Systemic Inflammatory Symptoms Research Articles

A Case of Idiopathic Multicentric Castleman Disease Developing in a Patient with a History of Biopsy Proven Membranous Nephropathy

Abstract Introduction/Objective Idiopathic multicentric Castleman disease (iMCD) is a lymphoproliferative disorder involving two or more lymph node sites. It is usually associated with systemic inflammatory symptoms and organ dysfunction related to hypercytokinemia. Renal involvement in iMCD has only been described in a limited number of studies and case reports. Of note, only one previous case report has described results from renal biopsies taken prior to the development of iMCD. Methods/Case Report Our patient is a 43 year old female who was first diagnosed with membranous nephropathy in early 2020. She had PLA2 R negative and Exostosin-2 positive disease. Age appropriate screening for malignancy was unremarkable. She had positive ANA titres and normal complement levels but did not meet criteria for SLE per rheumatology. Her proteinuria was improved and maintained on Lisinopril for 3 years. In October 2023, her proteinuria suddenly increased. Repeat renal biopsy was unchanged from the initial biopsy. This time, she also noticed acute swelling over her subpectoral region. PET-CT scan revealed multiple areas of avid lymphadenopathy on either sides of the diaphragm but the highest yield PET- avidity was in the subpectoral region. Biopsy of the right subpectoral lymph node was performed. According to the WHO Classification, 5th edition, diagnostic criteria for iMCD-NOS was met with the histological features displaying grade 3 plasmacytosis, grade 2 regressed germinal centers, follicular dendritic cell prominence, increased hyperplastic follicles and increased vascularity. Immunohistochemical staining for CD138 highlighted abundant plasma cells, CD21 highlighted follicular dendritic cell prominence. Vascular proliferation was seen by CD34 staining. Kappa and Lambda- ISH demonstrated polytypic staining pattern and HHV-8 was negative. Results (if a Case Study enter NA) NA Conclusion There is a significant clinical, histologic and immunologic overlap between iMCD, autoimmune or infectious disorders and malignancy. HHV-8 negative/iMCD is less well understood and has no specific biomarkers. It is important to follow the available clinicopathologic diagnostic criteria for early diagnosis, follow up and treatment. Timely recognition can help prevent multiple organ system dysfunction, systemic inflammatory symptoms, cytopenias and polyclonal lymphoproliferation. Although the pathophysiology maybe unclear, this case may also suggest that in patients with a previously diagnosed membranous nephropathy, iMCD may play a role in recurrence and worsening of the disease.

Research Advances in Pathogenesis of Idiopathic Multicentric Castleman Disease

Idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening lymphoproliferative disorder involving systemic inflammatory symptoms,polyclonal lymphoproliferation,cytopenia,and multiple organ dysfunction.Although interleukin-6-mediated cytokine storm is thought to be the key driver of iMCD,more than 50% of the patients fail to respond to the treatments targeting interleukin-6 or its receptors.This underscores the urgent need to identify other cytokines and pathogenic pathways that may underlie iMCD.Fortunately,recent years have witnessed notable research advances in the pathogenesis of iMCD.This article reviews the latest progress in this field,aiming to provide a theoretical foundation for further research and facilitate the optimization of treatment strategies to improve the prognosis of the patients.

Vanishing Abdominal Aorta.

Fewer than 1% of Takayasu arteritis (TA) cases are diagnosed in individuals over 60 years old.1 Early-stage TA generally presents with nonspecific systemic inflammatory symptoms, which can progress to the chronic, fibrotic occlusive phase,2 although there is significant heterogeneity in disease activity.3.

Exploring Headaches in Pediatric Behçet Disease: Prevalence, Clinical Impact, and Management.

Behçet's Disease (BD), also recognized as Behçet Syndrome, manifests uniquely in pediatric populations as Pediatric Behçet's Disease (PBD), characterized by multisystemic inflammatory symptoms including recurrent oral and genital aphthae, and diverse ocular, vascular, and neurological involvements. This review elucidates the prevalence, burden, and management strategies of headaches in children with PBD, focusing on both primary headaches, such as migraine and tension-type headaches, and secondary headaches linked to systemic disease manifestations. It explores the pathophysiological underpinnings specific to PBD-related headaches and discusses the intricate relationship between systemic inflammatory processes and neurological symptoms. By examining the literature from 2004 to 2024, this study highlights the high frequency of headache in PBD patients, underscoring its diagnostic and clinical significance. We aim to provide a detailed understanding of headache management in PBD, emphasizing tailored therapeutic strategies that address the unique challenges faced by this patient population. This review also underscores the importance of comprehensive clinical evaluations to optimize outcomes and mitigate long-term sequelae, proposing that awareness and understanding of headache in PBD can significantly enhance both diagnosis and management.

