IRF2BP2 mutation with autoimmune enteropathy, immune deficiency, and respiratory failure

Case history: We present the case of a 31-year-old Hispanic male with history of recurrent bronchiectasis, invasive aspergillosis, and severe persistent asthma, who is now status post lung transplant for end-stage lung disease. He initially presented at 7 years of age with diarrhea, failure to thrive, and nearly absent immunoglobulin levels (IgG < 33 mg/dL, IgA < 7 mg/dL, IgM = 11 mg/dL, IgE = 4 IU/dL) necessitating IVIG treatment. Small intestinal biopsy showed villous atrophy consistent with autoimmune enteropathy. Sweat chloride was reported as indeterminate (44 me/dL). Initial WBC, platelet, and T- and NK-cell counts were within normal range, and B-cell count and percentage were borderline low. Most recently, he was found to have increased immature B-cell count (CD21low), decreased memory B-cells, and poor pneumococcal vaccine antibody response. Patient has been hospitalized numerous times with increasingly severe bronchiectasis, pneumonitis, and COVID-19 infections twice despite vaccination, leading to respiratory failure and lung transplantation. Family history is negative for immune deficiency and lung diseases. Discussion(s): Of these 3 VUSs (see the table), the one in IRF2BP2 has the most pathogenic potential due to its autosomal dominant inheritance, its location in a conserved domain (Ring), and previous case reports of pathogenic variants at the same or adjacent alleles 1-3. Baxter et al reported a de novo truncating mutation in IRF2BP2 at codon 536 (c.1606CinsTTT), which is similar to our patient's mutation. This patient was noted to have an IPEX-like presentation, with chronic diarrhea, hypogammaglobulinemia, and recurrent infections. Variant Functional Prediction Score for our variant predicts a potentially high damage effect. There are 2 other case reports of heterozygous mutations in loci adjacent to this allele;one (c.1652G>A)2 with a similar clinical phenotype to our patient and the other (C.625-665 del)3 with primarily inflammatory features and few infections. Impact: This case highlights a variant in IRF2BP2 associated with severe hypogammaglobulinemia, recurrent pulmonary infections, and autoimmune enteropathy. [Table presented]Copyright © 2023 Elsevier Inc.

Whipple's Disease, An Overlooked Diagnosis

Whipple disease is a rare multisystem inflammatory disease. Because fewer than 1000 reported cases have been described, clinical experience with this disorder is sparse. We are reporting a case of a 46-year-old man who presented with fever, weight loss, and polyarthralgia for 2 months, and 1 month of diarrhea. The patient was thoroughly investigated for collagen diseases and COVID-19, with no definite diagnosis. A therapeutic trial by immunosuppressive drugs provided partial remission followed by a marked rebound of the symptoms. His occult blood in stool was positive and subsequent upper endoscopy with proximal small intestinal biopsies showed the pathological features of Whipple's disease. The patient showed a dramatic improvement following treatment with ceftriaxone and trimethoprim-sulfamethoxazole. Despite the rarity of Whipple's disease, its course mimics many rheumatological diseases, inflammatory bowel disease, and COVID-19 disease. It should always be a part of the differential diagnosis of obscure polyarthralgia and chronic diarrhea.Copyright © 2023 The Author(s).

Isolated Colonic Histoplasmosis in Renal Transplant Recipient Post Covid-19 Infection

