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Systematic review on fecal calprotectin in cystic fibrosis

Abstract

Objectives:

Fecal calprotectin is an inflammatory marker used for monitoring intestinal diseases. It has been studied as a marker of intestinal inflammation in cystic fibrosis (CF), a multi-systemic genetic disease caused by alterations to the CFTR gene. Manifestations of the disease favor a systemic inflammation not limited to the respiratory tract, therefore, calprotectin is a non-invasive and effective diagnostic method. The aim of the study was to perform a systematic review of the literature with a qualitative synthesis of studies.

Sources:

The articles were selected from PubMed, Web of Science, Scielo and Lilacs.

Summary of the findings:

Nine studies were selected for that qualitative synthesis, one was a randomized clinical trial, and eight were case-control or cohort designs. Most studies have indicated that calprotectin is a marker of systemic inflammation in CF and not just intestinal inflammation. Calprotectin is an aid in monitoring inflammatory bowel conditions in patients with cystic fibrosis.

Conclusion:

Further studies should be conducted to investigate the role of this marker in the systemic inflammation of CF.

KEYWORDS
Cystic fibrosis; Systematic review; Inflammation; Biomarkers; Calprotectin

Introduction

Fecal calprotectin is an inflammatory marker used to monitor patients with intestinal diseases.11 Nikniaz Z, Nikniaz L, Bilan N, Somi MH, Faramarzi E. Does probiotic supplementation affect pulmonary exacerbation and intestinal inflammation in cystic fibrosis: a systematic review of randomized clinical trials. World J Pediatr. 2017;13:307–13.,22 Lee JM, Leach ST, Katz T, Day AS, Jaffe A, Ooi CY. Update of faecal markers of inflammation in children with cystic fibrosis. Mediators Inflamm. 2012;2012:948367. A calcium and zinc-binding protein, a heterodimer composed of the proteins S100A8 and S100A9, has also been referred to as calgranulin A/B, 14/MRP8 (myeloid-related protein), or cystic fibrosis (CF) antigen, or L1 protein33 Pathirana WG, Chubb SP, Gillett MJ, Vasikaran SD. Faecal calprotectin. Clin Biochem Rev. 2018;39:77–90.,44 Vaos G, Kostakis ID, Zavras N, Chatzemichael A. The role of calprotectin in pediatric disease. Biomed Res Int. 2013;2013:542363. and found in the cytoplasm of cells such as granulocytes and macrophages when activated.33 Pathirana WG, Chubb SP, Gillett MJ, Vasikaran SD. Faecal calprotectin. Clin Biochem Rev. 2018;39:77–90.,44 Vaos G, Kostakis ID, Zavras N, Chatzemichael A. The role of calprotectin in pediatric disease. Biomed Res Int. 2013;2013:542363.,55 Walsham NE, Sherwood RA. Fecal calprotectin in inflammatory bowel disease. Clin Exp Gastroenterol. 2016;9:21–9. Calprotectin has antibacterial activity, induces apoptosis and chemotaxis, and is secreted by epithelial cells after the detection of cytokines or bacterial products.44 Vaos G, Kostakis ID, Zavras N, Chatzemichael A. The role of calprotectin in pediatric disease. Biomed Res Int. 2013;2013:542363.,55 Walsham NE, Sherwood RA. Fecal calprotectin in inflammatory bowel disease. Clin Exp Gastroenterol. 2016;9:21–9. It is an important protein in the acute phase of inflammation.33 Pathirana WG, Chubb SP, Gillett MJ, Vasikaran SD. Faecal calprotectin. Clin Biochem Rev. 2018;39:77–90.,44 Vaos G, Kostakis ID, Zavras N, Chatzemichael A. The role of calprotectin in pediatric disease. Biomed Res Int. 2013;2013:542363.

