Expert Review of Vaccines

ISSN: 1476-0584 (Print) 1744-8395 (Online) Journal homepage: https://www.tandfonline.com/loi/ierv20

The prevention of severe pertussis and pertussis

deaths in young infants

James D. Cherry

To cite this article: James D. Cherry (2019): The prevention of severe pertussis and pertussis
deaths in young infants, Expert Review of Vaccines, DOI: 10.1080/14760584.2019.1581065

To link to this article: https://doi.org/10.1080/14760584.2019.1581065

Accepted author version posted online: 08

Feb 2019.

Submit your article to this journal

Article views: 1

View Crossmark data

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=ierv20
1

Publisher: Taylor & Francis

Journal: Expert Review of Vaccines

DOI: 10.1080/14760584.2019.1581065
Perspective

t
The prevention of severe pertussis and pertussis deaths in young

ip
infants

cr
James D. Cherry

us
an
Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, USA
M
Correspondence:

James D. Cherry
ed

Department of Pediatrics, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue,
MDCC 12-363, Los Angeles, CA 90095-1752, USA
pt

Email: jcherry@mednet.ucla.edu
ce
Ac
2

ABSTRACT

Introduction: Today, in the developed world, virtually all deaths due to Bordetella pertussis

t
ip
illnesses occur in young infants. Therefore, it is important to discuss severe pertussis and its
prevention.

cr
Areas Covered: These infant deaths are frequently misdiagnosed. Pertussis in young infants is
characterized by an afebrile cough illness with coryza, apnea, seizures, cyanosis and emesis.

us
Severe illness is associated with high leukocyte and lymphocyte counts, rapid respiratory and
cardiac rates and pneumonia. The main treatment for severe pertussis in young infants is
an
exchange blood transfusion. Many routine intensive care treatment procedures are detrimental:
these include steroids and nitric oxide. Preventative measures include: quarantine, prophylactic
antimicrobial agents and immunizations of the mother to be with Tdap between 27 and 36
M
weeks gestation.

Expert Opinion: Infants deaths are due to the irreversible pulmonary hypertension which is
ed

caused by aggregates of leukocytes in the small vessels in the lung. The leukocytosis with
lymphocytosis is due to pertussis toxin. It can be treated by exchange blood transfusions.
However for this to be successful it needs to be started before shock or organ failure has
pt

occurred. To prevent pertussis in young infants, attention needs to be directed to the diagnosis
and treatment of pertussis in adolescents and adults. Also important in prevention of infant
ce

pertussis are antimicrobial prophylaxis in the infant and the immunization of mothers to be with
Tdap vaccine during all pregnancies.
Ac

Keywords: pertussis, leukocytes, lymphocytes, pertussis toxin, exchange transfusion, infants,

pulmonary hypertension
3

Article highlights

• Pertussis deaths in the United States were declining before the vaccine era.

• Today infant pertussis deaths still occur. About 5% of the infant pertussis cases die.
• The source of pertussis in infants is unrecognized pertussis in an adolescent or an adult.
Greater awareness of adolescent and adult pertussis is necessary to stop transmission
to infants.

t
ip
• Pertussis in infants is a distinctive illness but most cases are incorrectly diagnosed.
• The prompt diagnosis of infant pertussis and appropriate antimicrobial treatment will

cr
prevent death.
• Immunization of the pregnant woman with Tdap can be expected to prevent virtually all

us
pertussis deaths in the first 2 months of life.

• The cause of pertussis deaths in infants is irreversible pulmonary hypertension due to

an
leukocytosis with lymphocytosis.

