Eur J Pediatr DOI 10.1007/s00431-015-2579-4
ORIGINAL ARTICLE
Sweat test practice in pediatric pulmonology after introduction of cystic fibrosis newborn screening Céline Grimaldi 1 & François Brémont 2 & Michèle Berlioz-Baudoin 3 & Jacques Brouard 4 & Harriet Corvol 5 & Laure Couderc 6 & Guillaume Lezmi 7 & Isabelle Pin 8 & Isabelle Petit 9 & Philippe Reix 10 & Natacha Remus 11 & Cyril Schweitzer 12 & Caroline Thumerelle 13 & Jean-Christophe Dubus 14
Received: 22 February 2015 / Revised: 2 June 2015 / Accepted: 8 June 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract The influence of the generalization of cystic fibrosis newborn screening (CFNBS) in France on sweat test (ST) prescription is unknown. In this French retrospective, descriptive, and multicenter study, we studied the indications, number, methods, and results of STs prescribed by a pediatric pulmonologist in children who had a negative CFNBS and an ST for respiratory symptoms in 2012. We included 502 children with 523 STs, performed with four different methods. The main indication was asthma (71.3 %), then chronic cough (52.4 %), atypical lower airway infections (42.2 %), and bronchiectasis (7 %). Four children had a diagnosis of CF (0.8 %), all presenting with chronic productive cough and recurrent respiratory infections. Conclusion: Asthma is the most frequent indication of ST in our cohort. Because of the systematic CFNBS in France, some prescriptions should be avoided, particularly in case of
severe or moderate asthma with no other associated symptom. Moreover, methods of STs often do not follow the guidelines and need standardization. What is Known: • Newborn screening (NBS) has become the most frequent circumstance of the diagnosis of cystic fibrosis (CF) in France after its generalization. • The prescription of sweat test (ST) in children with respiratory symptoms who already had a negative NBS has not been studied. What is New: • In children with a negative CF NBS referred to a university hospital for respiratory diseases, despite important variations of ST methods, only 4 children among 502 have been diagnosed as CF. • Despite recommendations, ST prescription should be avoided in children with moderate to severe asthma and no other associated symptom.
Communicated by Peter de Winter * Céline Grimaldi [email protected]
Isabelle Petit [email protected]
François Brémont [email protected]
Philippe Reix [email protected]
Michèle Berlioz-Baudoin [email protected]
Natacha Remus [email protected]
Jacques Brouard [email protected]
Cyril Schweitzer [email protected]
Harriet Corvol [email protected]
Caroline Thumerelle [email protected]
Laure Couderc [email protected]
Jean-Christophe Dubus [email protected]
Guillaume Lezmi [email protected]
1
Service de pneumologie pédiatrique et CRCM, CHU Timone, 264 rue St Pierre, 13005 Marseille, France
Isabelle Pin [email protected]
2
Département de pédiatrie, Hôpital des enfants, 31026 Toulouse, France
Eur J Pediatr
Keywords Pediatric pulmonology . Sweat test . Prescription . Respiratory symptoms Abbreviations CF Cystic fibrosis NBS Newborn screening ST Sweat test
Introduction Cystic fibrosis (CF) is the most frequent and severe genetic disease among European and North American populations, with an incidence of 1/4136 newborns in France [19]. Among its many consequences, respiratory disease is the major cause of morbidity and mortality [14, 21]. Nowadays, the diagnosis of CF is established in three clinical circumstances [11, 23]: the newborn screening (NBS) which was generalized in our country in 2002, a history of CF in siblings, or the investigation of clinical signs compatible with CF. Laboratory pieces of evidence of CF transmembrane conductance regulator (CFTR) dysfunction are also necessary to confirm the diagnosis of CF. NBS allows the detection of new patients before the onset of symptoms and has induced major changes in the diagnosis of CF [13]. Indeed, in France in 2012, more than 97 % of the newborns participated in the CF NBS and 66 % of the new diagnosis of CF was made this way [3]. However, the sensitivity of NBS is not absolute. For instance, the rate of false-negative results during the 2002– 3
Service de pédiatrie et CRCM pédiatrique, Hôpitaux pédiatriques de Nice CHU-Lenval, 06200 Nice, France
