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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 3  |  Issue : 1  |  Page : 12-16

Pertussis in children in an era of vaccination


Department of Paediatric Medicine, KK Women's and Children's Hospital, Singapore

Date of Web Publication9-May-2019

Correspondence Address:
Alison Marion Snodgrass
KK Women's and Children's Hospital, 100 Bukit Timah Road
Singapore
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/prcm.prcm_2_19

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  Abstract 


Background: Pertussis incidence has been increasing despite high early childhood vaccination coverage. Various strategies have been recommended to combat this problem which includes cocooning, booster doses for adolescents and young adults, and more recently maternal intrapartum vaccination. A previous report had highlighted an increase in pertussis in infants. This review was done to evaluate if there has been any change in the prevalence in the subsequent 10 years. Materials and Methods: Retrospective cohort study of admissions for pertussis in patients aged 0–18 years in a single-center tertiary maternal-pediatric hospital in Singapore from January 1, 2008, to October 31, 2017. Results: There were 221 cases identified. The majority were infants <6 months (89%) and of Malay (46%) ethnicity. About 54% were male and 81% were delivered term. Nearly, 69.7% had not received pertussis immunization. 64.2% had exposure to an unwell family member with respiratory symptoms. Cough was the most common presenting complaint (100%). High dependency or intensive care treatment was required in 21 cases (9.5%). Length of stay was significantly longer for infants under 6 months of age compared to those aged 6 months or older (additional 1.63 days, 95% confidence interval 0.57–2.68, P = 0.003). Coinfection was found in 23 cases, associated comorbidities in 22 cases, and both conditions in 3 children. There were 2 deaths and 11 readmissions. Conclusions: Pertussis in young infants in Singapore remains a significant healthcare burden despite current immunization strategies. Routine maternal vaccination to confer passive immunity on the newborn child may be beneficial to address this problem.

Keywords: Infants and children, morbidity, pertussis, vaccination


How to cite this article:
Snodgrass AM, Goh AE. Pertussis in children in an era of vaccination. Pediatr Respirol Crit Care Med 2019;3:12-6

How to cite this URL:
Snodgrass AM, Goh AE. Pertussis in children in an era of vaccination. Pediatr Respirol Crit Care Med [serial online] 2019 [cited 2019 Aug 25];3:12-6. Available from: http://www.prccm.org/text.asp?2019/3/1/12/257937




  Introduction Top


The incidence of pertussis has been increasing despite the widespread availability of vaccination and inclusion in standard early childhood immunization programs worldwide.[1],[2] Various strategies to address the problem of waning immunity against pertussis after vaccination have included additional booster doses of pertussis vaccination to adolescents and young adults, as well as vaccination to individuals in close contact with infants such as healthcare workers, infant care workers, and family members (cocooning strategies). A prior retrospective review[2] of patients diagnosed with pertussis in KK Women's and Children's Hospital from 2004 to 2007 noted a resurgence of pertussis in recent years with high morbidity in children who had not been vaccinated and recommended consideration of a booster with Tdap vaccine for young adults and healthcare workers. In Singapore's national childhood immunization schedule, 2 booster doses of pertussis vaccination are given at 18 months and 11 years of age, following the initial 3 doses at ages 2, 4, and 6 months (as part of a combination vaccine that includes inactivated poliovirus, Haemophilus influenza B, and possibly hepatitis B). Singapore revised the immunization schedule to include a booster dose of pertussis at age 11 years for schoolgoing children since 2009, and healthcare workers have been offered booster doses of pertussis. Maternal vaccination in the third trimester of pregnancy, which aims to protect vulnerable infants from pertussis by providing passive immunity in those too young to be immunized, is effective[3] but was only recently approved at a national level in Singapore in November 2017. This review was done to look at the efficacy of the new strategies implemented since 2009 with the exception of maternal intrapartum immunization as this was initiated too recently to show effectiveness.


