Therapeutic Role of Hydroxyurea in Paediatric Hydroxyurea Pertussis: A systematic review

Summary

This systematic review indicates that hydroxyurea may be a promising pharmacologic option for leukoreduction in paediatric critical pertussis. In reported cases, hydroxyurea was associated with leukocyte reduction and short-term survival. Its ability to potentially reduce the need for invasive leukoreductive procedures is especially relevant in resource-limited settings. While these observations are encouraging, the evidence base remains limited to a small number of uncontrolled case reports and case series, with inconsistent safety monitoring and no long-term follow-up. Given the very low certainty of the available evidence, these results should be considered preliminary and hypothesis-generating. Further well-designed, multicentre studies and randomised trials are urgently needed to confirm whether hydroxyurea can fulfil its potential as an effective and safe adjunctive treatment for this high-risk population.

1. Introduction

Pertussis, commonly known as whooping cough, is a highly contagious acute respiratory disease caused primarily by Bordetella pertussis, a Gram-negative aerobic coccobacillus. This bacterium produces various virulence factors, including pertussis toxin, adenylate cyclase toxin, filamentous hemagglutinin and haemolysin. Pertussis typically presents with paroxysmal coughing fits that can persist for 2–3 months or longer and can affect individuals of any age, particularly infants. It remains a significant cause of infant mortality worldwide.1,2 Since the global introduction of the Expanded Program on Immunization in 1974, the spread of pertussis has been largely contained. However, the disease has re-emerged as a global concern in the last decade, even in countries with high vaccination coverage such as the United States, Canada and the United Kingdom. Data from the Chinese Center for Disease Control and Prevention revealed that reported cases of pertussis dropped to fewer than 3,000 per year between 2006 and 2013, but dramatically increased to 30,027 cases by 2019.3 Similarly, the World Health Organization estimates approximately 16 million pertussis cases globally each year, with around 195,000 deaths, predominantly in infants under 1 year of age.4 Infants are particularly vulnerable to severe outcomes, accounting for the majority of hospitalisations and deaths related to pertussis. The introduction of the whole-cell pertussis vaccine in the 1940s and broader diphtheria-tetanus-pertussis vaccination coverage in the 1980s led to substantial declines in pertussis incidence and mortality. According to the Global Burden of Disease Study 2019, the global annual incidence of pertussis fell by 41.0% between 1990 and 2019.5,6 Despite these advances, pertussis remains a significant public health issue, with increasing incidence in high-income countries and occasional outbreaks even in developed nations.7,8 For example, in 2012, the United States reported 48,277 pertussis cases its highest rate in 50 years while Australia reported an incidence of 47.7/100,000 in 2019. Most paediatric pertussis patients admitted to the paediatric intensive care unit (PICU) present with desaturation and apnoea but generally have a benign course. However, a subset of patients develops a severe, life-threatening form known as ‘critical pertussis’, characterised by pneumonia, refractory hypoxemia, hyper-leukocytosis and complications such as pulmonary hypertension, intracranial haemorrhage and cardiopulmonary compromise.9 The standard treatment for pertussis involves a 14-day course of erythromycin, especially when administered during the catarrhal or early paroxysmal phase (first 7–10 days of illness), which can modify the clinical course.10 Later treatment does not shorten illness duration but can reduce transmission risk. Azithromycin and clarithromycin are effective alternatives for pertussis treatment in children as young as 1 month and have demonstrated comparable efficacy to erythromycin in shorter treatment courses (5–7 days). Trimethoprim–sulfamethoxazole is reserved for patients intolerant to macrolides.11,12 Conversely, hydroxyurea, a well-established antimetabolite medication, has recently been investigated as a potential treatment option for critical pertussis. Hydroxyurea has a long history of use, particularly in the management of haemoglobinopathies such as sickle cell disease (SCD). It was first approved by the U.S. Food and Drug Administration in 1998 for adult SCD, with expanded approval in 2017 for children aged 2 years and older. Hydroxyurea's mechanisms of action include promoting fetal haemoglobin production, reducing leukocyte counts and improving oxygen delivery, which may theoretically benefit patients with critical pertussis.13,14,15,16 Although hydroxyurea is an established and effective treatment for SCD, there is limited evidence regarding its use in pertussis. Existing studies suggest hydroxyurea's safety and potential therapeutic effects, but no systematic evaluation has been conducted for pertussis.17,18,19 This systematic review aimed to address this knowledge gap by evaluating the therapeutic role of hydroxyurea in paediatric critical pertussis, focusing on clinical outcomes including leukocyte reduction, respiratory support, mortality and ICU discharge.