Introduction: Histoplasmosis is caused by the dimorphic fungus - Histoplasma capsulatum. The presentation of histoplasmosis is often disseminated, though primary intestinal involvement can rarely be seen in patients with cell mediated immune dysfunction like in patients with AIDS. We report a case of renal allograft recipient, who had history of COVID 19 infection and also underwent anti-rejection treatment for renal graft dysfunction, presented with chronic diarrhea and was diagnosed as a case of colonic histoplasmosis. Method(s): We report a case of 45 years old male who underwent renal transplant surgery one and a half year prior (February 2021) and was having stable graft function on tacrolimus, mycophenolate and steroid. He had history of fever and diarrhea in February 2022 and was diagnosed COVID-19 positive with RT-PCR, and was treated conservatively with intravenous dexamethasone and lowering of immunosuppressants. He had mild graft dysfunction in April 2022;renal graft biopsy had acute T-Cell mediated rejection (Banff Grade 1 B) and was treated with pulse steroids for 3 days. He had complaint of intermittent diarrhea, weight loss and intermittent fever since May 2022. He was evaluated and treated on outpatient basis with empirical oral antibiotics. He was admitted in June 2022 with complaint of high grade fever, loose stools leading to hypovolemic shock and renal dysfunction. He had marked thrombocytopenia and neutrophilic leukocytosis. He showed initial response to intravenous broad spectrum antibiotics and crystalloids, but intermittently symptoms of increased stool frequency and altered consistency were still persisting. Stool studies for ova, cyst, parasites and clostridium difficile were negative. Indian ink staining of stool sample had no evidence of Cryptococcosis. Serum PCR for cytomegalovirus was also negative. CT abdomen showed normal visualized bowel and other viscera. Upper GI endoscopy was unremarkable. Colonoscopy revealed multiple small ulcers with erythematous hue and clean base particularly in ceacum and along ascending colon. Multiple colonic biopsies were taken. Histopathology showed lymphoplasmacytic infilterate in the lamina propria. It also showed increased presence of foamy histiocytes, several of which also showed interacellular organism bearing a pseudocapsule. PAS stain also confirmed budding of these interacellular organisms which is consistent with Histoplasmosis. His HRCT chest revealed hyperinflated lungs, cylindrical bronchiectasis in left upper lobe. Urine for histoplasma antigenuria was negative. Result(s): He was treated with intravenous liposomal amphotericin B for initial two weeks followed by oral itraconazole. His symptoms responded remarkably to the treatment. In view of persisting thrombocytopenia and histoplasmosis his mycophenolate was stopped and tacrolimus was titrated as per trough levels Conclusion(s): Colonic histoplasmosis is associated with significant mortatlity and morbidity. Prolonged use of immunosuprresants, use of antirejection therapies (like high dose pulse methyl prednisolone and bortezomib) and even in some case reports COVID 19 infection have shown to increase the risk of histoplasmosis. Primary and isolated colonic histoplasmosis like in this case can be the atypical presentation which emphasizes the importance of maintaining a low threshold for consideration of histoplasmosis in renal allograft recipients. No conflict of interestCopyright © 2023

Bring your boots: wading through GI PCR panel diagnostic stewardship applications

Background. Infectious diarrhea is a common cause of emergency department (ED) visits and hospital admissions. Polymerase chain reaction (PCR) testing allows for quick and expansive pathogen identification and facilitates earlier targeted treatment. We implemented a multiplex gastrointestinal (GI) PCR panel in 2014. In collaboration with the Antimicrobial and Diagnostic Advisement Program (ADAP), post-launch optimization strategies have changed test use. We evaluate the impact of diagnostic stewardship initiatives. Methods. GI PCR testing was initially unrestricted for ED or inpatients within 72 hours of admission. After fielding many questions regarding interpretation, the ADAP developed a guidance document in June 2019 regarding treatment considerations for all potential organisms detected. In January 2020, organism-specific treatment considerations were embedded in the test results real-time treatment guidance (figure 1). A pre-post quality improvement assessment of the changes was performed. In August 2021, individual GI PCR panel orders were replaced with an order set containing a decision tree to provide passive guidance evaluating acute vs chronic diarrhea, assessing recent antibiotic use (to consider C. difficile testing), no testing scenarios, and avoiding repeat testing (figure 2). Results. GI PCR panel use peaked in 2019 with 3,142 tests processed. The guidance document was less helpful, requiring an external site link. Embedding organismspecific GI PCR guidance significantly improved appropriate antibiotic prescribing (77.9 vs 89.1%, p=0.001). A precipitous drop off in GI PCR test orders occurred after the COVID-19 pandemic began (1,774 in 2020), partly attributed to supply chain issues. When comparing intra-pandemic years (2020 vs 2021), implementation of a smart order set was associated with a 51.3% reduction in orders (1,774 vs 864) and $131,000 in savings despite significant patient volume increases in 2021. Low use rates have persisted into the first quarter of 2022 (n=229). Conclusion. Diagnostic stewardship changes should be proactive and contextually relevant at the time of result interpretation. Antimicrobial stewardship programs are uniquely positioned to lead optimization initiatives and drive clinical and costeffective solutions. (Figure Presented).

To Study the Association of Vitamin D Deficiency with ICU Mortality and Morbidity in Moderately-severe COVID-19 Patients

