Normal IgG Levels Research Articles

The epidemiology and clinical features of selective immunoglobulin M deficiency: A single-center study in China.

BackgroundSelective immunoglobulin M deficiency (SIgMD) is a rare primary immunodeficiency that is frequently reported in Western countries. However, large epidemiological and clinical studies of SIgMD in China are still lacking. Herein, we describe a cohort of SIgMD subjects in a large tertiary university hospital in China.MethodsA cross‐sectional study included 139 668 participants at First Affiliated Hospital of Wenzhou Medical University from January 2014 to October 2018 was conducted. Individuals with a serum IgM level less than 0.3 g/L with normal levels of serum IgA and IgG were defined as having SIgMD.ResultA total of 63 subjects met the criteria for SIgMD(63/139668, 0.045%), with a male‐to‐female ratio of 0.85, aged from 19 to 99 years. The most common clinical manifestation was autoimmune disorders (38/63, 60.32%), while the second most common manifestation was infections (21/63, 33.33%). Neither allergies nor tumors were found among these 63 SIgMD subjects. Most importantly, there were 30 patients with systemic lupus erythematosus among these 63 SIgMD subjects, accounting for 47.62% of all SIgMD subjects.ConclusionTo our knowledge, we describe here the first large single‐center cohort of adult patients affected by SIgMD in China. The most common clinical manifestation was autoimmune disorders, specifically systemic lupus erythematosus.

Immune status of children with complications of BCG/BCG-M vaccination

The objective of the study: to analyze certain parameters of immune status in children with complications after BCG/BCG-M vaccination.Subjects and methods. The immune status parameters were tested in 24 children who developed complications after TB vaccination such as BCG-ostitis, BCG-lymphadenitis. Lymphocyte population was assessed using flow cytofluorometry by Cytomics FC 500 (Bekman Coulter).The serum level of immunoglobulins IgG, IgA, IgM was tested by immunodiffusion in Mancini agar. The leukocyte phagocytic activity was tested using flow cytofluorometry (Cytofluorimeter Cytomics FC 500) with FITC-labeled staphylococcus.Results. Of the 24 children with BCG lymphadenitis or BCG ostitis, 22 (92%; 95% CI 73-99%) had abnormality in immune status.Of the 24 children, 7 had low CD3+count, while 9 had an elevated level of CD3+. The level of СD4+was low in 4 children and elevated in 15 pediatric patients. CD8+count was low in 21 children (88%; 95% CI 72-97%). 11 children had low СD16+number, and it was elevated in 2 children. In 10 children, low level of СD16+was combined with low level of CD8+. 10 children had low СD19+number, and it was elevated in 4 children. The leukocyte phagocytic index drastically decreased (down to 37%) only in 1 child, and in 23 children, it varied from 60 to 90%.IgG level was low in 13 (54%), and elevated in 2 (8%) children. IgA level was low in 6 (25%), and it was not detected at all in 8 (33.3%) children. IgM level was elevated in 4/24 (17%) children, while it was low in 1/24 (4%). In 8 children with no IgA detected, the IgG level was low in 5 of them, 3 had a normal level, and IgM level was elevated in 2 children, 6 children had a normal level of IgM. With IgA completely absent, 1 child had the normal level of IgG and IgM.

Immune status of splenectomized patients following vaccination against encapsulated bacteria

Aim: The current study aimed to observe the effectiveness of a pneumococcal vaccine and a Haemophilus influenzae vaccine in splenectomized patients by quantification of serum antibody and complement levels, analysis of T and B lymphocytes with flow-cytometry and determination of the percentage of Natural Killer cells and the CD4+ to the CD8+ lymphocyte ratio.Material and Methods: The study included 22 adult patients who had undergone splenectomy between May 1999 and December 2006. The Pneumo-23 vaccine was administered for protection against Streptococcus pneumonia to all patients, whereas the Act-HIB vaccine was administered for protection against Haemophilus influenzae type B to 12 patients after January 2002.Hemogram, IgG and IgM antibody concentrations, serum levels of Complement protein 3 and Complement Protein 4 were obtained and lymphocytes were analyzed whether they were CD3+ and CD19+ by flow cytometry. At the second time point, in 2009, CD4+/CD8+ T-cell ratio and the percentage of CD3/CD16+CD56 Natural Killer cells were evaluated in addition to aforementioned parameters.Results: All of the study patients had normal IgG levels. Three patients had low levels of IgM. C3 and C4 values were normal. Ten patients showed a low CD3+ T-cell distribution at 5 years. The percentage of CD19+ B-lymphocytes returned to normal. Sustained suppression of CD19 level was observed only in one patient with immune thrombocytopenic purpura. CD8 distribution was normal in all patients. At 5 years, reduced CD4 percentage was detected in 5 patients with immune thrombocytopenic purpura, 3 of whom had suppressed levels of Natural Killer cells concomitantly. Normal levels of IgG, C3, C4 and CD19+ B-cell percentages were found at the final laboratory assessment for all patients.Conclusion: Our findings indicate that immunological functions are restored following administration of the Pneumo-23 and Act-HIB vaccines. Further studies are needed to obtain a prognostic immune profile index that could help predict patients at high risk for post-splenectomy sepsis.

