Pediatric Pulmonology 44:970980 (2009)

Fulminant Pertussis:
A Multi-Center Study With New Insights Into
the Clinico-Pathological Mechanisms
Mohammad Sawal, MRCP,1 Marta Cohen, MD, CCPM,2 Jose E. Irazuzta, MD, FCCM,3
Ramani Kumar, FRCPath,4 Christine Kirton, FRCA,2 Marie-Anne Brundler, MD,1
Clair Anne Evans, FRCPath,2 John Andrew Wilson, FRCPath,4 Parakkal Raffeeq, FRCPCH,5
Amer Azaz, FRCPCH,4 Alexandre T. Rotta, MD,6 Ajay Vora, FRCPath,2 Amit Vohra, MD,7
Patricia Abboud, MD,7 L. David Mirkin, MD,7 Mehrengise Cooper, FRCPCH,8 Megan K. Dishop, MD,9
Jeanine M. Graf, MD,9 Andy Petros, FRCP,10 and Hilary Klonin, MRCP4*
Summary. Pertussis carries a high risk of mortality in very young infants. The mechanism of
refractory cardio-respiratory failure is complex and not clearly delineated. We aimed to examine
the clinico-pathological features and suggest how they may be related to outcome, by multi-center
review of clinical records and post-mortem findings of 10 patients with fulminant pertussis (FP). All
cases were less than 8 weeks of age, and required ventilation for worsening respiratory symptoms
and inotropic support for severe hemodynamic compromise. All died or underwent extra corporeal
membrane oxygenation (ECMO) within 1 week. All had increased leukocyte counts (from 54 to
132  109/L) with prominent neutrophilia in 9/10. The post-mortem demonstrated necrotizing
bronchitis and bronchiolitis with extensive areas of necrosis of the alveolar epithelium. Hyaline
membranes were present in those cases with viral co-infection. Pulmonary blood vessels were
filled with leukocytes without well-organized thrombi. Immunodepletion of the thymus, spleen, and
lymph nodes was a common feature. Other organisms were isolated as follows; 2/10 cases Para
influenza type 3, 2/10 Moraxella catarrhalis, 1/10 each with respiratory syncytial virus (RSV), a
coliform organism, methicillin-resistant Staphylococcus aureus (MRSA), Haemophilus influenzae,
Stenotrophomonas maltophilia, methicillin-sensitive Staphylococcus aureus (MSSA), and candida
tropicalis. We postulate that severe hypoxemia and intractable cardiac failure may be due to the
effects of pertussis toxin, necrotizing bronchiolitis, extensive damage to the alveolar epithelium,
tenacious airway secretions, and possibly leukostasis with activation of the immunological
cascade, all contributing to increased pulmonary vascular resistance. Cellular apoptosis appeared
to underlay much of these changes. The secondary immuno-compromise may facilitate
co-infection. Pediatr Pulmonol. 2009; 44:970980. 2009 Wiley-Liss, Inc.
Key words: Bordetella pertussis; pathology; symptoms; treatment.

Birmingham Childrens Hospital NHS Foundation Trust, Birmingham, UK.

Sheffield Childrens Hospital NHS Foundation Trust, Sheffield, UK.

University of Florida, Jacksonville, Florida.

Hull Royal Infirmary, Hull, UK.

City General Hospital, Stoke-on-Trent, Staffordshire, UK.

The clinical review was conducted at Hull Royal Infirmary and the
histological review was conducted at Sheffield Childrens NHS Foundation
Trust.
This paper was presented in part at the 11th Spring Meeting of the Royal
College of Paediatrics and Child Health, March 26th29th 2007, York and
was published in Abstract form in Archives Disease in Childhood, April
2007, Volume 92, supplement 1 (A84).

*Correspondence to: H. Klonin, MRCP, Paediatric Department, Hull Royal

Infirmary, Craven Building, Anlaby Road, Hull, HU3 2JZ, UK.
E-mail: hilary@lama.karoo.co.uk

8
St Marys Hospital, Imperial College Healthcare NHS Trust, Paddington,
London, UK.

Received 25 July 2008; Revised 10 February 2009; Accepted 13 February

2009.

DOI 10.1002/ppul.21082
Published online 1 September 2009 in Wiley InterScience
(www.interscience.wiley.com).

Driscoll Childrens Hospital, Corpus Christi, Texas.