Sharp corners of castleman diseaseclinical case

Castleman’s disease (CD) is a very rare condition that can occur at any age and affects 16:100000 patients/years. CD is characterized by systemic inflammatory symptoms, generalized lymphadenopathy, polyclonal lymphocyte proliferation and multiple organ system dysfunctions, often associated with autoimmune manifestations, which may precede diagnosis, may be identified concurrently or may follow diagnosis. The given article presents the major and minor criteria on the basis of which the diagnosis is established, as well as the importance of interdisciplinary work in identifying and making the differential diagnosis of the Castleman disease.

A rare manifestation of STING-associated vasculopathy with onset in infancy: a case report

BackgroundSTING-associated vasculopathy with onset in infancy (SAVI) is a rare type I interferonopathy caused by heterozygous variants in the STING gene. In SAVI, STING variants confer a gain-of-function which causes overactivation of type I interferon (IFN) signaling leading to autoinflammation and various degrees of immunodeficiency and autoimmunity.Case presentationWe report the case of a 5 year old child and his mother, both of whom presented with systemic inflammatory symptoms yet widely varying organ involvement, disease course and therapeutic response. Genetic testing revealed a heterozygous STING variant, R281Q, in the child and his mother that had previously been associated with SAVI. However, in contrast to previously reported SAVI cases due to the R281Q variant, our patients showed an atypical course of disease with alopecia totalis in the child and a complete lack of lung involvement in the mother.ConclusionsOur findings demonstrate the phenotypic breadth of clinical SAVI manifestations. Given the therapeutic benefit of treatment with JAK inhibitors, early genetic testing for SAVI should be considered in patients with unclear systemic inflammation involving cutaneous, pulmonary, or musculoskeletal symptoms, and signs of immunodeficiency and autoimmunity.

Periodontitis promotes bacterial extracellular vesicle-induced neuroinflammation in the brain and trigeminal ganglion.

Gram-negative bacteria derived extracellular vesicles (EVs), also known as outer membrane vesicles, have attracted significant attention due to their pathogenic roles in various inflammatory diseases. We recently demonstrated that EVs secreted by the periodontopathogen Aggregatibacter actinomycetemcomitans (Aa) can cross the blood-brain barrier (BBB) and that their extracellular RNA cargo can promote the secretion of proinflammatory cytokines, such as IL-6 and TNF-α, in the brain. To gain more insight into the relationship between periodontal disease (PD) and neuroinflammatory diseases, we investigated the effect of Aa EVs in a mouse model of ligature-induced PD. When EVs were administered through intragingival injection or EV-soaked gel, proinflammatory cytokines were strongly induced in the brains of PD mice. The use of TLR (Toll-like receptor)-reporter cell lines and MyD88 knockout mice confirmed that the increased release of cytokines was triggered by Aa EVs via TLR4 and TLR8 signaling pathways and their downstream MyD88 pathway. Furthermore, the injection of EVs through the epidermis and gingiva resulted in the direct retrograde transfer of Aa EVs from axon terminals to the cell bodies of trigeminal ganglion (TG) neurons and the subsequent activation of TG neurons. We also found that the Aa EVs changed the action potential of TG neurons. These findings suggest that EVs derived from periodontopathogens such as Aa might be involved in pathogenic pathways for neuroinflammatory diseases, neuropathic pain, and other systemic inflammatory symptoms as a comorbidity of periodontitis.

Impact of SARS-CoV-2 mRNA vaccine on arthritis condition in rheumatoid arthritis.