4
Service de pédiatrie, CHU Caen, 14033 Caen, France
5
Service de pédiatrie et pneumologie, Hôpital d’Enfants Armand-Trousseau, AP-HP, 75571 Paris, France
6
Département de pédiatrie médicale, CHU Hôpitaux de Rouen, 76031 Rouen, France
7
Service de pneumologie et allergologie pédiatriques, Hôpital Necker Enfants Malades, AP-HP, 75015 Paris, France
8
Département de pédiatrie—Centre mucoviscidose, CHU de Grenoble, Hôpital Albert Michallon, 38043 Grenoble, France
9
CRCM mixte, CHU Estaing, 63003 Clermont-Ferrand, France
10
Département de pneumologie pédiatrique, Hôpital Femme Mère Enfant, CHU de Lyon, 69500 Bron, France
11
Département de pédiatrie, Centre Hospitalier Intercommunal de Créteil, 94010 Créteil, France
12
Service de médecine infantile, Hôpital d’enfants de Nancy, Rue du Morvan, 54511 Vandoeuvre-Les-Nancy, France
13
Service de pneumologie pédiatrique, Pôle enfant Hôpital Jeanne de Flandre, CHRU de Lille, 59037 Lille, France
14
Service de pneumologie pédiatrique et CRCM, CNRS-URMITE 6236, CHU Timone, 264 rue St Pierre, 13005 Marseille, France
2006 period was 3.7 % [25]. Thus, whatever the clinical situation is, the sweat test (ST) remains the gold standard for the diagnosis of CF [26]. It is still recommended in every patient with symptoms suggestive of CF, regardless of the NBS results. The suggestive symptoms concern sinopulmonary, gastrointestinal, nutritional, metabolic, or genital troubles [10], and 21.8 % of the new CF diagnosis was made because of clinical symptoms in France in 2012. Respiratory symptoms concerned 68 % of these patients and are the second most frequent circumstance of CF diagnosis after CF NBS [3]. Most of the patients who had a diagnosis of CF based on clinical signs were adults or children who had not had the CF NBS, with a median age of 17 years. However, STs are also performed in children presenting respiratory symptoms who had a negative NBS. In order to characterize our habits and improve our prescription efficiency, we led a retrospective national multicenter study to describe the current indications of ST prescription and to evaluate their interest in children with negative CF NBS but referred to pediatricians specialized in respiratory diseases and working in university hospitals.
Patients and methods This retrospective, descriptive, and multicenter study took place in 13 French university hospitals located in Caen, Clermont-Ferrand, Créteil, Grenoble, Lille, Lyon, Marseille, Nancy, Nice, Paris (Necker Enfants Malades and Trousseau hospitals), Rouen, and Toulouse. This corresponded to 13 of the 16 French university hospitals with a specialized medical team in pediatric respiratory diseases, which agreed to participate to this study. The patients were identified from the ST laboratories of each hospital. We included children born in France after 1 January 2003, who had an a priori negative NBS, for whom a pediatric pulmonologist prescribed an ST between 1 January and 31 December 2012, for respiratory symptoms. These children could be inpatients or outpatients. Patients were not included if they were born out of France or before 1 January 2003 or did not have the NBS, if the test was made to confirm a positive CF screening or because of a meconium ileus or a diagnosis of CF in the siblings, if the test was not asked by a hospital pediatric pulmonologist or if its result was unknown. We collected the demographical characteristics of the children (age and gender), the medical position of the prescriber, and the respiratory signs which had led to the prescription: asthma (severity and treatment), bronchiectasis (confirmed by chest imaging), chronic cough (dry or productive), atypical infections of the lower airway (recurrent, persistent, or due to specific germs), chronic rhinosinusitis, nasal polyps, and digestive symptoms if associated (failure to thrive or chronic diarrhea). Persistent chest X-ray abnormalities (atelectasis or
Filter paper Macroduct Exsupatch® Macroduct coil+ +Schales +Exsudose® coil+Sweat coulometric and Check® titration Schales Exsupatch® Exsupatch® Nanoduct® Exsupatch® Filter paper Exsupatch® Exsupatch® Macroduct Method of collection Filter paper+ +Exsudose® +Exsudose® +Exsudose® +Schales +Exsudose® +Exsudose® coil+ Schales and and chloride and or Macroduct coulometric Schales dosage Schales +Sweat Check® titration