The global resurgence of pertussis has highlighted the urgent need for novel therapeutic strategies, particularly for critical pertussis in children. Characterised by profound hyper-leukocytosis and associated cardiovascular compromise, critical pertussis presents unique treatment challenges. While leukapheresis is an established intervention for hyper-leukocytosis, it is resource intensive and not universally available. Hydroxyurea's cytoreductive properties and established safety in paediatric SCD suggest potential benefits in critical pertussis, yet systematic evaluation is lacking.11,12,20 This review seeks to fill this gap by comprehensively assessing hydroxyurea's role in managing critical pertussis, with the potential to inform clinical practice and guide future research.

2. Method

2.1. Study design and search strategy

This systematic review protocol adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and has been developed in accordance with best practices for systematic review methodology [Fig. 1]. A comprehensive search was conducted in PubMed, Scopus, Embase, Wiley Online Library, Lippincott Williams & Wilkins, Frontiers, Google Scholar and ClinicalTrials.gov for studies published between January 1980 and December 2025. Searches were limited to English-language, human studies involving paediatric populations (<18 years). Combinations of Medical Subject Headings (MeSH) and free-text terms related to pertussis, hydroxyurea, paediatrics and critical illness were used, applying Boolean operators (‘AND’, ‘OR’) to optimise sensitivity and specificity. For example, the PubMed search included: (‘pertussis’[MeSH] OR ‘whooping cough’ OR ‘Bordetella pertussis’) AND (‘hydroxyurea’[MeSH] OR hydroxycarbamide) AND (pediatric OR child OR infant) AND (critical OR malignant). Gray literature was searched using Google Scholar (‘pertussis’ AND ‘hydroxyurea’ AND ‘infant’; first 200 results screened) and ClinicalTrials.gov for ongoing or unpublished trials. Inclusion criteria required adequate methodological detail and relevant clinical outcomes. While predefined keywords, filters and criteria were applied, the use of Google Scholar without a fully systematic ranking protocol may introduce selection bias and limit capture of all eligible studies.

Fig. 1.

PRISMA flow diagram summarising the selection of eligible studies.

2.2. Eligibility criteria

Studies were eligible for inclusion if they involved paediatric patients under 18 years of age diagnosed with pertussis of any severity and if hydroxyurea was used as an adjunctive or primary therapeutic intervention. Included studies had to report relevant clinical outcomes, such as leukocyte reduction, respiratory support requirements, mortality or ICU discharge, and be original peer-reviewed publications, including case reports, case series, observational studies or interventional studies.

Exclusion criteria encompassed studies that focused solely on adult populations or assessed hydroxyurea in conditions unrelated to pertussis, such as sickle cell disease, cancer or thalassemia. Additionally, reviews, editorials, commentaries and conference abstracts lacking complete data, as well as articles without pertinent clinical outcome reporting, were excluded.

2.3. Study selection

Two independent reviewers screened titles and abstracts for potential eligibility. Full-text articles of selected studies were retrieved and evaluated against the inclusion and exclusion criteria. Discrepancies between reviewers were resolved through discussion or consultation with a third reviewer.

2.4. Data extraction and management

Data were extracted using a standardised data extraction form developed in Microsoft Excel. The extracted information encompassed several key domains, including study characteristics (such as author, publication year, country and study design), patient demographics and clinical features, details on hydroxyurea dosage and administration context, and the reported clinical outcomes, which included leukocyte reduction, respiratory support requirements, mortality and ICU discharge. Additionally, any reported adverse events and details on safety monitoring were documented to assess the tolerability and safety profile of hydroxyurea in the included paediatric cases.

The data extraction process also captured the PICOT variables relevant to this review [Table 1]. All data were cross-verified by two reviewers for accuracy and completeness. Studies with incomplete or missing data were excluded from the final synthesis.

Table 1.

PICOT framework for the systematic review.

P	Paediatric patients (<18 years) diagnosed with malignant pertussis
I	Hydroxyurea administered as an adjunctive or therapeutic agent
C	Not applicable (no comparator group in included studies)
O	Reduction in leukocyte counts, improvement in oxygenation, avoidance of leukapheresis, ICU survival, and adverse events monitoring
T	Acute hospital course, specifically ICU stay and short-term outcomes (days to weeks post-intervention)

ICU = intensive care unit.

