Differential sensitivity of the 2020 revised comprehensive diagnostic criteria and the 2019 ACR/EULAR classification criteria across IgG4-related disease phenotypes: results from a Norwegian cohort.

BACKGROUND: We investigated sensitivity of the 2020 Revised Comprehensive Diagnostic Criteria (RCD) and the 2019 ACR/EULAR classification criteria across the four identified IgG4-related disease (IgG4-RD) phenotypes: "Pancreato-Hepato-Biliary", "Retroperitoneum and Aorta", "Head and Neck-limited" and "Mikulicz' and Systemic" in a well-characterized patient cohort. METHODS: We included adult patients diagnosed with IgG4-RD after comprehensive clinical assessment at Oslo University Hospital in Norway. We assigned patients to IgG4-RD phenotypes based on pattern of organ involvement and assessed fulfillment of RCD and 2019 ACR/EULAR classification criteria. Differences between phenotype groups were analyzed using one-way ANOVA for continuous variables, and contingency tables for categorical variables. RESULTS: The study cohort included 79 IgG4-RD patients assigned to the "Pancreato-Hepato-Biliary" (22.8%), Retroperitoneum and Aorta" (22.8%) "Head and Neck-limited" (29.1%), and "Mikulicz' and Systemic" (25.3%) phenotype groups, respectively. While 72/79 (91.1%) patients in total fulfilled the RCD, proportion differed across phenotype groups and was lowest in the "Retroperitoneum and Aorta" group (66.7%, p < 0.001). Among the 57 (72.2%) patients meeting the 2019 ACR/EULAR classification criteria, proportion was again lowest in the "Retroperitoneum and Aorta" group (27.8%, p < 0.001). CONCLUSION: The results from this study indicate that IgG4-RD patients having the "Retroperitoneum and Aorta" phenotype less often fulfill diagnostic criteria and classification criteria than patients with other IgG4-RD phenotypes. Accordingly, this phenotype is at risk of being systematically selected against in observational studies and randomized clinical trials, with potential implications for patients, caregivers and future definitions of IgG4-RD.

Outcomes of extracorporeal life support for respiratory failure in children with primary immunodeficiencies.

OBJECTIVE: Extracorporeal Membrane Oxygenation (ECMO) may serve as a life-saving rescue therapy in critically ill children with respiratory failure. While survival rates of ECMO in children with secondary immunodeficiency is considered relatively poor, survival rates in children with primary immunodeficiencies (PID) has yet to be thoroughly investigated. DESIGN: Retrospective analysis of prospectively collected data from children (29 days-18 years old). PID patients were identified by using International Classification of Diseases (ICD) codes. SETTING: Data were retrieved from Extracorporeal Life Support Organization Registry (1989-2018). INTERVENTIONS: ECMO for a pulmonary support indication. The survival-to-discharge rate was calculated and factors influencing outcomes were compared between survivors and non-survivors. MEASUREMENTS AND MAIN RESULTS: A total of 73 eligible ECMO runs were included. The survival-to-discharge rate in pediatric PID patients was 45.2%. No differences were noted in survival based on type of immunodeficiency (p = 0.42) or decade of support (p = 0.98). There was no difference in the rate of pre-ECMO infection in survivors versus non-survivors (p = 0.69). The survival-to-discharge rate in patients with a culture positive infection during the ECMO run was 45.0% versus 45.3% in those with no infection (p = 0.98). In multivariate analysis, only cardiac complications (OR 5.09, 95% CI: 1.15-22.53), pulmonary complications (OR: 13.00, 95% CI: 1.20-141.25), and neurologic complications (OR: 9.86, 95% CI: 1.64-59.21) were independently associated with increased mortality. CONCLUSION: Children with a PID who require extracorporeal life support due to respiratory failure have a reasonable chance of survival and should be considered candidates for ECMO. The presence of a pre-ECMO infection should not be considered an ECMO contraindication.

Anti-Endothelial Cell Antibodies are not frequently elevated in hospitalized patients with COVID-19.

n/a.

