Younger Age and Viral Triggers Were Associated With Post‐Infectious Bronchiolitis Obliterans in French Children

ABSTRACT

Aim

Post‐infectious bronchiolitis obliterans (PIBO) is a rare but severe chronic paediatric obstructive lung disease, characterised by the obliteration of small airways following severe lower respiratory tract infections. Epidemiological data in Europe remain limited.

Methods

This multicentre retrospective study examined the characteristics of paediatric patients diagnosed with PIBO from 2017 to 2023. Carried out by the French Reference Centre of Rare Lung Diseases network, it was based on clinical and radiological criteria and included age at diagnosis, medical history, symptoms, initial triggers, treatment, and outcomes.

Results

The study comprised 147 patients (58.5% male) diagnosed by 18 tertiary centres at a median age of 22 months. Most (83.7%) were hospitalised for the suspected initial infection: 36.7% in intensive care units and 47.0% in acute care wards. A younger age at diagnosis was associated with higher hospitalisation rates (p = 0.01). Microbiological triggers were identified in 66.0%, mostly adenoviruses (28.5%) and the respiratory syncytial virus (26.4%), often as co‐infections. Lung function tests were performed on 23.1% of patients and bronchoscopies on 66.9%. Treatment included inhaled corticosteroids (90.5%), azithromycin (59.2%) and intravenous corticosteroid pulses (40.8%).

Conclusion

Age and causative agents were key factors in the initial severity of the infection that led to paediatric PIBO in our study.

Summary.

• This multicentre French study focused on post‐infectious bronchiolitis obliterans, a rare but severe paediatric lung disease.

• The 147 children were diagnosed at a median age of 22 months and 83.7% were hospitalised for the suspected initial infection, with 36.7% admitted to intensive care units.

• Younger age at diagnosis and specific microbiological triggers, such as adenoviruses and the respiratory syncytial virus, were important factors in the disease severity.

Abbreviations

BO

bronchiolitis obliterans

CT

computed tomography

FEV1

forced expiratory volume in one second

ICUs

intensive care units

PIBO

post infectious bronchiolitis obliterans

RespiRare

Reference Centre of Rare Lung Diseases

RSV

respiratory syncytial virus

1. Introduction

Bronchiolitis obliterans (BO) is a chronic obstructive pulmonary disease, which is characterised by distal airway obstruction [1, 2, 3]. Contributory factors include viral infections, bacteria, toxins, and post‐transplant complications [1]. Post‐infectious BO (PIBO) is a severe condition that is most common in childhood and can lead to respiratory insufficiency over time. Classified under childhood interstitial lung diseases, PIBO is rare but globally present, with unknown incidence and prevalence. Most studies have come from South America and Korea, with none from Europe [4]. The largest cohort was from Argentina, and it described how 150 of 415 children with adenoviruses developed PIBO. The study focused on identifying PIBO risk factors, but did not provide details on diagnostic and management approaches [5].

The diagnostic criteria for PIBO are based on international consensus. They include a history of prior respiratory infections in previously healthy children, irreversible airway obstruction, evidence of small airway injuries on thoracic computed tomography (CT) and the exclusion of other pulmonary diseases [1, 2, 4]. CTs typically show mosaic attenuation, bronchial wall thickening, and sometimes bronchiectasis [6]. PIBO has been commonly associated with an initial adenovirus infection and particularly with serotypes 3, 7, 11, and 21 [7, 8]. It can also result from influenza, parainfluenza, measles, varicella virus, and Mycoplasma pneumoniae [8, 9]. There are no guidelines for PIBO management and long‐term treatment. Treating PIBO remains challenging because it is a rare and severe disease. Early diagnosis and inhaled and systemic corticosteroids with high‐dose intravenous steroids [10] have often been shown to reduce PIBO mortality [11] and airway fibrosis [12]. However, there has been limited randomised evidence to support their effectiveness [13, 14, 15]. Treatments have included inhaled corticosteroids, azithromycin, sometimes montelukast or acetylcysteine [9, 16], and oxygen for hypoxemia [17].

PIBO has a variable prognosis. One study showed that some patients experienced lung growth, but they still had irreversible airway obstruction, which either stabilised or progressively worsened with growth [18]. Although only a few patients with PIBO eventually require a lung transplant, this remains a devasting disease.

