OBJECTIVE: Determine comparative tolerance of daily oral and weekly parenteral cobalamin supplementation, in hypocobalaminaemic dogs with chronic enteropathy. Determine whether oral is as effective as parenteral supplementation at achieving eucobalaminaemia, in hypocobalaminaemic dogs with protein-losing enteropathy, severe hypocobalaminaemia or high canine inflammatory bowel disease activity index at inclusion.
METHODS: Thirty-seven client-owned dogs with hypocobalaminaemia and clinical signs of chronic enteropathy were prospectively enrolled in three UK referral centres. Dogs were randomly allocated to daily oral for 12 weeks or weekly parenteral cobalamin supplementation for 6 weeks and one additional dose 4 weeks later. Serum cobalamin, body condition score, canine inflammatory bowel disease activity index and bodyweight were assessed at inclusion, weeks 7 and 13. Serum methylmalonic acid concentration was evaluated at inclusion and at week 13. Owners completed treatment adherence, palatability, tolerance and satisfaction questionnaires at week 13.
RESULTS: Nineteen dogs completed the study. All dogs orally supplemented achieved normal or increased cobalaminaemia at weeks 7 and 13. There was no statistical difference in cobalamin concentration at week 13 in dogs treated with oral or parenteral supplementation, regardless of presence of protein-losing enteropathy, severity of hypocobalaminaemia or canine inflammatory bowel disease activity index at inclusion. Serum methylmalonic acid concentration was not significantly different between oral and parenteral groups, neither were treatment adherence, satisfaction, and tolerance scores at week 13.
CONCLUSIONS: Oral is as effective and as well-tolerated as parenteral cobalamin supplementation in hypocobalaminaemic dogs with chronic enteropathy and severe clinical or biochemical phenotypes, and should be considered as a suitable treatment option regardless of disease severity.

BACKGROUND: CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) is an ultra-rare genetic disorder characterised by intestinal lymphatic damage, lymphangiectasia, and protein-losing enteropathy caused by overactivation of the complement system. We assessed the efficacy and safety of pozelimab, an antibody blocking complement component 5.
METHODS: This open-label, single-arm, historically controlled, multicentre phase 2 and 3 study evaluated ten patients with CHAPLE disease. This study was conducted at three hospitals in Thailand, Türkiye, and the USA. Patients aged 1 year or older with a clinical diagnosis of CHAPLE disease and a CD55 loss-of-function variant identified by genetic analysis and confirmed by flow cytometry or western blot of CD55 from peripheral blood cells were eligible for this study. Patients received a single intravenous loading dose of pozelimab 30 mg per kg of bodyweight, followed by a once-per-week subcutaneous dose over the treatment period based on bodyweight at a concentration of 200 mg/mL as either a single injection (<40 kg bodyweight) or two injections (≥40 kg bodyweight). The primary endpoint was proportion of patients with serum albumin normalisation with an improvement in active clinical outcomes and no worsening in inactive clinical outcomes (frequency of problematic abdominal pain, bowel movement frequency, facial oedema severity, and peripheral oedema severity) at week 24 compared with baseline, assessed in the full analysis set. This study is registered with ClinicalTrials.gov (NCT04209634) and is active but not recruiting.
RESULTS: 11 patients were recruited between Jan 27, 2020, and May 12, 2021, ten of which were enrolled in the study and included in the analysis populations. The efficacy data corresponded to all patients completing the week 48 assessment and having at least 52 weeks of treatment exposure, and the safety data included an additional 90 days of follow-up and corresponded to all patients having at least 72 weeks of treatment. Patients were predominantly paediatric (with a median age of 8·5 years), and originated from Türkiye, Syria, Thailand, and Bolivia. Patients had markedly low weight-for-age and stature-for-age at baseline, and mean albumin at baseline was 2·2 g/dL, which was considerably less than the local laboratory reference range. After pozelimab treatment, all ten patients had serum albumin normalisation and improvement with no worsening in clinical outcomes. There was a complete inhibition of the total complement activity. Nine patients had adverse events; two were severe events, and one patient had an adverse event considered related to pozelimab.
CONCLUSIONS: Pozelimab inhibits complement overactivation and resolves the clinical and laboratory manifestations of CHAPLE disease. Pozelimab is the only currently approved therapeutic drug for patients with this life-threatening, ultra-rare condition. In patients with protein-losing enteropathy where known causes have been excluded, testing for a CD55 deficiency should be contemplated. A diagnosis of CHAPLE disease should lead to early consideration of treatment with pozelimab.
BACKGROUND: Regeneron Pharmaceuticals and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