Clinical Characteristics of 76 Patients with IgG4-Related Hypophysitis: A Systematic Literature Review

Background IgG4-related hypophysitis (IgG4-RH) is a rare disease, and its prevalence remains unclear. In recent years, an increasing number of cases have been reported because of the increasing recognition of this disease. We aimed to summarize case reports of IgG4-RH and outline the clinical features and outcomes. Methods We performed PubMed search of articles using the search terms “hypophysitis [AND] IgG4.” Consequently, only 54 English articles (76 cases) met Leporati's diagnostic criteria. Results Of the 76 cases, the ratio of men to women was 1.5 : 1, and the age at diagnosis was 54.1 ± 17.8 years. The median IgG4 concentration was 405.0 mg/dl. Anterior hypopituitarism, isolated central diabetes insipidus, and panhypopituitarism were observed in 14 (18.4%), 12 (15.8%), and 44 (57.9%) cases, respectively. The sequence of anterior hormone deficiency was as follows: gonadotropin (68.4%), ACTH (63.2%), TSH (59.2%), GH (48.7%), and prolactin (42.1%). The median number of involved organs was 1.5, and the lung (18.4%), retroperitoneum (17.1%), kidney (15.8%), submandibular glands (14.5%), and pancreas (13.2%) were the common involved organs. Elevated IgG4 concentration and normal IgG4 level were in 42 (76.4%) and 13 (23.6%) cases, respectively. Patients with elevated serum IgG4 concentration were older (60.9 ± 14.3 vs 45.6 ± 17.4, p=0.001) and male-prone (78.6% vs 40.4%, p=0.003) and had a susceptibility of multiple organ involvement (78.6% vs 35.0%, p=0.001) compared to those with normal serum IgG4 levels. Males were older at disease onset (61.5 ± 12.6 vs 42.9 ± 18.8, p < 0.001) and had a higher IgG4 concentration (425.0 vs 152.5, p=0.029) and a greater number of involved organs (2.0 vs 0.0, p=0.001), while isolated hypophysitis was more prominent in female (63.3% vs 26.1%, p=0.001). Conclusion In this review, we found that there were different characteristics between different genders. Patients with elevated serum IgG4 level in terms of some clinical features were also different from those with normal serum IgG4 level. However, the data in this review were limited by bias and confounding. Further clinical studies with larger sample sizes are warranted.

Hypogammaglobulinemia and Its Implications in Patients Treated with Daratumumab: A Single Institution Experience

Introduction: Daratumumab is an IgG Kappa monoclonal antibody (mAB) to CD38, a surface glycoprotein expressed on plasma cells. It was approved in 2015 as monotherapy for Multiple Myeloma (MM) patients who failed three prior lines of therapy. Its approval was then expanded to second line and most recently first line. As such, patients are now getting earlier and longer exposure to this mAB. Disease response to daratumumab is monitored by demonstrating a fall in paraprotein levels. It is becoming widely appreciated that hypogammaglobulinemia (HGGE) ie. (IgG&lt;600mg/dl) with risk of infection, is a potential complication for patients on daratumumab. The immune mediated attack by daratumumab on CD38 expressing plasma cells also results in destruction of normal lymphocytes, resulting in impaired production of polyclonal immunoglobulins and diminished immunity. We aim to explore the incidence, severity and clinical significance of HGGE in patients on daratumumab. Methods: We conducted a retrospective chart review of all patients treated with daratumumab as single agent or in combination (November 2015-June 2019), who had documented baseline and post therapy quantitative IgG levels. Demographics, subtype of plasma cell disease, bone marrow cytogenetics/FISH, serial IgG levels, incidence of significant infections and need for IVIG therapy were collected as part of this exploratory data analysis. Results: Among 145 eligible patients, 53% were male, 37% Hispanic, 19% Black/African American and 72% were age&lt;70 at diagnosis. The majority of patients had an IgG paraprotein (56.6%), followed by IgA (18.6%), Free Kappa only (13.1%) and Free Lambda only (9.7%). Hispanics were more likely to have high risk cytogenetics (OR=2.29, p=0.0804). 34.5% of patients had previous autologous stem cell transplant. At baseline 30.3% of all patients had HGGE; 58.1% non-IgG patients and only 9.6% IgG patients. The mean baseline IgG level in IgG patients was 1986.1 mg/dl and for non-IgG patients was 698.1 mg/dl. After being treated with daratumumab, 61.4 % of all patients developed HGGE; 42.2% of IgG patients and 87.1% of non-IgG patients. The mean Nadir IgG level for the IgG subtype cohort was 643.7 mg/dl and for the non-IgG cohort was 355.9 mg/dl. The incidence of significant infection in total group was 23.4% (21.7% in IgG vs 25.8% in non-IgG). Bacterial pneumonia and sepsis were the two most common infections. Despite the relatively high incidence of HGGE in this cohort, only 11 were treated with IVIG. (5 IgG vs 6 non-IgG). Using a univariate logistic regression model, Black/ African Americans and patients with higher baseline IgG were less likely, but non-IgG patients were more likely to develop HGGE (all p&lt;0.05) . Conclusion: Our study identifies a high incidence of meaningful HGGE in patients on daratumumab. In the non-IgG subtype, the relationship is straightforward, as any drop in IgG reflects a drop in polyclonal immunoglobulins and impaired humoral immunity. In contrast, in the IgG subtype, a fall in IgG levels has two components; a fall in the monoclonal protein (indicative of favorable disease response) as well as a fall in polyclonal IgG. There was a lower incidence of pre and post treatment HGGE in the IgG cohort compared to the non-IgG cohort( ie.IgA, IgD, Free Kappa and Free Lambda). In contrast the incidence of infection in both cohorts were very similar. This suggests that polyclonal HGGE in IgG subtype plasma cell disorders may be largely undetected and undertreated, due to apparently normal IgG levels caused by pathologic production of monoclonal IgG. When we attempt to subtract the monoclonal element (m-spike in the serum protein electrophoresis) from the total IgG, the magnitude of hypogammaglobulinemia in the IgG cohort approximates that of the non-IgG group. Given that daratumumab adds a small amount to the measured m-spike, further techniques to quantify true polyclonal IgG levels in the IgG cohort are needed. The incidence and depth of HGGE associated with daratumumab has not been previously well quantified. Our study demonstrates that the incidence of HGGE doubled after therapy with daratumumab (30.3% vs 61.4%). This data will sensitize physicians and possibly lead to generation of guidelines for closer monitoring of IgG, use of IVIG and other precautions in patients on daratumumab. In our own institution, we anticipate the detection of HGGE and use of IVIG in these patients to increase substantially. Disclosures Hoffman: Celgene: Speakers Bureau.