  Materials and Methods Top


Cases of pertussis in pediatric patients aged 0–18 years over an approximately 10-year period from January 1, 2008, to October 31, 2017 were obtained via diagnostic search of the online pediatric patient database (using the search terms “pertussis” and “whooping cough, unspecified”) with the assistance of the hospital's Department of Document Management Services. Confirmation of the coded diagnosis was performed in all cases by computerized database review of the results of real-time polymerase chain reaction assay targeting the insertion sequence IS 481,[4] used as described by Kösters et al. in the hospital's microbiology laboratory. The assay was optimized on the Rotorgene (Corbett Research, Australia). These cases were reviewed and analyzed using Microsoft Excel version 2013 and SPSS version 19.0 (IBM Corp. IBM SPSS Statistics for Windows, Armonk, NY: USA). Descriptive statistics was presented as n (%) for categorical variables and as mean (range) for quantitative variables. Statistical significance was set at P < 0.05 for the comparison of length of stay between the two age groups (<6 months vs. 6 months or more) using the 2-sample t-test if normality or homogeneity assumptions were satisfied, otherwise the nonparametric Mann–Whitney U-test was used. Ethics approval for the study was obtained from the Central Institutional Review Board of Singapore Health Services before commencement.


  Results Top


A total of 221 admissions for pertussis were identified during the study period [Figure 1].
Figure 1: Number of pediatric admissions for pertussis by year.

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The biodata of the study population is summarized in [Table 1]. Most individuals were aged <6 months (89%), male (54%), of Malay ethnicity (46%), and delivered at term gestation (82%). The majority (69.7%) had not received any immunizations against pertussis [Figure 2]. Of the 2 fully vaccinated children, one was a 10 years, 4-month-old girl with a background history of allergic rhinitis and eczema, and the other an 18 years, 9-month-old boy with preexisting epilepsy, attention-deficit hyperactivity disorder, and mental retardation. Both these children presented with cough and fever without any significant contact history and had mild disease responding to supportive treatment in the general ward with no need for ventilation.
Table 1: Study population demographics

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Figure 2: Age distribution of individuals by number of vaccination doses received.

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Exposure to an unwell family member with respiratory symptoms occurred in 142 cases (64.2%) – the patient's mother in 58 cases (26.2%), father in 23 cases (10.4%), sibling in 43 cases (19.5%), and other adult caregiver in 18 cases (8.1%). There were fourteen individuals (6.3%) who reported contact with an ill person outside the family, while 65 (29%) had no history of contact. In none of the patients was there a history suggestive of transmission from a healthcare provider.

Cough was the most common presenting complaint (100%), followed by cyanosis in 70 children (31.7%). Fever was present only in 55 children (24.9%). Fifty-one children (23.1%) presented with poor feeding requiring nasogastric tube feeding or intravenous hydration and 28 children (12.7%) with apnea.

All 21 cases requiring admission to high dependency unit (HDU) (5%) and intensive care unit (ICU) (5.9%) were <6 months of age. Most (8 cases, 38%) were ventilated for <1 day, and the majority (15 cases, 71.4%) did not experience any complications.

Coinfection with other organisms occurred in 23 cases. The majority of the children with coinfection (78.3%) were aged <6 months. The most common coinfecting organism was respiratory syncytial virus (RSV) in 44.4% of cases. Other organisms identified were Metapneumovirus, adenovirus, Parainfluenza type 1 virus, rhinovirus, Staphylococcus aureus (in sputum culture), Enterovirus (causing meningitis), and Citrobacter freundii (causing urinary tract infection). Pertussis remained the primary diagnosis in all these cases. These children were more symptomatic at presentation. Besides cough, 25% had apnea, 33.3% had cyanosis, 58.3% had fever, 50% had poor feeding requiring supplemental nasogastric tube feeding or IV hydration, and 50% had recurrent desaturation requiring supplemental oxygen. Despite the more severe disease, 77.8% recovered well in the general ward. One child required continuous positive airway pressure (CPAP) support in the HDU, and 3 children were admitted to the ICU where 1 child required CPAP ventilation and 2 children were intubated for ventilator support. Only 1 child in this age group presented with cyanosis. Culprit organisms in this older age group included RSV, Metapneumovirus, Mycoplasma pneumoniae, and Rotavirus.

