Advanced therapies for infantile malignant pertussis: A systematic review of hydroxyurea, leukapheresis, exchange transfusion, and extracorporeal membrane oxygenation

INTRODUCTION

Pertussis (whooping cough) is a highly contagious respiratory infection caused primarily by Bordetella pertussis and, less commonly, Bordetella parapertussis. The bordetellae are small, Gram-negative, aerobic coccobacilli. The genus Bordetella contains the species B. pertussis and B. parapertussis. Despite being vaccine-preventable, pertussis continues to pose a global health concern. The World Health Organization estimates nearly 16 million cases of pertussis annually worldwide, resulting in approximately 195,000 deaths, most of which occur among infants under 1 year of age.^[1,2]

The diphtheria–tetanus–pertussis vaccine was introduced into the Expanded Programme on Immunization in 1974. Since then, a marked reduction in the global burden of pertussis was noticed. A resurgence of cases has been observed since the 1980s, even in countries with high vaccination coverage, such as the United States, Canada, and Australia.^[3,4] This “pertussis resurgence” has been attributed to waning immunity, improved diagnostic capabilities, and possible genetic adaptations of the pathogen.

Malignant pertussis represents the most severe form of the disease and is characterized by refractory respiratory failure, profound hyperleukocytosis, and pulmonary hypertension, leading to exceptionally high mortality in early infancy.^[5,6] Reported predictors of fatal outcomes include age below 6 months, marked leukocytosis, pneumonia, and elevated inflammatory markers such as C-reactive protein.^[4,7] Clinically, infants often present with paroxysmal cough, apnea, cyanosis, and progressive respiratory distress. The leukemoid reaction induced by pertussis toxin contributes to increased blood viscosity and pulmonary vascular obstruction, precipitating cardiogenic shock and multiple organ dysfunction.

Several advanced interventions have been explored to mitigate the devastating hematologic and cardiopulmonary effects of malignant pertussis. Hydroxyurea, a pharmacologic cytoreductive agent originally used in hemoglobinopathies such as sickle-cell disease and b-thalassemia, has shown emerging promise as a non-invasive strategy for leukoreduction.^[8,9] Likewise, exchange transfusion (ET) and leukapheresis have been applied to rapidly lower leukocyte counts, although standardized thresholds for intervention remain undefined.^[10]

Meanwhile, extracorporeal membrane oxygenation (ECMO) has been used for over four decades in neonatal and pediatric respiratory failure. However, in pertussis, its benefit remains controversial; reports from the Extracorporeal Life Support Organization Registry indicate survival rates of only about 30%, markedly lower than for other ECMO indications.^[11-13] These observations underscore the potential importance of early, coordinated escalation and evidence-based escalation of therapy before the onset of multi-organ failure.

Given these uncertainties, the present systematic review was undertaken to evaluate the clinical effectiveness, safety, and survival outcomes of advanced therapeutic interventions, such as hydroxyurea, ET, leukapheresis, and ECMO in the management of malignant pertussis in infants.

Although several advanced interventions such as hydroxyurea, ET, leukapheresis, and ECMO have been utilized in malignant pertussis, the evidence base remains highly fragmented, with most data derived from isolated case reports and small series. Previous reviews have focused on individual therapies or specific regions, lacking an integrated comparative analysis of all advanced modalities. Given the persistently high mortality associated with malignant pertussis and the absence of standardized treatment guidance, a comprehensive synthesis of available clinical evidence is urgently needed to clarify the relative effectiveness, safety, and survival outcomes of these interventions.^[14,15]

What is the comparative clinical effectiveness, safety, and survival impact of advanced therapeutic interventions, such as hydroxyurea, ET, leukapheresis, and ECMO in infants diagnosed with malignant pertussis?

The objectives of the study are to systematically evaluate available evidence on the effectiveness, safety, and survival impact of hydroxyurea, ET, leukapheresis, and ECMO in the management of malignant pertussis among infants.

