# Exposure to inorganic particles in paediatric sarcoidosis: the PEDIASARC study

Nadia Nathan, Marie-Emeline Montagne, Odile Macchi, Paul-André Rosental, Simon Chauveau, Florence Jeny, Lucile Sesé, Rola Abou Taam, Manon Brocvielle, Jacques Brouard, et al.

► To cite this version:

Nadia Nathan, Marie-Emeline Montagne, Odile Macchi, Paul-André Rosental, Simon Chauveau, et al. Exposure to inorganic particles in paediatric sarcoidosis: the PEDIASARC study. Thorax, 2021, 10.1136/thoraxjnl-2021-217870. hal-03483878

HAL Id: hal-03483878

https://hal.science/hal-03483878

Submitted on 29 Jun 2022

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Exposure to inorganic particles in paediatric sarcoidosis: the PEDIASARC study

Nadia Nathan,¹ Marie-Emeline Montagne,² Odile Macchi,³ Paul-André Rosental,⁴ Simon Chauveau,⁵ Florence Jeny,⁵ Lucile Sesé,⁵ Rola Abou Taam,⁶ Manon Brocvielle,⁷ Jacques Brouard,⁸ Mickaël Catinon,⁹ Catherine Chapelon-Abric,¹⁰ Fleur Cohen-Aubart,¹¹ Christophe Delacourt,⁶ Céline Delestrain,¹² Antoine Deschildre,¹³ Antoine Dossier,¹⁴ Ralph Epaud,¹⁵ Julien Haroche,¹¹ Véronique Houdouin,¹⁶ Dominique Israel-Biet,¹⁷ Karine Juvin,¹⁷ Sylvain Le Jeune,¹⁸ Francois Lionnet,¹⁹ Ulrich Meinzer,²⁰ Marie Mittaine,²¹ Hilario Nunes,⁵ Sarah Mattioni,¹⁹ Jean-Marc Naccache,²² Marie-Hélène Odièvre,²³ Michel Vincent,⁹ Annick Clement,¹ Dominique Valeyre,⁵,²⁴ Catherine Cavalin,²⁵,²⁶,²⁷ for the French Sarcoidosis Group and the Silicosis Research Group

► Additional supplemental material is published online only. To view, please visit the journal online (http://dx.doi.org/10.1136/thoraxjnl-2021-217870).

For numbered affiliations see end of article.

**Correspondence to**

Dr Nadia Nathan, Pediatric Pulmonology Department and Reference Center for Rare Lung Diseases RespiRare, Inserm UMR_S933 Laboratory of Childhood Genetic Diseases, Armand Trousseau Hospital, AP-HP. Sorbonne Université, Paris, France; nadia.nathan@aphp.fr

NN and M-EM contributed equally.

Received 26 June 2021
Accepted 25 September 2021
Published Online First
21 October 2021

<figure><img src="image_2.png" /></figure>

► http://dx.doi.org/10.1136/thoraxjnl-2021-218249

<figure><img src="image_3.png" /></figure>

Check for updates

© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.

To cite: Nathan N, Montagne M-E, Macchi O, et al. Thorax 2022;77:404–407.

**ABSTRACT**

Inorganic antigens may contribute to paediatric sarcoidosis. Thirty-six patients matched with 36 healthy controls as well as a group of 21 sickle-cell disease (SCD) controls answered an environmental questionnaire. Patients' indirect exposure to inorganic particles, through coresidents' occupations, was higher than in healthy and SCD controls (median score: 2.5 (0.5–7) vs 0.5 (0–2), p=0.003 and 1 (0–2), p=0.012, respectively), especially for construction, exposures to metal dust, talc, abrasive reagents and scouring products. Wood or fossil energies heating were also linked to paediatric sarcoidosis. This study supports a link between mineral environmental exposure due to adult coresident occupations and paediatric sarcoidosis.