Total
502 28 (1–118) 538 4 19.5 (5–104) 5
M L
8 11.5 (6–78) 8 13 45 (9–104) 14
K J
26 24 31.5 (5–108) 32 (5–8) 29 24
I H
30 24 (1–107) 30 33 31 (4–96) 48
G F
33 38 (4–118) 36 41 26 (2–109) 46
E D
44 19 (4–110) 44 55 28 (1–114) 58
C B
74 29 (1–89) 75
A
We included 538 STs, performed in 502 children born after 1 January 2003 and prescribed for respiratory symptoms, despite a negative NBS (Table 1). These STs prescribed by respiratory pediatricians represented 15 to 25 % of all the STs performed in 2012 in each hospital. The other STs were performed in newborns with a positive NBS or in children born before 2003 or abroad and who had not had the NBS, or children visiting other pediatricians specialized in ENT, digestive, or other diseases, or STs that were performed, for about a
118 31 (1–105) 121
Descriptive analysis
Patients Age in months Number of ST
Results
Hospital
infiltrates) were classified as persistent respiratory infections. The presence of other symptoms or particular circumstances was noted if they influenced the prescription. We also collected the number of STs per patient, the methods of sweat chloride dosage, the ST results, the genetic analysis results if it was done, and the final diagnosis (no CF, classic CF, or atypical CF) [8]. The interpretation of the ST results was based on the current data and recommendations for sweat chloride reference values [2, 10, 13, 16, 24]. For patients over 6 months, the reference ranges are as follows: ≤39 mmol/L, negative ST and CF unlikely; 40–59 mmol/L, intermediate ST with the need for a new control; ≥60 mmol/L, positive ST, indicative of CF if another ST found an abnormal result. For infants up to 6 months, the normal values range up to 29 mmol/L instead of 39 mmol/L. We used the French and British recommendations for the interpretation of ST when using this indirect dosage of sweat chloride with conductivity [2, 24]: normal values 90 mmol/L (NaCl equivalent). When several sweat samples were collected on the same day with the same method, we considered that only one ST was performed [10, 16]. The CF diagnosis was made according to the current European definition [8, 13]: Classic CF included children with one or more phenotypic characteristics and a positive ST; atypical CF concerned children with a CF phenotype in at least one organ system and a normal or borderline ST, associated with one mutation on each CFTR gene, or an abnormal nasal potential difference measurement. Data were anonymously collected in a Microsoft Excel file. Results were expressed in percentage or average/median with extreme values. Quantitative data were compared with chi2 of Pearson and Fischer tests. To analyze the weight of one specific clinical sign for asking for an ST, a univariate and a multivariate analysis using a logistic regression process was made. A p value of less than 0.05 was considered as statistically significant.
Table 1 General data concerning 502 French children with negative newborn screening for cystic fibrosis but explored with one or more sweat tests (STs) for respiratory symptoms in 2012 in 13 university hospitals
Eur J Pediatr
Eur J Pediatr
half, in adults. The number of STs included per hospital ranged from 5 to 121. The mean age of the children was 36 ±28 months (median 28 months, ranging from 1 month to 10 years old). There were 282 boys (56.2 %, sex ratio= 1.28), with no difference in the distribution of age or gender between the different hospitals. Most of the children (94 %) had only one ST, 27 children (5.4 %) had two STs, and 3 children had three or more STs. Four methods of sweat collection and sweat chloride dosage were used (Table 1): Whatman® filter paper collection and manual titration using the Schales and Schales mercuric nitrate procedure in three hospitals, direct application of a selective chloride electrode on the skin (Exsudose®) in six hospitals, coulometric titration after collecting the sweat with a Macroduct® coil in two hospitals, and conductivity using Sweat Check Macroduct® Wescor or Nanoduct® Wescor in three hospitals. Four hospitals (30 %) collected two sweat samples per child on the same day.