BACKGROUND: More than 50% of dogs with protein-losing enteropathy (PLE) fail to respond to standard therapies. Octreotide, a somatostatin analogue, is used in cases of intestinal lymphangiectasia (IL) in humans with some success.
OBJECTIVE: Describe the use of octreotide in dogs with PLE including reason for and details of prescription, adverse effects, and apparent response.
METHODS: Eighteen dogs with PLE, 13 with histopathology available. Ninety-two percent (12/13) had IL diagnosed on biopsy. All 13 dogs had intestinal inflammatory infiltrates noted.
METHODS: Multicenter, retrospective, descriptive study. Cases were volunteered for inclusion by individual attending veterinarians who reported the use of octreotide in cases of PLE.
RESULTS: In 16/18 (89%) cases octreotide was prescribed to PLE dogs with a clinical suspicion or confirmed diagnosis of IL that were refractory to standard therapies. Median serum albumin at the time of octreotide prescription was 1.7 g/dL (range, 1.0-3.1 g/dL). The median dose of octreotide prescribed was 20 μg/kg, SQ, daily with a range of 4-39 μg/kg, SQ, daily. Adverse effects were noted in 3/18 (17%, 95% CI [4%, 41%]) of dogs; discontinuation of the drug was necessary in 1 dog. Improvement in clinical signs was noted in 6/12 (50%, 95% CI [21%, 79%]).
CONCLUSIONS: Octreotide was most commonly prescribed to dogs with PLE and suspected or confirmed IL that had failed to respond to standard therapies. Though a benefit to PLE dogs cannot be confirmed, octreotide was well tolerated by the majority of dogs at the doses prescribed in this study.

In the SVR trial (Single Ventricle Reconstruction), newborns with hypoplastic left heart syndrome were randomly assigned to receive a modified Blalock-Taussig-Thomas shunt (mBTTS) or a right ventricle-to-pulmonary artery shunt (RVPAS) at Norwood operation. Transplant-free survival was superior in the RVPAS group at 1 year, but no longer differed by treatment group at 6 years; both treatment groups had accumulated important morbidities. In the third follow-up of this cohort (SVRIII [Long-Term Outcomes of Children With Hypoplastic Left Heart Syndrome and the Impact of Norwood Shunt Type]), we measured longitudinal outcomes and their risk factors through 12 years of age.
Annual medical history was collected through record review and telephone interviews. Cardiac magnetic resonance imaging (CMR), echocardiogram, and cycle ergometry cardiopulmonary exercise tests were performed at 10 through 14 years of age among participants with Fontan physiology. Differences in transplant-free survival and complication rates (eg, arrhythmias or protein-losing enteropathy) were identified through 12 years of age. The primary study outcome was right ventricular ejection fraction (RVEF) by CMR, and primary analyses were according to shunt type received. Multivariable linear and Cox regression models were created for RVEF by CMR and post-Fontan transplant-free survival.
Among 549 participants enrolled in SVR, 237 of 313 (76%; 60.7% male) transplant-free survivors (mBTTS, 105 of 147; RVPAS, 129 of 161; both, 3 of 5) participated in SVRIII. RVEF by CMR was similar in the shunt groups (RVPAS, 51±9.6 [n=90], and mBTTS, 52±7.4 [n=75]; P=0.43). The RVPAS and mBTTS groups did not differ in transplant-free survival by 12 years of age (163 of 277 [59%] versus 144 of 267 [54%], respectively; P=0.11), percentage predicted peak Vo2 for age and sex (74±18% [n=91] versus 72±18% [n=84]; P=0.71), or percentage predicted work rate for size and sex (65±20% versus 64±19%; P=0.65). The RVPAS versus mBTTS group had a higher cumulative incidence of protein-losing enteropathy (5% versus 2%; P=0.04) and of catheter interventions (14 versus 10 per 100 patient-years; P=0.01), but had similar rates of other complications.
By 12 years after the Norwood operation, shunt type has minimal association with RVEF, peak Vo2, complication rates, and transplant-free survival. RVEF is preserved among the subgroup of survivors who underwent CMR assessment. Low transplant-free survival, poor exercise performance, and accruing morbidities highlight the need for innovative strategies to improve long-term outcomes in patients with hypoplastic left heart syndrome.
URL: https://www.
gov; Unique identifier: NCT0245531.