**INTRODUCTION**

Paediatric sarcoidosis is extremely rare with only three reported cohorts¹: Danish (Caucasian), French (Afro-Caribbean) and Louisiana (Afro-American) patients. Most patients were aged 11–13 years. The disease seemed severe in children, involving multiple organs, and often persistent in adulthood.¹,²

Granuloma formation in sarcoidosis might stem from an exaggerated inflammatory response to organic or inorganic environmental antigens in genetically predisposed patients.³,⁴ Beryllium or crystalline silica have been associated with 'sarcoidosis-like' diseases.⁵ This environmental factor is sustained by molecular studies involving foreign body reaction pathways such as auto-phagy in sarcoidosis.⁶ The PEDIASARC study aims at comparing the exposure to inorganic—mineral—particles in patients with paediatric-onset sarcoidosis to controls.

**METHODS**

PEDIASARC was a retrospective, multicentric, case-control study from 2015 to 2019. Patients whose sarcoidosis began before the age of 16 were recruited in the French Reference network for rare

lung diseases (RespiRare), without calculation of a suitable sample size. The diagnosis was confirmed by histology (91.7%) or multidisciplinary expert discussion. A control group of healthy children was matched by age ±2years and sex. In order to have a control population closer to the characteristics of the patients in terms of geographic origin, family migration experience, socioeconomic and genetic background, a second control group was recruited among patients with sickle-cell disease (SCD). Patients and controls and/or their adult representatives gave their consent and answered a detailed environmental questionnaire (online supplemental files 1,2) that evaluated inorganic exposures from birth to the age at sarcoidosis onset in both patients/ controls and their coresidents. Questions targeted living habits, occupational and non-work-related environmental exposures (hobbies, housing), particularly crystalline silica, talcum, wood dust, mould, pollution or metal dust. Each phone or face-to-face interview lasted 45 min. The environmental exposure score combined a direct score measuring patients' or controls' exposures, an indirect score measuring occupational and non-work-related activities and a housing score related to in-house exposures (online supplemental figure S1). Each exposure scored 1 point. Each exposure was compared between the three groups (n, percentage). A median score and an interquartile range (IQR: 25–75) of each group were calculated for each global exposure (direct, indirect, housing) and they were compared using a Wilcoxon-Mann-Whitney test. The housing score was divided by the number of questions. The study was authorised by French legal authorities (CPP, comité de protection des personnes; CNIL, commission nationale de l'information et des libertés).

**RESULTS**

Among the 53 patients with paediatric-onset sarcoidosis of the RespiRare network, 14 could not be reached, 3 refused to participate and 36 (68%) patients—mostly from Sub-Saharan and