Calprotectin is present in feces due to the migration of neutrophils to the intestinal cells when there is a pathogen present, causing inflammation. This molecule is resistant to intestinal proteases, as well as to pancreatic secretions that turn it stable in feces for up to one week, facilitating the transport of samples to the laboratory for analysis.33 Pathirana WG, Chubb SP, Gillett MJ, Vasikaran SD. Faecal calprotectin. Clin Biochem Rev. 2018;39:77–90.,44 Vaos G, Kostakis ID, Zavras N, Chatzemichael A. The role of calprotectin in pediatric disease. Biomed Res Int. 2013;2013:542363.,55 Walsham NE, Sherwood RA. Fecal calprotectin in inflammatory bowel disease. Clin Exp Gastroenterol. 2016;9:21–9.,66 Li F, Ma J, Geng S, Wang J, Liu J, Zhang J, Sheng X. Fecal calprotectin concentrations in healthy children aged 1-18 months. PLoS One. 2015;10:e0119574. It is widely used as a biomarker in inflammatory bowel diseases, such as Crohn's disease and irritable bowel syndrome. The main method of fecal calprotectin detection is by enzyme-linked immunosorbent assay (ELISA).33 Pathirana WG, Chubb SP, Gillett MJ, Vasikaran SD. Faecal calprotectin. Clin Biochem Rev. 2018;39:77–90. It has been studied as a diagnostic method of intestinal inflammation in CF.22 Lee JM, Leach ST, Katz T, Day AS, Jaffe A, Ooi CY. Update of faecal markers of inflammation in children with cystic fibrosis. Mediators Inflamm. 2012;2012:948367.,44 Vaos G, Kostakis ID, Zavras N, Chatzemichael A. The role of calprotectin in pediatric disease. Biomed Res Int. 2013;2013:542363.

CF is a multi-systemic disease caused by variants in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein, with clinical presentations that include increased secretion viscosity and subsequent epithelial obstruction of ducts.77 Firmida MC, Lopes AJ. Aspectos epidemiológicos da fibrose cística. Rev Hosp Univ Pedro Ernesto. 2011;10:12–22.,88 Ooi CY, Durie PR. Cystic fibrosis from the gastroenterologist’s perspective. Nat Rev Gastroenterol Hepatol. 2016;13:175–85. The pulmonary and gastrointestinal systems are usually affected, and intestinal inflammation requires further study and attention.77 Firmida MC, Lopes AJ. Aspectos epidemiológicos da fibrose cística. Rev Hosp Univ Pedro Ernesto. 2011;10:12–22.,88 Ooi CY, Durie PR. Cystic fibrosis from the gastroenterologist’s perspective. Nat Rev Gastroenterol Hepatol. 2016;13:175–85.,99 Garg M, Ooi CY. The enigmatic gut in cystic fibrosis: linking inflammation, dysbiosis, and the increased risk of malignancy. Curr Gastroenterol Rep. 2017;19:6.

The mechanisms of intestinal inflammation in CF are not fully understood. It is hypothesized that inflammation occurs as a primary consequence of a CFTR protein defect, which increases mucus viscosity, in addition to the acidic environment, a consequence of the insufficiency of pancreatic enzymes and mucin glycolysis.88 Ooi CY, Durie PR. Cystic fibrosis from the gastroenterologist’s perspective. Nat Rev Gastroenterol Hepatol. 2016;13:175–85.,99 Garg M, Ooi CY. The enigmatic gut in cystic fibrosis: linking inflammation, dysbiosis, and the increased risk of malignancy. Curr Gastroenterol Rep. 2017;19:6. Changes in the intestinal microbiota, the chronic use of antibiotics, and bacterial growth in the intestine are also probable causal factors.99 Garg M, Ooi CY. The enigmatic gut in cystic fibrosis: linking inflammation, dysbiosis, and the increased risk of malignancy. Curr Gastroenterol Rep. 2017;19:6.,1010 Mendes KG, Theodoro H, Rodrigues AD, Olinto MT. Prevalência de síndrome metabólica e seus componentes na transição menopáusica: uma revisão sistemática [Prevalence of metabolic syndrome and its components in the menopausal transition: a systematic review]. Cad Saude Publ. 2012;28:1423–37. Effective and non-invasive diagnostic methods improve assessment and to monitor intestinal inflammation in CF patients.

Objectives

This systematic review aimed to analyze the scientific evidence on fecal calprotectin in CF and its relevance to the disease.

Method

A systematic literature review is consisting of a search method divided into the steps of defining the question that (1) underpins the study, (2) defining a search strategy and databases used, (3) reviewing and selecting studies based on inclusion and exclusion criteria, and (4), evaluating the methodological quality of the studies.

