Severe pertussis in infants: a scoping review

Abstract

Background

Pertussis (Whooping Cough) is a respiratory infection caused by Bordetella pertussis. Pertussis usually occurs in childhood; severe infections are most common in infants. It can be fatal with severe complications such as pulmonary hypertension, heart failure, and encephalitis.

Objectives

We sought to synthesize the existing literature on severe pertussis in infants and inform further study.

Methods

A scoping review was performed based on the methodological framework developed by Arksey & O’Malley. Search in Pubmed and Embase databases, with no restrictions on the language and date of publication.

Results

Of the 1299 articles retrieved, 64 were finally included. The selected articles were published between 1979 and 2022, with 90.6% (58/64) of the studies in the last two decades. The studies covered epidemiology, pathology, clinical characteristics, risk factors, treatments, and burden of disease.

Conclusion

The literature reviewed suggests that studies on severe pertussis in infants covered a variety of clinical concerns. However, these studies were observational, and experimental studies are needed to provide high-quality evidence.

Keywords:

• Pertussis
• whooping cough
• infants

Introduction

Pertussis (Whooping Cough) is a respiratory infection caused by Bordetella pertussis and characterized by paroxysmal coughing ending in a prolonged crowing intake of breath. Pertussis usually occurs in childhood; severe infections are most common in infants. It can be fatal with severe complications such as pulmonary hypertension, heart failure, and encephalitis. Pertussis is a vaccine-preventable disease, and the implementation of pertussis vaccine immunization has led to a decline in the number of pertussis cases and deaths among children since the inception of the WHO Expanded Programme on Immunization in 1974 [1]. However, even in countries with widespread pertussis vaccine coverage, such as the United States, Canada, and Australia [2], the incidence of pertussis has been on the rise again after maintaining a low rate for many years, with outbreaks in some places, which is referred to as ‘re-emergence of pertussis’.

There are multiple challenges to the management of pertussis. The change in the mode of transmission, from the previous child-child epidemic mode to an adult-child epidemic mode after the introduction of the immunization program, makes infants and young children more susceptible to infection [3,4]. Furthermore, given the considerable side effects of whole-cell pertussis vaccine, the acellular pertussis vaccine was introduced at the end of the twentieth century and is already used in many countries and regions. Although acellular pertussis vaccination has fewer adverse events than whole-cell pertussis vaccination, many studies have shown that acellular pertussis vaccination is associated with a higher risk of pertussis morbidity over time [5–7]. The acellular pertussis vaccine only protects against disease, not the infection, which could make it possible for people who were vaccinated with the acellular pertussis vaccine to act as asymptomatic or mildly symptomatic carriers and play an important role in the spread of pertussis in the population [8]. In addition, since the first strain of erythromycin-resistant Bordetella pertussis isolated from a 2-month-old infant with pertussis was reported in Arizona, USA, in 1994, subsequent reports of antibiotic-resistant Bordetella pertussis have been reported in many countries, such as France, China, Iran, Viet Nam [9–13].

Nowadays, pertussis remains a public health problem of great concern, with high rates of morbidity and mortality. WHO estimates that about 24.1 million cases of pertussis and 160,700 children under 5 years of age die of pertussis in a year [14]. According to the United States Centers for Disease Control and Prevention, about one-third of infants with pertussis require hospitalization, and 1% of those cases die [15]. Pertussis is one of the significant causes of illness and death in infants. Therefore, we sought to synthesize the existing literature on severe pertussis in infants and inform further study.

The following research questions were used to guide this evidence review:

1. How many studies have been published on severe pertussis in infants?

2. What aspects of the study have been done on severe pertussis in infants?

3. What study designs have been used in studies on severe pertussis in infants?

Methods

A scoping review was performed based on the methodological framework developed by Arksey & O’Malley [16].

1. Information sources and Search strategies

   The following terms were used to construct the search strategies in the Pubmed and Embase databases: (Whooping cough or Pertussis) AND (Infant or Newborn or Neonate) AND (Critical illness or Severe or Fatal or Malignant or Fulminant) (Table 1). There were no restrictions on the language and date of publication. The literature was last searched on 30 June 2023.