<figure><img src="image_4.png" /></figure>
<table><caption>**Table 1** Clinical features of the included patients and controls</caption><thead><tr><th></th><th>Patients (n=36)</th><th>Healthy controls (n=36)</th><th>SCD controls (n=21)</th></tr></thead><tbody><tr><td>Gender, n (%)</td><td></td><td></td><td></td></tr><tr><td>Female</td><td>24 (67%)</td><td>24 (67%)</td><td>10 (48%)</td></tr><tr><td>Geographic origin, n (%)</td><td></td><td></td><td></td></tr><tr><td>Sub-Saharan Africa/West Indies</td><td>23 (64%)</td><td>0 (0%)</td><td>21 (100%)</td></tr><tr><td>North Africa</td><td>6 (17%)</td><td>0 (0%)</td><td>0 (0%)</td></tr><tr><td>Europe</td><td>5 (14%)</td><td>36 (100%)</td><td>0 (0%)</td></tr><tr><td>Asia/Middle East</td><td>2 (5%)</td><td>0 (0%)</td><td>0 (0%)</td></tr><tr><td>Age at diagnosis (years), median, (IQR)**</td><td colspan="3">12.4 (9.53-13.15)</td></tr><tr><td>Age at inclusion (years), median, (IQR)††</td><td>19.7 (15-23)</td><td>19.8 (5-38)</td><td>16.7 (3-30)</td></tr><tr><td>Number of coresidents, median (IQR)</td><td>3 (2.75-3)</td><td>3 (3-3)</td><td>2.7 (2-3)</td></tr><tr><td>Family cases, n (%)</td><td colspan="3">3 (8.3%)</td></tr><tr><td>Clinical features at diagnosis, n (%)</td><td></td><td></td><td></td></tr><tr><td>General fatigue</td><td>17 (47%)</td><td></td><td></td></tr><tr><td>Fever</td><td>13 (36%)</td><td></td><td></td></tr><tr><td>Weight loss</td><td>7 (47%)</td><td></td><td></td></tr><tr><td>Pulmonary localisation</td><td>34 (94%)</td><td></td><td></td></tr><tr><td>Extrapulmonary localisation</td><td>34 (94%)</td><td></td><td></td></tr><tr><td>Liver</td><td>21 (58%)</td><td></td><td></td></tr><tr><td>Lymphadenopathies</td><td>17 (47%)</td><td></td><td></td></tr><tr><td>Salivary glands</td><td>14 (39%)</td><td></td><td></td></tr><tr><td>Eyes</td><td>13 (36%)</td><td></td><td></td></tr><tr><td>Spleen</td><td>7 (19.4%)</td><td></td><td></td></tr><tr><td>Joints</td><td>7 (19.4%)</td><td></td><td></td></tr><tr><td>Skin</td><td>5 (14%)</td><td></td><td></td></tr><tr><td>Stomach</td><td>5 (14%)</td><td></td><td></td></tr><tr><td>Kidney</td><td>4 (11%)</td><td></td><td></td></tr><tr><td>Bone marrow</td><td>2 (5.5%)</td><td></td><td></td></tr><tr><td>Heart</td><td>2 (5.5%)</td><td></td><td></td></tr><tr><td>Tonsils</td><td>1 (2.7%)</td><td></td><td></td></tr><tr><td>Histology, n (%)</td><td></td><td></td><td></td></tr><tr><td>Non-caseating granuloma</td><td>33 (91.7%)</td><td></td><td></td></tr><tr><td>Treatments, n (%)</td><td></td><td></td><td></td></tr><tr><td>Corticosteroids, n (%)</td><td>34 (94%)</td><td></td><td></td></tr><tr><td>Oral only</td><td>12 (33%)</td><td></td><td></td></tr><tr><td>Intravenous pulse only</td><td>1 (2.9%)</td><td></td><td></td></tr><tr><td>Both oral and intravenous</td><td>21 (58%)</td><td></td><td></td></tr><tr><td>Other drugs‡</td><td>10 (27.7%)</td><td></td><td></td></tr><tr><td>No treatment</td><td>2 (5.5%)</td><td></td><td></td></tr></tbody></table>

The explorations assessing the sarcoidosis diagnosis of the 36 included patients are provided in online supplemental table S1.
IQR: 25-75.

*Extreme values (minimal-maximal) (1-15.9).

†Extreme values (minimal-maximal) (4-36), (5-38) and (3-30), respectively.

‡Methotrexate, azathioprine, hydroxychloroquine, mycophenolate mofetil.
SCD, sickle-cell disease.

Afro-Caribbean origins—were included in the study (table 1 and online supplemental table S1). None of the patients had to be excluded because of an absence of understanding of the questionnaire. They were matched with 36 paired healthy controls—mostly from Caucasian origin. Twenty-one SCD controls could be included.

Direct exposure scores did not differ between the three groups (figure 1). Exposure to scouring powder was the only one to be higher in patients' environment as compared with healthy controls (p=0.037) (online supplemental table S2). The global indirect exposure score was significantly higher in

the sarcoidosis group than in the SCD group (5.5 (1.75-9), 2.5 (1-5.25) (p=0.09), 1 (1-3) (p=0.009)), respectively for the sarcoidosis, healthy controls and SCD controls. The occupational exposure score of the patients' coresidents (whose number was similar among the three groups (table 1)), was higher than in both control groups (median scores 2.5 (0.5-7)) versus (0.5 (0-2), p=0.003 for healthy controls and 1 (0-2), p=0.012 for SCD controls), particularly exposure to abrasive material (silica), talcum, combustion or welding fumes in metal working industry. The coresidents were exposed to mineral dusts via construction works and cleaning with scouring reagents. Only the frequency of occasional do-it-yourself was found different between patients and controls regarding coresidents' non-work-related activities (online supplemental table S3) and figure 1.