• Some routine treatments in pediatric intensive care units may be contribute to pertussis
M

deaths in young infants.

ed

• The recommended treatment for extreme leukocytosis in young infants with pertussis is

exchange blood transfusion.

pt
ce
Ac
4

1.0 INTRODUCTION

Like many other primary infectious diseases of children, the number of deaths and death
rates from pertussis were falling prior to the use of pertussis vaccines or the availability of
antibiotics [1-6]. In the years 1900-1904, the death rate from pertussis in the United States in
infants was 434 per 100,000[1]. This rate, in a linear fashion, fell over the next 40 years to 86
per 100,000 in 1940-1944. Similarly, the death rate in children 1-4 years of age fell from 87 per

t
100,000 in 1900-1904 to 9 per 100,000 in 1940-1944.

ip
Interestingly, the number of deaths in the first year of life peaked in the 2nd and 3rd month

cr
of life; only a small percentage were noted in the first 4 weeks of life [2]. In a 1984 publication I
noted that pertussis deaths in infants were under reported; they were attributed to other

us
respiratory illnesses such as bronchitis and pneumonia [4]. It was also noted by Nicoll and
Gardener that additional pertussis deaths in England and Wales were signed out as Sudden
Infant Death Syndrome (SIDS). [7]
an
Our recent experiences in California suggest that pertussis deaths in young infants are
still often misdiagnosed. [8-10].
M

2.0 PERTUSSIS IN INFANTS

ed

2.1 The source

A number of studies in the United States and Europe have investigated the source
pt

persons who exposed young infants to pertussis. [11-21]. The source person is most often a
parent. Other family members, including grandparents are also important. In the most recent
ce

study in the United States, it was noted that now siblings were the most important source
persons [13]. The source persons are adolescence and adults with an afebrile cough illness.
Ac

When these persons are seen by internists or family physicians the diagnosis of pertussis is not
considered. Wrong diagnoses include: bronchitis, upper respiratory infections, cough variant
asthma and gastroesophageal reflux. [22.23]

In a study in university students there were 31 cases of pertussis. The student health
service physicians did not make the correct pertussis diagnosis in any of the students. [23].
5

2.2 Pertussis in Infants

In 2012 the Global Pertussis Initiative (GPI), reviewed the clinical manifestations of
pertussis in different age groups [24]. The characteristics in the 0-3 month’s age group were as
follows: a cough illness in an infant with no or minimal fever. The cough is of any duration that is
not improving. The cough may or may not be seen as paroxysmal. There is coryza which does
not become purulent. With cough there may be apnea, seizures, cyanosis and emesis.

t
Pneumonia is frequent. Coinfection with RSV or an adenovirus can confuse the picture because

ip
of expiratory distress and fever. There is an increased WBC count (≥ 20,000 with ≥ 10,000
lymphocytes).

cr
In 2008, Chris Padlock with other CDC investigations and myself described 15 fatal B.

us
pertussis cases [25]. Subsequently Chris Padlock and I relooked at pertussis deaths in infants
[26]. At the time of the first paper we suggested a mechanism for the cause of death.
Specifically, it was irreversible pulmonary hypertension, due to aggregates of leukocytes in the
an
small vessels in the lung.

In recent years our extended group in California has done a number of studies relating to
M
pertussis in young infants [8-10, 27-29]. In our first study we evaluated 31 young infants ≤90
days of age, with severe pertussis who were admitted to one of five Southern California
pediatric intensive care units [8]. We compared the characteristics of the illnesses in 8 infants
ed

that either died or had pulmonary hypertension with the 23 infants with less severe illnesses.
The 8 infants with more severe infections had many significant differences from the 23 infants
with less severe illnesses. The more severe cases had higher mean and median peak WBC
pt

counts and their counts, reached a higher value sooner. It took 5.1 days (mean) for the more
severe group, whereas it took 22.2 days in the less severe group. The mean maximum heart
ce

rate in the more severe group was 210.8 per minute whereas it was 188.5 per minute in the less
severe group. A heart rate of ≥170 in the more severe group occurred on day 6.1 (mean)
Ac

whereas it occurred on day 10.9 (mean) in the less severe group.