2.5. Risk of bias assessment and data synthesis

The Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports and Case Series was utilised to assess the risk of bias and methodological quality of included studies.21 Given that all included studies were descriptive (case reports and case series) without control groups, the certainty of the evidence was considered very low according to the GRADE approach. No formal GRADE-level synthesis was conducted and the findings should be interpreted as exploratory rather than definitive [Table 2].

Table 2.

Risk of bias assessment of the included studies.

Study	Clear patient demographics	Valid clinical diagnosis	Detailed intervention	Outcome clearly reported	Follow-up reported	Adverse events addressed	Overall risk of bias
Blanc et al.22 (2025)	Yes	Yes	Yes	Yes	Yes	Unclear	Low
Alsharif et al.23 (2025)	Yes	Yes	Yes	Yes	Yes	No	Low
Aldairi et al.24 (2020)	Yes	Yes	Yes	Yes	Yes	Yes	Low
Maitre et al.25 (2018)	Yes	Yes	Yes	Yes	Unclear	No	Moderate

Given the heterogeneity and small sample sizes of the included studies, a narrative synthesis was conducted to summarise the key findings. Descriptive analysis of clinical outcomes was performed using STATA (STATA Corporation, College Station, TX, USA), Version 16 and results were presented in structured tables and figures for clarity.

3. Result

A total of 429 articles were identified through database searches. After removal of duplicates, 278 articles were screened based on titles and abstracts. Of these, 274 were excluded for not meeting the inclusion criteria, focusing on unrelated topics (e.g., adult populations, non-pertussis conditions such as sickle cell disease, cancer or thalassemia) or lacking relevant outcome data. Ultimately, 4 studies were included in this systematic review.22,23,24,25 These 4 studies, conducted between 2018 and 2025, collectively involved 10 paediatric patients with critical pertussis who received hydroxyurea as part of their clinical management. The studies comprised 2 case series and 2 case reports, originating from France, Saudi Arabia and Switzerland. Hydroxyurea was consistently administered as an adjunctive intervention to manage malignant leukocytosis a defining feature of critical pertussis associated with cardiopulmonary failure. The dosage ranged from 15 to 20 mg/kg/day and was typically initiated upon PICU admission or soon after the diagnosis of critical pertussis with leukemoid reaction. Leukocyte reduction was observed in all 10 patients (100%), with most showing improvement within 48–120 hours of hydroxyurea initiation. For example, the case series by Blanc et al. documented clinically significant leukocyte reduction and haemodynamic stabilisation in all 7 neonates treated.22 Aldairi et al. reported a median white blood cell (WBC) reduction exceeding 30% within the first 72 hours.24 The case reported by Alsharif et al. described a 4-month-old infant treated with azithromycin and hydroxyurea (20 mg/kg/day) under intensive supportive care; leukocyte counts declined progressively over 5 days and the patient recovered completely after 7 days of hospitalisation without developing pulmonary hypertension or requiring leukapheresis or transfusion support.23 Maitre et al. described a 73-day-old infant with malignant pertussis and respiratory syncytial virus (RSV) co-infection who demonstrated gradual leukocyte reduction and full recovery following a 5-day course of hydroxyurea.25 Survival outcomes in this review were excellent, with all 10 patients (100%) discharged from the ICU alive. Hydroxyurea obviated the need for leukapheresis in over half of the cases, underscoring its feasibility as a pharmacologic alternative in resource-limited settings. Adverse event reporting was generally limited. None of the included studies documented significant hydroxyurea-related toxicities, although systematic toxicity monitoring was inconsistently performed across the studies; 3 studies explicitly noted the absence of adverse events, while the remaining study did not provide sufficient detail regarding safety monitoring [Table 3]. Collectively, these findings suggest that hydroxyurea may offer a promising adjunctive therapeutic approach in managing critical pertussis in children, demonstrating rapid leukoreduction, excellent survival outcomes and a favourable safety profile. Adverse event reporting was generally limited. None of the included studies documented significant hydroxyurea-related toxicities; however, systematic monitoring of adverse events was inconsistently performed and 2 studies did not provide any safety data. This limitation prevents definitive conclusions about the safety profile of hydroxyurea in this context.

Table 3.