The exposure score related to the current and previous housings was significantly higher for patients as compared with healthy controls (median scores: 0.069 (0.05-0.1) vs 0.05 (0.04-0.07), and 0.16 (0.11-0.16) vs 0.04 (0.025-0.065), p<0.001 for both current and previous housings) but not with SCD controls (median scores: 0.11 (0.08-0.11), p=0.3 and 0.118 (0.06-0.12), p=0.13, respectively) (figure 2 and online supplemental table S4). Wood, gas, butane, coal and fuel oil heating were more frequently reported by patients than healthy controls and SCD controls. In patients' previous housings, mould was more frequently present than in healthy controls but not in SCD controls (online supplemental table S5).

## DISCUSSION

Our study is the first one supporting the fact that the adult coresidents' occupational exposure (especially crystalline silica, metal and talcum—the toxicity of which has already been put forward) could play a promoting role in the pathophysiology of paediatrics sarcoidosis, whereas direct exposures at a paediatric age would not. We found that hazardous occupations were those releasing a lot of dust, especially in construction.⁷ These results are consistent with those produced in adults in the ACCESS study and the French pilot MINASARC study using also bronchoalveolar lavage (BAL) analysis of mineral dusts.⁴ ⁸ More recently, a Dutch study highlighted an increased exposure but also an increased immunoreactivity to metal and silica in adult sarcoidosis patients.⁹

As in the USA, paediatric sarcoidosis in France affects mostly black children.¹ The patients' histories often highlighted chaotic migratory trajectories, successive insalubrious homes, and parents having numerous short-contract occupations, few exposing hobbies and other extraprofessional social activities. Thus, our results could be only a characterisation of the patients' socioeconomic status, without this being an aetiological determinant for paediatric sarcoidosis. Since (1) the SCD control group allows checking social characteristics and (2) the housing score is not significantly different in patients and in the SCD control group, we consider that our results uncover findings specifically linked rather to paediatric sarcoidosis, than to socio-economic status.

Several studies have suggested that a genetic susceptibility could promote sarcoidosis. Moreover, Sub-Saharan Africa populations are more often affected.³ Despite probable similar exposures within families, only 3 (8.3%) kin-related sarcoidosis were reported. This observation questions the way how environmental exposure and genetic combine. The expansion of ongoing genetic family and trio studies may undoubtedly help to answer this question.⁶ ¹⁰
<figure><img src="image_5.png" /><figcaption>**Figure 1** Exposure scores of the patients and the controls. (A) Direct exposure score, (B) indirect exposure score due to occupational activities and (C) indirect exposure score due to non-work-related activities of the patients and controls. The box represents the interquartile range (the lower line of the box represents the 1st quartile, the horizontal line within the box is the median and the upper line is the 3rd quartile), the horizontal bars at the ends are the minimum and maximum values and the isolated points represent the extreme (exceptional) values. The theoretical maximal scores are as follows: direct exposure score = 26, indirect exposure score = 27, indirect extraprofessional exposure score = 15. The indirect exposure score due to occupational activities was higher in patients than in both control groups. No difference was found for the direct exposure score and the indirect exposure score due to non-work-related activities of the patients and controls. \*p<0.05.</figcaption></figure>

Despite several limitations (small population size—as in all rare diseases, retrospective design that can induce recall bias and selection bias, potential uncontrolled confounding, absence of perfect match between the SCD group and the patients regarding their number, gender and geographic origin, and the absence of

testing the immunoreactivity to suspected exposure), this study supports the hypothesis that mineral environmental risk factors, through occupational exposure to inorganic particles of the patients' co-residents are linked to paediatric granulomatous disorders with sarcoidosis presentation.