The Childrens Medical Center, Dayton, Ohio.

Texas Childrens Hospital, Houston, Texas.

10

Great Ormond Street Hospital for Children, London, UK.

2009 Wiley-Liss, Inc.

Fulminant Pertussis: Clinical-Pathological Findings

INTRODUCTION

Pertussis has been defined as a respiratory infection

which progresses to a paroxysmal cough with an
inspiratory whoop caused by Bordetella pertussis.1
Surridge has suggested that apnea should be added to
the clinical definition.2 A fulminant course of pertussis
develops in very young, incompletely immunized infants
that do not present the classical stages of pertussis.3,4
Fulminant pertussis (FP) is characterized by the development of pneumonia that rapidly evolves to respiratory
failure requiring cardiovascular support.5 Despite contemporary intensive care support the outcome for these
infants has remained extremely poor, with death in 7 out of
9 infants with a median age of 6 weeks, who presented
with pneumonia, to intensive care, over a 20 year period.5
Cortese using detailed analysis of Inpatient databases and
national surveillance systems noted a fatal outcome for 18
infants during 2000, and 14 infants during 2003, all under
3 months, from a total of 2,685 and 2,670 pertussis
hospitalizations respectively.4 The pathophysiology of
this condition has not been fully established leading to a
variety of therapeutic attempts and tentative recommendations. Nicholson6 suggested that elucidating it may help
to understand organ failure in the wider context of critical
illness and injury.
There are several hypotheses for the poor outcome of
FP, many focusing on the role of intractable pulmonary
hypertension or the relationship with pulmonary thrombosis.519 An association between high white blood cell
count (WBC) and increase in severity led to speculation
that vascular infiltration or hyperviscosity may play a
role in inducing pulmonary hypertension and heart
failure.8,13,14,1820 However, the absence of pulmonary
hypertension in some cases lead to the theory that
primary ventricular dysfunction may be a separate causal
entity and could be the focus of therapeutic interventions.5,10,12,15 An interesting observation is that associated
viral infection may be a linked co-morbidity that
contributes to prime the immunological system.21
After finding little information in the literature to
inform our understanding of the clinical histopathological
correlates, we undertook a multi-center analysis of a case
series of infants with FP over 6 years who succumbed
despite contemporary ICU treatments, correlating
detailed post-mortem evidence with clinical findings.
MATERIALS AND METHODS

A retrospective review of 10 infants who died from

pertussis in eight centers over a 6-year period (2001
2007) was performed. After the death of a case in the
clinical review center, other centers volunteered information, either as result of hearing about the study through
word of mouth, or by responding to a request for cases
lodged on the international pediatric intensive care

971

website (http://www.vpicu.org/piculist). In all cases the

diagnosis of B. pertussis was confirmed by culture or by
polymerase chain reaction (PCR) in respiratory secretions
or lung tissue.
Real-time PCR, performed in LightCycler, prepared:
easyMag assay (Roche ASR, Indianapolis, IN). Real-time
PCR, performed in SmartCycler, prepared: easyMag
assay (Kimberly-Clark, Chester, PA). In-house two target
real-time PCR, extracted using either a Qiagen kit or on
the MagNaPure Compact performed in a LightCycler
(Roche Diagnostics, Indianapolis, IN) by Health Protection Agency National Pertussis Research and Reference
Laboratory, Colindale, London.
Charts were reviewed for clinical and demographic data
and clinical management information. Pathological slides
were reported independently at each center (MAB, MC,
CE, MD, DM, and RK). Slides from four of the cases were
reviewed by a panel of three pathologists (MAB, MC, and
CE). The initial table design was based on these findings.
Six other cases were summarized by MC, from a chart and
slide review of the findings of the pathologists based at the
participating centers. Hematoxilin and Eosin stains
(H&E) were used and in one case Brown-Hopps.
Individual centers were responsible for ethical approval.
This consisted of gaining informed consent or receiving
waiver of need for informed consent by the institutions
responsible committee for research and ethics.
RESULTS

