High alpha‐1 antitrypsin clearance predicts severity of gut graft‐versus‐host disease (GVHD) in children

Abstract

The clinical evaluation and management of gut GVHD is a significant challenge in pediatric HSCT. It is often difficult to obtain pathological evidence to confirm diagnosis and/or to determine response to treatment. The severity of the disease itself may not be related to just the classic symptom of diarrhea. The objectives of this study were to prospectively evaluate patients with suspected gut GVHD for PLE as measured by AATC in stools at two different times for each patient and to compare the severity of the PLE with the severity of clinical acute gut GVHD. Thirteen patients were suspected of gut GVHD by clinical criteria (diarrhea > 10 mL/kg/24 h); one patient was excluded for being unable to complete the stool collection. Therefore, 12 patients, 10 boys and two girls, were studied. Median stool volume was 27.5 mL/kg/day (range 10.1-109.0).The median age at BMT was 11.1 yr (range 3.9-17.0 yr). All patients had negative stool electron microscopy for viruses and cultures for C. difficile on their first collection. Nine patients (75%) had two 24-h stool collections performed at a median of eight days apart (range 7-14 days). At the time of the first collection, six patients had ≥ stage 2 acute gut GVHD, and at second collection, four patients had ≥ stage 2 gut GVHD and four collections were of non-diarrheal stool (hence treatment response). Median AATC from all 21 collections was 19.0 mL/day (range 3.0-561.0), and levels >22 mL/day indicate the diagnosis of PLE. The four children initially suspected of GVHD but who had a negative biopsy completed a total of five collections with a median AATC of 5.0 mL/day (range 3.0-16.0) vs. a median of 33.5 for the remainder of the collections (range 3-561). Stage of gut GVHD correlated with elevated AATC and with stool volume. AATC > 22 mL/day showed a sensitivity of 70% and specificity of 82% for significant gut GVHD (≥ stage 2). Seven stool collections were taken at ≥ stage 3 gut GVHD; six of those seven patients were positive for PLE. Larger stool volumes were more predictive, and five collections with stool volumes >30 mL/kg/day were positive for PLE. We conclude that a significant positive correlation exists between the severity of PLE and the stage of gut GVHD (p < 0.04), particularly obvious in patients with stages 2-4 GVHD (p = 0.03). Despite the small number of patients recruited, this study emphasizes the need to consider PLE as a useful aspect of the clinical picture. We suggest that in order to see a response to therapy and therefore a decrease in AATC, clinicians should wait at least 2 wk from the initiation of therapy before repeating AATC test. In light of the significant morbidity and mortality associated with ≥ stage 2 gut GVHD, and as an important therapeutic decision for these patients, one may consider evaluating AATC if a biopsy is not an option.

Fecal calprotectin and alpha-1 antitrypsin predict severity and response to corticosteroids in gastrointestinal graft-versus-host disease

“…Similar to the level of calprotectin, the concentration of ␣ 1 -AT was near normal in patients with initial stage 1 GI-GVHD and was more frequently elevated in patients with initial stage 2 or higher GI-GVHD, confirming the findings of Weisdorf et al 14 and Hagen et al 27 Interpretation of elastase levels should be moderated by its interaction with gut disease. Although fecal elastase is a marker of exocrine pancreatic dysfunction, pancreatic secretion is impaired not only in patients with primary pancreatic insufficiency but also in those with a decreased production of cholecystokinin (the predominant hormonal regulator of postprandial pancreatic enzyme secretion).…”

“…Several decades ago, Weisdorf et al reported increased fecal ␣ 1 -AT concentration in patients with GI-GVHD until symptoms disappeared, whereas patients without GI-GVHD had normal values, except during GI symptoms related to conditioning regimen toxicity. 2 These findings have recently been confirmed in 7 children with GI-GVHD by Hagen et al 14 Fecal elastase has a high sensitivity to diagnose exocrine pancreatic insufficiency. However, villous atrophy of any origin leading to a decrease in cholecystokinin secretion may lead to pancreatic dysfunction.…”

Expanding the Clinical Indications for α1-Antitrypsin Therapy

“…Several lines of evidence support this approach. Of particular interest, a recent report describes an elevated loss of AAT during intestinal GVHD as a measure of GVHD severity in children (106). In addition, evidence points to a significant involvement of IL-1 during the progression of GVHD, albeit mostly in advanced stages of the pathology (107); in 16 of 17 patients with steroid-resistant GVHD, a 7-d continuous intravenous infusion of recombinant IL-1 receptor antagonist reduced the severity of the disease (108).…”

Alpha1-antitrypsin, an endogenous immunoregulatory molecule: distinction between local and systemic effects on tumor immunology

“…Clinically relevant settings for harnessing its benefits include recent onset autoimmune diabetes [1], immunosuppression-resistant graft-versus-host disease (GvHD) [3,4], allograft transplant rejection [5], multiple sclerosis [6] and inflammatory bowel diseases [7]. At present, over half a dozen clinical trials evaluate the outcomes of infusing clinical-grade AAT to individuals with no genetic deficiency in AAT, in the context of modulating unwanted immune responses 1 .…”