<figure><img src="image_6.png" /><figcaption>**Figure 2** Housing exposure score. Exposure scores of the current (A) and previous (B) housing of the patients and controls. The housing scores were divided by the number of questions. The box represents the interquartile range (the lower line of the box represents the 1st quartile, the horizontal line within the box is the median and the upper line is the 3rd quartile), the horizontal bars at the ends are the minimum and maximum values and the isolated points represent the extreme (exceptional) values. The exposure scores were significantly higher for patients as compared with healthy controls but not with sickle-cell disease controls. \*p<0.001.</figcaption></figure>
Author affiliations

¹Pediatric Pulmonology Department and Reference Center for Rare Lung Diseases
RespiRare, Inserm UMR_S933 Laboratory of Childhood Genetic Diseases, Armand
Trousseau Hospital, AP-HP, Sorbonne Université, Paris, France

²Pediatric Pulmonology Department and Reference Center for Rare Lung Diseases
RespiRare, Armand Trousseau Hospital, AP-HP, Sorbonne Université, Paris, France

³Observatoire, Samu Social de Paris, Paris, France

⁴Centre d'Histoire, Sciences Po, Paris, France

⁵Pulmonology Department and Inserm UMR 127, Avicenne Hospital, APHP. Université Sorbonne Paris Nord, Paris, France

⁶Pediatric Pulmonology Department and Reference Center for Rare Lung Diseases
RespiRare, Necker Enfants Malades Hospital, AP-HP. Centre - Université de Paris,
Paris, France

⁷Statistician, Marcq-en-Baroeul, France

⁸Pediatric Pulmonology Department, CHU Caen, Caen, France

⁹MINAPATH : SAS sociale et solidaire, Lyon, France

¹⁰Department of Internal Medicine and Clinical Immunology, La Pitié-Salpêtrière Hospital, APHP. Sorbonne Université, Paris, France

¹¹Department of Internal Medicine 2, La Pitié-Salpêtrière Hospital, e3m Institute, Reference Center for Rare Systemic Diseases, Lupus, Anti-Phospholipids Syndrome, AP-HP. Sorbonne Université, Paris, France

¹²Pediatric Department and Reference Center for Rare Lung Diseases RespiRare, INSERM, IMRB, Centre Hospitalier Intercommunal de Créteil, Université Paris Est Creteil, Paris, France

¹³Pediatric pulmonology and allergy department, Hôpital Jeanne de Flandre,
Université de Lille, Lille, France

¹⁴Department of Internal Medicine, Bichat Hospital, AP-HP. Nord - Université de Paris,
Paris, France

¹⁵Centre Hospitalier Intercommunal de Créteil, Pediatric Department and Reference center for rare lung diseases (RespiRare), INSERM, IMRB, Université Paris Est Creteil, Paris, France

¹⁶Pediatric Pulmonology department, Robert Debré Hospital, AP-HP. Nord - Université de Paris, Paris, France

¹⁷Pulmonology department, Georges Pompidou Hospital, AP-HP. Centre - Université de Paris, Paris, France

¹⁸Department of Internal Medicine, Avicenne Hospital, APHP. Université Sorbonne Paris Nord, Paris, France

¹⁹Department of Internal Medicine, Tenon Hospital, AP-HP. Sorbonne Université, Paris, France

²⁰Department of General Pediatrics, Pediatric Internal Medicine, Rheumatology and Infectious Diseases, National Referee Center for Rare Pediatric Inflammatory Rheumatisms and Systemic Auto-Immune Diseases RAISE, Robert Debré Hospital, AP-HP. Nord - Université de Paris, Paris, France

²¹Pediatric Pulmonology Department, Children Hospital, CHU Toulouse, Toulouse, France

²²Pulmonology Department, Groupe hospitalier Paris Saint-Joseph and Hôpital Foch, Paris, France

²³Department of Pediatrics and Sickle Cell Disease Center, Armand Trousseau Hospital, AP-HP. Sorbonne Université, Paris, France

²⁴Pulmonology department, Paris Saint Joseph Hospital Group, Paris, France

²⁵Institut de recherche interdisciplinaire en sciences sociales (IRISSO, UMR CNRS-INRA 7170-1427), Université Paris Dauphine, PSL, Paris, France

²⁶Laboratoire interdisciplinaire d'évaluation des politiques publiques (LIEPP), Sciences Po, Paris, France