Data on PIBO have been limited so far. This prompted the French Reference Centre of Rare Lung Diseases (RespiRare) to gather information from a large cohort of children diagnosed with PIBO in France from 2017 to 2023. The aim of the study was to outline the diagnostic criteria, triggers, and management strategies.

2. Methods

2.1. Patients

This retrospective, observational multicentre study was conducted from January 1, 2017 to September 30, 2023. We authors approached the 30 paediatric RespiRare tertiary centres across France and found that 18 of these followed children with PIBO. The inclusion criteria were previously healthy children under 16 years old who had been diagnosed with PIBO and had received care at the tertiary centres. They exhibited persistent clinical symptoms, such as tachypnoea, wheezing, and/or hypoxemia following a lower respiratory tract infection at least six weeks before. Chest CT findings showed mosaic attenuation on inspiratory or expiratory scans. The exclusion criteria included underlying chronic pulmonary conditions, such as cystic fibrosis or ciliary dyskinesia, immune deficiencies, tumour pathologies, or solid organ or stem cell transplants.

2.2. Data Collection

Patients were identified through the national database for rare diseases or directly by the RespiRare centres. Referring physicians completed a questionnaire after informing the families, who were told they could opt out. The data that were collected included demographics, birth details, neonatal respiratory history and age at PIBO diagnosis. Respiratory symptoms and complications were also recorded, including chronic respiratory insufficiency, defined by the need for respiratory support. They also included pulmonary arterial hypertension, which was assessed by echocardiography and defined as a mean pulmonary arterial pressure of ≥ 25 mmHg at rest. Infection severity and agents that were suspected of triggering PIBO were also documented. Diagnostic investigations carried out when PIBO was suspected were documented, including spirometry, CT scans, echocardiography, bronchoscopy with bronchoalveolar lavage, histopathology, immune function tests and sweat chloride tests. Treatment was also recorded. All patients underwent thoracic CT scans at diagnosis, and these revealed mosaic patterns with varying bronchiectasis severity. Non‐reversible airway obstruction was defined according to the American Thoracic Society and European Respiratory Society recommendations. These were a z‐score of forced expiratory volume in 1 s (FEV1)/forced vital capacity of < −1.645 or a resistance of the respiratory system z‐score or specific airway resistance of > +1.645. Positive bronchodilator responses were indicated by a change in FEV1 and forced vital capacity of more than 10% of the predicted values [19]. If children were unable to perform spirometry, some centres used non‐invasive techniques such as oscillometry or resistance of the respiratory system. The latter is an easier method, based on periodic pressure variations during the respiratory cycle.

Three age groups were defined: < 2 years, between 2 and 6 years, and more than 6 years. These groups were established based on developmental milestones during the first 1000 days of life, from conception to 2 years of age, their potential exposure to viral epidemics, and the feasibility of spirometry.

2.3. Statistical Analyses

Qualitative or categorical variables are presented as numbers and percentages, while quantitative or continuous variables are expressed as medians and ranges. Proportions were compared using chi‐square or Fisher's exact tests, with significance set at p < 0.05. Statistical analyses were conducted using SAS 9.4 software (SAS Institute Inc., North Carolina, USA).

2.4. Ethics

The study was approved by the French Paediatric Society ethics committee (CERSFP_2023_149) and did not require approval from the personal data protection committee. Parental consent was obtained using an information sheet, in accordance with French law, and none of the families refused to take part.

3. Results

3.1. Demographic Data

There were 147 patients (58.5% male) who fulfilled our PIBO criteria during the study period. The median age at PIBO diagnosis in the cohort was 22 months and ranged from one month to 16 years. Table 1 shows the clinical characteristics. The 21 children born premature, before 37 weeks of gestation, were more likely to be hospitalised, including in the intensive care units (ICUs). However, their microbiological distribution matched the rest of the cohort. Only four of the preterm children were born before 32 weeks of gestation and none of them had severe bronchopulmonary dysplasia.

TABLE 1.

Clinical characteristics of 147 French paediatric patients followed up for post‐infectious bronchiolitis obliterans.

	Total cases, n = 147
Age at diagnosis median (range)	22 months (1 month–16 years)
Age distribution
< 2 years	86 (58.5%)
Between 2 and 6 years	40 (27.2%)
> 6 years	21 (14.3%)
Sex n (% males)	86 (58.5%)
Birth weight median (range)	3100 g (820–4380)
Neonatal respiratory history n (%)	12 (8.2%)
Hospitalisation at the time of the initial suspected infection n (%)	123 (83.7%)

The annual distribution of the new PIBO cases was: 19 in 2017, 22 in 2018, 26 in 2019, 8 in 2020, 11 in 2021, 24 in 2022, and 37 in 2023.