Table 1 summarizes the clinical and microbiological

findings and Table 2 summarizes the histopathological
findings for all patients.
All 10 patients were 8 weeks of age or younger, had not
received immunization, and presented with cough and
coryzal symptoms. Median time from admission to
intubation was 1 day (range, immediately on admission
to 6 days after admission). All required mechanical
ventilation for worsening respiratory symptoms and
inotropic support for hemodynamic compromise.
Although there was some initial response to ventilatory
maneuvers such as non-invasive ventilation or conventional ventilation, respiratory failure escalated over time
to requirement for non-conventional ventilation, inhaled
nitric oxide (iNO), and extra corporeal membrane
oxygenation (ECMO) in 8/10 cases. In 2/10 cases
thick secretions from the respiratory tract were particularly problematic and thinning agents were not effective
in the case in which they were used. Three patients
developed pulmonary hypertension and one developed
mild tricuspid regurgitation. Four patients developed renal
failure, one of whom had an ultrasound finding of strands
in the renal and hepatic vasculature. Three cases had
hepatic failure or ascites. All had increased leukocyte
counts with a median count of 90  109/L, ranging from
Pediatric Pulmonology

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Sawal et al.

TABLE 1 Clinical Features and Microbiological Results of 10 Patients With Fulminant Pertussis

Case

Age
(weeks) Clinical picture

Total white
cell count:
neutrophils,
lymphocytes
(109/L)

Microbiology

Cough
Persistent tachycardia
Apneic episodes
Refractory hypotension

91.5
54.8
8.2 L

Cough
Apneic episode
Stiff clammy episode
Refractory hypotension
Thick secretions

94
43
27

106.8
54.48
25.63

Para influenza virus type 3on

respiratory cell culture on PM
Bordetella pertussis PCR positive
on PM PNS
Heavy growth of presumptive
Bordetella pertussis serotype1.3
in sputum

Cough
Tachycardia
Refractory hypotension
Ascites
Renal failure
Pulmonary hypertension
RV to RA gradient of
36 mmHg
Cough
Tachycardia
Refractory hypotension

107
62
16

54.0
17
22

Cough
Coryzal symptom
Intractable respiratory
failure
Cough
Respiratory distress
Poor lung compliance
Refractory hypotension
Acidosis, renal failure
Mild tricuspid regurgitation
Ultrasound findings.
Ultrasound strands in
renal and hepatic
vasculature
Nasal congestion
Tachypnea
Cough
Respiratory distress
Respiratory acidosis
Respiratory failure
Hemodynamic instability
Renal failure
Hepatic failure

Bordetella pertussis sero type 1.3

on PNS
Bordetella pertussis cultured on
ET secretions
Coliform organism cultured on
ET secretions
Bordetella pertussis PCR positive
RSV positive by ELISA

132
80
41

60
27.6
29.4

Bordetella pertussis on PNS

Bordetella pertussis PCR
positive on BAL
Para influenza virus Type 3 on BAL
Bordetella pertussis PCR positive
in post-mortem lung specimen
Bordetella pertussis PCR positive
on PM specimen
MRSA on NPA
Candida growth in sputum

Treatment
Antibiotics
Conventional ventilation

3 days
4 days

Antibiotic
Cuirass (non-invasive
ventilation)
Heliox
Conventional ventilation
HFO
Inhaled nitric oxide
Surfactant
DNA ase
Antibiotic
Cuirass
Heliox
Conventional ventilation
HFO
Partial plasma exchange
Steroid therapy
Inhaled nitric oxide
Antibiotic
Conventional
Ventilation
HFO

1 day
212 days

Antibiotic
HFO
APRV
ECMO
Bordetella pertussis PCR positive Antibiotic
on post-mortem nasal brushings Conventional ventilation
Exchange transfusion
CVVH

Bordetella pertussis PCR positive

on antemortem
tracheal secretions
Moraxella catarrhalis on
antemortem tracheal secretions
Candida tropicalis on antemortem
blood culture
Stenotrophomonas maltophilia on
antemortem blood culture

Time from
admission: to
intubation, to
death

Antibiotic
Conventional ventilation
HFV
CVVHD
ECMO
Steroid therapy

3 days
312 days

13 hr
1 day

Under 1 day
4 days

6 days
7 days

1 day
19 days

(Continued )

Pediatric Pulmonology

Fulminant Pertussis: Clinical-Pathological Findings

973

TABLE 1 (Continued)

