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Diagnosis

Sad IR, Higa LY, Leal T, Martins Rda S, de Almeida AC, Ramos EG, de Cabello GM, Peixoto MV.

J Clin Med Res. 2016 Jan;8(1):15-24. doi: 10.14740/jocmr2312w. Epub 2015 Dec 3.
 

Abstract

BACKGROUND
The genetic diversity of the Brazilian population results from three ethnic groups admixture: Europeans, Africans and Amerindians, thus increasing the difficulty of performing cystic fibrosis (CF) diagnosis. The nasal potential difference (NPD) evaluates thecystic fibrosis transmembrane conductance regulator (CFTR) and epithelial sodium channel (ENaC) activity. Despite being a useful CF diagnostic test and a biomarker of CFTR-modulator drugs, it is also highly operator dependent. Therefore, it may be difficult to get accurate results and to interpret them. Wilschanski and Sermet scores were proposed to address these issues. This study aimed to evaluate repeatability and diagnostic value of NPD parameters and Wilschanski and Sermet scores in a CF center in Rio de Janeiro.

METHODS
NPD was performed in 78 subjects. Maximal PD, amiloride response, total chloride response, and Wilschanski and Sermet scores were explored as means (confidence interval, CI). One-way ANOVA was used to compare mean differences and Scheffe test was used to pair-wise comparisons. Repeatability was evaluated by scatter and Bland-Altman plots. The Ethics Committee of the CF Center has approved the study protocol. Parents and adult participants signed an informed consent form.

RESULTS
Forty-eight healthy-volunteers, 19 non-CF and 11 CF patients were enrolled in this study. Significant differences were found when comparing CF patients’ NPD parameters to the other two groups (P = 0.000). Moreover, no significant differences were found when parameters from non-CF patients were compared with those from healthy volunteers (P > 0.05). The means of NPD parameters and diagnostic scores of each group were in concordance with disease/non-disease conditions. The repeatability data – Wilschanski and Sermet and NPD – allow NPD to be performed in this Brazilian CF Center.

CONCLUSIONS
The present study gathered consistent data for Bland-Altman plots. The results of Wilschanski and Sermet diagnostic scores suggest that they were concordant with CF/non-CF conditions. More NPD tests should be performed in the Rio de Janeiro CF dynamic cohort to contribute to international NPD validation studies and to provide NPD as a biomarker in Brazil.

Keywords: Cystic fibrosis; Diagnostic test; Nasal potential difference; Repeatability; Sermet score; Wilschanski index.

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Domingos MT, Magdalena NI, Cat MN, Watanabe AM, Rosário Filho NA.

J Pediatr (Rio J). 2015 Nov-Dec;91(6):590-5. doi: 10.1016/j.jped.2015.03.003. Epub 2015 Jun 16.

Abstract

OBJECTIVE
To compare the results obtained with the sweat test using the conductivity method and coulometric measurement of sweat chloride in newborns (NBs) with suspected cystic fibrosis (CF) in the neonatal screening program.

METHODS
The sweat test was performed simultaneously by both methods in children with and without CF. The cutoff values to confirm CF were >50 mmol/L in the conductivity and >60 mmol/L in the coulometric test.

RESULTS
There were 444 infants without CF (185 males, 234 females, and 24 unreported) submitted to the sweat test through conductivity and coulometric measurement simultaneously, obtaining median results of 32 mmol/L and 12 mmol/L, respectively. For 90 infants with CF, the median values of conductivity and coulometric measurement were 108 mmol/L and 97 mmol/L, respectively. The false positive rate for conductivity was 16.7%, and was higher than 50 mmol/L in all patients with CF, which gives this method a sensitivity of 100% (95% CI: 93.8-97.8), specificity of 96.2% (95% CI: 93.8-97.8), positive predictive value of 83.3% (95% CI: 74.4-91.1), negative predictive value of 100% (95% CI: 90.5-109.4), and 9.8% accuracy. The correlation between the methods was r=0.97 (p>0.001). The best suggested cutoff value was 69.0 mmol/L, with a kappa coefficient=0.89.

CONCLUSION
The conductivity test showed excellent correlation with the quantitative coulometric test, high sensitivity and specificity, and can be used in the diagnosis of CF in children detected through newborn screening.

Copyright © 2015 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Keywords: Conductivity; Condutividade; Coulometric measurement; Cystic fibrosis; Dosagem coulométrica; Fibrose cística; Neonatal screening; Pilocarpina; Pilocarpine; Sweat test; Teste do suor; Triagem neonatal.

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Gomez CC, Servidoni Mde F, Marson FA, Canavezi PJ, Vinagre AM, Costa ET, Ribeiro AF, Ribeiro MA, Toro AA, Pavan CR, Rondon MV, Lorena SL,Vieria FU Jr, Ribeiro JD.

BMC Pulm Med. 2014 Dec 13;14:198. doi: 10.1186/1471-2466-14-198.
 

Abstract

BACKGROUND
The classic sweat test (CST) is the golden standard for cystic fibrosis (CF) diagnosis. Then, our aim was compare the production and volume of sweat, and side effects caused by pulsed direct current (PDC) and constant direct current (CDC). To determine the optimal stimulation time (ST) for the sweat collection. To verify the PDC as CF diagnosis option.