After defining the guiding question, the search strategy consisted of using the following terms in English and Portuguese: “Leukocyte L1 Antigen Complex” OR Calprotectin OR “L1 Antigen” OR “L1 Protein, Leukocyte” OR Calgranulin AND “Cystic Fibrosis” OR Mucoviscidosis involving the platforms PubMed and Web of Science; and “Leukocyte L1 Antigen Complex” OR Calprotectin OR “L1 Antigen” OR “L1 Protein, Leukocyte” OR “Leukocyte L1 Protein” OR “Complexo Antígeno L1 Leucocitário” OR Calgranulin AND “Cystic Fibrosis” OR “Fibrose Cística” OR Mucoviscidose OR Mucoviscidosis OR “Fibrosis, Cystic” involving the platforms Scielo and Lilacs. The strategy was structured from the population, intervention, comparison, and outcome (PICO) method. A manual search of the bibliographic references contained in the articles was also performed to retrieve all existing information.

The inclusion criteria were:

  • Search in the period of the last ten years;

  • CF patients of different ages;

  • Use of fecal calprotectin as a marker of intestinal inflammation;

  • Texts in English and Portuguese;

  • Randomized clinical trials, cohort, and case-control studies.

The exclusion criteria were:

  • Use of calprotectin under other conditions;

  • CF citations in other contexts;

  • Study designs different from those of interest.

Next, the articles were sent to the Mendeley bibliographic reference manager, and duplicates were removed. Then titles and abstracts were analyzed to verify if they met the inclusion and exclusion criteria. Subsequently, the full article was read.

A form verified the population, type of intervention, if any, comparison group, and outcomes in the selected articles.

The quality of evidence represents the reliability of the effects presented in the studies. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) tool was used to check quality and risk of bias using 22 criteria. The method by Mendes et al.1010 Mendes KG, Theodoro H, Rodrigues AD, Olinto MT. Prevalência de síndrome metabólica e seus componentes na transição menopáusica: uma revisão sistemática [Prevalence of metabolic syndrome and its components in the menopausal transition: a systematic review]. Cad Saude Publ. 2012;28:1423–37. was used to score the articles, with each criterion being scored 0 and 1 for each article.

After evaluating all criteria, the scores were added. The articles studied received grades from 0 to 22 by each of two reviewers (EL, +), and the final grade was obtained through the mean. This score was analyzed as a percentage, and studies were considered good if the score was > 50%.

Results

According to the flowchart presented in Figure 1, the search in databases and other sources resulted in approximately 500 articles, of which 50 addressed the subject defined in the guiding question. After eliminating duplicates and reading the titles and abstracts, 30 articles were selected for a complete reading. Of the articles read, nine were selected for qualitative synthesis (Table 1).

Figure 1
Search strategy results flowchart.

Table 1
Scoring and quality analysis of articles selected for synthesis.

One of the studies included was a randomized, controlled, and double-blind clinical trial. The other articles were case-control and cohort studies (eight articles).

The largest number of patients evaluated was 171 in a study by Ellemunter et al.,1111 Ellemunter H, Engelhardt A, Schüller K, Steinkamp G. Fecal calprotectin in cystic fibrosis and its relation to disease parameters: a longitudinal analysis for 12 years. J Pediatr Gastroenterol Nutr. 2017;65:438–42. and the lowest was 14 patients in a study by Schnapp et al.1212 Schnapp Z, Hartman C, Livnat G, Shteinberg M, Elenberg Y Decreased fecal calprotectin levels in cystic fibrosis patients after antibiotic treatment for respiratory exacerbation. J Pediatr Gastroenterol Nutr. 2019;68:282–4. Predominantly, the studies presented sample collection and calprotectin measurement, except for a longitudinal study, in which 2,434 samples were collected and analyzed.1111 Ellemunter H, Engelhardt A, Schüller K, Steinkamp G. Fecal calprotectin in cystic fibrosis and its relation to disease parameters: a longitudinal analysis for 12 years. J Pediatr Gastroenterol Nutr. 2017;65:438–42.