Table 2 Clinical indications of a sweat test in 502 French children, with negative newborn screening for cystic fibrosis, and explored for respiratory symptoms in 2012 in 13 university hospitals
Table 2 shows the indications of the STs, the three more frequent being asthma (358 patients, 71.3 %), chronic cough (263 patients, 52.4 %) which was usually productive, and atypical lower airway infections (212 patients, 42.2 %). These symptoms were associated to other respiratory signs in most patents. For 20 children, ST was prescribed because of the pathogen found: Haemophilus influenzae, n=9; Pseudomonas aeruginosa, n=6; Staphylococcus aureus, n=3; Pneumocystis jiroveci, n=1; Cytomegalovirus, n=1. The first ST was normal 487 times (97 %), borderline 12 times (2.4 %), and positive 3 times (0.6 %). It was controlled for 30 patients (including the 15 ones with an abnormal first ST), and the second result was normal in 20 cases, borderline in 6 cases, and positive in 4 cases. Because of borderline results, two patients had three STs and one had five STs, the final results being all normal. Sixteen children (3.2 %) had a genetic analysis for the CF mutations, related to a positive or borderline ST for 12 of
Symptoms
Number of children (% of total)
CF diagnosisa (%)b
Asthma Severe/moderate asthma
358 (71.3) 182 (36.3)
1 (0.3) 0
Asthma isolated or associated with dry cough Chronic cough Productive or mixed cough Cough with no other symptom Lower airway infections Recurrent infections or radiological abnormalities Infections with particular pathogen Severe infections Bronchiectasis Other respiratory symptoms Chronic respiratory insufficiency Acute respiratory failure or unexplained dyspnea Pulmonary hypoplasia or atelectasis Nasal polyposis Chronic rhinosinusitis Digestive troubles associated to respiratory signs Failure to thrive Chronic diarrhea/constipation/rectal prolapsus Both Particular circumstances Familial case of CF or heterozygous relative Parental anxiety about CF Other abnormal ST out of the university hospital Acute dehydration episodes Chronic ear suppuration with P. aeruginosa
113 (22.5) 263 (52.4) 180 (35.8) 29 (5.8) 212 (42.2) 201 (40.0) 20 (4.0) 16 (3.2) 35 (7.0) 12 (2.4) 5 (1.0) 6 (1.2) 1 (0.2) 7 (1.4) 7 (1.4) 109 (21.7 91 (18.1) 9 (1.8) 9 (1.8) 20 (4.0) 9 (1.8) 5 (1.0) 3 (0.6) 2 (0.4) 2 (0.4)
0 4 (1.5)
a b
Total CF diagnosis n=4 Proportion among the children presenting this symptom
*pG
No mutation found (INNOLIPA KITa +total PCR sequencingb)
Double heterozygote: G551D+TG11T5
Genetic analysis
Positive: IRT=30 ng/mL +1 mutation found: G542X Negative neonatal ST:28 mmol/L
False negative: IRT
ORIGINAL ARTICLE
Sweat test practice in pediatric pulmonology after introduction of cystic fibrosis newborn screening Céline Grimaldi 1 & François Brémont 2 & Michèle Berlioz-Baudoin 3 & Jacques Brouard 4 & Harriet Corvol 5 & Laure Couderc 6 & Guillaume Lezmi 7 & Isabelle Pin 8 & Isabelle Petit 9 & Philippe Reix 10 & Natacha Remus 11 & Cyril Schweitzer 12 & Caroline Thumerelle 13 & Jean-Christophe Dubus 14
Received: 22 February 2015 / Revised: 2 June 2015 / Accepted: 8 June 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract The influence of the generalization of cystic fibrosis newborn screening (CFNBS) in France on sweat test (ST) prescription is unknown. In this French retrospective, descriptive, and multicenter study, we studied the indications, number, methods, and results of STs prescribed by a pediatric pulmonologist in children who had a negative CFNBS and an ST for respiratory symptoms in 2012. We included 502 children with 523 STs, performed with four different methods. The main indication was asthma (71.3 %), then chronic cough (52.4 %), atypical lower airway infections (42.2 %), and bronchiectasis (7 %). Four children had a diagnosis of CF (0.8 %), all presenting with chronic productive cough and recurrent respiratory infections. Conclusion: Asthma is the most frequent indication of ST in our cohort. Because of the systematic CFNBS in France, some prescriptions should be avoided, particularly in case of
severe or moderate asthma with no other associated symptom. Moreover, methods of STs often do not follow the guidelines and need standardization. What is Known: • Newborn screening (NBS) has become the most frequent circumstance of the diagnosis of cystic fibrosis (CF) in France after its generalization. • The prescription of sweat test (ST) in children with respiratory symptoms who already had a negative NBS has not been studied. What is New: • In children with a negative CF NBS referred to a university hospital for respiratory diseases, despite important variations of ST methods, only 4 children among 502 have been diagnosed as CF. • Despite recommendations, ST prescription should be avoided in children with moderate to severe asthma and no other associated symptom.