Comorbid conditions were present in 22 children. These included a suspected immunodeficiency syndrome, congenital structural airway anomaly such as laryngomalacia, atopic respiratory disease, neurological conditions including epilepsy and focal seizures, congenital renal disorders including duplex kidneys and hydronephrosis, and gastrointestinal conditions such as gastroesophageal reflux disease. Of these, the majority (72.7%) were <6 months of age, and these children were more symptomatic at presentation. There was an increased requirement for supportive care with 7 cases (43.8%) requiring supplemental feeding or hydration and 6 cases (37.5%) requiring supplemental oxygen. These young children with comorbid conditions were more likely to be admitted to HDU and ICU for ventilator support (33.3%).

Three children had an underlying comorbid condition as well as coinfection with another organism besides Bordetella pertussis. All were children below 6 months of age. The first child had conjugated hyperbilirubinemia and coinfection with RSV, while the second had an inborn error of metabolism and an atrial septal defect with influenza A. These two cases had mild disease and responded well to supportive treatment in the general ward. The third child had Parainfluenza type 2 virus infection as well as Candida peritonitis. This child was very unwell and was suspected to have an underlying immunodeficiency. After a prolonged course, this child eventually died.

The average length of stay was significantly longer for children <6 months old compared to those older (4.38 ± 4.994 days vs. 2.75 ± 1.917 days; 95% confidence interval 0.57–2.68, P = 0.003) [Figure 3].
Figure 3: Length of stay with respect to age.

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Admissions exceeding 10 days [range 11–44 days, depicted as outliers in [Figure 3] were seen in fifteen individuals. All these children were younger than 6 months of age and unvaccinated (66.7%). All required supplemental oxygen and/or assisted feeding or intravenous hydration. The majority required a higher level of care, with 26.7% needing ICU admission and 40% in HDU. Of those requiring higher level care, 26.7% had coinfection and 20% had comorbid conditions. Children who stayed longer in the general ward were due to recurrent desaturations and coinfection with respiratory viruses as well as parental inability to cope with the child postdischarge.

There were two deaths in this review. Both were female and <6 months of age at the time of presentation. The first child was an unvaccinated preterm baby aged 2 months who presented with cough, cyanosis, and poor feeding, as well as a positive contact history (mother). She required admission to ICU for invasive ventilation due to severe respiratory distress resulting in pulmonary hypertension. Hyperleukocytosis was present. Multiorgan failure developed after 8 days despite treatment with oral clarithromycin and the child eventually succumbed.

The second child was a term infant aged 1.5 months born in a neighboring country who presented with apnea in addition to cough, fever, and poor feeding. The child was commenced on oral erythromycin. She died after 12 days from severe pertussis complicated by septic shock with suspected underlying immunodeficiency. She developed jejunal perforation and candida peritonitis as well as coinfection with Parainfluenza type 2 virus infection. She succumbed despite being supported on extracorporeal membrane oxygenation and hemodialysis in the ICU.

Readmission was required in eleven cases. All were unvaccinated young infants aged <6 months. Four cases were male and 3 were born premature. The reasons for readmission were for persistent cough, cyanosis, and apneic episodes. Most readmissions were to the general ward, but two cases required admission to HDU and ICU for ventilatory support (noninvasive and invasive ventilation, respectively). Besides the 2 children who required ventilator support, most recovered well with supportive treatment including nasogastric feeding or intravenous hydration. Four children received a second course of macrolide treatment.