As for the location of the studies, a large proportion was derived from Europe (n = 5), mainly from countries such as Poland, Italy, and France. The second most frequent location was the Middle East (n = 4), with three studies from Israel and one from Iran, in addition to countries such as Australia (one study). Some studies included pancreatic insufficiency as a factor in the likelihood of patients having higher levels of calprotectin and inflammation.

Data such as the use of enzyme replacement therapy (ERT), weight and height, body mass index (BMI), pulmonary symptoms, liver insufficiency, and history of meconium ileus were also included. Patients with different genetic variants were analyzed in some of the studies in order to examine fecal calprotectin levels with disease phenotypes.

Most of the articles analyzed the possibility of fecal calprotectin testing functioning as an effective marker of intestinal inflammation.

The objectives of the studies and their results were summarized and are shown in Table 2.1313 Lisowska A, Madry E, Pogorzelski A, Szydłowski J, Radzikowski A, Walkowiak J. Small intestine bacterial overgrowth does not correspond to intestinal inflammation in cystic fibrosis. Scand J Clin Lab Invest. 2010;70:322–6.,1414 Fallahi G, Motamed F, Yousefi A, Shafieyoun A, Najafi M, Khodadad A, et al. The effect of probiotics on fecal calprotectin in patients with cystic fibrosis. Turk J Pediatr. 2013;55:475–8.,1515 Rumman N, Sultan M, El-Chammas K, Goh V, Salzman N, Quintero D. Werlin S. Calprotectin in cystic fibrosis. BMC Pediatr. 2014;14:133.,1616 Adriaanse MP, van der Sande LJ, van den Neucker AM, Menheere PP, Dompeling E, Buurman WA, et al. Evidence for a cystic fibrosis enteropathy. PLoSOne. 2015;10:e0138062.,1717 Więcek S, Woś H, Kordys-Darmolińska B, Sankiewicz-Szkółka M, Grzybowska-Chlebowczyk U. The concentration of calprotectin in the stools of children with diagnosed cystic fibrosis. Prz Gastroenterol. 2017;12:38–43.,1818 Garg M, Leach ST, Coffey MJ, Katz T, Strachan R, Pang T, et al. Age-dependent variation of fecal calprotectin in cystic fibrosis and healthy children. J Cyst Fibros. 2017;16:631–6.,1919 Parisi GF, Papale M, Rotolo N, Aloisio D, Tardino L, Scuderi MG, et al. Severe disease in cystic fibrosis and fecal calprotectin levels. Immunobiology. 2017;222:582–6.

Table 2
Results of the analysis of selected articles.

CF was an inclusion criterion. CRP: C-reactive protein; CF: cystic fibrosis; DBPC: double-blind placebo-controlled; FEV1: Forced expiratory volume in the first second; FOS: fructooligosaccharides; I-FAPB: intestinal fatty acid-binding protein; CFRD: cystic fibrosis-related diabetes; PI: pancreatic insufficiency; PS: pancreatic sufficiency; SIBO: small intestinal bacterial overgrowth; BT: breath testing with methane and hydrogen.; BMI: body mass index.

Discussion

This review evaluated the use of fecal calprotectin dosage as a marker of inflammation in CF, especially in intestinal inflammation. It evaluated the effectiveness of the marker and possible limitations of its clinical usefulness.

The fecal calprotectin test as a marker of intestinal inflammation is recognized in patients with gastrointestinal diseases in general and has become increasingly evident in CF subjects.2020 Chaabouni T, Manceau H, Peoc’h K. Interest of fecal calprotectine dosage in inflammatory bowel diseases, state of the art and perspectives. Ann Biol Clin (Paris). 2016;74:385–94.,2121 Grad C, David L, Portincasa P, Dumitraşcu DL. Diagnostic value of calprotectin in irritable bowel syndrome and in inflammatory bowel disease. Rom J Intern Med. 2012;50:3–6.

The determination of fecal calprotectin assists in differentiating between active and inactive inflammatory bowel diseases and between inflammatory bowel diseases and irritable bowel syndrome.2222 Kotze LM, Nisihara RM, Marion SB, Cavassani MF, Kotze PG. Fecal calprotectin: levels for the ethiological diagnosis in Brazilian patients with gastrointestinal symptoms. Arq Gastroenterol. 2015;52:50–4. However, the number of studies that demonstrated effectiveness for CF is low, and there are questions regarding their clinical relevance. Quantity and quality information on this topic is restricted. Some studies had a low number of patients, while others demonstrated analysis time as a limitation. The main issue observed in this review was that further studies are needed to specifically assess the use of this marker in CF.