Communicated by Peter de Winter * Céline Grimaldi [email protected]
Isabelle Petit [email protected]
François Brémont [email protected]
Philippe Reix [email protected]
Michèle Berlioz-Baudoin [email protected]
Natacha Remus [email protected]
Jacques Brouard [email protected]
Cyril Schweitzer [email protected]
Harriet Corvol [email protected]
Caroline Thumerelle [email protected]
Laure Couderc [email protected]
Jean-Christophe Dubus [email protected]
Guillaume Lezmi [email protected]
1
Service de pneumologie pédiatrique et CRCM, CHU Timone, 264 rue St Pierre, 13005 Marseille, France
Isabelle Pin [email protected]
2
Département de pédiatrie, Hôpital des enfants, 31026 Toulouse, France
Eur J Pediatr
Keywords Pediatric pulmonology . Sweat test . Prescription . Respiratory symptoms Abbreviations CF Cystic fibrosis NBS Newborn screening ST Sweat test
Introduction Cystic fibrosis (CF) is the most frequent and severe genetic disease among European and North American populations, with an incidence of 1/4136 newborns in France [19]. Among its many consequences, respiratory disease is the major cause of morbidity and mortality [14, 21]. Nowadays, the diagnosis of CF is established in three clinical circumstances [11, 23]: the newborn screening (NBS) which was generalized in our country in 2002, a history of CF in siblings, or the investigation of clinical signs compatible with CF. Laboratory pieces of evidence of CF transmembrane conductance regulator (CFTR) dysfunction are also necessary to confirm the diagnosis of CF. NBS allows the detection of new patients before the onset of symptoms and has induced major changes in the diagnosis of CF [13]. Indeed, in France in 2012, more than 97 % of the newborns participated in the CF NBS and 66 % of the new diagnosis of CF was made this way [3]. However, the sensitivity of NBS is not absolute. For instance, the rate of false-negative results during the 2002– 3
Service de pédiatrie et CRCM pédiatrique, Hôpitaux pédiatriques de Nice CHU-Lenval, 06200 Nice, France
4
Service de pédiatrie, CHU Caen, 14033 Caen, France
5
Service de pédiatrie et pneumologie, Hôpital d’Enfants Armand-Trousseau, AP-HP, 75571 Paris, France
6
Département de pédiatrie médicale, CHU Hôpitaux de Rouen, 76031 Rouen, France
7
Service de pneumologie et allergologie pédiatriques, Hôpital Necker Enfants Malades, AP-HP, 75015 Paris, France
8
Département de pédiatrie—Centre mucoviscidose, CHU de Grenoble, Hôpital Albert Michallon, 38043 Grenoble, France
9
CRCM mixte, CHU Estaing, 63003 Clermont-Ferrand, France
10
Département de pneumologie pédiatrique, Hôpital Femme Mère Enfant, CHU de Lyon, 69500 Bron, France
11
Département de pédiatrie, Centre Hospitalier Intercommunal de Créteil, 94010 Créteil, France
12
Service de médecine infantile, Hôpital d’enfants de Nancy, Rue du Morvan, 54511 Vandoeuvre-Les-Nancy, France
13
Service de pneumologie pédiatrique, Pôle enfant Hôpital Jeanne de Flandre, CHRU de Lille, 59037 Lille, France
14
Service de pneumologie pédiatrique et CRCM, CNRS-URMITE 6236, CHU Timone, 264 rue St Pierre, 13005 Marseille, France
2006 period was 3.7 % [25]. Thus, whatever the clinical situation is, the sweat test (ST) remains the gold standard for the diagnosis of CF [26]. It is still recommended in every patient with symptoms suggestive of CF, regardless of the NBS results. The suggestive symptoms concern sinopulmonary, gastrointestinal, nutritional, metabolic, or genital troubles [10], and 21.8 % of the new CF diagnosis was made because of clinical symptoms in France in 2012. Respiratory symptoms concerned 68 % of these patients and are the second most frequent circumstance of CF diagnosis after CF NBS [3]. Most of the patients who had a diagnosis of CF based on clinical signs were adults or children who had not had the CF NBS, with a median age of 17 years. However, STs are also performed in children presenting respiratory symptoms who had a negative NBS. In order to characterize our habits and improve our prescription efficiency, we led a retrospective national multicenter study to describe the current indications of ST prescription and to evaluate their interest in children with negative CF NBS but referred to pediatricians specialized in respiratory diseases and working in university hospitals.