The SARS-CoV-2 mRNA vaccine has been reported to cause various adverse reactions, including the development or exacerbation of autoimmune diseases, but the adverse reactions and the effects of the vaccines on disease activity in patients with rheumatoid arthritis (RA) remain unknown. We therefore investigated the arthritis condition in RA patients after SARS-CoV-2 vaccination. RA patients who visited our hospital from January to April 2022 completed a questionnaire regarding adverse reactions to the SARS-CoV-2 vaccine. We compared the frequency and duration of post-vaccination arthralgia between RA patients and health care workers in our hospital. For the RA patients who reported post-vaccination arthralgia, we collected medical records for the 6 months after vaccination. Of the 1198 vaccinated RA patients, 256 (21.4%) had systemic inflammatory symptoms, 18 (1.5%) had allergies including urticaria and asthma, and 37 (3.1%) had arthralgia. A few patients had extra-articular manifestations such as acute exacerbation of interstitial lung disease. Compared with health care workers, RA patients more frequently developed arthralgia, and the arthralgia was longer lasting than that in controls: only 9 (0.8%) of the 1117 health care workers reported arthralgia, and all cases resolved within 3 days. Data from 31 of the 37 RA patients with post-vaccination arthralgia were further analyzed; in these patients, disease activity was highest after 2 months, and 10 patients required additional DMARDs within 6 months. The proportion of concomitant use of PSL at vaccination was higher in these patients. No patients on biological DMARDs or targeted synthetic DMARDs prior to vaccination needed additional DMARDs or a change of regimen. RA patients had more frequent and longer-lasting arthralgia after vaccination than healthy subjects, and one-third of patients with post-vaccination arthralgia required additional DMARDs. Although the SARS-CoV-2 mRNA vaccine was administered safely in most RA patients, in some patients RA symptoms may worsen after vaccination.

Clinical and vascular features of stroke in Takayasu's arteritis: A 24-year retrospective study.

To investigate the clinical characteristics, vascular imaging features, and prognosis of Takayasu's arteritis (TA) patients with stroke in China. Medical charts of 411 in-patients who fulfilled the classification criteria of modified 1990 American College of Rheumatology (ACR) criteria for TA and with complete data from 1990 to 2014 were reviewed retrospectively. The demographic data, symptoms and signs, laboratory test results, radiological features, treatment, and interventional or surgical procedures were collected and analyzed. Patients with radiological confirmed stroke were identified. Chi-square test or Fisher exact test was used to compare the differences between patients with and without stroke. Twenty-two patients with ischemic stroke (IS) and 4 patients with hemorrhagic stroke were identified. The incidence of stroke in TA patients was 6.3% (26/411), of which 11 patients were considered to be the initial manifestation. Stroke patients had more visual acuity loss (15.4% vs. 4.7%, P = 0.042). Systemic inflammatory symptoms and inflammatory markers were less common in patients with stroke than in those without stroke [fever P = 0.007; erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), P < 0.001]. Cranial angiography showed that common carotid artery (CCA) (73.0%, 19/26) and subclavian artery (SCA) (73.0%, 19/26) were the most involved, followed by internal carotid artery (ICA) (57.7%, 15/26) in stroke patients. The intracranial vascular involvement rate of stroke patients was 38.5% (10/26); the middle cerebral artery (MCA) was the most common artery involved. The most common site of stroke was the basal ganglia region. The occurrence of intracranial vascular involvement was much higher in patients with stroke when compared to patients without stroke (38.5% vs. 5.5%, P < 0.001). Among all patients with intracranial vascular involvement, patients without stroke received more aggressive treatment than patients with stroke (90.4% vs. 20.0%, P < 0.001). There was no significant increase in in-hospital mortality in patients with stroke compared with patients without stroke (3.8% vs. 2.3%, P = 0.629). Stroke is the initial presentation in 50% of TA patients with stroke. The intracranial vascular involvement rate is significantly increased in stroke patients than in patients without stroke. The artery invloved in patients with stroke are cervical artery and intracranial involvement. Systemic inflammation is less in patients with stroke. Aggressive treatment for TA with glucosteroid (GC) and immunosuppressive agents combined with anti-stroke therapy is needed to improve the prognosis of TA complicated stroke.

The first experience of using a comprehensive detailed ultrasound examination of the foot in patients with diabetes mellitus

IntroductionAssessment of amputation risk has been discussed more than once in the management of patients with diabetes. Systemic inflammatory symptoms can serve as signs of an infectious process. However, not all patients show exhibit these symptoms in a timely manner. At the same time, a decrease in pain, tactile and temperature sensitivity fails as a part of the main assessment of risk factors in diabetes mellitus. MethodsUsing examination methods and comparing with clinical experience and the results of other researchers, a pilot study was carried out to diagnose structural changes in the foot in patients with diabetes. Nested examinations were carried out in several stages, on the expert class medical ultrasonographic apparatus Siemens Acuson NX3. The methods of ultrasound diagnostics in the diabetic foot can be significantly helpful when using a scale of criteria and guidelines for the examination. ConclusionThe main diagnostic criterion for determining the risks of developing a diabetic foot condition, could be a gradual transition from the phase of compaction of hyaline cartilage to the phase of synovitis, and then to the phase of development of bone tissue necrosis related to a part of the Charcot’s foot. It leads to disruption of the musculoskeletal system of the foot, and atherosclerotic plaques and stenosis of the dorsalis pedis artery and first toe, which form a deterioration in the nutrition of the soft tissues of the foot with their necrosis.