There were four cases transferred to our institution for management. One was from a local hospital and the other 3 were from a neighboring country. All were young-term infants aged <6 months with a positive contact history and were either unvaccinated or their vaccination status was not known. Clinical presentation in all cases involved severe symptoms such as cyanosis or required significant supportive care; 2 cases were placed on noninvasive ventilation in HDU and 2 cases were intubated and cared for in ICU. Only one case from overseas had coinfection with RSV, and none of the cases had any known comorbidities. Two cases survived to discharge; the status of the other 2 cases are not known as they were transferred back to their home country by specialized medical transport services for continuation of treatment.


  Discussion Top


The prevalence of pertussis is still high in children in Singapore, with higher rates occurring every few years. Over the last 3 years, the number of cases increased from about 21 cases in 2014 to 57 cases in 2015, 84 cases in 2016, and 77 cases in 2017.[5] These numbers may still be an underestimate as laboratory tests for pertussis were only done when clinical suspicion was high. The high prevalence of Malays in our study does not follow the ethnic distribution in Singapore, where Chinese form the majority at 74.3%, followed by Malays (13.4%), Indians (9%), and other ethnic groups (3.2%).[6] This reflects the choice of healthcare utility in the country as our hospital serves the public; the more affluent Chinese population may be utilizing healthcare providers from the private sector. In 64% of the cases, there was a history of contact with a family member who was coughing, most often the mother. This contrasts with the findings of the study conducted by Kowalzik et al.,[7] where pertussis in household contacts was found in only 36% of cases.

While DPT vaccine coverage in infants in Singapore remains very good, with 96% of children completing their primary course of pertussis immunizations,[8] undue delay between shots was noted in this study and may have contributed to pertussis infection, especially since a single dose of pertussis vaccination is not protective as demonstrated in the previous report by Goh et al.[3] Our study reaffirms the significant morbidity and mortality of this age-old infection in children, with the youngest being the most vulnerable. Renewed efforts at public education that emphasize the importance of timely vaccination in obtaining optimal disease protection, as well as the significant possibility of pertussis resurgence should such vaccination be omitted, may help to ensure that parents avoid delaying their childrens' immunizations.

Many reasons for the resurgence of pertussis in recent times have been proposed, including clinical underrecognition of the diagnosis, especially in adolescents and adults where the disease is usually mild, insufficient vaccine uptake or incomplete vaccination,[9] the possibility that the current vaccines do not provide optimal protection due to the evolution of vaccine escape mutants[10],[11],[12],[13] and the contribution of other Bordetella species[14],[15] to clinical symptoms, lack of awareness of the importance of the specific timing of vaccination and waning immunity following immunization. While the cyclical pattern of pertussis epidemics is well known, improvement in laboratory techniques and epidemiological surveillance has also likely contributed to the increased identification and detection of pertussis cases. The widespread use of acellular vaccines induce high titers against vaccine components as measured by antibody levels, as opposed to whole-cell vaccines which have been shown to induce a TH1 response that gives better infection clearance although antibody levels may be lower than that measured with acellular vaccines. The use of acellular vaccines has resulted in an increased number of pertactin-negative mutation strains.[16]

Prevention in the form of booster immunization in adults, especially pregnant women and caregivers of infants, as well as older siblings who are frequent sources of infection to these children too young to be immunized, is vital. This is because vaccine-induced immunity does weaken over time.[17],[18] This phenomenon has been documented in Singapore, where the seroprevalence rate was shown to decline with age from 92% in children aged <5 years to 63% in children from 5 to 9 years, 51% in those with 10–14 years of age, 50% in those with 15–19 years of age, and 60% in adulthood.[19] The apparent rise in seropositivity between adolescence and adulthood may be partly due to naturally occurring pertussis infection conferring natural immunity. Lai et al. assessed the seroepidemiology of pertussis in a cohort of 1092 highly immunized Singaporean children aged 1–17 years and found an overall pertussis seroprevalence of 60.8%; this figure fell from 85% among the individuals who had completed three doses of pertussis vaccination by the age of 2 years to 75%, then 63.1%, and finally remaining around 50% in those who had the last vaccination 1 year, 2 years, and 4 or more years before the study, respectively.[20] Adding an additional booster dose at late adolescence may potentially further boost immunity in this age group.