Case

Age
(weeks) Clinical picture

10

36-week premature
Apneic episodes/cyanosis
Cough and emesis
Tachypnea, thick secretions
Respiratory acidosis
Terminal lactic acidosi
Progressive right lung
pneumonias
Terminal refractory shock,
DIC
Cough
Poor feeding for 2 days
Apnea
Floppy
Prehospital BLS
Tachycardia
Refractory shock
Severe respiratory distress
Renal failure
Ascites
Pulmonary hypertension
Impaired RV function
Upper respiratory
infection symptoms
for 1 week
Cough
Fever
Increased work of breathing
Decreased oral intake and
urinary output for 2 days
Profound worsening hypoxia
and difficulty with
oxygenation
Tachycardia with progressive
hypotension and poor
perfusion
Pulmonary hypertension
Respiratory acidosis
Coagulopathy

Total white
cell count:
neutrophils,
lymphocytes
(109/L)

Microbiology

Time from
admission: to
intubation, to
death

Treatment

64.9
29.8
20.8

PCR positive for Bordetella

pertussis/Holmesii on PM NPA
MSSA on antemortem tracheal
aspirate culture

Antibiotics
High flow nasal cannula
Conventional ventilation
Inhaled nitric oxide

5 days
6 days
and 2 hr

88.7
44.6
36.4

Bordetella pertussis on PCR in

lungs

Antibiotics
HFO
Inhaled nitric oxide
Steroids
Peritoneal dialysis

On admission
32 hr

78.5
28.3
33

Bordetella pertussis positive by

PCR on pre-mortem respiratory
aspirate
(B. parapertussis negative by PCR)
Post-mortem lung and blood
cultures positive for
Haemophilus influenzae and
Moraxella catarrhalis

Antibiotics
Hydration
Conventional ventilation
Inhaled nitric oxide

A few hours
<24 hr

APRV, airway pressure release ventilation; BAL, broncho-alveolar lavage; BLS, basic life support; CVVH, continuous venovenous hemofiltration;
DIC, disseminated intravascular coagulation; ECMO, extracorporeal membrane oxygenation; ELISA, enzyme-linked immunadosorbent assay; ET,
endotracheal; HFO, high frequency oscillation; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus
aureus; NA, not available; NPA, nasopharyngeal aspirate; PCR, polymerase chain reaction; PM, post-mortem; PNS, per nasal swab; RA, right
atrium; RSV, respiratory syncytial virus; RV, right ventricle.

54 to 132  109/L. In 9/10 cases there was prominent

neutrophilia, median 49  109/L. All succumbed
with time to death ranging from 1 day or less after
admission (two cases) to 19 days for one patient who
underwent a 17-day ECMO run. Median time to death was
just under 4 days.
Other organisms were found as follows; 2/10 cases Para
influenza type 3, 2/10 Moraxella catarrhalis, and 1/10 each
were co-infected with respiratory syncytial virus (RSV), a

coliform organism, Haemophilus influenzae, Stenotrophomonas maltophilia, methicillin-resistant Staphylococcus aureus (MRSA), methicillin-sensitive Staphylococcus
aureus (MSSA), and Candida tropicalis on antemortem
blood culture associated with fungal organisms seen in the
bladder on post-mortem. Numerous B. pertussis were
identified with Gram stain (Fig. 1) in case 8, corresponding
to extensive right sided pneumonia, despite broad-spectrum
antibiotic cover, including a macrolide.
Pediatric Pulmonology

Pediatric Pulmonology

Severe necrotizing Areas of

bronchitis,
necrotizing
bronchiolitis, and
bronchitis and
necrotizing
bronchiolitis.
pneumonia.
Focal
Areas with
necrotizing
prominent
pneumonia.
neutrophilic
Areas of
infiltrate. Areas
neutrophilic
with
infiltrate.
superimposed
Moderate
acute DAD-like
congestion and
changes
intra-alveolar
No parainfluenza
hemorrhage and
viral inclusions
edema
identified

Thymus Advanced almost

Severe cortical
Total cortical
depletion
depletion with
W: 2 (E: 5) g
marked reduction
of thymus weight

Lungs

Case

10

(Continued )