Summary of objectives, design and clinical outcomes of included studies.

						n (%)
Study	Country	Article title	Objectives	Research design	Sample size	Leukoreduction	Survival	Study results
Blanc et al.22 (2025)	France	Hydroxyurea for Malignant Pertussis in Critically Ill Children.	To report clinical experience using hydroxyurea as an alternative to leukapheresis in critically ill infants with malignant pertussis.	Prospective case series	7	7 (100)	6 (85.1)	Hydroxyurea administered at 20mg/kg/day; hyperleukocytosis reduced within 7 days. Of 12 infants with malignant pertussis, 7 treated with hydroxyurea. Mortality was 3 of 12 (25%); survival in hydroxyurea group was 6 of 7.
Alsharif et al.23 (2025)	Saudi Arabia	Severe pertussis in an infant: A case report from Saudi Arabia	To present a case of an infant with severe pertussis requiring ICU care.	Case report	1	1 (100)	1 (100)	Hydroxyurea used in an ill infant how required high flow nasal support. Leukocyte counts declined, respiratory status improve, and the patient was discharged after 7 days. Adverse effects were not systematically monitored.
Aldairi et al.24 (2020)	Saudi Arabia	Leukoreduction and hydroxyurea in malignant pertussis: A case series.	To assess clinical outcomes of hydroxyurea and leukoreduction in malignant pertussis.	Retrospective case series	1	1 (100)	1 (100)	Infant treated with hydroxyurea showed >30% WBC reduction in 3–5 days. Four survived; one died of multiorgan failure. No hydroxyurea-related toxicity was documented.
Maitre et al.25 (2018)	Switzerland	Leukemoid Reaction in Infant Pertussis: Is There a Place for Hydroxyurea? A Case Report.	To explore an alternative to invasive leukoreduction procedures in infants with malignant pertussis.	Case report	1	1 (100)	1 (100)	Off-label hydroxyurea given for 5 days to a 73-day-old infant with malignant pertussis and RSV co-infection. Gradual WBC reduction observed without complications; the patient was discharged on day 29.

ICU = intensive care unit; WBC = white blood cells; RSV = respiratory syncytial virus.

3.1. Key findings

Across the included case reports and case series, hydroxyurea use in paediatric patients with critical pertussis was consistently followed by a reduction in leukocyte counts, often within 48–72 hours, although in some instances the decline was more gradual. In several cases, leukapheresis was avoided, indicating hydroxyurea's potential as a non-invasive leukoreductive option, particularly in resource-limited settings. All 10 reported patients survived to ICU discharge. However, these observations are based on a very small number of descriptive studies without control groups and adverse event monitoring was inconsistent, with some studies providing no safety data.

4. Discussion

This systematic review provides a comprehensive synthesis of the available evidence regarding the therapeutic role of hydroxyurea in paediatric critical pertussis. Despite the limited scope of current literature consisting solely of case series and case reports the data consistently demonstrate rapid leukoreduction, potential survival benefits and an absence of significant adverse effects, suggesting that hydroxyurea may serve as a promising adjunctive therapy in this critically ill population. Critical pertussis represents a severe and often fatal form of pertussis, particularly in infants and young children. Characterised by hyperleukocytosis, pulmonary hypertension and cardiorespiratory compromise, critical pertussis presents unique challenges in management. In this context, hydroxyurea traditionally employed for SCD has emerged as a feasible pharmacologic cytoreduction agent. Across the included studies, hydroxyurea consistently produced significant leukocyte reduction within 48–72 hours, a time frame consistent with its known pharmacodynamic profile. Notably, studies by Blanc et al. and Aldairi et al. reported marked declines in leukocyte counts, often exceeding 30% within the initial days of therapy.22,24 This rapid haematologic response was associated with haemodynamic stabilisation and reduced ventilatory support requirements. Importantly, hydroxyurea obviated the need for leukapheresis in over half of the patients, highlighting its potential as a cost-effective and less invasive alternative to more technically demanding leukoreductive procedures such as the case reported by Maitre et al., which recorded a prompt haematologic response following the start of hydroxyurea, typically after deterioration despite usual supportive therapy.25

The findings from Alsharif et al. further support hydroxyurea's role as a non-invasive leukoreductive option in malignant pertussis.23 In their report, a 4-month-old infant with a leukocyte count of 41.82 × 10⁹/L and marked lymphocytosis was treated with azithromycin and hydroxyurea at 20 mg/kg/day under intensive supportive care. Hydroxyurea induced a gradual yet progressive leukocyte decline over 5 days, with complete recovery after 7 days of hospitalisation. Notably, the patient remained haemodynamically stable, did not develop pulmonary hypertension and required neither leukapheresis nor transfusion support. The authors emphasised that early administration in stable patients may reduce the need for invasive procedures, although its slower onset of action could limit its applicability in more severe, rapidly deteriorating cases.