2. Literature selection and Inclusion criteria

   Study selection took place in two stages: first, titles and abstracts were reviewed, followed by the full text. Titles and abstracts were reviewed independently by two researchers, the abstracts that did not meet the inclusion criteria or that met the exclusion criteria were discarded. Articles without an available abstract or for which abstracts did not provide sufficient information to determine their exclusion were directly included in the full-text review stage. The full-text review was performed independently by two researchers, and disagreements were resolved by a third researcher. The inclusion of articles met the following criteria: (a) The study subjects were limited to infants under one year of age; (b) The study focuses on severe pertussis infections. Severe infection was defined as infants with pertussis who had hypoxemia, pulmonary hypertension, and heart failure, required respiratory support, were admitted to the intensive care unit, or died. Exclusion of review studies. The final search results were exported to EndNote and duplicate studies were removed.

3. Results synthesis and Data charts

   We summarize the information extracted from the included studies in the table. Two researchers developed data charts jointly and independently extracted data from articles that fit this study, and then exchanged them for validation. A third researcher solved the disagreement. Variables included author, journal, year of publication, country, language of publication, study design, sample size, sample characteristics, and purpose or topic of the study.

Table 1. Search strategy.

	Pertussis		Infants	Severe
MeSH terms	Whooping cough		Infant	Critical illness
Free-text terms	Pertussis		Newborn*	Severe
			Neonat*	Fatal
			Infan*	Malignant
				Fulminant
Search formula in Pubmed	(((Whooping cough[MeSH Terms]) OR (Pertussis[Title/Abstract])) AND ((((Infant[MeSH Terms]) OR (Newborn*[Title/Abstract])) OR (Neonat*[Title/Abstract])) OR (Infan*[Title/Abstract]))) AND (((((Critical illness[MeSH Terms]) OR (Severe[Title/Abstract])) OR (Fatal[Title/Abstract])) OR (Malignant[Title/Abstract])) OR (Fulminant[Title/Abstract]))
Search formula in Embase	#1	Pertussis.sh. or Whooping cough.ab.
	#2	Infant.sh. or Newborn.ab. or Neonate.ab.
	#3	Critical illness.sh. or Severe.ab. or Fatal.ab. or Malignant.ab. or Fulminant.ab.
	#4	1 and 2 and 3

Results

The search strategy identified 1299 articles, with 992 articles after deleted duplicates. Screening through titles and abstracts left 107 articles for full-text evaluation. The abstract and full text were not available for four articles, so sufficient information could not be obtained, and a total of 64 studies were finally included (Figure 1).

Figure 1. Study selection.

The selected articles were published between 1979 and 2022, with 90.6% (58/64) of the studies in the last two decades. Including studies from 22 countries, the top three numbers were from the United States (25.0%, 16/64), China (9.3%, 6/64), and France (9.3%, 6/64). Out of six publication languages, most studies were published in English (75.0%, 48/64). All study designs were observational studies, with the most case reports (62.5%, 40/64) (Table 2).

Table 2. Characteristics of the included studies.

Characteristic	Categories for each characteristic	Number of studies (n = 64)
Date of publication	2022–2018	15
	2017–2013	16
	2012–2008	13
	2007–2003	14
	2002–1998	2
	1997–1993	1
	Before 1992	3
Language of publication	Chinese	2
	Danish	1
	English	48
	French	9
	Portuguese	1
	Spanish	3
Study design	Case control study	5
	Cohort study	3
	Descriptive study (Case analysis)	15
	Descriptive study (Case report)	40
	Historical control study	1
Place of study	Argentina	1
	Australia	2
	Belgium	2
	Canada	3
	Chile	3
	China	6
	Denmark	2
	France	6
	India	1
	Indonesia	1
	Italy	1
	Netherlands	1
	New Zealand	3
	Oman	1
	Portugal	3
	Spain	1
	Switzerland	1
	Tunisia	2
	Türkiye	2
	UK	5
	USA	16
	Viet Nam	2

There are no standardized diagnostic criteria for severe pertussis. In these included studies, severe pertussis was defined as requiring respiratory support, admission to the intensive care unit, or resulting in death. The case reports (Table 3) [17–56] covered clinically severe manifestations and treatments; these severe manifestations are characterized by increased white blood cells, pulmonary hypertension, acute respiratory distress syndrome, encephalopathy, respiratory failure, cardiovascular collapse, and septic shock; of the treatments, most related to a reduction of white blood cells such as leukapheresis (10.0%, 4/40) and exchange transfusion (27.5%, 11/40), in addition to extracorporeal life support (10.0%, 4/40). In infants with severe pertussis and severe leukocytosis, early reduction of white blood cell therapy may be a helpful and rapid life-saving treatment before cardiopulmonary complications develop. Among other studies (except for case reports) (Table 4) [57–80], the major study designs were descriptive studies (62.5%, 15/24), case-control studies (20.8%, 5/24), and cohort studies (12.5%, 3/24); 45.8% (11/24) analyzed the risk factors associated with severe infection or death; Other contents involved epidemiology (12.5%, 3/24), clinical manifestations (8.3%, 2/24), pathological features (12.5%, 3/24), treatment (16.7%, 4/24), and disease burden (4.2%, 1/24). Increased white blood cell (81.8%, 9/11) is one of the risk factors associated with severe infection or death in infants with pertussis shown in most studies, as well as increased lymphocyte, apnea, co-infections, pulmonary hypertension, age, fever, cyanosis, and abnormal liver function.