No symptoms were specific to PIBO diagnoses. As expected, having a cough was the predominant symptom (Figure 1).

FIGURE 1.

Primary symptoms at the time of diagnosis among 147 French paediatric patients followed up for post‐infectious bronchiolitis obliterans.

3.2. Initial Infectious Episodes

The characteristics of lower respiratory tract infections were analysed. Most children (83.7%) were hospitalised for the initial suspected infection and 36.7% were admitted to ICUs, and 47.0% were admitted to acute care wards. Younger children were more likely to be admitted to acute care wards or ICUs (p = 0.01) (Figure 2). Preterm children were more likely to be hospitalised during the initial suspected infection (18/21), with 11 admitted to the ICUs. We were unable to specify the diagnosis delay from the initial event.

FIGURE 2.

The severity of the initial suspected infection was classified according to three age groups in French paediatric patients and followed up for post‐infectious bronchiolitis obliterans. Severity was based on no admission to hospital, acute care admission, or intensive care unit admission.

The infectious triggers were identified and analysed and a suspected microbiological agent was found in 97/147 (66.0%) of the cases. However, in 34.0% of patients, virological testing was either not performed at the time of the initial suspected infection or did not allow identification of the suspected agent. The most frequently identified viruses were adenoviruses (28.5%), then the respiratory syncytial virus (RSV) (26.4%). These were followed by rhinoviruses (16.0%), influenza (11.1%), parainfluenza (6.9%), the human metapneumovirus (5.4%) and the severe acute respiratory syndrome coronavirus 2, without an identified co‐infection (0.7%). Five cases of PIBO were reported following Mycoplasma pneumoniae infections, but only one occurred between 2021 and 2023. The microbiological results by age group are presented in Figure 3. It should be noted that no post‐adenovirus PIBO cases were reported after the age of six. Before six years of age, more than half of the children presented with co‐infections: 26/41 (63.4%) with adenoviruses and 22/38 (57.9%) with RSV.

FIGURE 3.

Microbiological agent linked to the initial suspected infection according to three age groups in French paediatric patients followed up for post‐infectious bronchiolitis obliterans. Expressed as absolute values.

3.3. Diagnosis Criteria and Features of PIBO

The investigations performed during the PIBO workup are reported in Table 2. Seeing a mosaic pattern on the CT scans was part of the inclusion criteria, and other abnormalities were bronchiectasis (36.1%) and atelectasis (48.3%). Only one‐third of the cohort had expiratory sections at a median of 3 years of age. Pulmonary function tests were not commonly performed at the time of diagnosis (23.1%) because the children were so young. The median age at the time of the tests was 6 years and 5 months (range 6 months to 14.4 years). Only 34 patients underwent flow‐volume curves: 31 had a beta‐2 agonist reversibility test, and the other three were only explored using the resistance of the respiratory system test. The median FEV1 was 65% (range 35.7% to 93%). We found a bronchial obstruction in 26 (83.9%) of the 31 patients who underwent the beta‐2 agonist reversibility test, and in 17 of these cases, it was irreversible. Only six of those 31 patients had a complete positive bronchodilation response, with no specific differences in viral distribution compared to the other patients. Notably, no adenoviruses were identified during the initial suspected infections in the subgroup with reversibility. The main pathogens were influenza viruses and Mycoplasma pneumoniae , which may be explained by the older age of these patients compared to the rest of the cohort. None had a history of asthma. The immune and sweat tests were unremarkable. Bronchoscopy data were available for 145 of the 147 patients, and 97 (66.9%) of these underwent this exam at the time of diagnosis. The bronchoalveolar lavage tests that were performed predominantly showed neutrophilic alveolitis in the 76 samples analysed. These had a median cellularity of 400 cells/mm³ (range 27 to 17 700/mm³) and a median neutrophilia of 45% (range 0% to 99%). Lymphocyte counts were low, with a median of 5% (range 0% to 80%), and there were no eosinophils, with a median of 0% (range 0% to 3%). Nearly three‐quarters (71%) of the 76 bronchoalveolar lavage examinations that were performed revealed bacterial superinfections. The pathogens included Haemophilus influenzae (n = 32), Moraxella catarrhalis (n = 12), Streptococcus (n = 16) or Pseudomonas aeruginosa (n = 5). Three out of five patients with Pseudomonas aeruginosa had both PIBO and bronchiectasis. A total of 15 children underwent a bronchial mucosal biopsy during bronchoscopy, mainly to assess ciliary motility. Only one patient had a surgical lung biopsy, which did not contribute to a differential diagnosis or alter their disease management. The biopsy revealed diffuse interstitial pneumonia in both upper and lower lobes, with a heterogeneous distribution and early fibrosis. No transbronchial biopsies were performed. Most patients with PIBO (88/147, 59.8%) underwent echocardiography, and 7/88 (8.0%) had pulmonary hypertension. All seven children required hospitalisation during their suspected initial infection, and three were admitted to ICUs. The median age of these patients when they were diagnosed with PIBO was 27 months, and they showed similar microbiology results to the rest of the cohort. Their CT scans showed mosaic attenuation, with bronchiectasis in two cases and atelectasis in another two. Six of the seven received intravenous corticosteroid pulses.