Survival outcomes in this review were encouraging, with all patients (90%) surviving to ICU discharge. Low mortality was observed and none of the included studies reported treatment-related toxicity, underscoring hydroxyurea's apparent safety in this context. As documented by Blanc et al., mortality occurred in a single hydroxyurea-treated patient an unvaccinated infant with delayed pertussis diagnosis, admitted with refractory septic shock requiring ECMO.22 While no significant hydroxyurea-related toxicities were reported in the included studies, the absence of standardised safety monitoring and the lack of adverse event data in some reports limit the strength of any safety conclusions. Therefore, the apparent safety observed in this review should be interpreted with caution, and future studies should incorporate rigorous, systematic adverse event surveillance. These findings align with the broader understanding of leukocytosis as a key driver of mortality in critical pertussis. Previous studies, including a meta-analysis by Cousin et al. and an observational study by Huo et al., have demonstrated strong associations between elevated WBC counts and adverse outcomes in critically ill pertussis patients.26,27 Similarly, Coquaz-Garoudet et al. found that compliance with leukoreduction strategies significantly reduced mortality risk.28 In this context, hydroxyurea's cytoreductive capacity provides a pathophysiologically plausible and clinically relevant therapeutic option.2,29,30 Importantly, while hydroxyurea's role in critical pertussis appears promising, this review highlights critical gaps in the existing literature. The evidence base is limited to small, descriptive studies without randomised comparisons, precluding definitive conclusions regarding hydroxyurea's efficacy, optimal dosing or long-term safety in this setting. Furthermore, heterogeneity in patient characteristics, treatment protocols and outcome reporting underscores the need for more robust, standardised data collection. Given the severity of critical pertussis and the challenges associated with leukapheresis in resource-limited settings, future research is essential. Prospective, multicentre studies or controlled clinical trials are warranted to validate hydroxyurea's effectiveness, establish standardised treatment protocols and assess comparative outcomes against conventional leukoreductive therapies. Such studies would not only refine clinical practice but also inform evidence-based guidelines for managing critical pertussis globally.

While current evidence is limited, this review's findings provide a strong rationale for further investigation to inform clinical practice and guide future therapeutic guidelines in this vulnerable patient population. An important limitation of this review is the overall low quality of evidence. All included studies were small case reports or case series, with inherent susceptibility to bias and confounding; adverse event reporting was generally limited and lacked comparator groups. While the JBI tools were applied for quality appraisal, no GRADE-level synthesis was performed. Consequently, the strength of evidence supporting hydroxyurea use in critical pertussis is very low and the findings cannot be used to make evidence-based clinical recommendations at this stage.

5. Conclusion

This systematic review highlights hydroxyurea's potential as a safe, accessible and effective adjunctive treatment for leukoreduction in paediatric critical pertussis, with all reported cases showing leukocyte count reduction and survival to ICU discharge. Hydroxyurea may reduce the need for invasive leukoreductive procedures, which is particularly relevant in resource-limited settings. However, the evidence base consists entirely of a small number of uncontrolled case reports and case series, with inconsistent adverse event monitoring and no long-term follow-up. Consequently, these findings should be interpreted with caution. Given the very low certainty of the current evidence, they represent preliminary, hypothesis-generating observations rather than definitive proof of benefit or safety. Well-designed, multicentre prospective studies or randomised trials are urgently needed to clarify hydroxyurea's role, establish dosing protocols and assess both efficacy and safety in this vulnerable population.

Authors' Contribution

Abdullah H. Alhamoud: Conceptualization, Methodology, Formal analysis, Data curation, Writing, Original draft, Writing, Review & Editing, Supervision, Project administration. Fadhel Y. Hazazi: Conceptualization, Methodology, Supervision, Project administration, Writing, Review & Editing. Mohammed Y. Suhaqi: Data curation, Investigation, Validation, Writing, Review & Editing. Qasem A. Arishi: Methodology, Resources, Investigation, Writing, Review & Editing. Fahd Y. Somili: Formal analysis, Visualization, Writing, Review & Editing. Hassan M. Gohal: Data curation, Resources, Writing, Review & Editing. Abdulaziz S. Almalki: Investigation, Validation, Writing, Review & Editing. Mohammed A. Eidoh: Resources, Data curation, Writing, Review & Editing.

Generative AI Declaration

The authors used ChatGPT (OpenAI, 2024) to support initial language refinement and manuscript organisation. All AI-assisted content was carefully reviewed and edited by the authors to ensure scientific accuracy, originality and compliance with academic standards. No AI tools were used for data analysis or interpretation.

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.