Table 3. Study characteristics from case reports.

First author	Journal	Year	Country	Language	Key element
Long S	Cureus	2022	USA	English	Leukapheresis
Liao Y	Open Forum Infect Dis	2022	China	English	Metagenomics next-generation sequencing
Son PT	Vox Sang	2021	Viet Nam	English	Exchange transfusion
Kolind RS	Ugeskr Laeger	2021	Denmark	Danish	Exchange transfusion
Fueta PO	Case Rep Infect Dis	2021	USA	English	Multidisciplinary management
Rossetti E	Blood Purif	2020	Italy	English	Leukapheresis
Chen X	Chinese J Appl Clin Pediatr	2020	China	Chinese	Leukapheresis
Wei XM	Zhongguo Dang Dai Er Ke Za Zhi	2019	China	Chinese	Exchange transfusion
Alkan G	Turk Klinikleri Pediatr	2017	Türkiye	English	Exchange transfusion
Ganeshalingham A	Arch Dis Child	2016	New Zealand	English	Pulmonary dystrophic calcification
Liko J	Public Health Rep	2015	USA	English	Burden of disease
Chantreuil J	Arch Pediatr	2015	France	French	Exchange transfusion
Assy J	Pediatr Infect Dis J	2015	France	English	Exchange transfusion and Extracorporeal membrane oxygenation
Kurvers RA	Eur J Pediatr	2014	Netherlands	English	C3 deficiency
Al Hanshi S	Oman Med J	2014	Oman	English	Exchange transfusion
Nataprawira HM	Case Rep Emerg Med	2013	Indonesia	English	Severe manifestations
Mata AF	Pediatrics	2013	USA	English	Bronchoscopy with instillation of N-acetylcysteine
Martinez M	Pediatr Crit Care Med	2011	Switzerland	English	Exchange transfusion
Menif K	Arch Pediatr	2010	Tunisia	French	Severe manifestations
Kundrat SL	Dimens Crit Care Nurs	2010	USA	English	Severe manifestations
Freitas J	Rev Port Pneumol	2010	Portugal	Portuguese	Severe manifestations
Berthomieu L	Arch Pediatr	2010	France	French	Severe manifestations
Couchot E	Ann Fr Anesth Reanim	2009	France	French	Extracorporeal membrane oxygenation
Theilen U	BMJ	2008	UK	English	Severe manifestations
Soares S	Rev Port Pneumol	2008	Portugal	French	Severe manifestations
Vaessen S	Rev Med Liege	2006	Belgium	French	Severe manifestations
Grzeszczak MJ	Pediatr Crit Care Med	2006	USA	English	Leukapheresis
Gonzalez-Escudero R	Acta Pediatr Esp	2006	Spain	Spanish	Severe manifestations
Donoso AF	Pediatr Infect Dis J	2006	Chile	English	Exchange transfusion
Donoso A	Scand J Infect Dis	2005	Chile	English	Severe manifestations
De Berry BB	Pediatr Surg Int	2005	USA	English	Extracorporeal membrane oxygenation
Cruces RP	Rev Chil Pediatr	2005	Chile	Spanish	Exchange transfusion
Wauters O	Rev Med Liege	2004	Belgium	French	Severe manifestations
Romano MJ	Pediatrics	2004	USA	English	Exchange transfusion
McEniery JA	J Paediatr Child Health	2004	Australia	English	Nitric oxide and Sildenafil
Pilorget H	Arch Pediatr	2003	France	French	Severe manifestations
Sreenan CD	Pediatr Surg Int	2001	Canada	English	Extracorporeal membrane oxygenation
Corkins M	Iowa Med	1991	USA	English	Severe manifestations
Tam AY	Arch Dis Child	1986	China	English	Salbutamol
Theilade D	Anaesthesia	1979	Denmark	English	Continuous positive airway pressure

Table 4. Study characteristics from studies other than case reports.