The mean respiratory rate in the severe group was 104.5 per minute whereas it was
70.5 per minute in the less severe group. A rate of ≥70 per minute occurred first on day 6.9
(mean) in the more severe group, whereas it occurred on day 21 in the less severe group. All 8
infants in the more severe group had pneumonia. In the infants with pneumonia it occurred
sooner (day 6.5 mean) in the more severe group than in the less severe group (day 21.1,
mean).
6

Our group did a study which looked at risk factors associated with infant deaths from
pertussis [9]. This study was a case control study in infants’ < 120 days of age; 53 fatal cases
were compared with 183 nonfatal hospitalized cases. The findings in this study confirmed the
findings in our first study. In addition, the fatal cases had lower birth weights, shorter gestational
ages, and were younger at the time of cough onset than the control infants. Fatal cases had
higher peak WBC and lymphocyte counts than the control infants. Fatal cases were less likely to
have revived macrolide antibiotics than infants in the control group. The fatal cases were more

t
ip
likely to have received steroids or nitric oxide treatment than the nonfatal cases. Also, fatal
cases were more likely to have received exchange blood transfusion and extra corporeal

cr
membrane oxygenation (ECMO) than the control group. Conclusions of this study included:
early recognition of pertussis and treatment with appropriate antimicrobial agents are important

us
in preventing death and the use of nitric oxide for treatment was a risk factor for death.

Our final study was an observational study of severe pertussis in 100 California infants’
an
≤120 days of age [29]. All the infants in this study were cared for in a pediatric intensive care
unit. There were 5 deaths. The WBC counts in the fatal cases were significantly higher than in
the nonfatal cases. The median age at the time of illness onset in the fatal cases was 23 days.
M
One third of the infants were intubated, 18% received inotropic and/or vasoactive support, 22%
received steroids, 4% received ECMO and 3% had exchanged blood transfusions. Of the
ECMO recipients 3 died and the survivor was deaf and blind.
ed

The findings in this study, as well as data from our other studies allowed us to suggest
updated strategies for the management of severe pertussis [30].
pt

We have determined that the many specific factors relate to death or survival [8, 9, 10,
27-30]. The most important risk factor for death is leukocytosis with lymphocytosis. This relates
ce

to both the total values and the rapidity of the rise. Other factors relating to death include: young
age, low birth weight and increased pulse and respiratory rates. Although pneumonia is present
Ac

in most fatalities, it is not a risk factor for death. However, the timing of the occurrence of
pneumonia is. Infants with the early onset of pneumonia are more likely to die than those with
delayed onset of pneumonia. Apnea it not a risk factor for death. In one study, we found that
some routine treatment modalities were unnecessary and likely detrimental [30]. These include:
steroids, pressures without evidence of hypotension and ECMO. The last important treatment
modality is the use of exchange blood transfusion for leukocytosis with lymphocytosis.
7

The cause of death in infant pertussis is irreversible pulmonary hypertension associated

with aggregates of white blood cells in pulmonary arterioles due to extreme leukocytosis with
lymphocytosis [25, 26]. A logical approach for the prevention of death would be exchange blood
transfusion to reduce the WBC counts. Several case reports suggested success with exchange
blood transfusion. However, in our case-control study all 11 infants who received an exchange
blood transfusion died. In another multicenter pediatric intensive care study, 11 infants had
exchange transfusion or leukopheresis and 9 survived and 5 died [31]. Members of our

t
ip
extended group looked carefully at exchange blood transfusion. In our study there were 10
infants who had exchange blood transfusions and 5 died and 5 survived [27]. The peak WBC

cr
counts were similar in the two groups. In our survivor group the exchange transfusions was
done before shock/hypertension and organ failure had occurred.

us
3.0 PREVENTION
an
3.1 Quarantine

Quarantining patients with recognized diseases has varying degrees of effectiveness