TABLE 2.

Investigations performed at the time of diagnosis in 147 French paediatric patients followed up for post‐infectious bronchiolitis obliterans.

Investigations	Numbers of cases	Percentage (%)
For diagnostic purpose
Computed tomography	147	100
x‐ray	93	63.3
Spirometry	34	23.1
For diagnostic purpose and phenotyping
Bronchoscopy	97	66.9
For complications
Echocardiography	88	59.9
To exclude differential diagnoses
Immune function tests	132	92.3
Sweat chloride test	105	74

3.4. PIBO Management

All the treatments are summarised in Table 3. Most of the 147 patients received inhaled corticosteroids (90.5%) and in 38.8% of cases they were combined with long‐acting beta‐2 agonists. We found that 87 (59.2%) of the cohort were treated with azithromycin and 18 (12.2%) with long‐term oral corticosteroids. Just under a fifth of the children (18.4%) required respiratory support: 25 received oxygen therapy alone, or in combination with advanced modalities. These included five treated with high‐flow nasal cannulas and five who received non‐invasive ventilation. Chest physiotherapy was prescribed for 43.5%, particularly when bronchiectasis or atelectasis were noted on their CT scans. Only seven patients required enteral supplemental dietary support, delivered using nasogastric or gastrostomy routes. A subgroup of 60 patients (40.8%) received intravenous corticosteroid pulses of 10 to 30 mg/kg/day for three consecutive days per month. Half of the preterm infants received intravenous corticosteroid pulses as part of their PIBO management. The treatment duration varied, as 29 children received it for 3 months, 20 for four to 6 months, and 11 for more than 6 months. They tended to be younger than the rest of the cohort at diagnosis, with a median age of 11 months (range 1 month to 12 years) and presented with severe clinical symptoms, such as persistent signs of respiratory distress or weight loss. In addition, seven had pulmonary hypertension. Additional CT findings included bronchiectasis (n = 22) and atelectasis (n = 28). Of the 21 patients who required oxygen support alone, seven needed it persistently after treatment. The mean duration of oxygen requirement from initiation to cessation was 3.4 months (range 0.07 to 17 months), with no significant age‐adjusted differences observed among the treatment duration groups (p = 0.20).

TABLE 3.

Therapeutic management of 147 French paediatric patients followed up for post‐infectious bronchiolitis obliterans.

	Long term treatment	Numbers of cases	Percentage (%)
Inhaled treatment	Inhaled corticosteroid	133	90.5
	Inhaled corticosteroid and long‐acting β2‐agonist	57	38.8
	Anticholinergic	9	6.1
Oral treatment	Azithromycin	87	59.2
	Systemic corticosteroids	18	12.2
	Antileukotriene	15	10.2
	Alternative continuous antibiotic therapy	20	13.6
Supportive care	Chest physiotherapy	64	43.5
	Respiratory support (oxygen, high‐flow nasal cannula, non‐invasive ventilation)	27	18.4
	Nutritional support (nasogastric tube or gastrostomy)	7	4.8
Intravenous treatment	Corticosteroid pulse	60	40.8

One death occurred in our cohort shortly after the patient was diagnosed with PIBO, following an adenovirus and influenza, associated with chronic hypercapnic respiratory failure. This meant that the overall mortality rate was 0.68%.