MATERIALS & METHODS

PRISMA flow diagram

The study selection process was illustrated using a PRISMA 2020 flow diagram, depicting the number of records identified, screened, assessed for eligibility, and included in the final review. The flow chart visually represents reasons for exclusion at each stage (e.g., duplicates, irrelevance, language limitations, or missing data) [Figure 1].

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Figure 1:

PRISMA 2020 flow diagram of the study selection process, including reasons (with counts) for full-text exclusions based on the predefined eligibility criteria.

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RESULTS

Comparative effectiveness and timing

Comparative synthesis of all included interventions [Table 4] suggested that earlier multimodal approaches were often associated with better outcomes across observational cohorts. Hydroxyurea and ET appeared to offer complementary leukoreduction mechanisms, while ECMO was generally utilized as supportive therapy to bridge cardiorespiratory stabilization in selected cases.

In some reports, centers adopting early-escalation approaches combining ET + ECMO or hydroxyurea + mechanical ventilation reported survival exceeding 70%, whereas lower survival rates were more frequently reported when interventions were delayed or applied as single-modality strategies. Temporal patterns [Table 5] suggested that initiation within 48 hours of clinical deterioration was associated with more favorable outcomes, while late ECMO initiation without prior leukoreduction was commonly associated with poorer survival. Figure 2 provides survival rates (minimum–maximum) of each intervention in infantile malignant pertussis, based on data synthesized from the included studies.^[19-64]

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Figure 2:

Survival rates (minimum–maximum) of each intervention in infantile malignant pertussis, based on data synthesized from the included studies.

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DISCUSSION

This systematic review provides an integrated synthesis of available evidence on advanced therapeutic interventions for malignant pertussis in infants, drawing on data from 46 studies published over a 25-year period. Collectively, the findings indicate that hyperleukocytosis in pertussis is not simply a laboratory abnormality but is closely associated with the development of severe respiratory failure, pulmonary hypertension, and increased mortality, particularly in infants younger than 2 months. Hydroxyurea exerts its effect through inhibition of ribonucleotide reductase, leading to reduced leukocyte production and blood viscosity, which may contribute to improvement in pulmonary vascular resistance and microvascular flow in malignant pertussis. By examining hydroxyurea, ET, leukapheresis, and ECMO together, this review offers a consolidated perspective on early escalation strategies used in the management of this life-threatening condition.

Across several included studies, hydroxyurea was associated with progressive leukoreduction over 5–7 days, with reported survival rates ranging from 70% to 90% and mortality between 10% and 30%.^[5,20,21] These observations suggest that hydroxyurea may represent a non-invasive and relatively accessible pharmacologic option, particularly in resource-limited settings where immediate access to ET or ECMO is not available. In contrast to the broader leucodepletion review by Annayev et al.,^[30] which did not demonstrate a significant survival difference between treated and untreated groups (47.5% vs. 41.7%), the present synthesis highlights the potential role of hydroxyurea in stabilizing infants before more invasive interventions and in minimizing risks related to fluid shifts and electrolyte imbalance. Nevertheless, differences in patient severity and timing of initiation across studies limit definitive conclusions.

Consistent with prior analyses,^[31] the reviewed literature supports an association between rapid leukocytosis, a lymphocyte-to-neutrophil ratio below 1, and echocardiographic evidence of pulmonary hypertension with poorer clinical outcomes. Early hematologic and echocardiographic assessment may therefore assist in identifying infants at higher risk who could benefit from earlier consideration of leukoreductive strategies before progression to multiorgan dysfunction. In addition, evolving antimicrobial resistance patterns further emphasize the importance of prompt diagnosis and comprehensive supportive care, as pharmacologic treatment alone may be insufficient to counteract disease severity once marked hyperleukocytosis has developed.^[32]

ET remains the most extensively reported leukoreductive intervention, with support from more than 20 studies.^[22,23,25] ET is consistently associated with rapid leukocyte reduction within 2–6 h and short-term improvements in oxygenation and pulmonary hemodynamics. Importantly, timing appears to play a critical role, as outcomes were more favorable when ET was performed before the onset of circulatory collapse or initiation of ECMO. Coquaz-Garoudet et al.,^[31] reported 100% survival among infants receiving early ET compared with no survivors in delayed cases (Relative Risk [RR] = 0.18). Although procedural complications such as rebound leukocytosis and coagulopathy have been described, ET continues to be widely utilized in clinical practice for infants with WBC counts exceeding 100 × 10⁹/L when appropriate hemodynamic and electrolyte monitoring is available.