Severe necrotizing Necrotizing

Necrotizing
Necrotizing
Severe necrotizing Severe necrotizing Severe necrotizing Severe necrotizing
bronchitis and
bronchopneumonia bronchiolitis and
bronchopneumonia bronchitis,
bronchitis and
bronchitis with
bronchitis and
bronchiolitis.
necrotizing
affecting all
with small
bronchiolitis, and
bronchiolitis, with
pneumonia.
bronchiolitis.
Less extensive
pneumonia.
lobes
abscesses
pneumonia
pneumonia
Interstitial edema.
Few bacilli
necrotizing
Hepatization
Interstitial
Focal necrotizing
associated with
associated with
Interstitial and
adherent to
pneumonia. Focal pneumonitis with
with minimal
bronchitis and
neutrophilic
neutrophilic
alveolar
ciliated
not prominent
area of aeration
inflammatory
bronchiolitis
infiltrate.
infiltrate.
hemorrhage.
respiratory
neutrophilic
DAD
infiltrate of
Squamous
Gram-negative
Apoptotic alveolar epithelium,
infiltrate. Focal
neutrophil
Disseminated
metaplasia of the
cocci were seen on cell and debris in
consistent with
acute DAD-like
pulmonary
alveoli and
the surface of the
the alveoli.
Bordetella
changes. Focal
hemorrhage
bronchopulmonary bronchial mucosa
Occasional hyaline organisms.
organizational
extending to the
dysplasia. Rare
Hyperplasia of
membranes. Focal
Bilateral lobar
changes.
bronchus,
fungal organisms
type II
neutrophilic
pneumonia and
Moderate
extensive areas of
identified. One
pneumonocytes
infiltrate
extensive
congestion and
hyaline membrane
embolic area with
was seen
Gram-positive and
bronchopneumonia.
intra-alveolar
disease
calcification
Gram-negative
Abundant
hemorrhage. No
Evidence of DIC
cocci seen in the
Gram-negative
parainfluenza
inflammatory cells bacteria in regions
viral inclusions
Small infarcts related of pneumonia,
identified
with fibrin thrombi consistent with
Haemophilus
influenzae and/or
Moraxella
catarrhalis. DAD
(focal acute
exudative). Pleural
and subpleural
hemorrhages
Severe cortical
Severe depletion
Normal
Advanced cortical
Severe cortical
Normal
Severe cortical
Marked involution
depletion
of cortical
W: 9.1 (E: 9) g
depletion
depletion with
W: 6 (E: 6.1) g
depletion
with severe
W: 10.8 (E: 7.8) g
lymphocyte with
W: 10.7 (E: 10) g
cystic changes
cortical lymphocyte
prominent Hassals
of Hassalls
depletion
corpuscle
corpuscles
W: 5.7 (E: 7.5) g

TABLE 2 Histopathological Features of 10 Patients With Fatal Pertussis

974
Sawal et al.

Severe lymphocyte Lymphocyte

No significant
depletion. Marked depletion with no
adenopathy
congestion
obvious follicular
reaction

No significant
abnormality

Within normal limits No complete involu

tion of fetal cortex
but unremarkable

Acute pancreatitis

Fungal organisms in
bladder. Extensive
extramedullary
hematopoiesis in
various organs

EMH present but

unremarkable

Subendocardial
infarct affecting
both ventricles

Necrosis of
zone 3 of
hepatic lobule

Congestion. Diffuse
mild microvesicular
steatosis
Stress changes (lipid
accumulation in
fetal cortex, lipid
depletion in
definitive cortex)
Bone marrow
left-shifted granulo
poiesis
Pleural effusions
(50 ml right,
50 ml left)
Heart, dilated right
ventricular
outflow tract
Brain, cerebral
edema and acute
hypoxic-ischemic
neuronal injury

Bridging necrosis

Mixed micro and

macrovacuolar
steatosis
Medullary
hemorrhage

Micro and
macrovacuolar
steatosis

Congestion. Otherwise
normal

Acute tubular
necrosis

Healing acute tubular

necrosis

Acute tubular
necrosis

10

Marked depletion
White pulp depletion Marked depletion of Congested
of the white pulp
the white pulp

NA

Lymphocyte
depletion, and no
follicular reaction
Peribronchial lymph
nodes with acute
lymphadenitis and
sinus histiocytosis
White pulp depletion.
Congestion.

Lymphocyte
Normal architecture. Severe lymphocyte
depletion
Expanded sinuses
depletion
No follicular reaction with pigmented
histiocytes

DAD, diffuse alveolar damage; DIC, disseminated intravascular coagulation; NA, not available; W, weight; E, expected; EMH, extramedullary hematopoiesis.