M

depending on the infectious disease in question. For example, historically, it worked well with
smallpox and in more recent times with Ebola. However, with diseases with a high degree of
ed

contagion like pertussis and measles, it is more difficult to implement. Never the less it should
be implemented when possible with pertussis. For example keeping grandparents and other
adults with upper respiratory findings (cough, coryza) away from young infants can be expected
pt

to work. However, the misdiagnosis of upper respiratory symptoms in adolescents and adults by
caregivers for adults is a problem.
ce

3.2 Antimicrobials
Ac

Post exposure prophylaxis is recommended by the Committee of Infection Diseases of

the American Academy of Pediatrics and the ACIP for all household contacts of an index case.
Post exposure prophylaxis is also recommended for close other contacts and for children in
childcare. Post exposure prophylaxis should be employed for all of the above regardless of their
immunization status. A close content is face-to-face exposure within 3 feet of a symptomatic
person; or direct content with respiratory, nasal or oral secretions of a symptomatic person; or
8

the sharing of the same contained space in close proximity to a symptomatic person for ≥1 hour.
Azithromycin, erythromycin or trimethoprim sulfamethoxazole are all recommended for post
exposure prophylaxis. However, trimethoprim sulfamethoxazole is generally contraindicated in
infants < 2 months of age. Clarithromycin can be used instead of azithromycin or erythromycin.
In general, compliance is best with azithromycin because the treatment course is only 5 days.
Since some B. pertussis strains are resistant to macrolides, trimethoprim sulfamethoxazole
should be used in apparent treatment failures.

t
ip
cr
3.3 Immunization

3.3A The Infant. Pertussis immunization with DTaP is recommended to commence at age 8

us
weeks. However, it has been shown that moving this from 8 weeks to 6 weeks will prevent both
hospitalizations and deaths [32].
an
3.3B The Mother to be. A number of studies have shown that vaccinating pregnant women with
Tdap between 27 and 36 weeks gestation will prevent most infections and virtually all deaths in
infants during the first 2 months of life [33-35].
M
ed

4.0 CONCLUSIONS

Throughout history most deaths due to pertussis have occurred in infants. Deaths from
B. pertussis infections were declining in the prevaccine/antibiotic eras. Infant pertussis cases
pt

and deaths are frequently misdiagnosed. The source of pertussis in infants is most often an
adolescent or an adult. Pertussis in infants occurs without fever and has prolonged cough,
ce

coryza, apnea, seizures, cyanosis and emesis. Pneumonia is common. Death is due to
irreversible pulmonary hypertension due to aggregates of leukocytes in the small vessels in the
Ac

lung. Infant death cases have very high leukocyte and lymphocyte counts, very rapid heart and
respiratory rates and pneumonia. Fatal cases were less likely to have received appropriate
antimicrobial treatment and more likely to have received steroids and nitric oxide in treatment.
Other factors relating to death include: young age and low birth weight. I suggest that certain
intensive care unit modalities are detriment in infant pertussis. These include: steroids, pressors
without evidence of hypertension and ECMO. The most important treatment is exchange blood
transfusion for leukocytosis with lymphocytosis.
9

Prevention of pertussis in infants includes post exposure antimicrobial treatment and

DTaP administration. Tdap vaccination of mothers to be between the 27th and 36th week of
gestation will prevent virtually all pertussis in the first 2 months of life.

5.0 EXPERT OPINION

t
Pertussis is a unique infectious disease in that it can be a severe and fatal, but unless a

ip
secondary bacterial or viral infection is present, it occurs without fever or other evidence of an
inflammatory illness. In the present era, virtually all deaths occur in young infants. Infant deaths

cr
are due to irreversible pulmonary hypertension which is caused by aggregates of leukocytes in
the small vessels in the lung. The leukocytosis with lymphocytosis is due to PT. It can be treated

us
by exchange blood transfusion. However for this to be successful it needs to be started before
shock or organ failure has occurred.
an
To prevent pertussis in young infants, attention needs to be directed to the diagnosis
and treatment of pertussis in adolescents and adults. Also important in prevention of infant
pertussis is antimicrobial prophylaxis in the infant and the immunization of mothers to be with
M

Tdap vaccine during all pregnancies.

