Pertussis has shown an alarming increase in global
incidence recently [1]. Disease burden is high despite
vaccination coverage of almost 85% among children [2]. Precise
data from low- and middle-income countries (LMICs) are
unavailable due to variable case definitions, limited
awareness, inadequate infrastructure and weak surveillance
systems. The exact cause of resurgence is unclear. Multiple
factors like antigenic shifts in bacteria, waning vaccine
immunity and reduced duration of protection by acellular
pertussis vaccine have been implicated [1]. Studies suggest
that source of infection may be identifiable only in about
27-43% of infant pertussis, and the most common source is
usually mothers or siblings [3-5]. Critical pertussis is
defined as pertussis requiring admission to an intensive care
unit (ICU) or resulting in death [6]. It can lead to
life-threatening complications like pulmonary arterial
hypertension (PAH), respiratory failure and shock. Mortality
rate ranges from 4.8-55% [7-13]. Data on critical pertussis is
scarce, with very few reports from LMICs like India [13,14].
In this case series we describe the clinical profile,
complications, intensive care needs and predictors of
mortality in children with critical pertussis.
Methods
This was a retrospective
study in the Pediatric Intensive Care Unit of a tertiary-level
teaching and referral hospital in Northern India. Cases were
identified from the electronic database of the unit over a
period of 3 years (2016-18), and those fulfilling the clinical
and critical pertussis criteria as per WHO case definition
were included. Clinical pertussis was defined as ‘any patient
with cough lasting ł2 weeks with at least one of the following
symptoms – paroxysmal cough, inspiratory whoop or post-tussive
vomiting [2]. Critical pertussis was defined as pertussis
requiring admission to an ICU or resulting in death. A total
of 36 children with critical pertussis were retrieved for
final analysis. No children were excluded. Demographic details
(age, immunization status), presenting complaints, intensive
care needs, complications, laboratory parameters and treatment
modalities were recorded on a pre-designed performa.
Hyperleukocytosis was defined as total leukocyte count (TLC)
>50,000/µL [15]. Real time polymerase chain reaction (PCR)
targeting IS481 and Ptxs1 was done in 28 children. Serology
using IgM ELISA antipertussis toxin was also done in 21
children. All children received azithromycin 10 mg/kg/day for
5 days and other supportive measures, which included
respiratory and vasoactive support, and exchange transfusion
depending on clinical need.
Statistical analysis:
Chi-square and Fisher’s exact tests were used to compare
proportions while Student t test and Mann Whitney test were
used for means. Survivors and non-survivors were compared by
univariate analysis to identify predictors of mortality. SPSS
version 21 was used for statistical analysis.
Results
Thirty-six cases (58.5% boys) of
critical pertussis were enrolled. Median (IQR) age was 3.5
(1.5, 7) months. Most children were infants (n=31, 86.1%),
with 10 (27.7%) being below six weeks and too young to be
immunized against pertussis. The rest 16 (61.5%) were
partially immunized or unimmunized against pertussis. Contact
history with respiratory illness was evident in only two
children. The major presenting symptoms were rapid breathing
in 32 (88.9%), typical paroxysmal cough in 31 (86.1%) and
apnea in 15 (41.7%) children. Most patients (35, 97.2%) had
hypoxemia (SPO2<94% in room air) at admission.
Hyperleukocytosis and thrombocytosis were noted in 22 (61.1%)
and 26 (72.2%) patients, respectively. Median (IQR) total
leukocyte count (TLC) (per µL) was 64,000 (23050, 100037). Out
of 28 children tested for pertussis RT-PCR, 19 (52.8%) were
positive. Of the 8 children in whom PCR was not done, 1 was
positive, 4 showed intermediate positivity and 3 were negative
by ELISA. When tested for co- infections with other viruses,
two children were positive for RSV, and all were negative for
H1N1.
Hypoxemia (35, 97.2%) was the commonest
complication, followed by hyperleukocytosis, encephalo-pathy
(19, 52.8%), seizures (17, 47.2%), and acute kidney injury
(6,16.6%). Out of 11 children who under-went neuroimaging,
multiple CNS infarcts were seen in 3 children and 8 were
normal. Pulmonary arterial hyper-tension (PAH) was seen in 5
of 15 children who under-went echocardiography (33.3%).
Intensive care needs were mechanical ventilation in 11
(30.6%), vasoactive support in 7 (19.4%) and exchange
transfusion (ET) in 3 (8.3%). The most common indication for
intubation was apneic spells in 9 children, out of which 4
were emergent during spells, and remaining 5 were elective for
recurrent spells and hypoxemic events. Two children were
intubated for encephalopathy. In majority (n=6), the
intubation was done within 24 hours. The problems faced during
ventilation were recurrent apnea (n=9), paroxysms of cough
(n=9), air leaks (n=2), and ventilator associated pneumonia
(n=1). Of the 7 ventilated children who underwent
echocardiography, 4 had pulmonary arterial hypertension (PAH).
Persistent hypoxemia and failure of conventional ventilation
was seen in four children who required high frequency
ventilation. Healthcare associated infections were seen in
four children; ventilator-associated pneumonia in one child
and blood stream infections in three children.