First author	Journal	Year	Country	Language	Study design	Sample size	Severe case definition/characterization	Study objective
Zhang C	BMC Infect Dis	2022	China	English	Case-control study	336	Infants with pertussis who also had hypoxemia, recurrent apnea, cardiovascular dysfunction, or pertussis encephalopathy were considered to have severe pertussis.	To identify risk factors associated with the prognosis of pertussis in infants.
Thuy Nga DT	Pediatr Infect Dis J	2022	Viet Nam	English	Case-control study	108	Severe disease was defined as a need for PICU admission or mechanical ventilation or death during hospitalization.	To evaluate associations of Ct values with disease severity and other clinical variables in children with pertussis.
Coquaz-Garoudet M	Ann Intensive Care	2021	France	English	Cohort study	23	Admitted to a PICU	To identify factors associated with death in infants affected by malignant pertussis.
Şık G	Turk Pediatri Ars	2020	Türkiye	English	Descriptive study	18	Admitted to a PICU	To evaluate the clinical characteristics, risk factors, and prognosis of pertussis in the PICU.
Liu C	BMC Infect Dis	2020	China	English	Case-control study	59	Admitted to a PICU	To explore risk factors for death from severe pertussis.
Kavitha TK	Indian Pediatr	2020	India	English	Descriptive study	36	Critical pertussis was defined as pertussis requiring admission to an ICU or resulting in death.	To delineate the clinical profile, complications, intensive care needs, and predictors of mortality in children with critical pertussis.
Cherry JD	Pediatr Infect Dis J	2018	USA	English	Descriptive study	100	Admitted to a PICU	To gain further insight relating to the characteristics and treatment of pertussis in young infants.
Macdonald-Laurs E	Pediatr Infect Dis J	2017	New Zealand	English	Cohort study	159	Admitted to a PICU	To describe changes in pertussis deaths and PICU admissions over the past 2 decades and to determine associations of rates of such severe disease with changes in pertussis identification and in vaccine policy over this period.
Straney L	Pediatr Crit Care Med	2016	Australia, New Zealand	English	Descriptive study	416	Admitted to a ICU	To describe admission rates, severity, mortality, and costs of pertussis infections in critically ill infants.
Winter K	Clin Infect Dis	2015	USA	English	Case-control study	236	Death	To identify factors for death in young infants hospitalized for B. pertussis infections.
Tiwari TS	Pediatrics	2015	USA	English	Cohort study	45404	Death	To investigate the role of ≥1 pertussis vaccinations in preventing pertussis-related deaths and risk markers for death among infants aged <42 days.
Rocha G	Pediatr Infect Dis J	2013	Portugal	English	Descriptive study	18	Admitted to a ICU	To better understand the clinical features of pertussis infection in newborns and nonvaccinated infants less than 2 months of age, and to correlate these findings with the outcome.
Nieves D	Pediatr Infect Dis J	2013	USA	English	Descriptive study	10	Admitted to a PICU	To analyze data from 10 young infants who received exchange blood transfusions for management of severe pertussis.
Murray EL	J Pediatric Infect Dis Soc	2013	USA	English	Descriptive study	31	Admitted to a PICU	To identify factors associated with the poorest outcomes, ie, death and pulmonary hypertension.
Taffarel P	Arch Argent Pediatr	2012	Argentina	Spanish	Descriptive study	41	Admitted to a PICU	To describe the evolution of a series of patients with severe pertussis, some of whom received exchange transfusion as an alternative treatment.
Rowlands HE	Pediatrics	2010	UK	English	Historical control study	19	Admitted to a PICU	To quantify possible benefits of aggressive leukodepletion.
Bouziri A	Med Trop	2010	Tunisia	French	Descriptive study	10	Admitted to a PICU	To determine the prevalence of malignant pertussis in infants admitted to a pediatric intensive care unit for severe acute respiratory failure associated with severe leukocytosis.
Sawal M	Pediatr Pulmonol	2009	UK	English	Descriptive study	10	Death	To examine the clinico-pathological features and suggest how they may be related to outcome.
Paddock CD	Clin Infect Dis	2008	USA	English	Descriptive study	15	Death	To report the pulmonary histopathologic characteristics of fatal infantile pertussis and use IHC techniques as a tool to provide insights into the complex pathogenesis of this infection.
Vitek CR	Pediatr Infect Dis J	2003	USA	English	Descriptive study	93	Death	To characterize the clinical course of the illness and factors potentially associated with a fatal outcome.
Pooboni S	Pediatr Pulmonol	2003	UK	English	Descriptive study	12	Respiratory support	To analysis highlight the course and outcome of severe B. pertussis infection treated with extracorporeal membrane oxygenation.
Mikelova LK	J Pediatr	2003	Canada	English	Case-control study	48	Death	To describe the clinical course of fatal cases of pertussis and identify predictors of death at the time of presentation for medical care.
Pierce C	Intensive Care Med	2000	UK	English	Descriptive study	13	Admitted to a PICU	To identify factors which may be associated with a fulminant course.
Hackman R	Pediatr Pathol Lab Med	1996	Canada	English	Descriptive study	2	Death	To describe fatal pertussis histopathology of the lung tissues, including transmission and immunoelectron microscopic studies, together with novel findings in pancreatic tissue.