1391 Too Much of a Good Thing: HIV and Immune Reconstitution in a Patient With IGG4-Related Pancreatitis

INTRODUCTION: Autoimmune pancreatitis accounts for 2% of cases of chronic pancreatitis. Autoimmune pancreatitis is differentiated into Type I (IgG4-related disease) and Type 2 (with normal IgG4 levels). Nearly 40% of patients with IgG4-related pancreatitis have involvement of salivary or lacrimal glands. CASE DESCRIPTION/METHODS: A 65 year-old-female with a history of HIV on anti-retroviral therapy (ART) (CD4 count of 588 cells/uL and undetectable viral load) and submandibular gland swelling presented with two weeks of epigastric discomfort and watery yellow diarrhea. The patient was noted to have elevated alkaline phosphatase to 802 U/L, aspartate aminotransferase to 284 U/L, alanine aminotransferase to 518, as well as total bilirubin of 2.8 mg/dL and direct bilirubin of 1.8 mg/dL. Amylase was 79 u/L and Lipase was 75 u/L. Four months prior to admission ART was changed from emtricitabine/tenofovir/raltegravir to bictegravir/emtricitabine/tenofovir; at that time CD4 count was 318 cells/uL. Liver tests were normal at that time. ART was held at the time of admission. Abdominal ultrasound demonstrated a diffusely enlarged, hypoechoic pancreas, consistent with pancreatitis. Magnetic resonance cholangiopancreatography showed abnormal morphology of the pancreas with loss of lobulation in the distal pancreatic body and tail, as well as irregularity of the pancreatic duct. Endoscopic ultrasound-guided biopsy with biliary stenting was performed. Prednisone was started empirically at 1 mg/kg/day for suspected IgG4 pancreatitis with rapid improvement in symptoms and liver tests. ART regimen was resumed simultaneously. Biopsy showed fibrosis with chronic inflammation, as well as the presence of IgG4 positive plasma cells. One month later, the patient's liver tests have returned to baseline. DISCUSSION: In this patient with a recent change in ART medications and newly elevated liver enzymes, drug-induced liver injury (DILI) can be considered initially. Imaging in this case showed diffuse edema and pancreatitis. Recent research suggests that patients with IgG4-related disease have over-activity of a specific class of cytotoxic CD4+ T cells driving the cytokine release that leads to its characteristic fibrosis. We suspect that this patient's flare of IgG4 pancreatitis may have been triggered by a recent change in her ART regimen. This allowed proliferation of all CD4+ T cell lines, leading to an response resembling the Immune Reconstitution Inflammatory Syndrome, resulting in the patient's clinical presentation.

Obez çocuklarda alkolik olmayan yağlı karaciğer hastalığı ve eşlik eden diğer karaciğer hastalıkları

