Calprotectin is a 36.5-kDa long calcium- and zinc-binding protein consisting of heterodimers of the S100A8 (MRP-8) and S100A9 (MRP-14) subunits.15–17 It is commonly found in neutrophilic granulocytes and may be elevated in inflammatory conditions. In particular, FC remains stable in feces for more than 1 week, and thus, it is a useful marker for intestinal inflammatory reactions. FC test is widely used to diagnose the activity of inflammatory bowel disease, and nowadays, it is gradually being used to diagnose infectious gastroenteritis, necrotizing enteritis, and other intestinal diseases.18–22
FC was used to investigate the association between HSP GI involvement and other clinical symptoms of HSP and to determine the prognosis and progression of the disease. Other prospective studies have explored the association between FC and HSP.13, 23 Because these studies were prospective in nature, they were able to determine the changes in FC levels caused by improvements in HSP symptoms; contrastingly, because our study had a retrospective design, we could not determine such changes. Our study, however, may have had an advantage in objective identification of disease prognosis or progression because the medical records of our patients were retrospectively reviewed. Moreover, because our study group comprised only HSP patients and not healthy controls, identifying the prognosis of GI involvement or recurrence in HSP patients proved to be advantageous. Our results revealed that FC levels were significantly correlated with GI involvement, GI symptom duration, fasting state/steroid treatment durations, and GI involvement site. FC results also showed a positive correlation with HSP clinical score, including the GI severity score. However, there was no correlation between joint or kidney involvement scores and FC levels, and unlike previous studies, there was no correlation between FC levels and inflammatory markers such as white blood cell count, absolute neutrophil count, and C-reactive protein or kidney involvement itself.13, 23 This can be attributed to the difference between the investigation groups. Because not all HSP patients, but only FC-tested patients, were included in the study, many other patients need to be investigated, including all HSP patients with a simple rash.
FC test has low specificity but high sensitivity for the early detection of intestinal inflammation.8 Owing to the nature of FC testing, we expected that FC testing might facilitate the prediction of GI involvement site or GI symptoms in patients who did not initially have GI symptoms. Mostly, HSP patients with GI involvement showed invasion in the upper parts of the GI tract including the duodenum. However, compared with the patients who experienced invasion limited to the upper parts of the GI tract, patients who experienced invasion to the lower parts of the GI tract, including the colon, showed a significantly high FC level (214.7 ± 150.5 vs. 581.8 ± 510.1 mg/kg; P = 0.008). Contrastingly, there was no significant difference in the clinical manifestations and prognosis between patients with positive FC results (> 50 mg/kg) and those with negative FC results (< 50 mg/kg). In our study, the cut-off FC level for GI involvement was 69.10 mg/kg, which was much lower than the value reported by Teng et al., i.e., 264.5 mg/kg. 23 This result was similar to the cut-off level for lower GI involvement reported in our study, i.e., 277.5 mg/kg, and it is evident that this is an interesting finding as opposed to the previous study. Therefore, if FC levels are elevated in HSP patients with GI symptoms, it is necessary to more carefully check the possibility of lower GI complications such as intussusception. Moreover, there was no correlation between HSP relapse and GI symptom recurrence. We expected that elevated FC levels would be a predictor of future GI symptoms in patients with only simple purpura, but no correlation was found.
Kanik et al. previously reported that FC levels were also associated with renal involvement.13 Hence, we identified the association of FC with kidney or joint involvements, which are other major symptoms of HSP. However, no significant associations were confirmed in our results. Moreover, these manifestations showed no correlation with severity of GI symptoms. Because FC is a marker for intestinal inflammation, it is believed that it has no correlation in cases where only kidney or joint involvement alone occurs while GI involvement is lacking. Furthermore, in another study by Teng et al., only the association of FC with GI involvement had been reported.23
In a study conducted by Hong et al.,14 various inflammatory markers, including FDP and D-dimer, showed correlations with GI involvement in HSP, but in our study, only FDP and D-dimer levels were higher when GI involvement occurred. It was also difficult to find relevance to FC levels and other symptoms. SOB and FC levels seemed to be the most meaningful laboratory results that showed highest correlation with GI symptoms.
Although we proved that FC is related to the characteristics and prognosis of GI involvement in HSP patients, our study had some limitations. First, the GI involvement group was retrospectively classified based on clinical symptoms, physical examinations, and imaging test results. Although patients who had abdominal pain likely caused by factors other than HSP were excluded from the study group, there still remains a possibility that these patients were included. However, of the 40 patients with abdominal pain, only one patient did not undergo ultrasonography, CT, or endoscopy. Contrastingly, no imaging tests were conducted when GI symptoms were absent; therefore, some patients with GI involvement might have been classified into the non-GI involvement group. It is especially likely that patients with high FC levels were classified into the non-GI involvement group. Second, FC was prescribed at the time of admission, but there were cases in which FC was prescribed only 2–3 days later. Furthermore, FC levels were tested only in inpatients and not in outpatients with only simple purpura or mild symptoms. However, this does not change our results because all such cases are expected to have a lower FC level than that noted for our study group, and if these limitations were not present, our results would be more strongly supported. Finally, in our results, of the 23 relapsed patients, GI symptoms relapsed in 19 patients. However, because many patients with simple purpura alone are likely to not visit the hospital, symptoms such as simple rash are expected to be reported more frequently than GI symptoms among all HSP patients.
Despite these limitations, FC testing is useful for predicting GI involvement, the involvement site, and the course of prognosis in pediatric HSP patients. Better results can be expected if a larger number of patients are investigated, including those with simple skin rashes alone.