More than one study indicated fecal calprotectin as a marker of systemic inflammation, and not just of intestinal inflammation since they showed variations in the presence of signs such as pulmonary exacerbation and use of antibiotics.1212 Schnapp Z, Hartman C, Livnat G, Shteinberg M, Elenberg Y Decreased fecal calprotectin levels in cystic fibrosis patients after antibiotic treatment for respiratory exacerbation. J Pediatr Gastroenterol Nutr. 2019;68:282–4. Another point to be considered is the association of intestinal inflammation with pancreatic function in CF.2323 Anthony H, Collins CE, Davidson G, Mews C, Robinson P, Shepherd R, et al. Pancreatic enzyme replacement therapy in cystic fibrosis: Australian guidelines. Pediatric Gastroenterological Society and the Dietitians Association of Australia. J Paediatr Child Health. 1999;35:125–9.

Several studies report an association of pancreatic insufficiency with intestinal inflammation using the pancreatic elastase marker as a parameter. However, others dispute this observation, as the fecal calprotectin dosage was similar in the two groups in some studies. According to the Australian guidelines for the use of pancreatic enzyme replacement therapy in CF, intestinal inflammation exists because pancreatic insufficiency can increase intestinal permeability. The difficulty in the secretion of enzymes into the duodenum influences the extent of inflammation detected by pancreatic elastase.2323 Anthony H, Collins CE, Davidson G, Mews C, Robinson P, Shepherd R, et al. Pancreatic enzyme replacement therapy in cystic fibrosis: Australian guidelines. Pediatric Gastroenterological Society and the Dietitians Association of Australia. J Paediatr Child Health. 1999;35:125–9.

A possible explanation for the similar results involving sufficient and insufficient pancreatic groups in the studies would be the use of Pancreatic Enzyme Replacement Therapy (PERT) in insufficient patients, impacting the analysis of fecal calprotectin. The enzymes used in therapy improve symptoms related to the pancreas and may consequently affect the intestinal system.2323 Anthony H, Collins CE, Davidson G, Mews C, Robinson P, Shepherd R, et al. Pancreatic enzyme replacement therapy in cystic fibrosis: Australian guidelines. Pediatric Gastroenterological Society and the Dietitians Association of Australia. J Paediatr Child Health. 1999;35:125–9.

It is speculated whether intestinal inflammation could be linked to the respiratory system or if it is a local disorder, still poorly understood, as an association between fecal calprotectin levels and lung disease occurs in some cases. Serum and sputum calprotectin are elevated in pulmonary exacerbation.2424 Ratjen F, Saiman L, Mayer-Hamblett N, Lands LC, Kloster M, Thompson V, et al. Effect of azithromycin on systemic markers of inflammation in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa. Chest. 2012;142:1259–66.,2525 Gray RD, Imrie M, Boyd AC, Porteous D, Innes JA, Greening AP. Sputum and serum calprotectin are useful biomarkers during CF exacerbation. J Cyst Fibros. 2010;9:193–8. Gray et al. have demonstrated that treatment of an exacerbation with antibiotic therapy in CF results in decreasing levels of sputum and serum calprotectin. Thus, the change in sputum calprotectin following antibiotic therapy implies a direct association of calprotectin with a changing state of airways inflammation. The assessment of the possible role of calprotectin as a pro-inflammatory molecule in the lung requires further work.2525 Gray RD, Imrie M, Boyd AC, Porteous D, Innes JA, Greening AP. Sputum and serum calprotectin are useful biomarkers during CF exacerbation. J Cyst Fibros. 2010;9:193–8.