METHODS
Prospective study with cross-sectional experimental intervention. Experiment 1 (right arm): PDC and CDC. ST at 10 min and sweat collected at 30 min. Currents of 0.5; 0.75; 1.0 and 1.5 mA and frequencies of 0, 200, 1,000 and 5,000 Hz applied. Experiment 2 (left arm): current of 1.0 mA, ST at 5 and 10 min and sweat collected at 15 and 30 min with frequencies of 0; 200; 1,000 and 5,000 Hz applied Experiments 1 and 2 were performed with current density (CD) from 0.07 to 0.21 mA/cm2. Experiment 3: PDC was used in typical CF patients with two CFTR mutations screened and or with CF diagnosis by rectal biopsy and patients with atypical CF.

RESULTS
48 subjects (79.16% female) with average of 29.54 ± 8.87 years old were enrolled. There was no statistical difference between the interaction of frequency and current in the sweat weight (p = 0.7488). Individually, positive association was achieved between weight sweat and stimulation frequency (p = 0.0088); and current (p = 0.0025). The sweat production was higher for 10 min of stimulation (p = 0.0023). The sweat collection was better for 30 min (p = 0.0019). The skin impedance was not influenced by ST and sweat collection (p > 0.05). The current frequency was inversely associated with the skin impedance (p < 0.0001). The skin temperature measured before stimulation was higher than after (p < 0.0001). In Experiment 3 (29 subjects) the PDC showed better kappa index compared to CDC (0.9218 versus 0.5205, respectively).

CONCLUSIONS
The performance of the CST with CDC and PDC with CD of 0.14 to 0.21 mA/cm2 showed efficacy in steps of stimulation and collection of sweat, without side effects. The optimal stimulation time and sweat collection were, respectively, 10 and 30 min.

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Mattar AC, Leone C, Rodrigues JC, Adde FV.

J Cyst Fibros. 2014 Sep;13(5):528-33. doi: 10.1016/j.jcf.2014.01.002. Epub 2014 Jan 31.

Abstract

BACKGROUND
Sweat chloride test is the gold standard test for cystic fibrosis (CF) diagnosis. Sweat conductivity is widely used although still considered a screening test.

METHODS
This was a prospective, cross-sectional, diagnostic research conducted at the laboratory of the Instituto da Criança of the Hospital das Clínicas, São Paulo, Brazil. Sweat chloride (quantitative pilocarpine iontophoresis) and sweat conductivity tests were simultaneously performed in patients referred for a sweat test between March 2007 and October 2008. Conductivity and chloride cut-off values used to rule out or diagnose CF were <75 and ≥90 mmol/L and <60 and ≥60 mmol/L, respectively. The ROC curve method was used to calculate the sensitivity, specificity, positive (PPV) and negative predictive value (NPV), as well as the respective 95% confidence intervals and to calculate the area under the curve for both tests. The kappa coefficient was used to evaluate agreement between the tests.

RESULTS
Both tests were performed in 738 children, and CF was ruled out in 714 subjects; the median sweat chloride and conductivity values were 11 and 25 mmol/L in these populations, respectively. Twenty-four patients who had received a diagnosis of CF presented mediansweat chloride and conductivity values of 87 and 103 mmol/L, respectively. Conductivity values above 90 mmol/L had 83.3% sensitivity, 99.7% specificity, 90.9% PPV and 99.4% NPV to diagnose CF. The best conductivity cut-off value to exclude CF was <75 mmol/L. Good agreement was observed between the tests (kappa: 0.934).

CONCLUSIONS
The sweat conductivity test yielded a high degree of diagnostic accuracy and it showed good agreement with sweat chloride. We suggest that it should play a role as a diagnostic test for CF in the near future.

Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Keywords: Conductivity; Cystic fibrosis; Pilocarpine; Sweat test.

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Servidoni MF, Sousa M, Vinagre AM, Cardoso SR, Ribeiro MA, Meirelles LR, de Carvalho RB, Kunzelmann K, Ribeiro AF, Ribeiro JD, Amaral MD.

BMC Gastroenterol. 2013 May 20;13:91. doi: 10.1186/1471-230X-13-91.
 

Abstract

BACKGROUND
Measurements of CFTR function in rectal biopsies ex vivo have been used for diagnosis and prognosis of Cystic Fibrosis(CF) disease. Here, we aimed to evaluate this procedure regarding: i) viability of the rectal specimens obtained by biopsy forceps for ex vivo bioelectrical and biochemical laboratory analyses; and ii) overall assessment (comfort, invasiveness, pain, sedation requirement, etc.) of the rectal forceps biopsy procedure from the patients perspective to assess its feasibility as an outcome measure in clinical trials.

METHODS
We compared three bowel preparation solutions (NaCl 0.9%, glycerol 12%, mannitol), and two biopsy forceps (standard and jumbo) in 580 rectal specimens from 132 individuals (CF and non-CF). Assessment of the overall rectal biopsy procedure (obtained by biopsy forceps) by patients was carried out by telephone surveys to 75 individuals who underwent the sigmoidoscopy procedure.

RESULTS
Integrity and friability of the tissue specimens correlate with their transepithelial resistance (r = -0.438 and -0.305, respectively) and are influenced by the bowel preparation solution and biopsy forceps used, being NaCl and jumbo forceps the most compatible methods with the electrophysiological analysis. The great majority of the individuals (76%) did not report major discomfort due to the short procedure time (max 15 min) and considered it relatively painless (79%). Importantly, most (88%) accept repeating it at least for one more time and 53% for more than 4 times.

CONCLUSIONS
Obtaining rectal biopsies with a flexible endoscope and jumbo forceps after bowel preparation with NaCl solution is a safe procedure that can be adopted for both adults and children of any age, yielding viable specimens for CFTR bioelectrical/biochemical analyses. The procedure is well tolerated by patients, demonstrating its feasibility as an outcome measure in clinical trials.

PMID: 23688510

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