Joshua L. Hermsen

Clostridium difficile Infection: A Surgical Disease in Evolution

IntroductionSeveral recent publications suggest an increase in the incidence of Clostridium difficile colitis. However, such studies commonly lack denominators over which to index this rise. There is also concern in the literature that disease virulence is increasing.MethodsBilling, admission, operative, and infection databases at a single tertiary care center identified patients admitted from 1990 to 2006 with a diagnosis of C. difficile infection. Grouped by era, case numbers were indexed against overall hospital, operative, and laboratory volumes. C. difficile colectomy cases were individually examined and analyzed.ResultsThe number of hospitalized patients diagnosed with C. difficile colitis increased in a linear fashion during the study period (1990, 14 cases; 2006, 927 cases). The colectomy per C. difficile case ratio did not change over the study period (era 1, 0.17%; era 2, 0.20%; era 3, 0.16%). Thirteen patients underwent colectomy with 54% surviving. The increase in patients admitted with a diagnosis of C. difficile was significantly associated with hospital volume (p = 0.04), operative volume (p < 0.001), and lab testing volume (p = 0.008).ConclusionThe number of C. difficile patients admitted to our hospital is rising at an alarming rate. This reflects national trends and urgent action seems warranted to prevent a C. difficile epidemic.

Phenotyping Clostridium septicum Infection: A Surgeon's Infectious Disease

BACKGROUND Clostridium septicum infection is associated with malignancy. Whether disease phenotype is affected by malignant status is not known. Surgical treatment is used frequently but its impact on survival has not been examined in a cohort >30 patients. METHODS A PubMed search of English language journal articles yielded 320 cases. Full information (infection location, cancer type, operative intervention, and survival) was available for 224 cases + 7 at our institution not previously reported. RESULTS Seventy-two percent of patients had malignancy or malady of the gastrointestinal (GI) or hematologic (HEME) organ systems. HEME survival was inferior to GI survival (35% versus 55%, P = 0.03). Overall, patients who underwent operation had improved survival (57% versus 26%; P < 0.0001) and this association was maintained within GI and HEME cohorts (P = 0.002 and 0.005, respectively). More GI than HEME patients underwent operation (81% versus 51%, P < 0.001). GI patients were more likely than HEME patients to experience infection of skin and soft tissues (SSTI, P = 0.006). Diabetics were more likely to experience SSTI than nondiabetics (77% versus 45%, P < 0.001). CONCLUSIONS C. septicum infectious phenotype varies with host milieu. The SSTI phenotype is more common in GI and diabetic patients. This recognition may aid in directing the search for occult malignancy, which must be performed given the >70% incidence of concomitant cancer. This infection is more fatal in HEME versus GI patients, perhaps due in part to less HEME group operative intervention. Primary surgical therapy should be considered in GI or HEME patients as operative intervention benefits both groups.

Scan, plan, print, practice, perform: Development and use of a patient-specific 3-dimensional printed model in adult cardiac surgery

Objective: Static 3‐dimensional printing is used for operative planning in cases that involve difficult anatomy. An interactive 3D print allowing deliberate surgical practice would represent an advance. Methods: Two patients with hypertrophic cardiomyopathy had 3‐dimensional prints constructed preoperatively. Stereolithography files were generated by segmentation of chest computed tomographic scans. Prints were made with hydrogel material, yielding tissue‐like models that can be surgically manipulated. Septal myectomy of the print was performed preoperatively in the simulation laboratory. Volumetric measures of print and patient resected specimens were compared. An assessment tool was developed and used to rate the utility of this process. Clinical and echocardiographic data were reviewed. Results: There was congruence between volumes of print and patient resection specimens (patient 1, 3.5 cm3 and 3.0 cm3, respectively; patient 2, 4.0 cm3 and 4.0 cm3, respectively). The prints were rated useful (3.5 and 3.6 on a 5‐point Likert scale) for preoperative visualization, planning, and practice. Intraoperative echocardiographic assessment showed adequate relief of left ventricular outflow tract obstruction (patient 1, 80 mm Hg to 18 mm Hg; patient 2, 96 mm Hg to 9 mm Hg). Both patients reported symptomatic improvement (New York Heart Association functional class III to class I). Conclusions: Three‐dimensional printing of interactive hypertrophic cardiomyopathy heart models allows for patient‐specific preoperative simulation. Resection volume relationships were congruous on both specimens and suggest evidence of construct validity. This model also holds educational promise for simulation of a low‐volume, high‐risk operation that is traditionally difficult to teach.

Intestinal polymeric immunoglobulin receptor is affected by type and route of nutrition.

