Two-month-old Isla presents to their local hospital following a prolonged apnoea at home.
They had a two-day history of reduced feeding. Their clinical examination is unremarkable: normal heart sounds, palpable femoral pulses bilaterally, and no rashes, bruises, or signs of injury. They have a soft anterior fontanelle and no focal neurology.
Because of their worsening respiratory acidosis, they were intubated in the ED,
The initial chest-x ray shows a right-sided consolidation, in keeping with bronchopneumonia.
The blood tests revealed lymphocyte-predominant leukocytosis with a white blood cell count (WBC) of 40 x 10/L, raising suspicion of Bordetella pertussis.
Because of this possible diagnosis, they were commenced on a macrolide antibiotic (azithromycin) in addition to treatment for neonatal sepsis +/- meningitis (ceftriaxone and acyclovir). The other investigations are unremarkable, including a normal CT head.
Before this admission, there was no significant past medical history. They were a well-grown, term infant born in good condition. The mother did not receive her antenatal booster vaccination for Pertussis.
Sounding familiar? The Pertussis Outbreak of 2024
The UK experienced a major outbreak of Pertussis in 2024. According to the latest available data from the UK Health Security Agency, 14,453 laboratory-confirmed cases of Pertussis were reported in England between January and October 2024, compared to just 856 confirmed cases throughout 2023.
Pertussis is highly contagious and spreads through respiratory droplets. This sharp rise in cases is thought to be due to a steady reduction in the uptake of the Pertussis vaccine in pregnant women and children, combined with an increase following the exceptionally low incidence during the COVID-19 pandemic.
Unfortunately, unimmunised infants are at the highest risk of harm following pertussis. Since January 2024, more than 50 infants have required admission to the PICU, and eleven have died, significantly more than in previous years.
Since the introduction of the Pertussis vaccination in pregnancy, from 2013 to the end of October 2024, there have been 31 deaths in infants under 3 months with confirmed Pertussis (eleven of which occurred in 2025). Sadly, of the 31 infants that died, 25 had mothers who were not vaccinated in pregnancy.
We know that vaccination is key for protection, as there were 63 deaths in just one year before the vaccination was recommended in pregnancy in 2012.
How does pertussis present… What should we be looking out for?
Pertussis or “whooping cough” is caused by the gram-negative bacterium Bordetella pertussis, which, unlike other pathogens, causes damage to the respiratory tree by producing adhesins and toxins, the most important being the Pertussis toxin. The diagnosis can be confirmed on a per nasal viral respiratory swab. It is a notifiable illness in the UK.
The clinical presentation of this condition varies based on factors such as the patient’s age, immune status, the virulence of the strain, vaccination history, and the time since vaccination. Typically, in children, the illness progresses through three distinct phases. These are marked by paroxysmal (sudden and intense) coughing and cramps that last between two and six weeks.
A hallmark of the condition is lymphocytosis (white blood cell count exceeding 20 × 10⁹/L), which becomes apparent during the disease’s second week or second phase. However, this characteristic may not be present in partially immunised patients or if a secondary bacterial infection develops.
Infants usually present in a non-specific manner, following an apnoea, cough, cyanosis, or seizure– so a high index of suspicion is required in this age group.
All patients with suspected pertussis should be treated with a macrolide antibiotic before confirmation of viral swabs.
Bacterial and viral co-infections are common across all age groups, often involving pathogens such as adenovirus, respiratory syncytial virus (RSV), parainfluenza, and metapneumovirus. These co-infections can alter the clinical course and laboratory findings, increasing the risk of complications and hospitalisation.
It is important to note that neutrophilia (an increase in neutrophils) without lymphocytosis may indicate a bacterial co-infection. However, this should not rule out a diagnosis of pertussis. Co-infections are thought to arise due to immunosuppression caused by pertussis toxin, which creates an opportunity for secondary pathogens to take hold.
Isla is transferred to the PICU, where she remains mechanically ventilated and develops worsening hypoxaemia. New infiltrates appear on the CXR bilaterally, so they are managed with a lung protective ventilation strategy, according to paediatric ARDS management.
Within the first 24 hours of admission, her WBC rises to 50 x109/L). The nasal respiratory viral swab confirms Bordetella pertussis, and a viral co-infection is present.
An echocardiogram shows a structurally normal heart with good bi-ventricular function and no evidence of raised pulmonary pressures. She does not require any cardiovascular support at present.
Severe Pertussis in infants
Infants under 3 months are at the greatest risk of developing complications from pertussis, often requiring admission to the Paediatric Intensive Care Unit (PICU) for what is termed ‘severe pertussis’. This typically involves managing secondary bacterial infections and addressing complications such as neurological and renal issues, including hyponatraemia.