Introduction: The severity of COVID-19 is determined by the presence of pneumonia, severe ARDS, cytokine storms, and small vessels thrombosis, all involves underlying inflammation. Vitamin D is a fat-soluble vitamin with immuno-modulating and anti-inflammatory properties. The high prevalence of vitamin D deficiency is usually due to inadequate sunlight exposure, sedentary lifestyle, diet poor in vitamin D, and traditional clothing. Vitamin D deficiency is a modifiable risk factor their identification and management can improve outcomes. Materials and methods: This was a prospective observational single centre study of moderatelysevere COVID-19 patients. All consecutive, moderately-severe COVID-19 patients with ICU stay >48 hours were included. Exclusion criteria: consent refusal, pregnant and lactating mothers, Age <18 years, post-cardiac arrest resuscitated patient before ICU admission, patient on multivitamin or Neutraceuticals supplements, chronic diarrhea, and cancer patients. Based on vitamin D levels on ICU admission, patients were stratified into two groups, i.e., ≤20 ng/mL deficient and >20 ng/mL non-deficient group. After demographic data, we collected data of underlying disease;cause of admission;APACHE II on admission and daily SOFA scoring, various morbidities during ICU stay (mechanical ventilation, inotropes/vasopressor, nosocomial infections, etc.), length of ICU stay, ICU mortality and 30 days mortality. Results and discussion: A total of 88 patients were studied, 73 (82.9%) patients had vitamin D deficiency. Median [IQ range] vitamin D levels of the deficient and non-deficient group were 11 [5-17] and 27 [22-35]. Groups did not differ in demographic or clinical characteristics except for age. The elderly age group had a higher prevalence of deficiency and was statistically significant, mean (±SD) age of the deficient vs non-deficient group was 54.78 (±13.30) vs 46.47 (±5.75), p value 0.02. The overall mortality rate of the cohort was 42.05%. Percentage mortality in the deficient group (46.5%) was lower than the non-deficient group (20%) but failed to show statistical significance p value 0.058. In continuous data, deficient group had a poor association with ICU morbidities vs nondeficient group as mean (±SD) duration of mechanical ventilation 4.59 (±2.78) vs 4.07 (±3.21) p value 0.521, and length of ICU stay 8.04 (±2.82) vs 8.53 (±3.04) p value 0.545. In categorical data, deficient group showed increased ICU morbidities vs non-deficient group but were not statistically significant, inotropes/vasopressor requirement 60.3% vs 53.3% p value 0.619, hospital-acquired infection incidence 45.2% vs 40% p value 0.712 and 30 days mortality 75.6% vs 24.4% p value 0.059. In severity scoring, deficient group had higher severity vs non-deficient group but statistical significance was not demonstrated APACHE II 10.74 (±4.42) vs 8.73 (±3.39) p value 0.101 and mean SOFA score 4.17 (±3.33) vs 2.51 (±2.68) p value 0.074. Mean (±SD) levels of vitamin D in survivor vs non-survivors were 11.54 (±5.76) vs 15.45 (±6.92) p value 0.006 showed a correlation between mortality and low vitamin D deficiency levels. However, vitamin D levels failed as an independent risk factor for mortality in multivariate analysis OR (95% C.I.) 1.198 (0.732-1.672), p value 0.296. Conclusion: In moderately-severe COVID-19, vitamin D deficiency was associated with a greater incidence of mortality and morbidity, although the relationship was not statistically significant. Vitamin D deficiency was not found to be an independent risk factor for mortality.

INDICATIONS AND DIAGNOSTIC YIELD OF SINGLE-BALLOON ASSISTED ENTEROSCOPY: AN EXPERIENCE IN A TERTIARY CARE CENTER OF A LOW INCOME COUNTRY

AIM: Enteroscopy is an endoscopic procedure to approach the small intestine in order to diagnose and treat various pathologies. The aim of this study is to share the experience of our center with this modality and highlight the main indications and diagnostic yield pf the procedure. METHODS: This is a single center retrospective study at Aga Khan University Hospital Karachi, Pakistan in which we included all the enteroscopies done in last five years. RESULTS: A total of 37 enteroscopies were done in past five years, the numbers has reduced significantly in the Covid-19 era. The mean age was 50.4 ± 16.5 years with 19 (51.4%) females and 18 (48.6%) males. The most common indications were jejunal thickening on CT scan 17 (45.9%) followed by obscure gastrointestinal bleeding 7 (18.9%) and chronic diarrhea 5 (13.5%). Most of the enteroscopies showed no gross pathology 17 (45.9%). However, jejunal ulcers 6 (16.2%), arteriovenous malformations 4 (10.8%), jejunal polyps 3 (8.1%), erythematous mucosa 2 (5.4%), pale mucosa 2 (5.4%), jejunal mass 2 (5.4%) and gastric polyp 1 (2.7%) are the findings noticed in rest of the enteroscopies performed. In 18 (48.6%) no biopsies were taken due to normal findings. 12 (32.4%) had nonspecific chronic inflammation in the jejunum. The remaining seven patient's histopathology showed giardiasis, MALTOMA, high grade B cell lymphoma, moderately differentiated adenocarcinoma, inflammatory polyp, hamartomatous polyp and adenomatous polyp. CONCLUSIONS: We shared the five year experience of enteroscopies done in our center which belongs to a low income country. The number of enteroscopies has greatly affected by the cost, low socioeconomic status of patients. Covid-19 has further reduced the number of diagnostic procedures in general. Most of the enteroscopies didn't reveal significant findings however there are cases where lymphoma and adenocarcinoma has been diagnosed.