BACKGROUND: The role of diet in the pathogenesis and treatment of chronic enteropathies (CE) in dogs is unresolved.
OBJECTIVE: To compare the ability of diets composed of hydrolyzed fish, rice starch, and fish oil without (HF) or with prebiotics, turmeric, and high cobalamin (HF+) against a limited ingredient diet containing mixed nonhydrolyzed antigens and oils (control) to resolve clinical signs and maintain serum cobalamin and folate concentrations in dogs with nonprotein losing CE (non-PLE). To determine the ability of hydrolyzed fish diets to support recovery and remission in dogs with PLE.
METHODS: Thirty-one client-owned dogs with CE: 23 non-PLE, 8 PLE.
METHODS: Randomized, blinded, controlled trial. Diets were fed for 2 weeks; responders continued for 12 weeks. Nonresponders were crossed over to another diet for 12 weeks. Response was determined by standardized clinical evaluation with long-term follow-up at 26 weeks. Concurrent medications were allowed in PLE.
RESULTS: Nineteen of 23 (83%; 95% confidence interval [CI], 60%-94%) non-PLE CE responded clinically to their initial diet, with no difference between diets (P > .05). Four nonresponders responded to another diet, with sustained remission of 18/18 (100%; 95%CI, 78%-100%) at 26 weeks. Serum cobalamin concentration was increased (P < .05) and maintained by diet. Serum folate concentration decreased posttreatment (P < .05) but was restored by dietary supplementation. Hydrolyzed fish diets supported weight gain, serum albumin concentration, and recovery (P < .05) in dogs with PLE.
CONCLUSIONS: Changing diet, independent of antigen restriction or supplemental ingredients, induced long-term remission in dogs with non-PLE CE. Serum cobalamin and folate concentrations were maintained by diet. Hydrolyzed fish diets supported clinical recovery and remission in PLE.

BACKGROUND: The impact of undernutrition in dogs with protein-losing enteropathy (PLE) caused by inflammatory enteritis, intestinal lymphangiectasia, or both and which variables are most predictive of outcome are unknown.
OBJECTIVE: Develop an undernutrition screening score (USS) for use at the time of diagnosis of PLE in dogs, which is predictive of outcome.
METHODS: Fifty-seven dogs with PLE prospectively recruited from 3 referral hospitals in the United Kingdom.
METHODS: An USS based on the presence and severity of 5 variables: appetite, weight loss, and body, muscle, and coat condition and scored out of 15, with higher scores reflecting worse undernutrition, was calculated at the time of diagnosis. Follow-up information was obtained for at least 6 months.
RESULTS: Dogs that failed to achieve clinical remission within 6 months had higher USS at diagnosis compared with dogs that achieved remission (median, 7.5; range, 2-14 and median, 5; range, 0-14, respectively). The USS at diagnosis gave an area under the receiver operating characteristic curve (AUC) of 0.656 for predicting nonclinical remission within 6 months, whereas a score consisting of just epaxial muscle loss and coat condition resulted in a larger AUC of 0.728.
CONCLUSIONS: Of the 5 variables assessed in the USS, a combination of epaxial muscle loss and coat condition was most predictive of not achieving clinical remission within 6 months in dogs with PLE. Additional studies will help determine the effect of changes in USS and the 5 associated variables after diagnosis on outcome variables in these dogs.

Patients after Fontan palliation represent a growing pediatric population requiring heart transplant (HTx) and often have lymphopenia (L) and/or hypogammaglobinemia that may be exacerbated by protein-losing enteropathy (PLE, P). The post-HTx effects of this altered immune phenotype are not well studied.
In this study of the Pediatric Heart Transplant Society Registry, 106 Fontan patients who underwent HTx between 2005 and 2018 were analyzed. The impact of lymphopenia and PLE on graft survival, infection, rejection, and malignancy was analyzed at 1 and 5 years post-HTx.
The following combinations of lymphopenia and PLE were noted: +L+P, n = 37; +L-P, n = 23; -L+P, n = 10; and -L-P, n = 36. Graft survival between the groups was similar within the first year after transplant (+L+P: 86%, +L-P: 86%, -L+P: 87%, -L-P: 89%, p = .9). Freedom from first infection post-HTx was greatest among -L-P patients compared to patients with either PLE, lymphopenia, or both; with a 22.1% infection incidence in the -L-P group and 41.4% in all others. These patients had a significantly lower infection rate in the first year after HTx (+L+P: 1.03, +L-P: 1, -L+P: 1.3, -L-P: 0.3 infections/year, p < .001) and were similar to a non-single ventricle CHD control group (0.4 infections/year). Neither freedom from rejection nor freedom from malignancy 1 and 5 years post-HTx, differed among the groups.
Fontan patients with altered immunophenotype, with lymphopenia and/or PLE, are at increased risk of infection post-HTx, although have similar early survival and freedom from rejection and malignancy. These data may encourage alternative immunosuppression strategies and enhanced monitoring for this growing subset of patients.