1796. Evaluation of Asymptomatic Bacteriuria in Critical Access Hospitals

Abstract Background The University of Washington Tele-Antimicrobial Stewardship Program (UW-TASP) provides antimicrobial stewardship education and training to rural and critical access hospitals (CAHs) in the United States through collaborative tele-mentoring. In 2021, UW-TASP implemented a pilot stewardship cohort to reduce antibiotic treatment of asymptomatic bacteriuria (ASB). We sought to quantify the overall prevalence of ASB and proportion treated in participating hospitals. Methods Patients undergoing urine testing were identified through local electronic medical records and microbiology data. CAHs adjudicated their own cases and reported demographics, symptoms of urinary tract infection, systemic inflammatory response symptoms (SIRS), location at the time of culture, laboratory results, and antibiotic treatment through a RedCap collection tool. The data form was created and analyzed by UW-TASP faculty. This study was waived by the University of Washington institutional review board. Results Nineteen CAHs in 5 states participated in this pilot. Eight submitted urine analysis and culture data for 417 patients. Seventy-seven percent of patients were female and the median age was 70. The emergency department was the most common culture collection location (274/417, 66%), followed by ambulatory care clinics (111/417, 27%), and nursing facilities (13/417, 3%). SIRS criteria and/or organ dysfunction were present in 149/417 patients (36%). Two hundred sixty patients (62%) had a positive culture with Escherichia coli being the most common implicated organism (167/260, 64%). ASB was identified in 69/260 patients (27%), and antibiotics were prescribed for 53/69 (77%) of those with ASB. Oral antibiotics were prescribed for 311 (75%) patients. Of those, 22% were prescribed a fluoroquinolone. Median treatment duration was 7 days (range, 1-14). Conclusion Although the prevalence of ASB was only 27% among 417 patients, treatment of ASB was high at 77%. High numbers of culture collections from the emergency department and ambulatory care settings identify these locations as future foci for stewardship interventions in CAHs. Low hanging fruit for intervention include reducing unnecessary fluoroquinolone use and reducing duration of antibiotic therapy. Disclosures Chloe Bryson-Cahn, MD, Alaska Airlines: Advisor/Consultant.

S41 Unusual Case of Tongue Deviation

Case: Background: Anti-tumor necrosis factor-α (TNFα) therapy is the mainstay of treatment for inflammatory bowel disease such as Crohn’s Disease (CD) and ulcerative colitis (UC). Despite its widespread use, anti-TNFα leads to significantly altered inflammatory response and increased risk of severe skin and soft tissue infections. Here, we highlight an uncommon presentation of severe soft tissue infection in a patient with ileal CD maintained on anti-TNFα therapy. Case Presentation: A 50-year-old female with a 25-year history of Crohn's ileitis maintained on certolizumab for 3 years presented to the emergency department (ED) with an expanding left, lateral neck mass resulting in decreased cervical range of motion. This was accompanied by a left-sided tongue deviation. She first presented to our ED 8 weeks earlier with severe throbbing headaches without focal neurologic symptoms. A head MRI only showed non-specific T2/FLAIR hyperintensities. Her vital signs and labs were normal, and these headaches were presumed to be complex migraines. Three weeks after her first presentation, she came back to the ED with worsening headaches, neck pain and a new left-sided tongue deviation. Again, her vital signs and laboratory evaluation were normal apart from an ESR of 68 mm/hr (nl: 0-30 mm/hr) and CRP of 10.34 mg/dL (nl<0.5 mg/dL). Her repeat imaging studies did not show any evidence of stroke; however, opacification of the paranasal sinuses and left mastoid air cells were observed. Nonetheless, given her lack of systemic inflammatory symptoms, she was discharged home with close outpatient otolaryngology (ENT) referral. As an outpatient, she was diagnosed with bacterial sinusitis which was treated with a 15-day course of cefdinir and dexamethasone. Her symptoms initially improved; however, she eventually experienced dysphagia with pus drainage from her sinuses. Another antibiotic and steroid course was prescribed. Despite this, approximately 8 weeks after her initial presentation, she developed a rapidly expanding neck mass which prompted her return to the ED. Physical examination revealed a tender neck mass limiting her cervical range of motion and a more pronounced tongue deviation. She was afebrile, non-tachycardiac, and normotensive. Laboratory testing again revealed elevated inflammatory markers (ESR 83 mm/hr, CRP 8.59 mg/dL) but otherwise her WBC was normal (8310 cells/ µL, nl: 10400 cells/µL) with no evidence of sepsis-related end-organ dysfunction (Cr 0.89 mg/dL, AST 20, ALT 55 mg/dL, T-bili 0.3 mg/dL, platelets 348000 platelets/µL). Neck imaging showed multifocal ring-enhancing collections within the left paravertebral soft tissue with left hypoglossal nerve involvement. Intravenous vancomycin, cefepime, and metronidazole were started. Surgical debridement of the left posterior paraspinal abscess was performed. Intraoperative cultures were positive for Streptococcus anginosus. She completed a 6-week course of ceftriaxone but follow up imaging 2 weeks later showed recurrence of her neck abscesses. This again required surgical debridement. Her infections finally cleared with 24 weeks of piperacillin/tazobactam. Her certolizumab remains permanently discontinued. Conclusions: Hallmark symptoms of severe infection may not be present in patients on anti-TNF therapy. A high index of suspicion for an underlying infectious etiology must be maintained when treating this population.