Discussion

We conducted a scoping review for studies of severe pertussis in infants. These patients’ common critical illness characteristic was a need for intensive care treatment, with specific definitions of severe pertussis given in individual studies. Most of the studies (40/64) were case reports and gave limited information. More than half of the studies described characteristics (or risk factors) of severe course or death from pertussis. There was a significant association between elevated white blood cell counts/pulmonary hypertension and increased severity of the disease/death.

Pulmonary histopathology [74,75,80] demonstrated abundant leukocyte aggregates in small pulmonary arteries, veins, and lymphatics; it was supposed that vascular infiltration and blood hyperviscosity by elevated leukocyte counts may be a factor for pulmonary hypertension and heart failure. Virulence factors, the key pathogenicity determinants of B. pertussis, mediate different stages of disease pathology. The postmortem was pathologically characterized by necrotizing bronchitis, bronchiolitis, pulmonary hemorrhage, edema, and extensive areas of alveolar epithelial necrosis, indicating that toxin-mediated processes or invasive infections damage the bronchi and alveolar epithelium, which could also be responsible for the secondary increased pulmonary vascular resistance, pulmonary hypertension, and subsequent fatal cardiac failure. In the first few months of life, especially in neonates, there is still a prominent muscular component in the arteries, and these vessels are very reactive to constrictive stimuli [81]. Hypoxemia, or coexistent acidosis, can trigger pulmonary vasoconstriction, and result in an acute increase in pulmonary vascular resistance. Thus, critical hypoxemia and heart failure may be due to a combination of factors, and further studies are needed to clarify the pathogenesis of refractory cardiopulmonary failure caused by severe pertussis.

Although the association between leukocyte counts and disease severity is well known, as well as strategies such as leukapheresis and exchange transfusion to reduce high leukocyte counts have been used clinically, there are still no standardized leukocyte cut-off values for initiating the treatment. A total of 18 articles (15 case reports, 3 case series studies) reported the use of leukoreduction therapy in severe pertussis with increased leukocytes, which ranged from 45–204.9 × 10⁹/L. Only one study had proposed a specific quantified leukodepletion strategy, patients were given a suitable treatment respectively based on a leukocyte count greater than 50/70/100 × 10⁹/L with or without cardiopulmonary dysfunction, which made a marked decrease in mortality [72]. Five articles (four case reports and one case series study) reported extracorporeal membrane oxygenation (ECMO). There is no optimal management method for pertussis infants treated with ECMO. Some researchers consider the early use of ECMO as the key to obtaining a good treatment effect and improving survival.

There are some limitations to our review. Due to the strict criteria, that is, the age of infants was younger than 1 year, studies that had a portion of the subjects meet the age criteria may have been missed. We minimized this shortcoming by including studies that had the majority of subjects meet the age criteria. Furthermore, 62.5% of the articles were case reports, which lacked a comprehensive description of the topic they covered. It was difficult to unify the variables in the data charts of the 64 articles, so we characterized case reports by developing the data chart separately.

In summary, the 64 articles included studies on epidemiology, pathology, clinical characteristics, risk factors, treatments, and burden of disease. Although these studies covered a variety of clinical concerns, most of them are descriptive, and targeted studies are still insufficient. Experimental studies are needed to provide high-quality evidence.

Authors contributions

GS and WCM conceptualized the review. ZY and GQ conducted the title/abstract and full-text screening. GS extracted and synthesized data with inputs from all authors. GS drafted the manuscript. ZY, GQ, and WCM revised for critical content. All authors contributed to the interpretation of findings and approved the version for submission.

Ethical approval

This study was a summary and analysis of the existing literature and ethical approval was not applicable.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Additional information

Funding

Pediatric Clinical Research Center Foundation of Sichuan Province, China [No. 2017-46-4]. National Project for Clinical Key Specialty Development.