4. Discussion

This was the largest paediatric study of PIBO in a single European country and 147 cases were diagnosed by 18 French RespiRare centres during the 6‐year study period. Our findings showed variations in the microbiological distribution of suspected agents among different age groups, as well as differences in the severity of the initial suspected infection. Younger children often required hospitalisation. It was notable that a considerable percentage of the children (40.8%) received treatment with intravenous corticosteroid pulses. PIBO cases significantly decreased during the COVID‐19 pandemic and then increased. Child hospitalisations for viral infections dropped and this was probably due to the widespread use of masks and reduced social interactions during the pandemic [20].

Important recent epidemiological findings were seen in 66.0% of the children with complete diagnostic assessments. The most common pathogens that were identified and presumed to cause PIBO were adenoviruses, followed by RSV. A Chinese study by Li et al. analysed 42 PIBO cases from 2008 to 2013 and reported that adenoviruses were the main microorganisms, followed by Mycoplasma pneumoniae , RSV and influenza [9]. The prominent role of RSV in our study, especially among the youngest patients, suggests the need for RSV infection prevention strategies. These could include an extended half‐life monoclonal antibody [21] or maternal vaccination and could have altered the epidemiology of PIBO observed in our cohort. Rhinoviruses were rarely linked to PIBO [22], but our study reported that 23 children developed PIBO after rhinoviruses and only six of these did not have any coinfections. The other viruses associated with these cases were adenoviruses or RSV. One case followed the severe acute respiratory distress syndrome from COVID‐19 [23]. The impact of multiple viruses or bacterial combinations on the risk of PIBO remains unknown. Lim et al.'s systematic review and meta‐analysis of respiratory viral coinfections in children suggested that these did not increase clinical severity [24]. Our cohort showed a high rate of polymicrobial infections. Mycoplasma pneumoniae was common among older patients. Physicians reported bacterial superinfections, which are seen as secondary infections in children already weakened by initial infections, but they did not consider them causal. It remains challenging for retrospective analyses to establish causative agents and link infections to the development of PIBO. Only 83.7% of the children with PIBO were hospitalised during the initial suspected infection, indicating that the infection was mild in some cases. This was reflected by the 16.3% of children in this study who were not hospitalised. No specific guidelines exist for PIBO management and long‐term treatment [2], resulting in a lack of standardisation across centres. CT scans that show a mosaic pattern remain the primary diagnostic criterion for PIBO. However, obtaining good quality inspiratory and expiratory CT scans for young children can be challenging and may necessitate anaesthesia. Therefore, decubitus imaging can be used to assess air trapping and supine images may help identify areas that require further evaluation [25].

Bronchoscopy was available in every centre, but the decisions about whether to perform them were made on clinical grounds by the medical team treating the children. In our experience, lung biopsies had little value when the evidence for PIBO was strong and the results did not alter management strategies. Echocardiography was performed based on clinical severity, particularly oxygen requirements, and at the discretion of the treating medical team. Pulmonary function tests at the time of diagnosis were rare, but typically showed an obstructive pattern. A systematic review by Lee et al. showed reduced pulmonary function in paediatric PIBO, with a mean FEV1 of 54.4%, forced vital capacity ratio of 68.8%, and positive bronchodilator responses of 30.0%–83.3% [26]. Lee's findings challenge the traditional definition of PIBO, which includes irreversible airway obstruction. The Colom study showed that 47 patients with PIBO experienced decreased pulmonary function during childhood after a 12‐year follow‐up [27]. Our study produced limited data on the usefulness of respiratory system resistance because this parameter was only evaluated in three children.

Three‐quarters of our cohort had predominant neutrophilic alveolitis. There has been limited research on bronchoalveolar lavage cytology, and one study found that it indicated neutrophilic alveolitis and a slight increase in lymphocytes [28]. Neutrophils are essential innate immune phagocytes, and they play critical roles in pathogen clearance and immune regulation. Advances in this area have highlighted that neutrophil extracellular traps are key markers in the severity of bronchiectasis and in treatment responses [29].

