Skin Exposure Contributes to Chemical-Induced Asthma: What is the Evidence? A Systematic Review of Animal Models

It is generally assumed that allergic asthma originates primarily through sensitization via the respiratory mucosa, but emerging clinical observations and experimental studies indicate that skin exposure to low molecular weight (LMW) agents, i.e. "chemicals," may lead to systemic sensitization and subsequently develop asthma when the chemical is inhaled. This review aims to evaluate the accumulating experimental evidence that adverse respiratory responses can be elicited upon inhalation of an LMW chemical sensitizer after previous sensitization by dermal exposure. We systematically searched the PubMed and Embase databases up to April 15, 2017, and conducted forward and backward reference tracking. Animal studies involving both skin and airway exposure to LMW agents were included. We extracted 6 indicators of "selective airway hyper-responsiveness" (SAHR)-i.e. respiratory responses that only occurred in previously sensitized animals-and synthesized the evidence level for each indicator into strong, moderate or limited strength. The summarized evidence weight for each chemical agent was graded into high, middle, low or "not possible to assess." We identified 144 relevant animal studies. These studies involved 29 LMW agents, with 107 (74%) studies investigating the occurrence of SAHR. Indicators of SAHR included physiological, cytological/histological and immunological responses in bronchoalveolar lavage, lung tissue and airway-draining lymph nodes. Evidence for skin exposure-induced SAHR was present for 22 agents; for 7 agents the evidence for SAHR was inconclusive, but could not be excluded. The ability of a chemical to cause sensitization via skin exposure should be regarded as constituting a risk of adverse respiratory reactions.status: publishe

The Value of Ex Situ CT Imaging of Donor Lungs Prior to Transplantation.

PURPOSE: Donor shortage remains a major obstacle associated with considerable mortality in patients waiting for lung transplantation (LTx). Objective donor lung assessment is crucial to obtain sufficient grafts of acceptable quality. We hypothesized that out of body chest CT may be an innovative way to assess grafts prior to LTx. Therefore, this study prospectively investigated the value of CT scan of donor lungs prior to LTx. METHODS: Between 12/2016 and 01/2018, all potential donor lungs were inspected in-situ, recovered and ex situ CT scanned during standard cold preservation. The transplant team and radiologist were blinded for the CT scan, which thus did not change the decision to transplant. CTs were scored for CT abnormalities and were compared between transplanted (Tx) and non-Tx grafts. In addition, CT of Tx grafts were compared between recipients developing PGD3 within 72 h ('PGD3') and recipients who did not ('No PGD3'). RESULTS: In total, 75 lungs were transplanted and 25 were not transplanted, of which 19 were declined for poor graft quality and 6 for extrapulmonary malignancies or logistics. CT abnormalities (CSL, GGO, EMPHY) differed between Tx and non-Tx grafts (Figure 1A). In lungs declined for poor graft quality (n=19), the reason for decline was confirmed in 13 lungs, however 4 lungs had only limited CT abnormalities present. In 2 out of 7 lungs declined at retrieval for clinical suspicion of emphysema, no emphysema was present on CT. In addition, CT abnormalities (CSL, RET/IST) of Tx grafts also significantly differed between recipients with PGD 3 and without PGD 3 (Fig 1B). CONCLUSION: Ex situ CT imaging of donor grafts during preservation is feasible and demonstrated significant differences between Tx and non-Tx grafts. Also grafts of patients with or without PGD3 differed in CT parameters. CT imaging could not confirm the reason for decline in 6 lungs, which might indicate an undisclosed graft potential and a role of CT imaging in donor assessment. The prognostic value of CT parameters on long-term outcomes remains elusive.status: publishe

Intragraft donor-specific anti-HLA antibodies in phenotypes of chronic lung allograft dysfunction

INTRODUCTION: Circulating anti-human leukocyte antigen (HLA) serum donor-specific antibodies (sDSAs) increase the risk of chronic lung allograft dysfunction (CLAD) and mortality. Discrepancies between serological and pathological/clinical findings are common. Therefore, we aimed to assess the presence of tissue-bound graft DSAs (gDSAs) in CLAD explant tissue compared with sDSAs. METHODS: Tissue cores, obtained from explant lungs of unused donors (n=10) and patients with bronchiolitis obliterans syndrome (BOS; n=18) and restrictive allograft syndrome (RAS; n=18), were scanned with micro-computed tomography before elution of antibodies. Total IgG levels were measured via ELISA. Anti-HLA class I and II IgG gDSAs were identified using Luminex single antigen beads and compared with DSAs found in serum samples. RESULTS: Overall, mean fluorescence intensity was higher in RAS eluates compared with BOS and controls (p<0.0001). In BOS, two patients were sDSA+/gDSA+ and two patients were sDSA-/gDSA+. In RAS, four patients were sDSA+/gDSA+, one patient was sDSA+/gDSA- and five patients were sDSA-/gDSA+. Serum and graft results combined, DSAs were more prevalent in RAS compared with BOS (56% versus 22%; p=0.04). There was spatial variability in gDSA detection in one BOS patient and three RAS patients, who were all sDSA-. Total graft IgG levels were higher in RAS than BOS (p<0.0001) and in gDSA+versus gDSA- (p=0.0008), but not in sDSA+versus sDSA- (p=0.33). In RAS, total IgG levels correlated with fibrosis (r= -0.39; p=0.02). CONCLUSIONS: This study underlines the potential of gDSA assessment as complementary information to sDSA findings. The relevance and applications of gDSAs need further investigation.status: publishe