BACKGROUND Secretory immunoglobulin A (SIgA) prevents adherence of pathogens at mucosal surfaces to prevent invasive infection. Polymeric immunoglobulin receptor (pIgR) is located on the basolateral surface of epithelial cells and binds dimeric immunoglobulin A (IgA) produced by plasma cells in the lamina propria. This IgA-pIgR complex is transported apically, where IgA is exocytosed as SIgA to the mucosal surface. Our prior work shows that mice fed intragastric (IG, an elemental diet model) and IV parenteral nutrition (PN) solution have reduced intestinal T and B cells, SIgA, and interleukin-4 (IL-4) compared with mice fed chow or a complex enteral diet (CED). Prior work also demonstrates a reduction in IgA transport to mucosal surfaces in IV PN-fed mice. Because IL-4 up-regulates pIgR production, this work studies the effects of these diets on intestinal pIgR. METHODS Male Institute of Cancer Research (ICR) mice were randomized to chow (n = 11) with IV catheter, CED (n = 10) or IG PN (n = 11) via gastrostomy and IV PN (n = 12) for 5 days. CED and PN were isocaloric and isonitrogenous. Small intestine was harvested for pIgR and IL-4 assays after mucosal washing for IgA. IgA and IL-4 levels were analyzed by enzyme-linked immunosorbent assay and pIgR by Western blot. RESULTS Small intestinal pIgR expression, IgA levels, and IL-4 levels decreased significantly in IV PN and IG PN groups. CONCLUSIONS Lack of enteral stimulation affects multiple mechanisms responsible for decreased intestinal SIgA levels, including reduced T and B cells in the lamina propria, reduced Th-2 IgA-stimulating cytokines, and impaired expression of the IgA transport protein, pIgR.

Parenteral nutrition induces organ specific alterations in polymeric immunoglobulin receptor levels

BACKGROUND Secretory immunoglobulin A (IgA) prevents pathogen adherence at mucosal surfaces to prevent infection. Polymeric immunoglobulin receptor (pIgR), located on the basolateral surface of mucosal cells, binds dimeric IgA produced by B cells with the cooperation of T cells in the lamina propria. This IgA-pIgR complex is transported apically, where it is exocytosed as secretory IgA to the mucosal surface. Our prior work shows that parenteral nutrition (PN) impairs both airway and small intestine mucosal immunity by reducing T and B cells and IgA levels. This work examines intestinal and respiratory tissue-specific pIgR responses to PN. METHODS Cannulated male Institute of Cancer Research mice were randomized to Chow (n = 10) or PN (n = 10). After 5 days, animals were sacrificed and lavages obtained from the small intestine, lung (BAL = bronchoalveolar lavage), and nasal airways (NAL). Small intestine, lung, and nasal passage tissues were also collected. Lavage and tissue homogenate IgA levels were quantified by enzyme-linked immunosorbent assay and pIgR by Western blot. RESULTS PN group SIL and NAL IgA levels dropped significantly compared with Chow. PN significantly reduced pIgR levels in the SI while no pIgR change was noted in nasal passages and lung pIgR actually increased with PN. Tissue homogenate IgA levels did not change with PN in the SI while levels in the nasal passage and lung decreased. CONCLUSIONS PN impairs airway mucosal immunity by reduction in IgA available for transport rather than via a reduction in pIgR levels. In the small intestine, diminished pIgR is implicated in the deterioration of antibody-mediated mucosal immunity.

Parenteral nutrition maintains pulmonary IgA antibody transport capacity, but not active transport, following injury.

BACKGROUND Parenteral nutrition (PN) increases post-trauma pneumonia versus enteral feeding. PN impairs murine immunoglobulin A (IgA) airway defenses and abrogates a normal IgA increase following injury. This work investigates the effect of type/route of nutrition on lung IgA and its transport protein, polymeric immunoglobulin receptor (pIgR), after injury. METHODS Catheterized mice were randomized to Chow or PN for 5 days and sacrificed without injury (Chow: n = 12; PN n = 11), or 8 hours after laparotomy + neck incisions (Chow-injury: n = 11, PN-injury: n = 13). Bronchoalveolar lavage (BAL) and lung IgA levels were analyzed by enzyme-linked immunosorbent assay (ELISA) and lung pIgR by Western blot. RESULTS BAL IgA levels increased in Chow-injury versus PN-injury (P <.01) with no differences in pIgR. PN-injury tissue IgA levels decreased versus Chow (P <.01), Chow-injury (P <.01), and PN (P <.05). CONCLUSIONS PN impairs the airway IgA response to injury but not due to impaired IgA transport capacity/pIgR level.

Food Fight!: Parenteral Nutrition, Enteral Stimulation and Gut-Derived Mucosal Immunity

IntroductionNutrition support is an integral component of modern patient care. Type and route of nutritional support impacts clinical infectious outcomes in critically injured patients.DiscussionThis article reviews the relationships between type and route of nutrition and gut-derived mucosal immunity in both the clinical and laboratory settings.