Tocilizumab in addition to standard of care in the management of COVID-19: a meta-analysis of RCTs.

OBJECTIVE: We performed a systematic review and meta-analysis for exploring clinical benefits and safety of tocilizumab in addition to standard of care (SOC) in treating patients with coronavirus disease 2019 (COVID-19). METHODS: An electronic search was carried out in PubMed, EMBASE, Cochrane Library, and Science Direct, as well as in medRxiv preprint server, to identify eligible studies. Only randomized Controlled Trials (RCTs) that compared mortality events and/or adverse events between a tocilizumab + SOC group and a SOC-only control group were included. The primary outcome was 28-day mortality. Secondary outcomes include progression to severe disease, defined as need for mechanical ventilation (MV) or intensive care unit (ICU) admission, and adverse events (AE). RESULTS: A total of nine studies (6,490 participants) could be included in this meta-analysis, with 3,358 participants in the tocilizumab + SOC group and 3,132 participants in the SOC-only group. The overall mortality rate was lower in the tocilizumab group compared to the SOC-only group, though the difference was not statistically significant (odds ratio [OR], 0.87; 95% CI, 0.73-1.04; I2, 15%). This finding was unaffected by subgroup analyses based on initial use of steroids or mechanical ventilation at baseline. Patients receiving tocilizumab were 26% less likely to progress to MV, and this difference was statistically significant (OR, 0.74; 95% CI, 0.64-0.86; I2, 0%). Among patients who were not in ICU at randomization, the tocilizumab group had 34 % lower rate of ICU admission compared to the SOC-only group (OR, 0.66; 95% CI, 0.40-2.14; I2, 29%). The occurrence of serious infections was lower in the tocilizumab group (OR, 0.57; 95% CI, 0.36-0.89; I2, 21%). CONCLUSION: Tocilizumab is generally well-tolerated in COVID-19. Although this drug does not appear to have a significant benefits on survival, it may have a role in preventing progression to intensive care and MV.

Anti-Endothelial Cell Antibodies are not frequently elevated in hospitalized patients with COVID-19.

COVID-19 is now established to be associated with a thrombotic phenomenon, now called COVID-19 associated coagulopathy (CAC). Anti-Endothelial Cell Antibodies (AECA) are a heterogenous group of autoantibodies targeting various endothelial cell antigens or antigens adhering to endothelial cells, They are commonly observed in a variety of auto-immune and rheumatologic conditions, and were observed in patients with the severe acute respiratory syndrome (SARS) in 2005. We aimed to assess AECA status in patients with COVID-19 and their potential contributing role to endothelial injury and CAC. AECA identification was a relatively infrequent finding in COVID-19 patients on admission, and their presence, albeit in only 2/33 patients, was not associated with disease severity. However, as the autoantibodies were only measured at admission, we cannot exclude the possibility of pathogenic AECA developing later in the course of diseaseFurther studies using additional methods are needed to evaluate the presence and potential pathogenic role of AECA in later stages of COVID-19.

Complement levels at admission as a reflection of coronavirus disease 2019 (COVID-19) severity state.

Complement system hyperactivation has been proposed as a potential driver of adverse outcomes in severe acute respiratory syndrome coronavirus 2 infected patients, given prior research of complement deposits found in tissue and blood samples, as well as evidence of clinical improvement with anticomplement therapy. Its role in augmenting thrombotic microangiopathy mediated organ damage has also been implicated in coronavirus disease 2019 (COVID-19). This study aimed to examine associations between complement parameters and progression to severe COVID-19 illness, as well as correlations with other systems. Blood samples of COVID-19 patients presenting to the emergency department (ED) were analyzed for a wide panel of complement and inflammatory biomarkers. The primary outcome was COVID-19 severity at index ED visit, while the secondary outcome was peak disease severity over the course of illness. Fifty-two COVID-19 patients were enrolled. C3a (p = 0.018), C3a/C3 ratio (p = 0.002), and sC5b-9/C3 ratio (p = 0.021) were significantly elevated in with severe disease at ED presentation. Over the course of illness, C3a (p = 0.028) and C3a/C3 ratio (p = 0.003) were highest in the moderate severity group. In multivariate regression controlled for confounders, complement hyperactivation failed to predict progression to severe disease. C3a, C3a/C3 ratio, and sC5b-9/C3 ratio were correlated positively with numerous inflammatory biomarkers, fibrinogen, and VWF:Ag, and negatively with plasminogen and ADAMTS13 activity. We found evidence of complement hyperactivation in COVID-19, associated with hyperinflammation and thrombotic microangiopathy. Complement inhibition should be further investigated for potential benefit in patients displaying a hyperinflammatory and microangiopathic phenotype.