Objective: The prevalence of non-alcoholic fatty liver disease (NAFLD) in children increased parallel to the increment of childhood obesity. Also, NAFLD may be the presenting feature of different liver diseases in non-obese children. We aimed to determine whether there were co-existing liver diseases in overweight and obese children with NAFLD. Material and Methods: Pediatric gastroenterology outpatient clinic records of obese and overweight patients, aged between 5-18 years, were retrospectively reviewed. Seventy patients who had liver steatosis on ultrasonography, and alanine aminotransferase (ALT) levels were higher than 1.5 times the upper limit of normal were recruited to the study. The demographic findings, laboratory tests for infectious, metabolic, and autoimmune causes, abdominal ultrasonography and liver biopsy findings of patients were recorded. Results: At presentation, 94.2% of the patients (n: 66) had mild transaminase elevation. All patients were negative for viral hepatitis, anti-tissue transglutaminase immunoglobulin (Ig) A, anti-liver-kidney-microsome type 1 and anti-smooth muscle antibody. They had normal erythrocyte sedimentation rate (ESR) , C-reactive protein (CRP), ceruloplasmin, and total IgG levels . O nly one patient with low alpha-1 antitrypsin levels had heterozygotes of the PiMZ phenotype. Three (4.3%) patients had antinuclear antibody ( ANA) positivity. 44.7% of patients were given ursodeoxycholic acid treatment. On follow-up, normalization of ALT was achieved in 31 (44.2%) patients at mean 6.1 ±4.6 (2-19) months, but no relation was found between normalization and ursodeoxycholic acid treatment. A patient with ANA positivity had increased ALT, ESR , CRP , IgG levels and ANA titers o n follow-up, and she was diagnosed with autoimmune hepatitis with the support of liver biopsy. Under prednisolone and azathioprine treatment, ESR and IgG levels were normalized, ALT and ANA titers decreased. Conclusion: Other causes of chronic hepatitis should be screened in obesity-related non-alcoholic fatty liver disease and the development of autoimmune hepatitis should be kept in mind in the presence of ANA.

Safety and Efficacy of Belimumab Plus Standard Therapy for Up to Thirteen Years in Patients With Systemic Lupus Erythematosus.

ObjectiveTo investigate the long‐term safety and efficacy of intravenous (IV) belimumab plus standard of care (SOC) therapy for systemic lupus erythematosus (SLE) in patients with active, autoantibody‐positive SLE.MethodsThe study was designed as a multicenter, open‐label, continuation study of IV belimumab given every 4 weeks in conjunction with SOC therapy in patients with SLE who completed a phase II, double‐blind study. Adverse events (AEs) and laboratory data were monitored from the first belimumab dose (in either study) until 24 weeks after the final dose. Efficacy assessments included SLE Responder Index (SRI) and flare index scores (each assessed at 16‐week intervals) and glucocorticoid use (assessed at 4‐week intervals).ResultsOf the 476 patients in the parent study, 298 (62.6%) entered the continuation study, of whom 96 (32.2%) remained in the study. Patients received belimumab for up to 13 years (median duration of exposure 3,334.0 days [range 260–4,332 days], total belimumab exposure 2,294 patient‐years, median number of infusions 115.5 [range 7–155]). The percentage of patients with AEs each year remained stable or decreased. Normal serum IgG levels were maintained in the majority of patients over the study, and the rate of infections remained stable. The percentage of patients who achieved an SRI response increased from 32.8% (year 1) to 75.6% of those remaining on treatment at year 12. The glucocorticoid dose was decreased in patients who had been receiving >7.5 mg/day at baseline.ConclusionThis study is the longest to date to assess belimumab treatment in patients with SLE in clinical trials. Belimumab was well tolerated with no new safety concerns, and efficacy was maintained in patients who continued the study. For patients who initially exhibited a satisfactory response to belimumab, the treatment continues to be well tolerated and provides long‐term disease control.

A Rare Case of Malbranchea Species Pulmonary Infection in the Setting of Suspected Selective Immunoglobulin M Deficiency

Abstract Humoral immunodeficiencies are traditionally associated with prolonged and recurrent respiratory tract infections, including unusual pathogens. We describe a case of a 63-year-old man with a history of chronic obstructive pulmonary disease and recurrent pneumonias (including Pseudomonas) who presented with cough, dyspnea, and respiratory failure with computed tomography imaging showing bilateral consolidations and cavitary lesions. The bronchoalveolar lavage fungal culture grew Malbranchea species, whereas viral, bacterial, and mycobacterial cultures were negative. Because of multiple hospitalizations for pneumonia and the presence of this unusual pathogen, quantitative immunoglobulin levels were obtained, revealing an undetectable total immunoglobulin M (IgM) level (&lt;5 mg/dL) with normal levels of IgG (1270 mg/dL) and IgA (108 mg/dL). Complete blood count with differential and lymphocyte subsets (ie, CD4, CD8) showed no deficiency in immune cell counts, and human immunodeficiency virus antibody/antigen testing was negative. The patient improved clinically after antifungal therapy with posaconazole, and he additionally received prophylactic inhaled tobramycin given his history of recurrent pulmonary infections and suspected selective IgM deficiency.

Relapsing IgG4-related orbital inflammatory pseudotumor after achieving success with rituximab

IgG4-related disease (IgG4-RD) is a disease of fibroinflammatory with infiltration of IgG4-positive plasma cells. The lesions show focal or diffuse nodular formations in one or multiple organs; due to the infiltration of lymphocytes and plasma cells with fibrosis. The IgG4-DR is recognized as an important cause of idiopathic inflammatory disease that must be differentiated with other pathologies. The measurement of normal IgG4 levels is not enough to exclude IgG4-RD. The treatment covers the symptomatic aspect and use of systemic corticosteroids (CS), and immunomodulatory and biological therapy. The relapsing is might be misdiagnosis. We propose to consider the imaging follow-up for the therapeutic management

Screening for Humoral Immunodeficiency in Patients with Community‐Acquired Pneumonia