A smaller group of infants with severe pertussis may experience a more aggressive form of the disease, known as ‘malignant pertussis’. This condition is characterised by acute respiratory failure (paediatric ARDS), pulmonary hypertension, hyperleukocytosis (white blood cell count exceeding 50 × 10⁹/L), and multi-organ failure.
In a prospective multi-centre study, Berger et al. showed that hyperleukocytosis correlated with a tenfold increased risk of death.
Risk factors for severity and death: Alarm bells should ring if an infant develops pertussis and is:
Under 3 months old
Non-immunised
If there is a rapid rise in WBC (>12g/l/day within 12- 24 hours)
A hyperleukocytosis (WBC > 50)
A neutrophil predominance
Persistent tachycardia
Hyperleukocytosis is believed to play a critical role in the development of malignant pertussis. The condition increases blood viscosity and pulmonary vascular resistance, leading to pulmonary hypertension, haemodynamic collapse, and, ultimately, death due to hypoxaemia and refractory shock.
Infants are particularly vulnerable to pulmonary hypertension due to the small calibre and high reactivity of their pulmonary arteries. Additionally, their immature coagulation and fibrinolytic systems make them more prone to complications from leucosequestration.
To manage severe or malignant pertussis, leukoreduction therapies have been used alongside specific antibiotic treatments and supportive intensive care. The goal of leukoreduction is to lower the total white blood cell count and reduce circulating pertussis toxin levels.
Management involves placing an arterial line and a peripheral venous cannula, followed by an elective exchange transfusion in the PICU. This is done to address worsening hypoxaemia in the context of a rising white blood cell count.
WHAT is Leucodepletion:
- An exchange transfusion (ET) involves replacing an infant’s circulating blood volume, typically performing a ‘double volume’ exchange to optimise the procedure. This is done by manually removing small aliquots of blood and simultaneously infusing blood products. The procedure generally requires an arterial or central line for efficient blood removal and replacement.
- Leucofiltration is another technique in which a leucocyte filter is added to an ECMO circuit to remove white blood cells from the patient’s circulation. While other methods, such as plasmapheresis or leukapheresis, are available, they are less commonly used in this patient group.
WHO and WHEN… exploring the evidence for leucodepletion in severe Pertussis
Leucodepletion was first suggested as a treatment for infants under 3 months old with severe or ‘malignant’ pertussis in the 2000s. Case reports from this time highlighted improved oxygenation and survival rates following the use of exchange transfusion (ET).
No randomised controlled trials (RCTs) have evaluated the efficacy of leucodepletion in severe pertussis to date. As a result, current practice has been shaped by evidence from case series and observational studies.
Severe pertussis is a relatively rare condition, making it difficult to design a randomised controlled trial (RCT) due to the long recruitment period needed to obtain a sufficiently large sample size to detect a significant improvement in mortality. Additionally, some studies suggest a lack of equipoise regarding the perceived benefits of leucodepletion, which adds further complexity to the design and feasibility of conducting an RCT.
Rowlands et al. published one of the largest single-centre case series in the UK, demonstrating that an aggressive leucocyte depletion strategy effectively reduced circulating white blood cell (WBC) counts in infants with severe pertussis. According to the Rowlands algorithm:
Exchange transfusion (ET) was indicated for infants who did not require ECMO if their WBC count was greater than 50 × 10⁹/L or earlier if there was evidence of pulmonary hypertension or a deteriorating cardiorespiratory condition.
Leucofiltration was recommended for infants requiring ECMO support if their WBC count exceeded 30 × 10⁹/L. This involved routing a leucocyte filter into the ECMO circuit.
Figure 1 shows the Rowlands leucodepletion protocol, image taken from Rowlands, Pediatrics 2010
The infants treated using the Rowlands strategy achieved a 90% survival rate, compared to 55% in the control group, which included historical patients and case mix-adjusted mortality data. However, the observed survival benefit in the leucodepletion group may be influenced by selection bias, as cases were compared to historical controls, or by unrelated improvements in clinical practices over the study period.
Despite these limitations, multiple similar case reports demonstrate that single or double-volume exchange transfusion (ET) effectively reduces leucocytosis. This reduction is consistently associated with improved outcomes in infants with severe pertussis.
Other case series have shown that early leucodepletion, performed before the onset of pulmonary hypertension and cardiovascular collapse, is associated with better outcomes. For instance, a multi-centre case series examining infants treated with exchange transfusion (ET) for severe pertussis revealed the following:
- Among the 10 infants studied, none of the 5 survivors had evidence of organ failure or required ECMO at the time of ET.
- In contrast, of the 5 infants who died, 4 were in multi-organ failure, and 3 were already on ECMO when ET was performed.
The study emphasised the importance of timely intervention, recommending that ET should be considered urgently if:
- WBC is rising rapidly,
- WBC exceeds 30 × 10⁹/L, or
- Heart or respiratory rates continue to rise.