Phase II Study of a JAK1/2 Inhibitor Ruxolitinib for Systemic Chronic Active Epstein-Barr Virus Disease: An Investigator-Initiated Trial

Background: Systemic chronic active Epstein-Barr virus disease (sCAEBV) is a rare EBV-positive T- or NK-lymphoproliferative disease. Although the only curative treatment for sCAEBV available now is allogeneic hematopoietic stem cell transplantation (allo-HSCT), the presence of disease activity, persistent inflammation, at the time of allo-HSCT is associated with poor outcomes (Am J Hem.2022, 97, p780). STAT3 is constitutively activated contributing to cytokine production and cell survival of EBV-infected cells in sCAEBV (Oncotarget. 2019, 9, p31077). Thus, STAT3 inhibition by ruxolitinib, a JAK1/2 inhibitor, may be effective against disease activity of sCAEBV. Methods: We conducted an investigator-initiated trial of open-label, phase 2, prospective and multicenter to assess the efficacy and safety of ruxolitinib in sCAEBV patients with disease activity. The diagnostic criteria were as follows: elevated EBV-DNA load in the peripheral blood (PB) (>102.5 copies/µg DNA); EBV infected T or NK cells detected in affected tissues or PB; systemic inflammatory symptoms persisting for more than three months; exclusion of other possible diagnoses, such as immune deficiencies, autoimmune diseases, or lymphoma (Blood adv. 2021, 4, p2918). sCAEBV patients ≥13 y.o. with fever (≥ 37.5 ºC), and/or liver dysfunction (ALT ≥ 2.0 × ULN) were enrolled. Anti-VCA-IgM-positive patients were excluded. The initiation dose of ruxolitinib was 5-20 mg twice a day determined by the platelet count in PB. The treatment effects were classified as complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD). CR was defined as the disappearance of all the elements of disease activity such as fever, liver dysfunction, uveitis, progressive skin lesions, and vasculitis. PR was defined as the disappearance of at least one of the elements listed above. PD was defined as the conversion to active disease, exacerbation of active disease, or the development of overt T- or NK-cell lymphoma. SD was defined as presenting no progression. Ruxolitinib was administered for eight weeks. If CR was observed and allo-HSCT was scheduled, ruxolitinib was terminated early even if these events had occurred within less than eight weeks after initiating investigational drug administration. The primary endpoint of efficacy assessments was CR rate at eight weeks after the initiation of drug administration or at the time of early termination. Safety was assessed based on the frequency of adverse events defined by Common Terminology Criteria for Adverse Events, version 4.0. Results: Nine patients were enrolled between January 2019 and August 2021; five males and four females aged 13-64 y.o.; median age of 40 y.o. The types of EBV-infected cells were as follows: four were CD4, one was CD8, and four were CD56. Seven patients completed the study. Five among them received ruxolitinib for eight weeks and were treated as outpatients. Two patients fulfilled the criteria of early termination and each was treated for 35 and 12 days. The responses are shown in the figure. CR rate and OR rate after eight weeks or at early termination, the primary and the secondary endpoints were 28.6% (2/7) and 42.9% (3/7), respectively. No one showed progressive disease. One patient developed a grade 4 adverse event of oral bleeding during the treatment and resulted in discontinuing the administration of ruxolitinib on day 13. Seven patients received allo-HSCT. Five patients achieved undetectable level of EBV-DNA PB after allo-HSCT. Conclusion: The results indicate that ruxolitinib has demonstrated encouraging effects and is a potent therapeutic reagent against sCAEBV with active disease. Further analysis shall complete its assessment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