Immunodeficiency is an underrecognized risk factor for infections, such as community-acquired pneumonia (CAP). We evaluated patients admitted with CAP for humoral immunodeficiency. Prospective Cohort Study. Inpatients. We enrolled 100 consecutive patients admitted with a diagnosis of CAP from February 2017 to April 2017. Serum IgG, IgM, IgA, and IgE levels were obtained within the first 24 hours of admission. CURB-65 score and length of hospital stay were calculated. The Wilcoxon rank-sum test, Kruskal-Wallis test, and simple linear regression analysis were used in data analysis. The prevalence of hypogammaglobinemia in patients with CAP was 38% (95% confidence interval: 28.47% to 48.25%). Twenty-seven of 100 patients had IgG hypogammaglobinemia (median: 598 mg/dL, IQ range: 459-654), 23 of 100 had IgM hypogammaglobinemia (median: 38 mg/dL, IQ range: 25-43), and 6 of 100 had IgA hypogammaglobinemia (median: 36 mg/dL, IQ range: 18-50). The median hospital length of stay for patients with IgG hypogammaglobinemia was significantly higher when compared to patients with normal IgG levels (five days, IQ range [3-10] vs three days, IQ range [2-5], P = .0085). Fourteen patients underwent further immune evaluation, resulting in one diagnosis of multiple myeloma, three patients diagnosed with specific antibody deficiency, and one patient diagnosed with selective IgA deficiency. There is a high prevalence of hypogammaglobinemia in patients hospitalized with CAP, with IgG and IgM being the most commonly affected classes. IgG hypogammaglobinemia was associated with an increased length of hospitalization. Screening immunoglobulin levels in CAP patients may also uncover underlying humoral immunodeficiency or immunoproliferative disorders.

Duloxetine as a Primary Cause of Microscopic Colitis: A Case Report

Introduction: Lymphocytic colitis is a subtype of microscopic colitis (MC), an inflammatory condition characterized by excessive watery diarrhea and endoscopically normal colonic tissue. Many etiologies, including adverse effects from medications, are thought to lead to this condition via an exaggerated immune response. This is evident by lymphocyte aggregates visible on histological specimens. Case: This is a case of a 33-year-old female who presented with a chief complaint of loose, watery diarrhea of 4 weeks duration. She reported abdominal pain with up to 10 bowel movements per day. She denied any other symptoms, including GI alarm symptoms. Her pertinent medical history included GERD and fibromyalgia, managed with duloxetine for the past 4 months. Additional medications included gabapentin and valacyclovir. Other history included no recent use of antibiotics, travel, sick contacts, or changes in diet or medication. Initial stool studies noted a negative pathogen panel and normal pancreatic elastase level. However, fecal calprotectin and lactoferrin levels were elevated, raising the index of suspicion for an inflammatory process. Other labs included normal levels of TTG IgG and IgA antibodies, ESR, CRP, Saccharomyces cerevisiae IgG and IgA antibodies, and Anti-Neutrophil Cytoplasmic Antibodies. Colonoscopy was subsequently performed which noted a normal terminal ileum, scattered mild erythematous mucosa in the sigmoid colon, and internal hemorrhoids. Random and focused biopsies were obtained in the terminal ileum and throughout the colon. Small bowel biopsies were unremarkable. Biopsies of the ascending, transverse, descending, and sigmoid colon revealed colonic mucosa with acute and chronic inflammation in the lamina propria and chronic cryptitis. These findings were consistent with active MC, lymphocytic subtype. She subsequently began to decrease her dose of duloxetine with an eventual plan to discontinue the medication altogether. Budesonide was also prescribed for 8 weeks. Within 1 week, her symptoms improved. However, it was not until she fully discontinued the duloxetine that her symptoms completely resolved. Discussion: This patient's clinical course demonstrates a likely case of duloxetine induced MC. While there have been 6 published case reports of duloxetine induced MC, it remains a rarely reported entity. When evaluating for causes of MC, one should always pay close attention to a patient's medications as the possible causative agent.

Escitalopram Induced Pancreatitis: An Unusual Culprit

Drug-induced pancreatitis accounts for 3-5% of all cases of acute pancreatitis. Over 12% of US adolescents and adults use antidepressants. We hereby report a case of acute Escitalopram-induced non-necrotizing pancreatitis in a 27-year-old male complaining of epigastric pain. He had no family history of pancreatitis or pancreatic cancer, and reported drinking less than 2 alcoholic drinks weekly. His only medication was Escitalopram, which he started 2 weeks prior for panic disorder and denied any supplement use. His diagnostic evaluation revealed (a)A normal CBC and kidney function (b)Serum lipase of 1746 U/L (c) Abdomen CT-scan with no pancreatic masses and evidence of acute pancreatitis(d) Absence of gallstones, biliary sludge or CBD dilation on ultrasound (e)Normal serum glucose,calcium and triglyceride levels (f)Normal IgG and IgG subclass levels. Intravenous hydration was initiated, and Escitalopram was discontinued with complete symptom resolution in 4 days. No re-challenge was performed. A Naranjo adverse drug reaction score was 6 suggesting a probable reaction given no previous reports on Escitalopram. Three cases of sertraline-induced pancreatitis have been reported in the literature with a latency period of a few days to 4 weeks reported [1,2]. A population study in Taiwan suggest a class effect given an association between recent SSRI use and risk of acute pancreatitis [3]. This wasn't re-demonstrated in a different population cohort in Sweden, however, a much longer latency period was studied which is inconsistent with the reported cases [4]. Further research and population studies are required to better characterize the risk of drug-induced acute pancreatitis with SSRI use, given the high prevalence of use of these agents and the significant morbidity with this adverse effect.