The influence of Fontan-associated protein-losing enteropathy\'s (PLE) severity, duration, and treatment on heart transplant (HTx) outcomes is unknown. We hypothesized that long-standing PLE and PLE requiring more intensive therapy are associated with increased post-HTx mortality.
This 12-center, retrospective cohort study of post-Fontan patients with PLE referred for HTx from 2003 to 2015 involved collection of demographic, medical, surgical, and catheterization data, as well as PLE-specific data, including duration of disease, intensity/details of treatment, hospitalizations, and complications. Factors associated with waitlist and post-HTx outcomes and PLE resolution were sought.
Eighty patients (median of 5 per center) were referred for HTx evaluation. Of 68 patients listed for HTx, 8 were removed due to deterioration, 4 died waiting, and 4 remain listed. In 52 patients undergoing HTx, post-HTx 1-month survival was 92% and 1-year survival was 83%. PLE-specific factors, including duration of PLE pre-HTx, pre-HTx hospitalizations, need for/frequency of albumin replacement, PLE therapies, and growth parameters had no association with post-HTx mortality. Immunosuppressant regimen was associated with mortality; standard mycophenolate mofetil immunotherapy was used in 95% of survivors compared with only 44% of non-survivors (p = 0.03). Rejection (53%) and infection (42%) post-HTx were common, but not associated with PLE-specific factors. PLE resolved completely in all but 1 HTx survivor at a median of 1 month (interquartile range 1 to 3 months); resolution was not affected by PLE-specific factors.
PLE severity, duration, and treatment do not influence post-HTx outcome, but immunosuppressive regimen may have an impact on survival. PLE resolves in nearly all survivors.

BACKGROUND: Hypovitaminosis D has previously been shown to be prevalent amongst dogs with protein losing enteropathy (PLE). The hypothesis of this study was that Low 25-hydroxyvitamin D (25(OH) D) serum concentrations could be a risk factor for negative outcome in dogs with PLE. Forty-three dogs diagnosed with PLE (2005-2014) and which serum Vitamin D serum concentrations were collected and archived at -80 Degrees C were analyzed. Post-diagnostic communication with referring veterinarians was made to determine outcome of PLE dogss: Dogs which died due to PLE within 4 months after diagnosis (negative outcome group, n = 22) and dogs alive or which died due to another disease at the end point of the study (1 year after diagnosis, good outcome group, n = 21). Serum samples taken at the time of diagnosis were analysed for ionized calcium (iCa) concentrations and serum 25(OH) D concentration.
RESULTS: Clinical (CCECAI) scores, age at PLE diagnosis, and iCa concentrations were not significantly different between dog groups. A significantly greater (p < 0.001) number of PLE dogs treated with hydrolyzed or elimination diet alone showed good outcome as compared to the PLE negative outcome group. Median serum 25(OH) D concentration was significantly (p = 0.017) lower in dogs with negative outcome versus PLE dogs with good outcome. Using logistic regression analysis, 25(OH) D serum concentration was shown to be a statistically significant factor for outcome determination. Cox regression analysis yielded a hazard ratio of 0.974 (95% CI 0.949, 0.999) per each one nmol/l increase in serum 25(OH) D concentration.
CONCLUSIONS: Low serum 25(OH) D concentration in PLE dogs was significantly associated with poor outcome. Further studies are required to investigate the clinical efficacy of Vitamin D (cholecalciferol) as a potential therapeutic agent for dogs with PLE.

OBJECTIVE: Severe gastrointestinal involvement of Henoch-Schönlein purpura (HSP) is rare but potentially life-threatening. Management of severe gastrointestinal involvement in HSP is not codified. Symptomatic care and steroids are a first-line therapy. Nonsteroidal immunomodulatory therapies have been anecdotally used to treat steroid-refractory forms. The aim of this study was to describe the outcome of patients with severe gastrointestinal involvement of HSP who required nonsteroidal immunomodulatory therapy.
METHODS: A French retrospective case series study was conducted. Pediatric consultants at 31 French academic pediatric centers were contacted. Patients were identified from memory or via an informatics diagnosis-related code system. Clinical, paraclinical, and therapeutic data were collected.
RESULTS: Twenty-nine responding centers provided nine cases, one of which was excluded. Five boys and three girls, aged 3-15years (median: 5.5years) from seven centers were included. Severe gastrointestinal involvement of HSP mainly included intense pain, digestive bleeding, and protein-losing enteropathy. All children had been treated with steroids at first line and intravenous immunoglobulins (IVIg) at second line. Six out of eight showed a complete response to IVIg within 7days and two out of eight had a partial response. Two out of eight relapsed with less severe gastrointestinal involvement requiring a second dose of IVIg and they did not relapse thereafter. Tolerance was good, but two out of eight developed high proteinuria on the day following IVIg infusion.
CONCLUSIONS: Although a possible link with a flare-up of proteinuria needs to be addressed, IVIg appears to be a good candidate for treatment of severe gastrointestinal involvement of HSP.