These findings highlight the need for proactive management to prevent the progression to severe complications.
A collaborative study involving over 15 Paediatric Intensive Care Units (PICUs) across the UK is analysing data from the ongoing pertussis pandemic. The study aims to provide insights into the physiological improvements and potential complications associated with exchange transfusion (ET). While results are still awaited, the findings are expected to enhance understanding and guide future management strategies for severe pertussis.
The exchange transfusion was performed without immediate complications. Over the next 12–24 hours, there was a gradual improvement in oxygenation. The patient remained ventilated for 7 days without any cardiovascular or neurological complications. After successful extubation at the end of the 7 days, the patient unfortunately required re-intubation for an additional 3 days due to a secondary bacterial chest infection.
Exchange transfusion considerations
There are significant risks associated with ET, which include coagulopathy, electrolyte disturbance, hypoglycaemia and circulatory overload.
Most side effects associated with exchange transfusion (ET) can be effectively monitored and managed in the Paediatric Intensive Care Unit (PICU). However, the procedure is time-intensive and often requires the placement of invasive lines, which carries its own risks.
Estimating the overall mortality rate associated with ET in infants with severe pertussis is challenging due to significant variations in how these cases are managed internationally. Differences in protocols, resource availability, and intervention timing contribute to this variability.
In neonates undergoing exchange transfusion (ET) for hyperbilirubinaemia, the mortality rate is relatively low (approximately 3 per 1000). However, in infants with pertussis, the risks are significantly higher due to their clinical condition at the time of ET. These infants are often hypoxic, haemodynamically unstable, and septic, which increases the complexity and potential complications of the procedure.
Post-ET, careful monitoring is essential, particularly for secondary bacterial infections and sepsis. ET not only removes pertussis toxin but also key components of the infant’s native immune response, which may leave them immunodeficient and more vulnerable to infections. This heightened risk underscores the need for vigilant supportive care and proactive management in these cases.
What about ECMO?
The most recent data from the Extracorporeal Life Support Organisation (ELSO) registry highlights a high mortality rate for infants with pertussis who require extracorporeal membrane oxygenation (ECMO). Between 2002 and 2015, 200 infants with pertussis were placed on ECMO, but only 56 survived, representing a survival rate of just 28%. This underscores the severity of pertussis in this population and the limited success of ECMO as a rescue therapy in these critically ill infants.
Interestingly, while the overall survival rate for infants with pertussis requiring ECMO is low, those who underwent leucodepletion before ECMO had a higher survival rate than those who did not (50% vs 25%). This suggests that pre-ECMO leucodepletion may confer a survival advantage.
However, this finding is based on retrospective data and may be confounded by unaccounted factors, such as differences in illness severity at presentation. Additionally, these results may not fully apply to the current patient population, as advancements in PICU care and ECMO management have likely improved survival rates since the data were collected.
The optimal use of extracorporeal membrane oxygenation (ECMO) in infants with severe pertussis remains somewhat controversial and is typically decided on a case-by-case basis. Factors such as patient size, weight, comorbidities (e.g., bleeding risk and infection status), and the clinical scenario play a critical role in determining suitability for ECMO.
The choice between Veno-Venous (VV) and Veno-Arterial (VA) ECMO support also varies depending on the centre’s expertise and the specific needs of the patient. However, detailed discussion of these considerations falls outside the scope of this article.
Take-home messages
Pertussis is on the rise; be suspicious in infants with respiratory presentations and apnoeas, so monitor the WBC and add a macrolide antibiotic EARLY.
Early referral to PICU if Pertussis is suspected/ diagnosed in infants with risk factors for severe illness (<3 months, persistent tachycardia, rapid rise in WBC, CXR changes)
Get an urgent echocardiography to look for features of pulmonary hypertension – these patients have poor outcomes.
Leucodepletion, often performed via exchange transfusion (ET), can effectively and rapidly lower the white blood cell (WBC) count in infants under three months old with severe pertussis. To maximise its potential benefit, it should be performed before the onset of pulmonary hypertension.
Some observational data suggest that leucodepletion may improve survival, mainly when performed before cardiovascular collapse occurs. However, there is currently no evidence-based consensus on its use, and further research is needed to establish its efficacy and optimal timing.
About PICSTAR
PICSTAR is a trainee-led research network open to all doctors, nurses and allied health trainees within Paediatric Intensive Care. We are the trainee arm of the Paediatric Critical Care Society – Study Group (PCCS-SG) and work with them on research, audit and service evaluation.
If you would like to join PICSTAR and get involved in projects, have ideas you would like to propose or get advice/mentorship via PCCS-SG, don’t hesitate to contact us at picstar.network@gmail.com. See their website for more: https://pccsociety.uk/research/picstar/
References
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- Unpublished data from national audit on behalf of PCCS-SG
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