Virtually all infant deaths can be prevented by Tdap vaccination of all pregnant women
ed

during each pregnancy. At present, Tdap vaccination rates in pregnant women are suboptimal.
It is anticipated that in 5 years the rate of immunization of pregnant women with Tdap will be
close to 100%. If this comes to pass, pertussis deaths in the first 2 months of life will be
pt

relegated to the past.

ce
Ac
10

Funding

This paper was not funded.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity

t
ip
with a financial interest in or financial conflict with the subject matter or materials discussed in
the manuscript. This includes employment, consultancies, honoraria, stock ownership or

cr
options, expert testimony, grants or patents received or pending, or royalties.

us
Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
an
M
ed
pt
ce
Ac
11

REFERENCES

Papers of special note have been highlighted as:

* of interest

** of considerable interest

t
ip
1. Mortimer EA Jr, Jones PK. An evaluation of pertussis vaccine. Rev Infect Dis. 1979;
1:927-934.

cr
2. Brooks G.F. and Buchan T.M. Pertussis in the United States. The Journal of Infectious
Disease.1970;122:123-125

us
3. Lapin JH. Whooping Cough. Springfield, IL: Charles C Thomas; 1943
4. Cherry JD. The epidemiology of pertussis and pertussis immunization in the United
Kingdom and the United States: a comparative study. Curr Probl Pediatr. 1984; 14:1-78
an
5. Cherry JD, Brunell PA, Golden GS, et al. Report of the Task Force on Pertussis and
Pertussis Immunization: 1988. Pediatrics. 1988; 81(suppl):939-984.
6. Mattoo S, Cherry JD. Molecular pathogenesis, epidemiology. And clinical manifestations
M
of respiratory infection due to Bordella pertussis and other Bordella subspecies. Clin
Microciol Rev. 2005; 18:326-382.
7. Nicoll A, Gardener A. Whooping cough and unrecognized post perinatal mortality. Arch
ed

Dis Child. 1988; 63:41-47.

8. Murray EL, Nieves D, Bradley JS, et al. Characteristics of severe Bordella pertussis
pt

infection among infants < 90 days of age admitted to pediatric intensive care units-
Southern California, September 2009-June 2011. J Pediatrics Infect Dis Soc. 2013, 2:1-
ce

6.
9. Winter K, Zipprisch J, Harriman K et al. Risk factors associated with infant deaths from
pertussis: a case-control study. Clin Infect Dis. 2015; 61:1099-1106.
Ac

10. Cherry J.D., Wendorf, K.A., Bregman, B., Lehman, D.L., Nieves, D.J., Bradley, J.S.,
Mason, W.H., Sande-Lopez, M., Federman, M.D., Chen, T.K., Blumberg, D.A.,
Johnston, S.J., Schwenk, H.T., Wientrub, P.S., Quinn, K.K., Winter, K., & Harriman, K.H.
(2018). An Observational Study or Severe Pertussis in 100 Infants ≤ 120 Days of Age.
Pediatr Infect Dis. 2018. 37 3, 202-205.
11. Schmitt-Grohe S, Cherry JD, Heininger U, et al. Pertussis in German adults. Clin Infect
Dis. 1995; 21:860-866.
12

12. Wendelboe AM, Njamkepo E, Bourillon A, et al. Transmission of Bordella pertussis to

young infants. Pediatr Infect Dis. 2007; 26:293-299.
13. Skoff TH, Kenyon C, Cocoros N, et al. Sources of infant pertussis infection in the United
States. Pediatrics. 2015; 136:635-641.
14. Kowalzik F, Barbosa AP, Fernandes VR, et al. Perspective multinational study of
pertussis infection in hospitalized infants and their household contact. Pediatr Infect Dis
J. 2007; 26:238-242.

t
ip
15. Fedele G, Carollo M., Palazzo R., et al. Parents as a source of pertussis transmission in
hospitalized young infants. Infection. 2017; 45:171-178.