IL-17A )rs2275913; G197A) gene polymorphism as predictor for disease severity and its correlation with IL-17 serum levels in COVID-19 patients

Severity of symptoms in COVID-19 has been shown to result from a cytokine storm. Interleukin (IL)-17 is one of these various cytokines, which results in a proinflammatory response, systemic inflammatory symptoms, inflammatory cell infiltration of lung tissue and thus leads to the massive lung pathology and multiorgan failure. Gene polymorphisms in the regulatory regions of cytokine-encoding genes affect the amounts of cytokines produced and possess a fundamental role in infectious diseases. This study aimed to investigate the role of IL-17A (rs2275913; G197A) gene polymorphism as predictor of disease severity and its correlation with IL-17 serum levels in COVID-19 patients. A group of 70 COVID-19 patients and 17 age and sex-matched control subjects were enrolled in the present work. Patients were classified into two groups moderate, severe and acute respiratory distress (ARDS) cases, defined according to the criteria established by the world health organization. Quantitative real time-polymerase chain reaction was done to detect IL-17A (rs2275913; G197A). Serum IL-17 levels were assessed by an enzyme-linked immunosorbent assay in both patients and controls. The distribution of different IL-17A G/A genotypes among COVID-19 patients were 44.3% for GG genotype, 44.3% for AG genotype and 11.4% for AA genotype. Genotypes among the control group were 43.8% for GG genotype, 50% for AG genotype and 6.3% for AA genotype. G allele distribution was 66.4%, 68.8% in patient and control group, respectively, and A allele was 33.6% and 31.3%, respectively. There was no association between the different genotypes, disease severity or IL-17 serum levels in the patient group. In conclusion, despite the possible role of IL-17 in the pathogenesis of inflammation, there was no association between IL-17 polymorphism and disease severity or IL-17 serum levels among Egyptian COVID-19 patients.

Auditory and Vestibular Characteristics of NLRP3 Inflammasome Related Autoinflammatory Disorders: Monogenic Hearing Loss Can Be Improved by Anti-interleukin-1 Therapy.

Inflammasomes are large multimeric protein complexes which regulate the activation of the proinflammatory cytokines interleukins-1β and−18 and inflammatory cell death called pyroptosis. NLRP1, NLRP3, NLRC4, AIM2, and pyrin can induce the formation of inflammasomes. Of these, the NLRP3 inflammasome is the most well-characterized. Recent studies revealed that variants of the NLRP3 gene cause genetic diseases, including systemic inflammatory syndrome called cryopyrin-associated periodic syndrome (CAPS) and non-syndromic sensorineural hearing loss DFNA34. NLRP3 variants cause CAPS and DFNA34 by constitutively activating the NLRP3 inflammasome and increasing IL-1β release. Patients with CAPS show systemic inflammatory symptoms, and hearing loss is a characteristic feature. Patients with CAPS and DFNA34 show progressive bilateral sensorineural hearing loss. Hearing loss has unique characteristics that can be improved or stabilized by anti-interluekin-1 therapy, although it is usually difficult to alleviate genetic hearing loss by drugs. However, it should be noted that there is a window of opportunity to respond to treatment, and younger patients are most likely to respond. It is important to know the characteristics of CAPS and DFNA34 for early diagnosis, and mutation analysis of NLRP3 will lead to a definite diagnosis. In this review, we summarize the current understanding of the mechanisms of the NLRP3 inflammasome and characteristics of patients with CAPS and DFNA34, especially focused on auditory and vestibular findings.

Treatment and Outcome in Deficiency of Adenosine Deaminase 2: A Literature Review.