Characterisation of immunoparesis in newly diagnosed myeloma and its impact on progression-free and overall survival in both old and recent myeloma trials

We measured immunosuppression at myeloma diagnosis and assessed the impact on survival in 5826 UK myeloma trial patients. Polyclonal immunoglobulin levels were below normal in 85% of patients and above normal in only 0.4% of cases for IgA, 0.2% for IgM and no cases for IgG. Immunoparesis had a greater impact in recent trials: median overall survival (OS) was up to 3 years longer for patients without immunoparesis compared to the old trials, less than 1 year longer. Median progression-free survival (PFS) was 39%, 36% and 57% longer for patients with normal IgG, IgA and IgM levels, respectively. The depth of IgM suppression, but not the depth of IgG or IgA suppression, was prognostic for survival: the most severely suppressed IgM tertile of patients OS was 0.9 years shorter than those in the top tertile, and 2.6 years shorter than OS of those with normal IgM levels (p = .007). The degree of suppression of polyclonal IgM levels below normal was associated with worse PFS (p = .0002). Infection does not appear to be the main mechanism through which immunoparesis affects survival. We hypothesise that IgM immunoparesis impacts through a combination of being associated with more aggressive disease and reduced immune surveillance against relapse.

Young Investigator: A Rare Case of Crohnʼs Disease-Associated Aortitis

RESULTS: A 33 year-old woman with history of Crohn's disease complicated by enteropathic arthropathies presented with symptoms of complete gastrointestinal obstruction. She had history of ongoing ileocolitis despite therapy with certolizumab. Due to persistent obstruction symptoms, she underwent an uneventful laparoscopic ileocecectomy. On post-operative day number two, she developed fever, chest pain, tachycardia and shortness of breath. Her WBC was elevated to 10 K/microL, with CRP 10 mg/L, total IgG and IgG2 noted to be elevated with normal IgG4 levels. Interferon release assay for tuberculosis was negative. A chest CT revealed ascending aortitis, which was later confirmed with MR angiography. She was started on high-dose corticosteroids and ultimately transitioned to infliximab (5 mg/kg) and subcutaneous methotrexate with resolution of aortitis on follow-up imaging. While her aortitis has remained in remission, her intestinal Crohn's symptoms and arthralgias are recurring despite recently increasing infliximab dose to 10mg/kg every 6 weeks, with therapeutic levels and no evidence of anti-infliximab antibodies. CONCLUSION(S): Extraintestinal manifestations (EIM) of inflammatory bowel disease are commonly found in approximately one-third of patients. They typically manifest as peripheral or axial arthropathies, dermatologic manifestations including pyoderma gangrenosum and erythema nodosum, ocular involvement including uveitis or episcleritis, and primary sclerosing cholangiopathy. While very uncommon, there also appears to be some degree of overlap between Crohn's disease and large vessel vasculitides. Initial evaluation should exclude diagnoses of Takayasu's arteritis, Behcet's disease, sarcoidosis, ankylosing spondylitis, and connective tissue disorders. Infectious etiologies such as tuberculosis and syphilis should also be eliminated. Upon exclusion of these disease processes causing aortic inflammation, the diagnosis of a Crohn's-related EIM should be considered. Only a few cases of aortitis associated with Crohn's disease have been reported in the literature but this appears to be a very rare phenomenon. Severe cases of aortitis carry the risk of aortic rupture when inflammation is left untreated. Fortunately, aortitis appears to be readily responsive to high dose corticosteroid therapy, as was the case in our patient. If significant valvular disease is present (i.e. severe aortic regurgitation), this may require valvular replacement surgery. Interestingly, there have been reports of Crohn's-related aortitis developing in the setting of anti-TNF therapy, again requiring corticosteroid therapy for resolution. As such, we will need to monitor our patient closely to detect any signs of recurrent aortitis.

Delayed diagnosis in X-linked agammaglobulinemia and its relationship to the occurrence of mutations in BTK non-kinase domains

ABSTRACTBackground: X-linked agammaglobulinemia (XLA) is characterized by the absence of immunoglobulin and B cells. Patients suffer from recurrent bacterial infections from early childhood, and require lifelong immunoglobulin replacement therapy. Mutations in BTK (Bruton’s Tyrosine Kinase) are associated with this phenotype. Some patients that present XLA do not show typical clinical symptoms, resulting in delayed diagnosis due to the lack of a severe phenotype. This study presents a report of five XLA patients from four different families and attempts to determine a relationship between delayed diagnosis and the occurrence of BTK mutations.Methods: Samples from patients with antibody deficiency were analyzed to determine BTK expression, immunophenotyping and mutation analysis. Clinical and laboratory data was analyzed and presented for each patient.Results: Most patients presented here showed atypical clinical and laboratory data for XLA, including normal IgM, IgG, or IgA levels. Most patients expressed detectable BTK protein. Sequencing of BTK showed that these patients harbored missense mutations in the pleckstrin homology and Src-homology-2 domains. When it was compared to public databases, BTK sequencing exhibited a new change, along with three other previously reported changes.Conclusions: Delayed diagnosis and atypical manifestations in XLA might be related to mutation type and BTK expression.