Patients and methods This retrospective, descriptive, and multicenter study took place in 13 French university hospitals located in Caen, Clermont-Ferrand, Créteil, Grenoble, Lille, Lyon, Marseille, Nancy, Nice, Paris (Necker Enfants Malades and Trousseau hospitals), Rouen, and Toulouse. This corresponded to 13 of the 16 French university hospitals with a specialized medical team in pediatric respiratory diseases, which agreed to participate to this study. The patients were identified from the ST laboratories of each hospital. We included children born in France after 1 January 2003, who had an a priori negative NBS, for whom a pediatric pulmonologist prescribed an ST between 1 January and 31 December 2012, for respiratory symptoms. These children could be inpatients or outpatients. Patients were not included if they were born out of France or before 1 January 2003 or did not have the NBS, if the test was made to confirm a positive CF screening or because of a meconium ileus or a diagnosis of CF in the siblings, if the test was not asked by a hospital pediatric pulmonologist or if its result was unknown. We collected the demographical characteristics of the children (age and gender), the medical position of the prescriber, and the respiratory signs which had led to the prescription: asthma (severity and treatment), bronchiectasis (confirmed by chest imaging), chronic cough (dry or productive), atypical infections of the lower airway (recurrent, persistent, or due to specific germs), chronic rhinosinusitis, nasal polyps, and digestive symptoms if associated (failure to thrive or chronic diarrhea). Persistent chest X-ray abnormalities (atelectasis or
Filter paper Macroduct Exsupatch® Macroduct coil+ +Schales +Exsudose® coil+Sweat coulometric and Check® titration Schales Exsupatch® Exsupatch® Nanoduct® Exsupatch® Filter paper Exsupatch® Exsupatch® Macroduct Method of collection Filter paper+ +Exsudose® +Exsudose® +Exsudose® +Schales +Exsudose® +Exsudose® coil+ Schales and and chloride and or Macroduct coulometric Schales dosage Schales +Sweat Check® titration
Total
502 28 (1–118) 538 4 19.5 (5–104) 5
M L
8 11.5 (6–78) 8 13 45 (9–104) 14
K J
26 24 31.5 (5–108) 32 (5–8) 29 24
I H
30 24 (1–107) 30 33 31 (4–96) 48
G F
33 38 (4–118) 36 41 26 (2–109) 46
E D
44 19 (4–110) 44 55 28 (1–114) 58
C B
74 29 (1–89) 75
A
We included 538 STs, performed in 502 children born after 1 January 2003 and prescribed for respiratory symptoms, despite a negative NBS (Table 1). These STs prescribed by respiratory pediatricians represented 15 to 25 % of all the STs performed in 2012 in each hospital. The other STs were performed in newborns with a positive NBS or in children born before 2003 or abroad and who had not had the NBS, or children visiting other pediatricians specialized in ENT, digestive, or other diseases, or STs that were performed, for about a
118 31 (1–105) 121
Descriptive analysis
Patients Age in months Number of ST
Results
Hospital
infiltrates) were classified as persistent respiratory infections. The presence of other symptoms or particular circumstances was noted if they influenced the prescription. We also collected the number of STs per patient, the methods of sweat chloride dosage, the ST results, the genetic analysis results if it was done, and the final diagnosis (no CF, classic CF, or atypical CF) [8]. The interpretation of the ST results was based on the current data and recommendations for sweat chloride reference values [2, 10, 13, 16, 24]. For patients over 6 months, the reference ranges are as follows: ≤39 mmol/L, negative ST and CF unlikely; 40–59 mmol/L, intermediate ST with the need for a new control; ≥60 mmol/L, positive ST, indicative of CF if another ST found an abnormal result. For infants up to 6 months, the normal values range up to 29 mmol/L instead of 39 mmol/L. We used the French and British recommendations for the interpretation of ST when using this indirect dosage of sweat chloride with conductivity [2, 24]: normal values 90 mmol/L (NaCl equivalent). When several sweat samples were collected on the same day with the same method, we considered that only one ST was performed [10, 16]. The CF diagnosis was made according to the current European definition [8, 13]: Classic CF included children with one or more phenotypic characteristics and a positive ST; atypical CF concerned children with a CF phenotype in at least one organ system and a normal or borderline ST, associated with one mutation on each CFTR gene, or an abnormal nasal potential difference measurement. Data were anonymously collected in a Microsoft Excel file. Results were expressed in percentage or average/median with extreme values. Quantitative data were compared with chi2 of Pearson and Fischer tests. To analyze the weight of one specific clinical sign for asking for an ST, a univariate and a multivariate analysis using a logistic regression process was made. A p value of less than 0.05 was considered as statistically significant.