The anti-inflammatory cytokine response characterized by elevated interleukin-10 is a stronger predictor of severe disease and poor outcomes than the pro-inflammatory cytokine response in coronavirus disease 2019 (COVID-19).

OBJECTIVES: Severe coronavirus disease 2019 (COVID-19) is associated with a dysregulated immune state. While research has focused on the hyperinflammation, little research has been performed on the compensatory anti-inflammatory response. The aim of this study was to evaluate the anti-inflammatory cytokine response to COVID-19, by assessing interleukin-10 (IL-10) and IL-10/lymphocyte count ratio and their association with outcomes. METHODS: Adult patients presenting to the emergency department (ED) with laboratory-confirmed COVID-19 were recruited. The primary endpoint was maximum COVID-19 severity within 30 days of index ED visit. RESULTS: A total of 52 COVID-19 patients were enrolled. IL-10 and IL-10/lymphocyte count were significantly higher in patients with severe disease (p<0.05), as well as in those who developed severe acute kidney injury (AKI) and new positive bacterial cultures (all p≤0.01). In multivariable analysis, a one-unit increase in IL-10 and IL-10/lymphocyte count were associated with 42% (p=0.031) and 32% (p=0.013) increased odds, respectively, of severe COVID-19. When standardized to a one-unit standard deviations scale, an increase in the IL-10 was a stronger predictor of maximum 30-day severity and severe AKI than increases in IL-6 or IL-8. CONCLUSIONS: The hyperinflammatory response to COVID-19 is accompanied by a simultaneous anti-inflammatory response, which is associated with poor outcomes and may increase the risk of new positive bacterial cultures. IL-10 and IL-10/lymphocyte count at ED presentation were independent predictors of COVID-19 severity. Moreover, elevated IL-10 was more strongly associated with outcomes than pro-inflammatory IL-6 or IL-8. The anti-inflammatory response in COVID-19 requires further investigation to enable more precise immunomodulatory therapy against SARS-CoV-2.

Lymphopenia and neutrophilia at admission predicts severity and mortality in patients with COVID-19: a meta-analysis.

BACKGROUND: There is a compelling need to identify clinical and laboratory predictors of unfavorable clinical course and death in patients with coronavirus disease (COVID-19). A trend towards low lymphocyte count and high neutrophil counts in patients with poor outcomes has been reported by earlier studies. We aim to synthesize existing data evaluating the relationship between clinical outcomes and abnormal neutrophil and lymphocyte counts at admission in COVID-19 patients. METHODS: An electronic search was carried out in PubMed, China National Knowledge Infrastructure (CNKI) and Cochrane Central Register of Controlled Trials (CENTRAL) to identify eligible studies reporting frequency data on neutrophilia and lymphopenia at admission in hospitalization in COVID-19 patients. Pooled odds ratios of clinical outcomes for each parameter were calculated using Comprehensive Meta-Analysis. RESULTS: A total of 22 studies (4,969 patients) were included in this meta-analysis. Lymphopenia at admission was found to be significantly associated with increased odd of progression to severe disease (odds ratio [OR], 4.20; 95% confidence interval [95CI%], 3.46-5.09) and death (OR, 3.71; 95%CI, 1.63-8.44). Neutrophilia at admission was also found to be significantly associated with increased odd of progression to severe disease (OR, 7.99; 95%CI, 1.77-36.14) and death (OR, 7.87; 95%CI, 1.75-35.35). Subgroup analysis revealed that COVID-19 patients with severe lymphopenia (<0.5 x10×9/L) had 12-fold increased odds of in-hospital mortality. CONCLUSION: Admission lymphopenia and neutrophilia are associated with poor outcomes in patients with COVID-19. Regular monitoring and early and even more aggressive intervention shall hence be advisable in patients with low lymphocyte and high neutrophil counts. These variables may be useful in risk stratification models.

