussi R, Langley JM, Miller B, Eastwood BJ. Seven days of erythromycin estolate is as effective as fourteen days for the treatment of Bordetella pertussis infections. Pediatrics. 1997;100:65-71. Canada 1997	Controlled, randomized, double blind study 168	Time of erythromycin use for bacteria eradication	Seven days of erythromycin as effective as 14 days for bacterial eradication in the nasopharynx
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Bass JW⁴¹41. Bass JW. Erythromycin for treatment and prevention of pertussis. Pediatr Infect Dis J. 1986;5:154-7. Hawaii 1986	Controlled, double-blind, randomized clinical trial 50	Classical study: use of erythromycin for treatment and prevention	Erythromycin more effective than other antibiotics for bacterial eradication
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Langley JM⁴³43. Langley JM, Halperin SA, Boucher FD, Smith B, Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC). Azithromycin is as effective as and better tolerated than erythromycin estolate for the treatment of pertussis. Pediatrics. 2004;114:e96-101. Canada 2004	Randomized, double blind clinical study 477	Azithromycin and erythromycin Eradication of bacteria, clinical and adverse effects	Seven days of azithromycin as effective as 14 days of erythromycin, with fewer adverse effects
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Lund M⁴⁶46. Lund M, Pasternak B, Davidsen RB, Feenstra B, Krogh C, Diaz LJ, et al. Use of macrolides in mother and child and risk of infantile hypertrophic pyloric stenosis: nationwide cohort study. BMJ. 2014;348:g1908. USA 2014	Multicenter cohort study 999,378	Hypertrophic pyloric stenosis as an adverse effect of macrolides	Use of macrolides in neonates increased the risk of hypertrophic pyloric stenosis
Surridge J⁴⁷47. Surridge J, Segedin ER, Grant CC. Pertussis requiring intensive care. Arch Dis Child. 2007;92:970-5. New Zealand 2007	Cohort 72	Severe pertussis: clinic and severity criteria	Apnea and early paroxysms (less than a week of symptoms) are signs of severity and require ICU admission
Romano MJ⁴⁹49. Romano MJ, Weber MD, Weisse ME, Siu BL. Pertussis pneumonia, hypoxemia, hyperleukocytosis, and pulmonary hypertension: improvement in oxygenation after a double volume exchange transfusion. Pediatrics. 2004;114:e264-6. USA 2004	Case report 1	Severe pertussis: supportive treatment	Exchange transfusion effective for leukoreduction
Nieves D⁵⁰50. Nieves D, Bradley JS, Gargas J, Mason WH, Lehman D, Lehman SM, et al. Exchange blood transfusion in the management of severe pertussis in young infants. Pediatr Infect Dis J. 2013;32:698-9. Canada 2013	Descriptive study10	Severe pertussis: supportive treatment	Exchange transfusion effective if performed early, before organ failure
Rowlands HE⁵¹51. Rowlands HE, Goldman AP, Harrington K, Karimova A, Brierley J, Cross N, et al. Impact of rapid leukodepletion on the outcome of severe clinical pertussis in young infants. Pediatrics. 2010;126:e816-27. England 2010	Descriptive study19	Severe pertussis: supportive treatment	Leukoreduction therapies may be considered safe in critically ill patients
Grzeszczak MJ⁵²52. Grzeszczak MJ, Churchwell KB, Edwards KM, Pietsch J. Leukopheresis therapy for severe infantile pertussis with myocardial and pulmonary failure. Pediatr Crit Care Med. 2006;7:580-2. USA 2006	Case report 1	Severe pertussis: supportive treatment	There was success in treatment with leukopheresis
Halasa NB⁵³53. Halasa NB, Barr FE, Johnson JE, Edwards KM. Fatal pulmonary hypertension associated with pertussis in infants: does extracorporeal membrane oxygenation have a role? Pediatrics. 2003;112:1274-8. USA 2003	Case report 4	Severe pertussis: supportive treatment	Use of ECMO was controversial. All patients died.
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[1] *Corresponding author. E-mail: marcianathalia@gmail.com (M.B. Machado)