The current national adult immunization schedule in Singapore aims to provide passive immunity to the fetus as well as protect the mother from becoming a possible source of pertussis infection to her infant after delivery. Maternal immunization has recently been introduced in Singapore since November 2017. The impact of this strategy can only be evaluated in the next few years. It is also worth considering offering Tdap immunization to fathers and other adult caregivers (such as grandparents, childcare, and kindergarten teachers) in this regard. Widespread implementation of this cocooning strategy may be difficult as it depends on the patient's family members voluntarily coming forward to be vaccinated, and effectiveness may vary as nonhousehold sources of infection are also well documented.[21] Vaccination of healthcare workers has been regularly offered in our hospital, and this may account for the absence of nosocomial transmission of pertussis noted in this study.

The deaths, extended length of inpatient stays, and readmissions in our study illustrate the persisting vulnerability of the infant to pertussis, particularly those too young to be immunized. In 2017, Chong et al. reviewed patients admitted for pertussis over a 10-year period and reported that the risk factors for admission to the ICU and HD were age ≤3 months, comorbid conditions, cyanosis, pneumonia, and leukocytosis on multivariate analysis.[22] Risk factors identified by univariate analysis in the same study for ICU/HD admissions were absent DTaP vaccination, contact history, prematurity, and laboratory abnormalities such as lymphocytosis and hyperleukocytosis (white blood cells ≥50 × 109/L). All the children that were admitted to the ICU/HD had never received pertussis vaccination as they were too young. Prior DTaP vaccination with at least 1 dose had a vaccine effectiveness of 86.5% in preventing ICU and HD admissions and 82.1% in preventing intubation and noninvasive ventilation.


  Conclusions Top


Pertussis in young children remains a significant healthcare burden despite current immunization strategies. Routine maternal vaccination to confer passive immunity on the newborn child may be beneficial to address this problem.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Schellekens J, von König CH, Gardner P. Pertussis sources of infection and routes of transmission in the vaccination era. Pediatr Infect Dis J 2005;24:S19-24.  Back to cited text no. 1
    
2.
Goh A, Chong CY, Tee N, Loo LH, Yeo JG, Chan YH. Pertussis – An under-diagnosed disease with high morbidity in Singapore children. Vaccine 2011;29:2503-7.  Back to cited text no. 2
    
3.
Gkentzi D, Katsakiori P, Marangos M, Hsia Y, Amirthalingam G, Heath PT, et al. Maternal vaccination against pertussis: A systematic review of the recent literature. Arch Dis Child Fetal Neonatal Ed 2017;102:F456-63.  Back to cited text no. 3
    
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Kösters K, Reischl U, Schmetz J, Riffelmann M, Wirsing von König CH. Real-time lightCycler PCR for detection and discrimination of Bordetella pertussis and Bordetella parapertussis. J Clin Microbiol 2002;40:1719-22.  Back to cited text no. 4
    
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Ministry of Health. Weekly Infectious Disease Bulletin. Singapore: Ministry of Health. Available from: http://www.moh.gov.sg/content/moh_web/home/statistics/InfectiousDiseaseStatistics/weekly_infectiousdiseasesbulletin.html. [Last accessed on 2018 Oct 08, 08:45h].  Back to cited text no. 5
    
6.
Population Trends 2017 – Singapore Department of Statistics. Available from: www.singstat.gov.sg. [Last accessed on 2018 Oct 08, 08:45h].  Back to cited text no. 6
    
7.
Kowalzik F, Barbosa AP, Fernandes VR, Carvalho PR, Avila-Aguero ML, Goh DY, et al. Prospective multinational study of pertussis infection in hospitalized infants and their household contacts. Pediatr Infect Dis J 2007;26:238-42.  Back to cited text no. 7
    