Other

Adrenal

Spleen White pulp with

White pulp depletion White pulp depletion.Marked congestion Marked white pulp
depletion/
advanced depletion
Marked congestion depleted white
of red pulp
pulp and poorly
congested red
developed red pulp pulp
Kidneys
Large (58 g) but
Focal calcified casts
otherwise normal
in tubules. Acute
tubular necrosis
Liver
Congested
Autolysis with patchy
congestion

Lymph Massive lymphocyte No lymph node

node
depletion
available

Case

TABLE 2 (Continued)

Fulminant Pertussis: Clinical-Pathological Findings

975

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Sawal et al.

Fig. 1. Gram negative cocci on the surface of bronchial lining.

Brown-Hopps stain (case 8  100).

In all cases, post-mortem demonstrated necrotizing

bronchitis and bronchiolitis with extensive areas of
necrosis of the alveolar epithelium. Apoptosis of the
alveolar epithelium and sloughing of the pneumocytes
into the air space is demonstrated in Figure 2. Extensive
denudation of the alveolar epithelium was a frequent
finding (Fig. 3). Neutrophilic infiltrate was identified,
although with variable intensity. In two cases with viral
co-infection with Para influenza virus type 3 and one case
with RSV, diffuse alveolar damage with the presence of
hyaline membrane was present (Fig. 4). The blood vessels
were filled with leukocytes but there were no organized
thrombi with associated pulmonary infarction (Fig. 5).
The 8/10 cases where the thymus was sampled at the
post-mortem depicted advanced cortical depletion with
reduction of organ weight in some cases, as shown in
Table 2, when compared to charts according to the age of
each patient.22 The lymph nodes were examined in
7/10 cases and showed severe lymphocyte depletion with
no follicular reaction in 6/7. The spleen revealed a state of
advanced depletion of the white pulp in 9/10 cases. The
liver was described in 7/10 cases, showed congestion in
2 cases, conspicuous fatty changes in 3, and patchy
necrosis in 2 other cases. All three cases with hepatic
failure or ascites had evidence of necrosis or steatosis of
the liver. The kidney showed acute tubular necrosis in the
4/10 cases with renal failure.
DISCUSSION

We report a case series of 10 infants with FP in whom

full post-mortem examinations had been performed.
These infants were 8 weeks of age or younger, presented
with pneumonia, required intubation and ventilation
within the first week of presentation, had a high WBC
with neutrophilia and required inotropic support. All the
Pediatric Pulmonology

Fig. 2. Denuded alveolar lining which is seen sloughing into the

air spaces (asterisks) suggesting a necrotizing process. Note
that the inflammatory infiltrate is not prominent (H&E, case
3  20). Inset: at higher magnification, necrotic/apoptotic cells
are readily seen (arrows).

infants were unresponsive to intensive care management

and succumbed or required ECMO support within 1 week
of institution of invasive ventilation. In this case series of
FP we found evidence of necrotizing bronchitis, bronchiolitis, and alveolitis (necrotizing pneumonia) but
not of primary thrombosis of pulmonary vessels. A
conspicuous feature was the lack of severe neutrophilic
infiltrate in most cases, which has not previously been
described in the literature. Features of diffuse alveolar
damage were superimposed on those cases with an
identified viral co-infection, as well as one where a viral
co-infection was not delineated. Severe lymphocyte
depletion was found in the thymus, lymph nodes, and
spleen.
The age distribution of pertussis has changed since the
late 1970s, following increased vaccine coverage. The
proportion and the absolute number of cases are increasing
under the age of 3 months,23 showing a disproportionately
high mortality due to FP.5,9,12,13,2326 In our series, the
alveolar epithelium of the lungs was severely affected.
This lends support to the proposal that the consequence of

Fulminant Pertussis: Clinical-Pathological Findings

977

Fig. 5. Pulmonary vessels displayed leukocytosis (arrow) but

definitive thrombi were not identified (H&E, case 4  40).