Although leukapheresis offers a theoretical advantage through selective leukocyte removal, its application in malignant pertussis was limited to three reports.^[21,26,27] Reported outcomes were inconsistent, with only transient clinical improvement and frequent procedural instability in neonates. These findings, in line with Annayev et al.,^[30] underscore the technical complexity and vascular access challenges associated with leukapheresis in this age group. In addition, reported complications such as thrombocytopenia and hypocalcemia (Cousin et al., 2024)^[29] further limit its routine applicability in young infants.

ECMO was evaluated in 10 studies^[11,28] and was most commonly employed as salvage support for refractory respiratory or cardiovascular failure. Survival outcomes varied considerably and were strongly influenced by both timing and integration with leukoreductive therapy. Domico et al.,^[11] reported a survival rate of 28% when ECMO was used alone, with a threefold improvement observed when ET or hydroxyurea preceded ECMO initiation (odds ratio [OR] = 3.36, P = 0.03). Similarly, Cousin et al.,^[19] reported improved outcomes when ECMO was introduced earlier in combination with ET and optimized ventilatory strategies. Earlier case reports and small retrospective series have also described the use of exchange transfusion and ECMO in infants with severe pertussis complicated by hypoxemia, hyperleukocytosis, and pulmonary hypertension, demonstrating transient physiological improvement in some cases but overall variable and often poor survival outcomes.^[65-68] These findings suggest that ECMO may be most effective when used as a supportive bridge within a multimodal treatment framework rather than as an isolated intervention.

Variation in reported survival across studies likely reflects differences in disease severity, timing of intervention, and use of combined therapeutic approaches. Lower survival rates, such as those reported for ECMO alone, were more commonly observed when intervention occurred late in critically unstable infants, whereas higher survival rates were associated with earlier initiation alongside leukoreductive strategies. Similarly, variability in outcomes following ET and hydroxyurea may be influenced by baseline severity, timing of therapy, and concurrent multimodal management.

• Hydroxyurea may be considered an accessible first-line or bridging therapy when ET or ECMO is delayed or unavailable

• ET is widely used in clinical practice as an early leukoreductive intervention, particularly when initiated before cardiovascular compromise

• Leukapheresis has shown limited and inconsistent benefit and is not routinely applied due to technical and physiologic limitations

• ECMO is most often utilized in salvage situations and appears to provide benefit primarily when used in combination with early leukoreduction

• Observational data suggest that early, integrated escalation strategies, initiating hydroxyurea (HU) or ET before clinical deterioration and escalating to ECMO when necessary, may be associated with improved survival.

Overall, this review highlights that outcomes in malignant pertussis may depend less on a single intervention and more on the timing, integration, and accessibility of supportive and leukoreductive strategies. Hydroxyurea appears to be a practical adjunct in settings where immediate access to advanced extracorporeal support is limited, while ET remains the most frequently reported and commonly used intervention for rapid leukoreduction in published cohorts. A time-sensitive, integrated approach has been reported in several studies and may provide a useful foundation for future multicenter protocols and more standardized management pathways.

CONCLUSION

Observational evidence suggests that early leukoreductive strategies may be associated with improved outcomes in infants with malignant pertussis, particularly when initiated before cardiovascular deterioration. ET and hydroxyurea were the most consistently reported interventions and were associated with leukocyte reduction and favorable survival ranges across studies. ECMO appeared to provide benefit mainly when used as adjunctive support following leukoreduction, whereas leukapheresis showed limited and inconsistent results. Given the heterogeneity and non-randomized nature of the available data, these findings should be interpreted cautiously and regarded as hypothesis-generating. Further prospective multicenter studies are required to better define optimal timing and treatment sequencing in this rare condition.