Parenteral Feeding Depletes Pulmonary Lymphocyte Populations

BACKGROUND The effect of parenteral nutrition (PN) on lymphocyte mass in the lung is unknown, but reduced mucosal lymphocytes are hypothesized to play a role in the reduced immunoglobulin A-mediated immunity in both gut and lung. The ability to transfer and track cells between mice may allow study of diet-induced mucosal immune function. The objectives of this study are to characterize lung T-cell populations following parenteral feeding and to study distribution patterns of transferred donor lung T cells in recipient mice. METHODS In experiment 1, cannulated male Balb/c mice are randomized to receive chow or PN for 5 days. Lung lymphocytes are obtained via collagenase digestion, and flow cytometric analysis is used to identify total T (CD3+) and B (CD45/B220+) cells. In experiment 2, isolated lung T cells from chow-fed male Balb/c mice are pooled and labeled in vitro with a fluorescent dye (carboxyfluorescein diacetate succinimidyl ester [CFSE]), and 1.1 x 10(8) CFSE+ cells (3.1 x 10(6) T cells) are transferred to chow-fed Balb/c recipients. Cells recovered from recipient lungs and intestinal lamina propria (LP) are analyzed by flow cytometry to determine CFSE/CD3+ T cells at 1, 2, and 7 days. In experiment 3, cells are transferred to PN-fed recipients. RESULTS In experiment 1, PN significantly decreases lung T- and B-cell populations compared with chow feeding. In experiment 2, CFSE+ T-cell retention is highest on day 1 in lung and LP, and decreases on day 2. Cells are gone by day 7; 98.1% of retained donor lung T cells migrate to recipient lungs and 1.9% to the intestine on day 1. Similar results are seen in experiment 3 after transfer of cells to PN-fed recipients. CONCLUSIONS PN reduces pulmonary lymphocyte populations consistent with impaired respiratory immunity. Transferred lung T cells preferentially localize to recipient lungs rather than intestine with maximal accumulation at 24 hours. Limited cross-talk of transferred lung T cells to the intestine indicates that mucosal lymphocyte traffic might be programmed to localize to specific effector sites.

Small intestine mucosal immune system response to injury and the impact of parenteral nutrition.

BACKGROUND Both humans and mice increase airway immunoglobulin A (IgA) after injury. This protective response is associated with TNF-α, IL-1β, and IL-6 airway increases and in mice is dependent upon these cytokines as well as enteral feeding. Parenteral nutrition (PN) with decreased enteral stimulation (DES) alters gut barrier function, decreases intestinal IgA, and decreases the principal IgA transport protein pIgR. We investigated the small intestine (SI) IgA response to injury and the role of TNF-α, IL-1β, IL-6, and PN/DES. METHODS Expt 1: Murine kinetics of SI washing fluid (SIWF) IgA; SI, SIWF and serum TNF-α, IL-1β, and IL-6, was determined by ELISA from 0 to 8 hours after a limited surgical stress injury (laparotomy and neck incisions). Expt 2: Mice received chow or PN/DES before injury and SIWF IgA and SI pIgR levels were determined at 0 and 8 hours. Expt 3: Mice received PBS, TNF-α antibody, or IL-1β antibody 30 minutes before injury to measure effects on the SIWF IgA response. Expt 4: Mice received injury or exogenous TNF-α, IL-1β, and IL-6 to measure effects on the SIWF IgA response. RESULTS Expt 1: SIWF IgA levels increased significantly by 2 hours after injury without associated increases in TNF-α or IL-1β whereas IL-6 was only increased at 1 hour after injury. Expt 2: PN/DES significantly reduced baseline SIWF IgA and SI pIgR and eliminated their increase after injury seen in Chow mice. Expt 3: TNF-α and IL-1β blockade did not affect the SIWF IgA increase after injury. Expt 4: Exogenous TNF-α, IL-1β, and IL-6 increased SIWF IgA similarly to injury. CONCLUSION The SI mucosal immune responds to injury or exogenous TNF-α, IL-1β, and IL-6 with an increase in lumen IgA, although it does not rely on local SI increases in TNF-α or IL-1β as it does in the lung. Similar to the lung, the IgA response is eliminated with PN/DES.

Injury stimulates an innate respiratory immunoglobulin a immune response in humans.

BACKGROUND Secretory immunoglobulin A (SIgA) is the specific immune antibacterial defense. Since pneumonia frequently complicates the course of trauma patients, we studied early airway immune responses after injury. METHODS Twelve severely injured, intubated (expected for >/=5 d) patients had tracheal and bilateral lung lavage (BAL) within 30 hours of injury (n = 12). Epithelial lining fluid (ELF) volume and SIgA were measured by urea dilution and enzyme-linked immunosorbent assay (ELISA), respectively. Control BAL specimens were obtained from eight healthy elective surgical patients. Anatomically based comparisons were made between groups with Welchs unpaired t test. To verify human data, 30 male mice received no injury (time 0, n = 7) or injury with abdominal and neck incisions and were killed for airway IgA at 4 (n = 7), 8 (n = 8), and 24 (n = 8) hours. Analysis of variance (ANOVA) and Fishers protected least significant difference testing was used to analyze animal data. RESULTS Initial trauma patient SIgA concentration (SIgA/mL ELF) increased compared with control in the lungs bilaterally (p < 0.05 both right and left). ELF volume was significantly higher in the right lung (p = 0.02) and just missed statistical significance (p = 0.07) on the left. Mouse IgA increased 8 hours after stress (p < 0.05 versus 0, 4, and 24 hours) and returned to normal by 24 hours. CONCLUSION A previously unrecognized innate human airway mucosal immune response with increased airway SIgA and ELF occurs after severe injury and is reproducible experimentally. This accessible, quantifiable human response allows study of clinical strategies to reduce infections via mucosal immune therapies.