The onset of respiratory infections in patients and colonization by microorganisms can also induce increased fecal calprotectin since it interacts with inflammation levels, and, therefore, marker levels are likely to be increased in CF-related to lung disease. High levels of fecal calprotectin were found in some other gastrointestinal tract disorders, infectious gastroenteritis diverticular disease, microscopic colitis, cystic fibrosis, and patients treated with non-steroidal anti-inflammatory drugs or proton pump inhibitors.66 Li F, Ma J, Geng S, Wang J, Liu J, Zhang J, Sheng X. Fecal calprotectin concentrations in healthy children aged 1-18 months. PLoS One. 2015;10:e0119574.,2626 Manceau H, Chicha-Cattoir V, Puy H, Peoc’h K. Fecal calprotectin in inflammatory bowel diseases: update and perspectives. Clin Chem Lab Med. 2017;55:474–83.

Essentially, this information only guarantees that there is an intestinal presentation of the disease but not a relationship with the pancreatic condition. Some authors suggest that the two factors are independent. Until recently, the diagnosis of inflammatory bowel diseases was mainly based on both clinical and endoscopic arguments. Fecal calprotectin is the most documented method in this situation because it is an easy, fast, reliable, non-invasive, and inexpensive biological assay not only in diagnosis but also in progress and therapeutic monitoring. This marker allows the discrimination between functional and organic bowel processes with good performance.2626 Manceau H, Chicha-Cattoir V, Puy H, Peoc’h K. Fecal calprotectin in inflammatory bowel diseases: update and perspectives. Clin Chem Lab Med. 2017;55:474–83.

The use of antibiotics was addressed in a few studies. Schnapp et al., demonstrated that fecal calprotectin levels decreased with antibiotic treatment of acute pulmonary exacerbations. The treatment of one system can affect the other, acting on both lung and intestinal microbiota, thus reducing intestinal inflammation.1212 Schnapp Z, Hartman C, Livnat G, Shteinberg M, Elenberg Y Decreased fecal calprotectin levels in cystic fibrosis patients after antibiotic treatment for respiratory exacerbation. J Pediatr Gastroenterol Nutr. 2019;68:282–4.

CF pulmonary exacerbation may represent part of a systemic inflammatory exacerbation that includes the GI tract, even with no GI complaints, possibly representing “silent” GI inflammation. Antibiotic treatment may alter the microbiome in both organs reducing the inflammatory burden.

The use of antibiotics impacts the microbial population present in the body, causing changes due to their frequent use.2525 Gray RD, Imrie M, Boyd AC, Porteous D, Innes JA, Greening AP. Sputum and serum calprotectin are useful biomarkers during CF exacerbation. J Cyst Fibros. 2010;9:193–8.,2727 De Lisle RC, Borowitz D. The cystic fibrosis intestine. Cold Spring Harb PerspectMed. 2013;3:a009753.

Changing the intestinal microbiota positively impacts some patients, modifying the inflammation in response to the presence of opportunistic microorganisms.2828 de Freitas MB, Moreira EA, Tomio C, Moreno YM, Daltoe FP, Barbosa E, et al. Altered intestinal microbiota composition, antibiotic therapy and intestinal inflammation in children and adolescents with cystic fibrosis. PLoSOne. 2018;13:e0198457.,2929 Ooi CY, Syed SA, Rossi L, Garg M, Needham B, Avolio J, et al. Impact of CFTR modulation with Ivacaftor on Gut Microbiota and Intestinal Inflammation. Sci Rep. 2018;8:17834. The microbiota of CF patients has been shown to change from birth. Therefore, this aspect must be considered since the microbiome composition can lead to intestinal dysbiosis and imbalance in the microbiota responsible for reducing nutrient absorption capacity.2929 Ooi CY, Syed SA, Rossi L, Garg M, Needham B, Avolio J, et al. Impact of CFTR modulation with Ivacaftor on Gut Microbiota and Intestinal Inflammation. Sci Rep. 2018;8:17834.,3030 Enaud R, Hooks KB, Barre A, Barnetche T, Hubert C, Massot M, et al. Intestinal inflammation in children with cystic fibrosis is associated with Crohn’s-like microbiota disturbances. J Clin Med. 2019;8:645.