Lactate dehydrogenase levels predict coronavirus disease 2019 (COVID-19) severity and mortality: A pooled analysis.

Coronavirus disease 2019 (COVID-19) infection has now reached a pandemic state, affecting more than a million patients worldwide. Predictors of disease outcomes in these patients need to be urgently assessed to decrease morbidity and societal burden. Lactate dehydrogenase (LDH) has been associated with worse outcomes in patients with viral infections. In this pooled analysis of 9 published studies (n = 1532 COVID-19 patients), we evaluated the association between elevated LDH levels measured at earliest time point in hospitalization and disease outcomes in patients with COVID-19. Elevated LDH levels were associated with a ~6-fold increase in odds of developing severe disease and a ~16-fold increase in odds of mortality in patients with COVID-19. Larger studies are needed to confirm these findings.

Do sex-specific immunobiological factors and differences in angiotensin converting enzyme 2 (ACE2) expression explain increased severity and mortality of COVID-19 in males?

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), shares similarities with the former SARS outbreak, which was caused by SARS-CoV-1. SARS was characterized by severe lung injury due to virus-induced cytopathic effects and dysregulated hyperinflammatory state. COVID-19 has a higher mortality rate in men both inside and outside China. In this opinion paper, we describe how sex-specific immunobiological factors and differences in angiotensin converting enzyme 2 (ACE2) expression may explain the increased severity and mortality of COVID-19 in males. We highlight that immunomodulatory treatment must be tailored to the underlying immunobiology at different stages of disease. Moreover, by investigating sex-based immunobiological differences, we may enhance our understanding of COVID-19 pathophysiology and facilitate improved immunomodulatory strategies.

Hyperinflammation and derangement of renin-angiotensin-aldosterone system in COVID-19: A novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis.

Early clinical evidence suggests that severe cases of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are frequently characterized by hyperinflammation, imbalance of renin-angiotensin-aldosterone system, and a particular form of vasculopathy, thrombotic microangiopathy, and intravascular coagulopathy. In this paper, we present an immunothrombosis model of COVID-19. We discuss the underlying pathogenesis and the interaction between multiple systems, resulting in propagation of immunothrombosis, which through investigation in the coming weeks, may lead to both an improved understanding of COVID-19 pathophysiology and identification of innovative and efficient therapeutic targets to reverse the otherwise unfavorable clinical outcome of many of these patients.

Tubulointerstitial nephritis and uveitis syndrome. / Tubulointerstitiell nefritt og uveitt-syndrom.

BACKGROUND: Uveitis and acute renal failure can be seen in various immune-mediated systemic diseases. Here we present a case of a young man with a rare inflammatory oculorenal syndrome. CASE REPORT: A man in his thirties was admitted with a constellation of fatigue, flank pain, weight loss and bilateral acute anterior uveitis. Laboratory tests showed anaemia, leukocytosis with eosinophilia, as well as elevated creatinine and C-reactive protein, and urine analyses demonstrated mild proteinuria. Work-up excluded sarcoidosis, Sjögren's syndrome, systemic lupus erythematosus, ANCA-associated vasculitides, Behçet disease, spondyloarthritis and infection. Renal biopsy showed severe tubulointerstitial nephritis. INTERPRETATION: Following exclusion of the abovementioned disorders, a diagnosis of tubulointerstitial nephritis and uveitis (TINU) syndrome was made. TINU syndrome is a rare inflammatory disorder which can be diagnosed in patients presenting with uveitis and tubulointerstitial nephritis after exclusion of other causes of similar oculorenal involvement.

Tolerability and safety of long-term rituximab treatment in systemic inflammatory and autoimmune diseases.