Fig. 3. Immunostain with cytokeratin 7 highlights the necrosis of

the alveolar epithelium (curved arrows) as compared with the
preserved areas (straight arrow) (CK 7, case 1  20).

toxins mediated process or an aggressive infection

affecting the bronchial and alveolar epithelium may lead
to problems with secondary pulmonary vascular resistance, a degree of pulmonary hypertension and subsequent
fatal refractory cardiac failure.5,11,12,14,19,26 Small infants
may be particularly at risk, as pulmonary vessel walls are
relatively muscular and only thin down over the first
few months of life.27
The extensive damage to the alveolar and bronchiolar
epithelium, as well as the presence of hyaline membranes
further aggravates hypoxemia. The necrotic alveolar and
bronchial epithelium which accumulate in the airway

Fig. 4. Hyaline membranes (arrows) were seen in the cases

associated with a viral co-infection (H&E, case 3  20).

contribute to the tenacious secretions which are a hallmark

of the disease. Tenacious secretions increase ventilation
perfusion abnormalities. The ensuing hypoxemia may
exacerbate pulmonary hypertension.2830
The sum of these factors possibly led to a vicious cycle,
thereby increasing the effect of poor oxygen delivery to
the damaged respiratory tree and other end organs.31 The
rapid deterioration seen in all our cases sustains the
hypothesis that a presentation with pneumonia requiring
inotropic support has a particularly poor outcome.5,18,24
Halasa et al.8 described leukocyte thrombi in pulmonary arteries of one infant with pertussis who developed
extreme leukocytosis and required ECMO. While these
findings suggest a mechanism where thrombosis may be
a secondary rather than a primary event, Pierce et al.18
attributed the cause of fatal pulmonary hypertension in
4 out of 13 cases to vascular obstruction, although this
hypothesis was not confirmed by lung biopsy. We found
that small and medium sized arteries and veins were filled
with lymphocytes and neutrophils (see Fig. 5). However,
like Paddock et al.,19 we did not observe pulmonary
thrombosis defined by the presence of a solid mass of
blood constituents formed within the vascular system in
life and immersed in a dense fibrin mesh that makes it
adherent to the vessels wall.32 The sole presence of
leukocytes filling the lumen of the blood vessels in a
patient with leukocytosis is not sufficient evidence of
thrombosis, as this is a common feature in patients with a
fatal infection. If these were actual thrombi, associated
pulmonary infarctions would have been present.
Leukostasis affecting the pulmonary vasculature has
been described in patients with chronic lymphocytic
leukemia and hyperleukocytosis syndrome. Cytokines
such as IFN-gamma and TNF-alpha released from
activated lymphocytes trapped within the microvasculature are responsible for increased leukocyte adhesion and
endothelial cell damage.33 Although it may be feasible
Pediatric Pulmonology

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Sawal et al.

that the tendency to occlusion of small and medium size

blood vessels in the lung vasculature is due to an extremely
high leukocyte count, the reported WBC in FP is still far
lower and with different characteristics than that described
in adults with granulocyte leukemia and respiratory
distress syndrome.34 The literature describes that a double
volume exchange transfusion reduced the WBC in an
infant with pertussis from 104,000 to 15,200  109/mm3
which improved the patients oxygenation.35 ECMO in
conjunction with leukopheresis has resulted in survival for
a 5-week-old infant with pertussis with 59  109/L
neutrophils. In this case leukopheresis was started 3 hr
after initiation of ECMO, so it is not possible to separate
out the effects of the two therapies.20 Attempts to decrease
the white cell count in this series were not effective, which
may reflect the differences in the complex interplay of
cellular and chemokine/cytokine cross talk in adult
leukemia as compared to infants with pertussis. Whereas
in leukemia, the cells are by and large not functionally
activated and therefore physical stasis may play a more
important role in causation, in the case of infection driven
leukocytosis the T lymphocytes are activated and produce
a host of cytokines which will promote vascular
endothelial inflammatory change and damage. We
hypothesize that the increased pulmonary vascular
resistance and pulmonary hypertension demonstrated in
some cases is not due to physical leucostasis alone but a
combination of stasis and pulmonary vascular endothelial
cell damage by cytokines released from the accumulated
lymphocytes. The timing of the intervention may also be
an important factor. Leucopheresis may be only helpful in
preventing stasis related problem but would not be
expected to improve existing tissue damage. It is possible
that attempts to decrease the white cell mass would have
been more helpful, when attempted in this series, if it were
to be performed before cellular injury has ensued.
Pertussis is characterized by a lack of adequate
immunological response.5,21,36 However pertussis is not
uniformly fatal even in this age group. All patients in this
series were unimmunized. Epidemiological studies from
developing countries suggest that even a single dose of
pertussis vaccine imparted some protection, although
there was also an effect of vaccine-induced herd
immunity.37 Maternally transmitted antibodies decrease
after birth.38 These two factors may contribute to the
inability of the very young infant to mount an immune
response to B. pertussis itself. This is supported by work
on adult pertussis, which may be more severe where
vaccination has lapsed.39
While pertussis toxin has multiple harmful effects
through a single cell receptor,15,40 B. pertussis produces
numerous toxins, some affecting immune regulation.15,4145 Immunoparalysis with failure to overcome
primary or associated secondary infections has been
postulated as a potential mechanism for the severity of the
Pediatric Pulmonology