Deficiency of adenosine deaminase 2 (DADA2) is a rare disease with varying phenotypes and disease outcomes. We evaluated the treatment of DADA2 and explored the factors associated with disease outcome. A systemic literature review of DADA2 was conducted. Cases were included if they had documented detailed genotypes, phenotypes, treatment protocols, and outcomes. Patients were categorized as having uncontrolled and controlled disease. Factors associated with disease outcome were analyzed using logistic regression models. The study population comprised 242 DADA2 patients with data on treatment protocols and responses, of whom 17 required no treatment. Tumor necrosis factor a inhibitors (TNFi) were effective in 78.6% (103/131). Hematological abnormalities and increased acute phase reactants are independently associated with the effectiveness of TNFi (OR, 0.21 [95%CI, 0.07-0.661; P=.007] and 9.62 [95%CI, 2.31-40.00; P=.002, respectively). Among the 225 patients requiring active treatment, 157 (69.8%) had controlled disease and 68 (30.2%) uncontrolled disease. Neither age of disease onset nor genotype was associated with disease outcome. Increased acute phase reactant values, constitutional symptoms, neurological symptoms, and treatment with TNFi were independently associated with disease control, while recurrent infections and severe vascular events were the main causes of mortality (10/21 and 6/21, respectively). In patients requiring treatment, symptoms of systemic inflammation and vasculitis and treatment with TNFi are associated with disease control. Recurrent infections and severe vascular events should be treated intensively, as they are the main causes of death. Hematological abnormalities should be monitored, as they decrease the effectiveness of TNFi.

REVOLUTION (Routine EValuatiOn of people LivIng with caNcer)—Protocol for a prospective characterisation study of patients with incurable cancer

IntroductionThere is a pressing need for a holistic characterisation of people with incurable cancer. In this group, where quality of life and improvement of symptoms are therapeutic priorities, the physical and biochemical manifestations of cancer are often studied separately, giving an incomplete picture. In order to improve care, spur therapeutic innovation, provide meaningful endpoints for trials and set priorities for future research, work must be done to explore how the tumour influences the clinical phenotype. Characterisation of the host-tumour interaction may also provide information regarding prognosis, allowing appropriate planning of investigations, treatment and referral to palliative medicine services.MethodsRoutine EValuatiOn of people LivIng with caNcer (REVOLUTION) is a prospective observational study that aims to characterise people with incurable cancer around five key areas, namely body composition, physical activity, systemic inflammatory response, symptoms, and quality of life by developing a bio-repository. Participants will initially be recruited from a single centre in the UK and will have assessments of body composition (bio-impedance analysis [BIA] and computed tomography [CT]), assessment of physical activity using a physical activity monitor, measurement of simple markers of inflammation and plasma cytokine proteins and three symptom and quality of life questionnaires.DiscussionThis study aims to create a comprehensive biochemical and clinical characterisation of people with incurable cancer. Data in this study can be used to give a better understanding of the ‘symptom phenotype’ and quality of life determinants, development of a profile of the systemic inflammatory response and a detailed characterisation of body composition.

Comparison of enzyme-linked fluorescent assay and electrochemiluminescence immune assay in procalcitonin measurement

Abstract Background Procalcitonin (PCT) measurement is required for intensive care patients with systemic inflammation symptoms, early diagnosis of possible infections, and evaluation of sepsis severity and prognosis. Objectives We aimed to determine the analytical performance of PCT measurement in a Roche Modular E170 (ECLIA) analyzer and compare the performance with VIDAS (BRAHMS/ELFA) analyzer findings. Material and methods Within-day and between-day precision value, linearity was determined, and two methods were compared with regression and Bland–Altman analysis. Results Both ECLIA and ELFA assays indicated excellent precision, where within-day precision varied between 1.18% and 3.97% CV, and between-day precision varied between 1.77% and 3.93% CV. The ECLIA method was linear up to 62.15 ng/mL. The arithmetic mean was 6.02 ng/mL with the ECLIA method and 8.02 ng/mL with the ELFA method. The correlation coefficient was r=0.996 and p=0.001. The correlation was linear between the two methods. Regression equation was found y=0.78x − 0.23. The Bland–Altman figure was revealed the difference between the methods was specifically in lower concentrations (&lt;0.15 ng/mL). Conclusions Both methods show good precision and correlation. It was determined that the difference between methods was significant, especially at &lt;0.15 ng/mL concentration.

Red Blood Cell Morphological Changes and Enlarged Platelets Found in Idiopathic Multicentric Castleman Disease