The structure of intestinal microbiota of CF patients is probably shaped by the microecological effects resulting from these alterations in gut functions and also by the increased local concentrations of antimicrobials, either secreted by bile or accessing the intestinal tract after inhalation.3131 del Campo R, Garriga M, Pérez-Aragón A, Guallarte P, Lamas A, Máiz L, et al. Improvement of digestive health and reduction in proteobacterial populations in the gut microbiota of cystic fibrosis patients using a Lactobacillus reuteri probiotic preparation: a double blind prospective study. J Cyst Fibros. 2014;13:716–22.

A double-blind prospective study reported the positive impact of probiotics on intestinal microbiota since there may also be changes in the organism microbiota, helping the growth of beneficial microorganisms and balancing intestinal microbiota after treatment with probiotics.3333 Koninckx CR, Donat E, Benninga MA, Broekaert IJ, Gottrand F, Kolho KL, et al. The use of fecal calprotectin testing in paediatric disorders: a position paper of the European Society for Paediatric Gastroenterology and Nutrition Gastroenterology Committee. J Pediatr Gastroenterol Nutr. 2021;72:617–40.

The studies report the possibility of interference in cases in which patients swallow sputum, which contains a certain amount of calprotectin. However, the amount swallowed does not seem to affect fecal calprotectin, as it is partially degraded in the intestinal transit.1313 Lisowska A, Madry E, Pogorzelski A, Szydłowski J, Radzikowski A, Walkowiak J. Small intestine bacterial overgrowth does not correspond to intestinal inflammation in cystic fibrosis. Scand J Clin Lab Invest. 2010;70:322–6. Lisowska et al. compared marker levels in sputum and feces samples, reporting that, despite the high levels, there was little interference by sputum in feces samples.1313 Lisowska A, Madry E, Pogorzelski A, Szydłowski J, Radzikowski A, Walkowiak J. Small intestine bacterial overgrowth does not correspond to intestinal inflammation in cystic fibrosis. Scand J Clin Lab Invest. 2010;70:322–6.

The inflammatory condition in CF becomes an impacting factor in defining the functionality of the fecal calprotectin marker since it appears, in many cases, to be changed in inflammatory conditions resulting from the disease.3232 Downey DG, Martin SL, Dempster M, Moore JE, Keogan MT, Starcher B, et al. The relationship of clinical and inflammatory markers to outcome in stable patients with cystic fibrosis. Pediatr Pulmonol. 2007;42:216–20.

Despite the outcomes found and studies showing the need for larger numbers of patients and longer analysis time, fecal calprotectin seems to be a useful marker of intestinal inflammation in CF, although some studies reported it as a marker of systemic inflammation.3333 Koninckx CR, Donat E, Benninga MA, Broekaert IJ, Gottrand F, Kolho KL, et al. The use of fecal calprotectin testing in paediatric disorders: a position paper of the European Society for Paediatric Gastroenterology and Nutrition Gastroenterology Committee. J Pediatr Gastroenterol Nutr. 2021;72:617–40.

Conclusion

In summary, this systematic review showed that serial fecal calprotectin measurements could aid in following-up on inflammatory bowel conditions in CF patients.

In-depth studies with appropriate methods should be conducted aiming at understanding the role of this marker in CF and to determine its potential as a marker of systemic inflammation.

Acknowledgments

The authors are grateful to the Postgraduate Program in Internal Medicine and Health Sciences for providing the facilities for the conduction of the experiments and data analysis and Editage for the translation and editing services.