illness.10,21,36,41,42,45,46 Supporting this is the fact that 8/10

patients in this series had evidence of co-infection, despite
the short duration of the illness and associated the hospital
admission (Table 1). Case 8 demonstrates multiple B.
pertussis organisms still present in the lung specimen
despite broad spectrum antibiotics including a macrolide,
which is similar to the findings of Paddock et al.19
(see Fig. 1). B. pertussis produces an invasive adenylate
cyclase that impairs the bactericidal function of immune
effector cells and inhibits neutrophil recruitment to
lungs.41 This suggests that the inability to mount an
effective immunological defense to the organism may be a
key factor in the adverse outcome. Lymphocytosis
promoting factor of B. pertussis appears to act directly
on lymphoid cells, causing immunodepletion in the
thymus,42 which has been reported by Smith and Vyas26
in four post-mortem cases of pertussis. We suggest that
the depletion of lymphocytes experienced by the thymus,
the lymph nodes and the spleen of these patients made the
infants more vulnerable to co-infection, whilst potentially,
failing to clear the original infection from the bronchial
epithelium.
During infancy, lung epithelial cell apoptosis seems to
be a crucial mechanism of acute lung injury.47 In FP the
pertussis toxin, alone or in combination with another coinfecting agent may cause immunosupression through
lymphocyte apoptosis and secondary multi-organ failure
as in sepsis.48,49 Supporting this view, the finding of
extensive denudation of the alveolar and bronchiolar
epithelium associated with frequent apoptotic cells (see
Fig. 2) indicate that apoptosis was involved in the
pathogenic pathways in our cases of FP.
A noteworthy difference between our case series and
those described in much of the literature is the presence
of a very high neutrophil count compared to lymphocyte
count1820,22,24 although both Pierce et al.18 and
Namachivayam et al.5 have found that a high total WBC
to be significantly associated with a fatal outcome.
Lymphocytosis has traditionally been considered to
represent a direct response to pertussis toxin.44 A high
neutrophil count has been found to be associated with
increased mortality by Pooboni et al.13 who state that
pertussis may cause an exaggerated inflammatory
response even in immunologically nave infants. Neutrophilia could also reflect the level of added co-infection, as
bacterial infection was proven in seven cases.
Our patients experienced a rapidly progressive disease
where previously described therapies such as conventional and high frequency ventilation, steroids, inhaled
nitric oxide, ECMO or attempts to decrease the
white cell count such as partial plasma exchange or
exchange transfusion were tried but were not successful.8,10,13,15,16,22,26,5053 It appears that in our case series
B. pertussis had a devastating effect on lung tissue,
with secondary cardiovascular effects and evidence of

Fulminant Pertussis: Clinical-Pathological Findings

multi-organ dysfunction. Although the therapies used may

provide supportive care, the overwhelming immunological compromise with inability to clear infection may have
contributed to the fatal outcome.
B. pertussis is fastidious and difficult organism to
culture and may be overlooked,54 as illustrated by some of
our cases, where the diagnosis of pertussis was made at
post-mortem with PCR tests. Future directions in research
need to include more sophisticated tests in order to further
elucidate the immunopathogenetic mechanisms that result
in the extensive damage to the alveolar and bronchial
epithelium55 and documentation of lymphocyte function
tests. However the most practical approach undoubtedly
remains increasing public awareness about infantile
pertussis infection, early use of a macrolide to prevent
transmission and developing effective communal vaccination programs.2,3,12,22,25,56
ACKNOWLEDGMENTS

We thank Dr. J. Carcillo for reviewing this manuscript

and providing insightful comments on the pathophysiology of septic shock with respect to Bordetella pertussis
and Mrs. Faith Chinganga for administering the study
across multiple centers and typing up this manuscript. Dr.
Tim Harrison from the Health Protection Agency has
kindly supplied details of the PCR assays performed in the
UK by the National Reference Laboratory. We have no
known conflict of interest.
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