Elevated EBNA-1 IgG in MS is associated with genetic MS risk variants.

Objective:To assess whether MS genetic risk polymorphisms (single nucleotide polymorphism [SNP]) contribute to the enhanced humoral immune response against Epstein-Barr virus (EBV) infection in patients with MS.Methods:Serum anti-EBV nuclear antigen 1 (EBNA-1) and early antigen D (EA-D) immunoglobulin γ (IgG) levels were quantitatively determined in 668 genotyped patients with MS and 147 healthy controls. Anti–varicella-zoster virus (VZV) IgG levels were used as a highly prevalent, non-MS–associated control herpesvirus. Associations between virus-specific IgG levels and MS risk SNPs were analyzed.Results:IgG levels of EBNA-1, but not EA-D and VZV, were increased in patients with MS compared with healthy controls. Increased EBNA-1 IgG levels were significantly associated with risk alleles of SNP rs2744148 (SOX8), rs11154801 (MYB), rs1843938 (CARD11), and rs7200786 (CLEC16A/CIITA) in an interaction model and a trend toward significance for rs3135388 (HLA-DRB1*1501). In addition, risk alleles of rs694739 (PRDX5/BAD) and rs11581062 (VCAM1) were independently associated and interacted with normal EBNA-1 IgG levels. None of these interactions were associated with EA-D and VZV IgG titers.Conclusions:Several MS-associated SNPs significantly correlated with differential IgG levels directed to a latent, but not a lytic EBV protein. The data suggest that the aforementioned immune-related genes orchestrate the aberrant EBNA-1 IgG levels.

Chronic Pulmonary Aspergillosis Progressing to Invasive Disease

SESSION TITLE: Fungal Infections 1 SESSION TYPE: Affiliate Case Report Poster PRESENTED ON: Tuesday, October 31, 2017 at 01:30 PM - 02:30 PM INTRODUCTION: Pulmonary aspergillosis has a wide clinical spectrum. Distinctions can be made between invasive versus non-invasive disease and chronic versus acute disease; this helps guide treatment and follow-up. Our patient proposes an interesting discussion; she presents with an overlapping chronic clinical picture with features of both invasive (Chronic Necrotizing Pulmonary Aspergillosis (CNPA)) and non-invasive (Chronic Pulmonary Aspergillosis (CPA)) disease. CASE PRESENTATION: A 74-year old lady with a history of breast cancer (status-post lumpectomy and radiation), COPD, and smoking, presented complaining of fatigue and cough. A lesion in the chest was incidentally appreciated on screening mammogram. A chest X-ray demonstrated a nodule in the right upper lobe (RUL) of the lung. Suspecting malignancy, a PET scan was done demonstrating nodules in the RUL, right middle lobe, and left upper lobe, with imaging favoring an inflammatory versus malignant process. She was treated for an upper respiratory tract infection. On six week follow-up, her symptoms persisted and a CT-scan showed new nodules in the RUL and lingula. Needle biopsy showed fungal colonization, necrosis and giant cell reaction with adjacent fibrosis. Subsequent testing revealed elevated Aspergillus fumigatus IgE levels, normal IgG levels and negative Galactomannan antigen. She was treated with Itraconazole and remained stable without progression of disease. DISCUSSION: Pulmonary Aspergillosis often presents with non-specific symptoms overlying chronic respiratory disease. Our patient presented with cough and fatigue in the background of COPD and chest radiation. But for incidental mammogram findings, her symptoms could have been attributed to chronic disease and diagnosis may have been missed. A high index of suspicion is needed for timely intervention to prevent progression of disease. Classically, CPA presents with non-progressive nodules, fungal balls or peri-cavitary infiltration. Whereas CPNA presents with progressive infiltrates cavitating over 3 months or less. Our patient presented with lung nodules suggestive of nodular CPA. Subsequent development of new nodules indicated progression, raising suspicion for CPNA. Ultimately, biopsy findings did not demonstrate the cavitation characteristically seen in CPNA. Given concern for invasive disease, anti-fungals were prescribed. CONCLUSIONS: This unique case places the concept of CPA and CPNA being distinct entities under scrutiny. It suggests that they may represent a spectrum of the same disease. Our patient’s progression from non-invasive to invasive Aspergillosis could be attributed to localized pulmonary immunodeficiency secondary to emphysematous lung disease and radiation. It is important to suspect a necrotizing process with risk of fibrosis or invasion in patients with CPA, especially if localized lung immunosuppression is suspected. Reference #1: Pulmonary aspergillosis: a clinical review. Kousha M1, Tadi R, Soubani AO. Eur Respir Rev. 2011 Sep. DISCLOSURE: The following authors have nothing to disclose: Reema Qureshi, Patricia Russo-Magno No Product/Research Disclosure Information