²⁷Centre d'études de l'emploi et du travail (CEET, CNAM), CNAM, Paris, France

**Acknowledgements** We wish to thank the patients and their families for their participation in the study. We thank the French sarcoidosis group (GSF) (https://

splf.fr/groupes-de-travail/sarcoidose-francophone-gsf/le-ggsf/), the Société de Pneumologie de langue française (SPLF) and the Silicosis research team (http://www.sciencespo.fr/silicosis/fr). We thank the Assistance Publique-Hôpitaux de Paris and Sorbonne Université Paris, France, and the national networks for rare lung diseases: Centre de référence des maladies respiratoires rares (RespiRare), Centre de référence des maladies pulmonaires rares (OrphaLung) and Filière de soins pour les maladies respiratoires rares (RespiFIL). The RespiRare cohort is developed in collaboration with the RaCOrt Disease (RaDiCo)-ILD project (ANR-10-COH0-0003), the FP7-305653-child-EU project, the COST Action European network for translational research in children's and adult interstitial lung disease (COST-ILD) project (CA16125) and the ERS Clinical Research Collaboration for chILD.

**Collaborators** The French Sarcoidosis Group, The Silicosis Research Group.

**Contributors** NN and CC designed the study. CC, OM, P-AR and MV designed the questionnaires. M-EM, CC, NN, MB, LS and FJ analysed and interpreted the data. M-EM, NN, P-AR, DV and CC wrote the manuscript.NN, M-EM, SC, FJ, LS, RA-T, JB, CC-A, FC-A, MC, ChD, CeD, ADe, ADo, RE, JH, VH, DI-B, KJ, SL-J, FL, UM, MM, HN, SM, J-MN, M-HO, AC, DV provided the patients' clinical data and facilitated the contacts to make the interviews with patients and SCD controls. All authors reviewed and approved the manuscript.

**Funding** Contract grant sponsor: European Research Council (ERC) / SILICOSIS project / Principal investigator: Paul-André Rosental; Contract grant number: ERC-2011-ADG_20110406 Project ID: 295817. Statistical analysis: RespiFIL funds.

**Competing interests** None declared.

**Patient consent for publication** Not applicable.

**Provenance and peer review** Not commissioned; externally peer reviewed.

ORCID iDs

Nadia Nathan http://orcid.org/0000-0001-5149-7975

Ralph Epaud http://orcid.org/0000-0003-3830-1039

REFERENCES

1 Nathan N, Sileo C, Calender A, et al. Paediatric sarcoidosis. *Paediatr Respir Rev* 2019;29:53-9.

2 Chauveau S, Jeny F, Montagne M-E, et al. Child-Adult transition in sarcoidosis: a series of 52 patients. *J Clin Med* 2020;9:2097.

3 Valery D, Prasse A, Nunes H, et al. Sarcoidosis. *The Lancet* 2014;383:1155-67.

4 Newman LS, Rose CS, Bresnitz EA, et al. A case control etiologic study of sarcoidosis: environmental and occupational risk factors. *Am J Respir Crit Care Med* 2004;170:1324-30.

5 Beijer E, Meek B, Kromhout H, et al. Sarcoidosis in a patient clinically diagnosed with silicosis; is silica associated sarcoidosis a new phenotype? *Respir Med Case Rep* 2019;28:100906.

6 Calender A, Lim CX, Weichhart T, et al. Exome sequencing and pathogenicity-network analysis of five French families implicate mTOR signalling and autophagy in familial sarcoidosis. *Eur Respir J* 2019;54:1900430.

7 Newman KL, Newman LS. Occupational causes of sarcoidosis. *Curr Opin Allergy Clin Immunol* 2012;12:145-50.

8 Catinon M, Cavalin C, Chemarin C, et al. Sarcoidosis, inorganic dust exposure and content of bronchoalveolar lavage fluid: the MINASARC pilot study. *Sarcoidosis Vasc Diffuse Lung Dis* 2018;35:327-32.

9 Beijer E, Meek B, Bossuyt X, et al. Immunoreactivity to metal and silica associates with sarcoidosis in Dutch patients. *Respir Res* 2020;21:141.

10 Calender A, Rollat Farnier PA, Buisson A, et al. Whole exome sequencing in three families segregating a pediatric case of sarcoidosis. *BMC Med Genomics* 2018;11:23.