References

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    Nikniaz Z, Nikniaz L, Bilan N, Somi MH, Faramarzi E. Does probiotic supplementation affect pulmonary exacerbation and intestinal inflammation in cystic fibrosis: a systematic review of randomized clinical trials. World J Pediatr. 2017;13:307–13.
  • 2
    Lee JM, Leach ST, Katz T, Day AS, Jaffe A, Ooi CY. Update of faecal markers of inflammation in children with cystic fibrosis. Mediators Inflamm. 2012;2012:948367.
  • 3
    Pathirana WG, Chubb SP, Gillett MJ, Vasikaran SD. Faecal calprotectin. Clin Biochem Rev. 2018;39:77–90.
  • 4
    Vaos G, Kostakis ID, Zavras N, Chatzemichael A. The role of calprotectin in pediatric disease. Biomed Res Int. 2013;2013:542363.
  • 5
    Walsham NE, Sherwood RA. Fecal calprotectin in inflammatory bowel disease. Clin Exp Gastroenterol. 2016;9:21–9.
  • 6
    Li F, Ma J, Geng S, Wang J, Liu J, Zhang J, Sheng X. Fecal calprotectin concentrations in healthy children aged 1-18 months. PLoS One. 2015;10:e0119574.
  • 7
    Firmida MC, Lopes AJ. Aspectos epidemiológicos da fibrose cística. Rev Hosp Univ Pedro Ernesto. 2011;10:12–22.
  • 8
    Ooi CY, Durie PR. Cystic fibrosis from the gastroenterologist’s perspective. Nat Rev Gastroenterol Hepatol. 2016;13:175–85.
  • 9
    Garg M, Ooi CY. The enigmatic gut in cystic fibrosis: linking inflammation, dysbiosis, and the increased risk of malignancy. Curr Gastroenterol Rep. 2017;19:6.
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    Mendes KG, Theodoro H, Rodrigues AD, Olinto MT. Prevalência de síndrome metabólica e seus componentes na transição menopáusica: uma revisão sistemática [Prevalence of metabolic syndrome and its components in the menopausal transition: a systematic review]. Cad Saude Publ. 2012;28:1423–37.
  • 11
    Ellemunter H, Engelhardt A, Schüller K, Steinkamp G. Fecal calprotectin in cystic fibrosis and its relation to disease parameters: a longitudinal analysis for 12 years. J Pediatr Gastroenterol Nutr. 2017;65:438–42.
  • 12
    Schnapp Z, Hartman C, Livnat G, Shteinberg M, Elenberg Y Decreased fecal calprotectin levels in cystic fibrosis patients after antibiotic treatment for respiratory exacerbation. J Pediatr Gastroenterol Nutr. 2019;68:282–4.
  • 13
    Lisowska A, Madry E, Pogorzelski A, Szydłowski J, Radzikowski A, Walkowiak J. Small intestine bacterial overgrowth does not correspond to intestinal inflammation in cystic fibrosis. Scand J Clin Lab Invest. 2010;70:322–6.
  • 14
    Fallahi G, Motamed F, Yousefi A, Shafieyoun A, Najafi M, Khodadad A, et al. The effect of probiotics on fecal calprotectin in patients with cystic fibrosis. Turk J Pediatr. 2013;55:475–8.
  • 15
    Rumman N, Sultan M, El-Chammas K, Goh V, Salzman N, Quintero D. Werlin S. Calprotectin in cystic fibrosis. BMC Pediatr. 2014;14:133.
  • 16
    Adriaanse MP, van der Sande LJ, van den Neucker AM, Menheere PP, Dompeling E, Buurman WA, et al. Evidence for a cystic fibrosis enteropathy. PLoSOne. 2015;10:e0138062.
  • 17
    Więcek S, Woś H, Kordys-Darmolińska B, Sankiewicz-Szkółka M, Grzybowska-Chlebowczyk U. The concentration of calprotectin in the stools of children with diagnosed cystic fibrosis. Prz Gastroenterol. 2017;12:38–43.
  • 18
    Garg M, Leach ST, Coffey MJ, Katz T, Strachan R, Pang T, et al. Age-dependent variation of fecal calprotectin in cystic fibrosis and healthy children. J Cyst Fibros. 2017;16:631–6.
  • 19
    Parisi GF, Papale M, Rotolo N, Aloisio D, Tardino L, Scuderi MG, et al. Severe disease in cystic fibrosis and fecal calprotectin levels. Immunobiology. 2017;222:582–6.
  • 20
    Chaabouni T, Manceau H, Peoc’h K. Interest of fecal calprotectine dosage in inflammatory bowel diseases, state of the art and perspectives. Ann Biol Clin (Paris). 2016;74:385–94.
  • 21
    Grad C, David L, Portincasa P, Dumitraşcu DL. Diagnostic value of calprotectin in irritable bowel syndrome and in inflammatory bowel disease. Rom J Intern Med. 2012;50:3–6.
  • 22
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Publication Dates

  • Publication in this collection
    13 Feb 2023
  • Date of issue
    Jan-Feb 2023

History

  • Received
    02 Sept 2021
  • Accepted
    03 Jan 2022
  • Published
    03 May 2022
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