An
increasing trend of hospital incidence (2 cases in 2016, 7 in
2017 and 27 in 2018), and mortality (no mortality in 2016, 1
in 2017 and 7 in 2018) of critical pertussis was observed over
the 3 year study period. Eight patients (22.2%) with median
(IQR) age of 3.5 (1.1, 5.5) months died; all were unimmunised
including three who being <6 weeks old had yet to begin
primary immunisation. All non survivors except one required
mechanical ventilation. Major causes of death were hypoxemia
and refractory shock (4), massive brain infarcts (2),
secondary infection (1), and acute kidney injury and
hyperkalemia (n=1 each). Female gender (P=0.04), apnea
(P=0.01), hyperleukocytosis (P=0.01), encephalopathy (Glasgow
coma score <14) (P=0.04), need for vasoactive support
(P<0.001) and mechanical ventilation (P<0.001) were
significantly associated with mortality on univariate
analysis. PAH and need for ET did not determine mortality (Table
I).
Table I Predictors of Mortality in Children with Critical Pertussis (N=36)
|
Predictors of mortality |
Survivors (n=28) |
Non-survivors (n=8) |
Odds ratio (CI) |
P value | |
Male gender |
19 (67.8) |
2 (25) |
0.15 (0.02-0.94) |
0.043 | |
Apnea |
14 (50) |
8 (100) |
2 (1.38-2.89) |
0.01 | |
Hyperleukocytosis |
14 (50) |
8 (100) |
2 (1.38-2.89) |
0.01 | |
*Peak leucocyte count, per µL |
44900 (17225-91357) |
100025 (68200-144512) |
- |
0.002 | |
Encephalopathy (GCS<14) |
12 (42.8) |
7 (87.5) |
2.04 (1.23-3.37) |
0.04 | |
Vasoactive support needed |
1 (3.5) |
6 (75) |
21 (2.94-149.95) |
<0.001 | |
Mechanical ventilation |
4 (14.2) |
7 (87.5) |
6.12(2.38-15.74) |
<0.001 | |
Exchange transfusion |
1(3.5) |
2 (25) |
7 (0.72-67.63) |
0.12 | |
All values in n (%) except *median (IQR); GCS: Glasgow coma scale. |
Discussion
Our study has shown an
increased hospital incidence of critical pertussis in young
infants before completion of their primary vaccination. Major
complications noted were hypoxemia, hyperleukocytosis,
encephalopathy and seizures. PAH was present in few children.
Intensive care needs were ventilation, vasoactive support and
exchange transfusion. Female gender, apnea, hyperleukocytosis,
encephalopathy, need for vasoactive support and mechanical
ventilation were predictors of mortality.
The study:
however, suffers from the inherent drawbacks of a
retrospective analysis. Diagnostic tests like PCR could not be
done in all. Details of maternal immunization status were
unavailable and leukocyte count threshold for initiating
exchange transfusion was not clearly defined.
Incidence
of pertussis is increasing globally with periodic outbreaks
being reported from different parts of the world including
India [16-19]. Resurgence of a vaccine preventable disease
like pertussis causing increasing hospitalization, costs and
mortality is a worrisome trend, and has led to calls for
relook of immunization schedules [16,20]. However, our
patients were mostly young infants similar to previously
published reports [8,13]. Over half of the patients were
unimmunized against pertussis. Critical pertussis occurring
before primary immunization highlights the importance of
maternal immunization against pertussis. Pertussis
masquerading as any other acute respiratory infection often
runs the risk of under-diagnosis and under-reporting. None of
our patients were suspected to have pertussis nor received
macrolide antibiotics before referral. Delayed diagnosis can
make ‘benign’ pertussis ‘critical’ due to evolving
complications. The prevalence of seizures, encephalopathy,
hyperleukocytosis in this cohort was significantly higher
compared to earlier studies on critical pertussis which have
reported seizures in 9-16%, encephalopathy in nearly 20% and
hyperleukocytosis in 21-35% of children [8-13]. One-third of
the screened patients had PAH. Increased pulmonary vascular
resistance is postulated to be secondary to obstruction of
pulmonary vasculature by lymphocytes accumulation resulting
from hyper-leukocytosis [21]. Leucocytosis, especially in
young infants, was shown to be associated with PAH,
encephalopathy, greater risk of PICU admission and mortality
but a causal link is yet to be proven [10,15]. Therefore
screening of all patients of critical pertussis for PAH is
essential. Children with critical pertussis often require
mechanical ventilation and inotropic support for hypoxemia,
apnoea, shock, PAH and encephalopathy [13]. Exchange
transfusion for hyperleukocytosis especially if done before
organ failure or immediately at the onset of shock was found
to be associated with improved hemodynamics, hypoxemia and
mortality in few case series and reports; the clear cut
indications and mortality benefits are yet to be conclusively
proven on a larger scale [14,22,23]. Mortality in critical
pertussis varies between 4.8-55% [7-13]. Recognized predictors
of mortality include younger age, comorbidities, need for
ventilation, vasoactive use, PAH and a rapid course, similar
to those identified in this study [7-13].
We have
highlighted the important complications; intensive care needs
and our limited experience with exchange transfusion in
patients with hyperleukocytosis. To conclude, resurgence of
pertussis demands attention due to its varied presentation,
increased complications and higher mortality. The importance
of clinical recognition and empirical treatment in such a
setting cannot be overemphasised. Prospective studies on
critical pertussis, its complications and the utility of
various therapies are the need of the hour.
Contributors: TKK, MS: collected and analysed the data and
prepared the initial draft of the manuscript; MJ designed the
study, finalized the manuscript; VG and LS provided the
laboratory support and gave critical inputs for the
manuscript. All authors approved the final version.
Funding: None; Competing interests: None stated.
|
What This Study Adds?
•
There was a high prevalence of seizures, encephalopathy,
hyperleukocytosis and pulmonary artery hypertension in this
cohort of critical pertussis compared to earlier studies.
|
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