Table 1 General data concerning 502 French children with negative newborn screening for cystic fibrosis but explored with one or more sweat tests (STs) for respiratory symptoms in 2012 in 13 university hospitals
Eur J Pediatr
Eur J Pediatr
half, in adults. The number of STs included per hospital ranged from 5 to 121. The mean age of the children was 36 ±28 months (median 28 months, ranging from 1 month to 10 years old). There were 282 boys (56.2 %, sex ratio= 1.28), with no difference in the distribution of age or gender between the different hospitals. Most of the children (94 %) had only one ST, 27 children (5.4 %) had two STs, and 3 children had three or more STs. Four methods of sweat collection and sweat chloride dosage were used (Table 1): Whatman® filter paper collection and manual titration using the Schales and Schales mercuric nitrate procedure in three hospitals, direct application of a selective chloride electrode on the skin (Exsudose®) in six hospitals, coulometric titration after collecting the sweat with a Macroduct® coil in two hospitals, and conductivity using Sweat Check Macroduct® Wescor or Nanoduct® Wescor in three hospitals. Four hospitals (30 %) collected two sweat samples per child on the same day.
Table 2 Clinical indications of a sweat test in 502 French children, with negative newborn screening for cystic fibrosis, and explored for respiratory symptoms in 2012 in 13 university hospitals
Table 2 shows the indications of the STs, the three more frequent being asthma (358 patients, 71.3 %), chronic cough (263 patients, 52.4 %) which was usually productive, and atypical lower airway infections (212 patients, 42.2 %). These symptoms were associated to other respiratory signs in most patents. For 20 children, ST was prescribed because of the pathogen found: Haemophilus influenzae, n=9; Pseudomonas aeruginosa, n=6; Staphylococcus aureus, n=3; Pneumocystis jiroveci, n=1; Cytomegalovirus, n=1. The first ST was normal 487 times (97 %), borderline 12 times (2.4 %), and positive 3 times (0.6 %). It was controlled for 30 patients (including the 15 ones with an abnormal first ST), and the second result was normal in 20 cases, borderline in 6 cases, and positive in 4 cases. Because of borderline results, two patients had three STs and one had five STs, the final results being all normal. Sixteen children (3.2 %) had a genetic analysis for the CF mutations, related to a positive or borderline ST for 12 of
Symptoms
Number of children (% of total)
CF diagnosisa (%)b
Asthma Severe/moderate asthma
358 (71.3) 182 (36.3)
1 (0.3) 0
Asthma isolated or associated with dry cough Chronic cough Productive or mixed cough Cough with no other symptom Lower airway infections Recurrent infections or radiological abnormalities Infections with particular pathogen Severe infections Bronchiectasis Other respiratory symptoms Chronic respiratory insufficiency Acute respiratory failure or unexplained dyspnea Pulmonary hypoplasia or atelectasis Nasal polyposis Chronic rhinosinusitis Digestive troubles associated to respiratory signs Failure to thrive Chronic diarrhea/constipation/rectal prolapsus Both Particular circumstances Familial case of CF or heterozygous relative Parental anxiety about CF Other abnormal ST out of the university hospital Acute dehydration episodes Chronic ear suppuration with P. aeruginosa
113 (22.5) 263 (52.4) 180 (35.8) 29 (5.8) 212 (42.2) 201 (40.0) 20 (4.0) 16 (3.2) 35 (7.0) 12 (2.4) 5 (1.0) 6 (1.2) 1 (0.2) 7 (1.4) 7 (1.4) 109 (21.7 91 (18.1) 9 (1.8) 9 (1.8) 20 (4.0) 9 (1.8) 5 (1.0) 3 (0.6) 2 (0.4) 2 (0.4)
0 4 (1.5)
a b
Total CF diagnosis n=4 Proportion among the children presenting this symptom
*pG
No mutation found (INNOLIPA KITa +total PCR sequencingb)
Double heterozygote: G551D+TG11T5
Genetic analysis
Positive: IRT=30 ng/mL +1 mutation found: G542X Negative neonatal ST:28 mmol/L
False negative: IRT