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Health Facts. Health Information Management. InfoComm Division. Ministry of Health. Available from: http://www.moh.gov.sg. [Last accessed on 2017 Apr 07].  Back to cited text no. 8
    
9.
Fisman DN, Tang P, Hauck T, Richardson S, Drews SJ, Low DE, et al. Pertussis resurgence in Toronto, Canada: A population-based study including test-incidence feedback modeling. BMC Public Health 2011;11:694.  Back to cited text no. 9
    
10.
Pawloski LC, Queenan AM, Cassiday PK, Lynch AS, Harrison MJ, Shang W, et al. Prevalence and molecular characterization of pertactin-deficient Bordetella pertussis in the United States. Clin Vaccine Immunol 2014;21:119-25.  Back to cited text no. 10
    
11.
Lam C, Octavia S, Ricafort L, Sintchenko V, Gilbert GL, Wood N, et al. Rapid increase in pertactin-deficient Bordetella pertussis isolates, Australia. Emerg Infect Dis 2014;20:626-33.  Back to cited text no. 11
    
12.
Zeddeman A, van Gent M, Heuvelman CJ, van der Heide HG, Bart MJ, Advani A, et al. Investigations into the emergence of pertactin-deficient Bordetella pertussis isolates in six European countries, 1996 to 2012. Euro Surveill 2014;19. pii: 20881.  Back to cited text no. 12
    
13.
Warfel JM, Zimmerman LI, Merkel TJ. Acellular pertussis vaccines protect against disease but fail to prevent infection and transmission in a nonhuman primate model. Proc Natl Acad Sci U S A 2014;111:787-92.  Back to cited text no. 13
    
14.
Watanabe M, Nagai M. Whooping cough due to Bordetella parapertussis: An unresolved problem. Expert Rev Anti Infect Ther 2004;2:447-54.  Back to cited text no. 14
    
15.
Pittet LF, Emonet S, Schrenzel J, Siegrist CA, Posfay-Barbe KM. Bordetella holmesii: An under-recognised Bordetella species. Lancet Infect Dis 2014;14:510-9.  Back to cited text no. 15
    
16.
van Gent M, Heuvelman CJ, van der Heide HG, Hallander HO, Advani A, Guiso N, et al. Analysis of Bordetella pertussis clinical isolates circulating in European countries during the period 1998-2012. Eur J Clin Microbiol Infect Dis 2015;34:821-30.  Back to cited text no. 16
    
17.
Jenkinson D. Duration of effectiveness of pertussis vaccine: Evidence from a 10 year community study. Br Med J (Clin Res Ed) 1988;296:612-4.  Back to cited text no. 17
    
18.
Christie CD, Marx ML, Marchant CD, Reising SF. The 1993 epidemic of pertussis in Cincinnati. Resurgence of disease in a highly immunized population of children. N Engl J Med 1994;331:16-21.  Back to cited text no. 18
    
19.
Committee on Epidemic Diseases. Prevalence of pertussis antibody in children and adults in Singapore. Epidemiol News Bull 1995;21:65-7.  Back to cited text no. 19
    
20.
Lai FY, Thoon KC, Ang LW, Tey SH, Heng D, Cutter JL, et al. Comparative seroepidemiology of pertussis, diphtheria and poliovirus antibodies in Singapore: Waning pertussis immunity in a highly immunized population and the need for adolescent booster doses. Vaccine 2012;30:3566-71.  Back to cited text no. 20
    
21.
Wiley KE, Zuo Y, Macartney KK, McIntyre PB. Sources of pertussis infection in young infants: A review of key evidence informing targeting of the cocoon strategy. Vaccine 2013;31:618-25.  Back to cited text no. 21
    
22.
Chong CY, Yung CF, Tan NW, Acharyya S, Thoon KC. Risk factors of ICU or high dependency requirements amongst hospitalized pediatric pertussis cases: A 10 year retrospective series, Singapore. Vaccine 2017;35:6422-8.  Back to cited text no. 22
    


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