Most patients underwent multiple therapies in our studies, and corticosteroids and azithromycin were the most common approaches. However, our study did not contain placebo‐controlled trials. Our study was the largest cohort to treat children with PIBO with intravenous corticosteroid pulses, and half of the patients received treatment for severe symptoms, such as respiratory distress, hypoxia, weight loss or pulmonary arterial hypertension. Retrospective series have supported the efficacy of intravenous corticosteroid pulses in PIBO. For example, Yoon et al.'s retrospective study found that nine out of 17 children with PIBO responded to intravenous corticosteroid pulses, as evidenced by reduced air trapping on CT scans. However, there have not been any placebo‐controlled studies. Responders were younger, at 2 years versus seven and half years, and had shorter intervals between initial episodes, at four versus 50 months [13]. Some case reports have suggested that early corticosteroid pulse interventions may improve PIBO outcomes [7, 15]. Tomikawa et al. followed 40 children who received early treatment with systemic corticosteroids and they demonstrated reduced airway hyperresponsiveness, wheezing and hospitalisations. Pulse therapy ranged from six to 40 months [15]. Again, there was no placebo group. International recommendations suggest intravenous corticosteroid pulses and do not specify prioritisation criteria [1, 2, 4]. This seems to be due to the fact that the natural history of PIBO varies, based on the severity of the initial viral trigger and the child's age, as children's lungs continue to develop. Our study confirmed that childhood PIBO had a low early mortality rate compared to other aetiologies of BO. A Hong Kong study also reported no PIBO deaths over 20 years, in contrast to two deaths in post‐haematopoietic stem‐cell transplant BO cases [22]. It is likely that improved diagnosis, especially with advanced CT imaging, has contributed to the decreased mortality rate. However, the long‐term prognosis, with a risk of complications, requires transition and prolonged follow‐up. PIBO is currently classified as a paediatric interstitial and diffuse lung disease, and it is considered a disorder that is influenced by both host and environmental exposure [10, 30]. CT findings consistently show bronchial involvement, which is often accompanied by bronchiectasis.

4.1. Strengths and Limitations

The main strength of this study was that it was the largest paediatric study of PIBO in a single European country, and 147 cases were diagnosed by 18 French centres during the six‐year study period. The study also had limitations due to its retrospective design, which led to some missing patient information and follow‐up issues. Defining PIBO and distinguishing it from other chronic lung diseases was complicated by the lack of clear guidelines. However, we reduced bias by excluding children with chronic lung or oncological conditions and using established clinical, CT and spirometric criteria.

5. Conclusion

This French multicentre study found that PIBO was a rare but clinically significant disease and warrants further and thorough investigation. The disease trajectory varied across age groups, with younger children often experiencing more severe initial suspected infections and distinct viral distributions. Being able to assess disease severity precisely is critical at the time of diagnosis and during long‐term follow‐up periods, particularly when the child makes the transition to adult care. Further research is essential on how to define PIBO phenotypes more effectively by using advances in imaging, pulmonary function testing, bronchoscopic sampling, and biomarker identification. These efforts would inform the development of targeted and personalised therapeutic approaches that would ultimately optimise patient management and improve long‐term outcomes for children with this complex and heterogeneous disease.

Author Contributions

Julie Mazenq: conceptualization, investigation, writing – original draft, methodology, validation, visualization, writing – review and editing, supervision. Marine Crebassa: data curation, investigation, writing – review and editing. Alice Hadchouel: investigation, writing – review and editing, validation. Souad Ghattas: investigation, validation, writing – review and editing. Philippe Reix: investigation, validation, writing – review and editing. Laurianne Coutier: investigation, validation, writing – review and editing. Christophe Marguet: investigation, writing – review and editing, validation. Nadia Nathan: investigation, writing – review and editing, validation. Lisa Giovannini‐Chami: writing – review and editing, validation, investigation. Caroline Thumerelle: investigation, writing – review and editing, validation. François Galode: investigation, validation, writing – review and editing. Marie‐Catherine Renoux: investigation, validation, writing – review and editing. Léa Roditis: validation, investigation, writing – review and editing. Eglantine Hullo: investigation, validation, writing – review and editing. Pierrick Cros: investigation, validation, writing – review and editing. Laurence Weiss: validation, investigation, writing – review and editing. Sébastien Kiefer: investigation, validation, writing – review and editing. Marie Tochon: writing – review and editing, validation, investigation. Brahim Allali: investigation, validation, writing – review and editing. Katia Bessaci Kabouya: writing – review and editing, investigation, validation. Céline Delestrain: investigation, validation, writing – review and editing. Louisa Goumidi: writing – review and editing, methodology, formal analysis. Hortense Petat: investigation, validation, writing – review and editing, visualization. Véronique Houdouin: investigation, validation, visualization, conceptualization. Jean‐Christophe Dubus: conceptualization, validation, investigation, writing – review and editing, visualization, methodology.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

FIGURE S1. Study design.