Syphilitic Hepatitis

40 year-old woman with a history of Guillain-Barré syndrome, Bell's Palsy, hypertension, and migraines presented with jaundice with aspartate aminotransferase (AST) 172 U/L, alanine aminotransferase (ALT) 230 U/L, total bilirubin 6.0 mg/dL, direct bilirubin 3.6 mg/dL, and alkaline phosphatase 412 U/L. Full viral hepatitis serologies and anti-smooth muscle Ab were negative, anti-nuclear antibodies (ANA) was positive at 1:640 with a normal IgG level. MRI/MRCP demonstrated a normal appearing liver with a few prominent retroperitoneal lymph nodes. Labs on follow-up six weeks later demonstrated AST 144 U/L, ALT 222 U/L, total bilirubin 15.0, direct bilirubin 9.1, alkaline phosphatase 866 U/L with a positive Antimitochondrial Antibody (AMA) at 1:320. Percutaneous liver biopsy demonstrated organizing microabscesses, mild mixed portal inflammation with bile duct damage, endotheliitis of portal veins, and mild lobular mixed inflammation. After biopsy, she developed a hyperpigmented papulosquamous rash affecting bilateral palms and forearms. Serum rapid plasma regain (RPR) was 1:32768 with positive serum syphilis IgG Ab and negative HIV testing. She was treated with a two-week course of continuous IV Penicillin G 24 million units daily, with resolution of liver chemistries one-month later. While Warthin Starry stain of her liver biopsy at our institution was negative for spirochetes, the Centers for Diseases Control (CDC) reported positive Treponema spp. immunohistochemistry confirming syphilitic hepatitis. Liver abnormalities characterized by a disproportionally elevated alkaline phosphatase and normal or mildly increased bilirubin and aminotransferases are reported in 30-40% of early syphilis cases, and typically rapidly normalize with antibiotic treatment. However, severe cholestasis, jaundice, and one episode of acute liver failure has been reported. As in our patient, AMA positivity has been reported with syphilitic hepatitis. There are nine mitochondrial autoantigens (M1-9), of which M2 is specific for primary biliary cholangitis (PBC). In syphilis, antibodies to cardiolipin (M1) can form which explains the positive result. M1 and M2 can be distinguished by M2-specific ELISA testing. Early syphilis is on the rise in the US, and must remain on the differential for clinicians evaluating acute cholestatic liver injury. Furthermore, clinicians must be aware of the potential false-positive AMA, as the pattern of liver injury could be confused with PBC.Figure: Histologic sections of the liver demonstrate organizing microabscesses, composed of numerous neutrophils, lymphocytes, plasm cells, and histiocytes. H&E stain, original magnification 400x.Figure: Histologic sections of the hepatic portal tracts demonstrate mild mixed inflammation with bile duct damage (larger arrows) and endothelitis of portal veins (smaller arrows). Periportal hepatocytes show intracytoplasmic cholestasis (arrowheads). H&E stain, original magnification 400x.Figure: Hyperpigmented papulosquamous rash affecting the patient's bilateral palms and forearms.

A Case of IgG 4 Seronegative Type I Autoimmune Pancreatitis

Introduction IgG related diseases (IgG4-RD) are rather distinct autoimmune gastrointestinal conditions including autoimmune pancreatitis (AIP) and sclerosing cholangitis. Patients present with organomegaly or mass, lymphadenopathy, obstructive jaundice and weight loss. The most common extra-pancreatic finding of Type 1 AIP is IgG4 Sclerosing Cholangitis which resembles Primary Sclerosing Cholangitis or cholangiocarcinoma. Case 67 y.o male with PMH of GERD, presented with 2 wk H/O generalized abdominal discomfort, weight loss, fatigue and painless jaundice. Physical Exam: Vitals WNL and positive scleral icterus. Elevated LFTs, bilirubin and Ca 19-9 were detected with normal CEA. Total IgG: 12.9 and IgG4: 0.67. Autoantibody screen negative. CT Abd/pelvis showed mediastinal lymphadenopathy, bulky pancreatic head along with tiny foci of calcifications throughout and evidence of intra and extra-hepatic biliary dilatation. MRCP showed widespread intra-hepatic duct dilatation suggestive of PSC. ERCP showed 3cm stricture in CBD and biliary stricture involving both right and left hepatic ducts. Biopsy ruled out malignancy. Patient showed clinical and lab normalization after steroid therapy which was confirmed by normal internal MRCP. Based on this clinical response and radiological evidence, a seronegative AIP with extra-pancreatic IgG4 related SC was diagnosed. Discussion Type 1 AIP, the prototype of IgG4RD is prevalent worldwide, typically affecting middle aged and older men. Sensitivity and specificity of seropositive AIP have been found to be as low as 62% and 59% respectively and studies show IgG4 seronegativity in as many as 24% cases. Despite lack of serological and histological evidence, AIP with IgG4 related SC can still be diagnosed based on history, imaging and therapeutic response as also suggested by International Consensus Diagnostic Criteria (ICDC). Conclusion: This case stresses the advantage of timely identification and treatment of seronegative IgG4 AIP and SC. Normal IgG4 levels and lack of definite histology shouldn't exclude the diagnosis when there are characteristic clinical findings and extra-pancreatic manifestations, along with distinctive imaging results. It is imperative to treat patients with steroid trial and close clinical monitoring to avoid unnecessary pancreatobiliary procedures.