cr
16. Bisgard KM, Pacual FB, Ehresmann KR, et al. Infants pertussis: who was the source?
Pediatr Infect Dis J. 2004; 23:985-989.

us
17. Baron S, Njamkepo E, Grimprel E, et al. Epidemiology of pertussis in French hospitals in
1993 and 1994: thirty years after a routine use of vaccination. Pediatr Infect Dis. 1995;
17:412-418.
an
18. Deen JL, Mink CA, Cherry JD, et al. Household contact study of Bordella pertussis
infections. Clin Infect Dis. 1995; 21:1211-1219.
19. Crowcroft NS, Booy R, Harrison T, et al. Severe and unrecognized: pertussis in UK
M
infants. Arch Dis Child. 2003; 23:246-252.
20. Elliott E. McIntyre P, Ridley G, et al. National study of infants hospitalized with pertussis
in the acellular vaccine era. Pediatr Infect Dis J. 2004; 23:246-252.
ed

21. Curtis C, Baughman A, DeBolt C., et al. Risk Factors associated with Bordetella
pertussis among infants ≤ 4 months of age in the Pre-Tdap era. Pediatr Infect Dis J.
pt

2017; 36:726-735.
22. Cherry JD. The present and future control of pertussis. Clin. Infect Dis. 2010;51: 663-
ce

667.
23. Mink CM, Cherry JD, Christenson P, et al. A search for Bordetella pertussis infection in
university students. Clin Infect Dis. 1992; 14;464-471.
Ac

24. Cherry JD, Tan T, Wirsing von Konig CH, et al. Clinical Definitions of Pertussis:
Summary of a Global Pertussis Initiative Roundtable Meeting, February 2011. Clinical
Infectious Disease. 2012;54(12):1756-64.
25. Paddock CD, Sanden GN, Cherry JD, et al. Pathology and pathogenesis of fatal
Bordetella pertussis infection in infants. Clin Infect Dis. 2008;47:328-338.
26. Cherry JD, Paddock CD. Pathogenesis and histopathology of pertussis: implications for
immunization. Expert Rev Vaccines. 2014;13:1115-23.
13

27. Nieves D, Bradley JS, Gargas J, et al. Exchange blood transfusion in the management
of severe pertussis in young infants. Pediatr Infect Dis J. 2013; 32:698-699.
28. Cherry JD. Pertussis in Young Infants throughout the World. Clinical Infectious Disease.
2016;63(S4):S119-22
29. Cherry JD, Wendorf K, Bregman B. An observational study of severe pertussis in 100
infants < 120 days of age. Pediatr Infect Dis J 2018; 37:202-205.
30. Cherry JD. Treatment of Pertussis -2017. Journal of the Pediatric Infectious Disease

t
ip
Society. 2017;00(00):1-3
31. Berger JT, Carcillo JA, Shanley TP, et al. Critical pertussis illness in children: a

cr
multicenter prospective cohort study. Pediatr Crit Care Med. 2013; 14:0-0.
32. Tejpratap S.P. Tiwari, Andrew L. Baughman, Thomas A. Clark: 2015. Pediatrics. 2015;

us
135 (6) 990-999.
33. Amirthalingam G, Andrews N, Campbell H et al. Effectiveness of maternal pertussis
vaccination in England: an observational study. Lancet 2014; 384:1521–8.
an
34. Dabrera G, Amirthalingam G, Anderews N, et al. A case-control study to estimate the
effectiveness of maternal pertussis vaccination in protecting newborn infants in England
and Wales, 2012–2013. Clin Infect Dis 2015; 60:333–7.
M
35. Winter K, Cherry JD, Harriman K; Effectiveness of Prenatal Tetanus, Diphtheria, and
Acellular Pertussis Vaccination on Pertussis Severity in Infants, Clinical Infectious
Diseases. 2017 Jan 1;64(1):1-6.
ed
pt
ce
Ac