SHOULD WE BE TESTING FOR SPIROCHETOSIS IN COVID PATIENTS PRESENTING WITH PERSISTENT DIARRHEA? A CASE STUDY

Purpose/Background: In the US, intestinal spirochetosis (IS) as a cause of infectious colitis has mainly been described in the HIV positive population. This case describes IS in an HIV negative, COVID positive patient suggesting the need for a broader differential of chronic diarrhea in the COVID era. Hypothesis/Aim: To increase awareness of the need for a potentially broader differential of chronic diarrhea in the COVID era. Methods/Interventions: This is a case study describing an association between COVID and intestinal spirochetosis. Results/Outcome(s): Spirochetes, gram negative spiral-shaped flagellated bacteria, are best known for their ability to cause systemic disease in the form of Syphilis and Lyme Disease, but the genus Brachyspiraceae (Brachyspira aalborgi, Brachyspira pilosicoli) has also been described as both a commensal organism and an invasive pathogen causing intestinal spirochetosis (IS). IS in the US has largely been described in the MSM HIV population as a colitis presenting with abdominal pain and persistent diarrhea secondary to epithelial invasion with destruction of the intestinal brush border leading to malabsorption. IS remains an important part of the work up of infectious colitis in this population. In this case study, IS was diagnosed in an HIV negative, COVID positive patient whose COVID diagnosis coincided with the symptomatic presentation of IS suggesting that it is important to include IS in the differential diagnosis of chronic diarrhea in the COVID population regardless of HIV status. In this study, a 60 yo HIV negative MSM presented with abdominal pain x 3 weeks followed by persistent watery diarrhea refractory to imodium. No history of recent travel. No known infectious contacts. Prior colonoscopy 9 years prior to presentation WNL. After one episode of hematochezia, CT abd/pelvis was performed demonstrating colitis and COVID-related changes to the lung bases. Testing confirmed COVID infection, which was self-limited. Initial work up for infectious colitis was negative for gonorrhea, chlamydia, HIV, HSV, O+P, and C. Difficile. Colonoscopy was performed revealing no evidence of gross colitis. Histopathology demonstrated microscopic colitis w/ spirochete colonization of the intestinal epithelium (image 1). A course of metronidazole led to resolution of symptoms. Limitations: This is a descriptive study describing an association, but it does not imply causation. Conclusions/Discussion: Intestinal spirochetosis has been described as a cause of abdominal pain and refractory diarrhea in the US mainly in an immunosuppressed, HIV positive population. This case describes symptomatic intestinal spirochetosis in an HIV negative, COVID positive patient who hitherto COVID diagnosis had no risk factors for immunosuppression suggesting a link between COVID and IS. Further review is necessary to establish a true association, but this case suggests that IS should be considered during the work up of chronic diarrhea in COVID positive patients. (Figure Presented).

LIPOID PNEUMONIA DUE TO PHARYNGOESOPHAGEAL DYSPHAGIA CAUSING PARAFFIN BRONCHOASPIRATION

TYPE: Case Report TOPIC: Occupational and Environmental Lung Diseases INTRODUCTION: We present a case of exogenous lipoid pneumonia caused by paraffin broncoaspiration due to pharyngoesophageal motor dysphagia. CASE PRESENTATION: A 57 year old female consulted for diarrhea. She had a previous history of ischemic stroke related to hypercoagulability syndrome, causing oropharyngeal dysphagia due to pharyngo-esophageal motor incoordination. Owing to possible neurogenic dysfunction she also presented megadolichocolon with chronic diarrhea-constipation syndrome. Due to the epidemiological situation caused by SARS-COV2, a chest X-ray was performed showing increased density of the right middle lobe. The control X-ray exhibited a persistence of this alteration, therefore a thoracic tomographic study was performed (findings included in image), as well as a bronchoalveolar lavage. The bronchoalveolar lavage fluid was initially turbid white which, posterior to resting, revealed a superficial layer of fat, supporting the diagnosis of lipoid pneumonia. The patient was subsequently interrogated. She associated the consumption of oily materials from herbalists and paraffin in order to palliate her constipation symptoms, which in relation to her esophageal motor-pharyngeal incoordination produced bronchoaspiration of the referred oily material. DISCUSSION: Oily substance ingestion was suspended. Subsequently she underwent a corticosteroid treatment and is currently under clinical control. CONCLUSIONS: The ground glass pattern is a finding that causes a wide differential diagnosis in the radiological study, therefore it is of great importance to take an adequate clinical history and to take into account the motor dysfunctions related to swallowing, due to the high consumption of herbalist products that contain oily materials that can cause exogenous lipoid pneumonia. DISCLOSURE: Nothing to declare. KEYWORD: Exogenous_Lipoid_Pneumonia