BACKGROUNDIdiopathic multicentric Castleman disease (iMCD) is a rare polyclonal lymphoproliferative disorder characterized by systemic inflammatory symptoms, cytopenias, generalized lymphadenopathy, and multiple organ system dysfunction. iMCD is subclassified into iMCD-TAFRO, with thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis/renal failure, and organomegaly, and iMCD-NOS (not otherwise specified), with high platelet counts and hypergammaglobulinemia. Despite recent diagnostic guidelines, iMCD diagnosis remains challenging because many of the histopathologic features and clinical/laboratory abnormalities are non-specific. Characterization of easily measurable findings from minimally invasive procedures, such as peripheral blood smear, could help to improve the accuracy of diagnosis as well as potentially providing insights into disease pathogenesis. Peripheral blood smears are often performed during routine clinical evaluation and enable morphologic evaluation of red blood cells (RBCs) and white blood cells (WBCs). In this study, we systematically characterized peripheral blood smear morphologic findings in iMCD for the first time.METHODSPeripheral blood smear morphologic findings in medical records from 68 iMCD patients, who were enrolled in an international registry for CD patients and had been confirmed to meet iMCD criteria by an expert panel, were reviewed and analyzed. Patients were also categorized into iMCD-TAFRO (N=39) or iMCD-NOS (N=29) based on clinical and laboratory data. Two-sample proportion tests were used to compare the frequency of features between iMCD-TAFRO and iMCD-NOS, when the abnormality was present in ≥ 5 subjects in both subtypes. P-value correction was not performed as findings are preliminary and hypothesis generating.RESULTSAmong the 68 iMCD patients, average age was 35.8 years (14-61); 46% were female, 54% were male; racial distribution was 62% white; 10% Black; 15% Asian; 13% other. The most common peripheral blood smear findings across all iMCD patients included abnormalities in RBC size and color, with anisocytosis (58.8%), polychromasia (57.4%), hypochromia (55.9%), and microcytosis (50.0%) being the most prevalent findings in the overall cohort (Table 1). Other RBC abnormalities were observed but less frequently, including abnormalities in shape such as poikilocytosis (44.1%). Giant or large platelets were found in 47% of iMCD cases. Abnormalities in WBCs, including toxic granulation, atypical lymphocytes, and toxic vacuolization, were detected less frequently. When comparing the two clinical subtypes, patients with iMCD-TAFRO had more frequent anisocytosis (p=0.043), hypochromia (p=0.002), polychromasia (p=0.022), and giant/large platelets (p<0.001) versus iMCD-NOS.DISCUSSIONHere, we have characterized peripheral blood morphologic abnormalities in iMCD for the first time. The most common findings in this cohort included abnormalities in RBC size and color. These abnormalities can be found in a number of conditions, including myelofibrosis, autoimmune diseases, and other inflammatory conditions. In iMCD, they are likely related to cytokine-driven anemia of chronic inflammation. The presence of large or giant platelets in nearly half of iMCD patients, with significantly more in iMCD-TAFRO than iMCD-NOS, is particularly notable since this has not been described in iMCD. These enlarged platelets, which can be found in immune thrombocytopenic purpura, myeloproliferative disorders, pseudothrombocytopenia, and inherited platelet disorders, may reflect hyperactivity of megakaryocytes and/or early release from the bone marrow in response to peripheral platelet sequestration. Though less common in this cohort, there are additional changes in RBC shape and WBC features that may be more specific to iMCD and potentially informative in increasing the index of suspicion for iMCD. These findings suggest that the peripheral blood smear may be able to support the diagnosis of iMCD and result in faster treatment administration. Future work is needed to determine whether the constellation of findings in the peripheral blood identified herein is unique to iMCD or seen in various other infectious, malignant, and autoimmune diseases. [Display omitted] DisclosuresFajgenbaum: Pfizer: Other: Study drug for clinical trial of sirolimus; EUSA Pharma: Research Funding; N/A: Other: Holds pending provisional patents for ‘Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition’ and ‘Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease’.

A Rare Lymphoproliferative Disease: Castleman Disease

Castleman disease is a rare lymphoproliferative disease also known as angiofollicular lymph node hyperplasia. It is classified as hyaline vascular and plasmacytic variants histologically but characteristics of both types can coexist. Most unicentric cases of the disease are hyaline vascular while most multicentric cases are of the plasmacytic type. Although the pathogenesis is not completely understood, the role of interleukin (IL)-6 in unicentric disease and the roles of IL-6 and human herpes virus-8 in multicentric disease are well defined. Unicentric disease is typically localized and symptoms are minimal and treated locally. Multicentric disease is systemic and clinically characterized by generalized lymphadenopathy, splenomegaly, anemia, and systemic inflammatory symptoms. Systemic therapies are primarily given. Several malignant diseases including lymphomas, POEMS syndrome, follicular dendritic cell sarcomas, paraneoplastic pemphigus, Kaposi sarcoma, and amyloidosis can be associated with Castleman disease. In this paper, recent information about Castleman disease, which is a rare disease, is summarized.