Rituximab, an anti-CD20 monoclonal antibody causing selective B-cell depletion, is used for various systemic inflammatory and autoimmune diseases (SIADs). Long-term safety data on rituximab are limited. The objectives of this study were to evaluate the long-term safety and tolerability of rituximab treatment for SIADs. A retrospective, single-center observational study including all patients ≥ 16 years treated with rituximab for SIADs was performed. The electronic medical records were reviewed, and data concerning indication and duration of rituximab treatment, prior and concurrent immunosuppressive therapy, and adverse events such as infections requiring hospitalization, dysgammaglobulinemia and end organ damage, were collected. A total of 70 patients were included, with a median treatment duration of 54 months, ranging 30-138 months. The most common indications for rituximab treatment were granulomatosis with polyangiitis (22.9%), primary Sjögren's syndrome (20.0%) and systemic lupus erythematosus (14.3%). Infections and persistent dysgammaglobulinemia were the most common adverse events, occurring in 34.3% and 25.7%, respectively. A total of 64 infections were observed in 24 (34.3%) patients, including 1 case of fatal infection. Seventeen patients performed B-cell quantitation during the first 2 years following discontinuation, of which only four (19.0%) demonstrated B-cell reconstitution. End organ damage occurred in two patients, presenting as pyoderma gangrenosum and interstitial pneumonitis. No opportunistic infections were observed. Three patients died during the observational period, of which one was due to lethal infection. This study presents observational data with long treatment duration. It demonstrates that long-term rituximab treatment is relatively well tolerated, and that no cumulative side effects were observed.

Purple urine bag syndrome. / Lilla urinpose-syndrom.

BACKGROUND: Purple urine bag syndrome (PUBS) can occur in cases of bacteriuria with species expressing enzymes capable of converting tryptophan metabolites to red and blue pigments which are excreted in urine, leaving a characteristic purple colour. Risk factors include urinary catheterisation, constipation and chronic kidney disease. Treatment includes catheter replacement, and antibiotics in case of urinary tract infection. CASE PRESENTATION: A man in his 70s with myelodysplastic syndrome, stage 5 chronic kidney disease and chronic indwelling urinary catheterisation due to benign prostatic hyperplasia was admitted for transfusion for symptomatic anaemia. On the second day of hospitalisation, his urine turned purple. There was no sign of transfusion reaction, haemoglobinuria, myoglobinuria or bilirubinuria. Urine cultures were positive for Proteus vulgaris and Enterococcus faecalis, two species associated with PUBS. INTERPRETATION: The constellation was consistent with PUBS. His bacteriuria was considered colonisation not requiring antibiotic treatment. The catheter was replaced and the urine colour returned to normal.

The prevalence and anatomy of parathyroid glands: a meta-analysis with implications for parathyroid surgery.

PURPOSE: The anatomy of parathyroid glands (PTG) is highly variable in the population. The aim of this study was to conduct a systematic analysis on the prevalence and location of PTG in healthy and hyperparathyroidism (HPT) patients. METHODS: An extensive search of the major electronic databases was conducted to identify all studies that reported relevant data on the number of PTG per patient and location of PTG. The data was extracted from the eligible studies and pooled into a meta-analysis. RESULTS: The overall analysis of 26 studies (n = 7005 patients; n = 23,519 PTG) on the number of PTG showed that 81.4% (95% CI 65.4-85.8) of patients have four PTG. A total of 15.9% of PTG are present in ectopic locations, with 11.6% (95% CI 5.1-19.1) in the neck and 4.3% (95% CI 0.7-9.9) in mediastinum. The subgroup analysis of ectopic PTG showed that 51.7% of ectopic PTG in the neck are localized in retroesophageal/paraesophageal space or in the thyroid gland. No significant differences were observed between the healthy and HPT patients and cadaveric and intraoperative studies. CONCLUSIONS: Knowledge regarding the prevalence, location, and anatomy of PTG is essential for surgeons planning for and carrying out parathyroidectomies, as any unidentified PTG, either supernumerary or in ectopic location, can result in unsuccessful treatment and need for reoperation.

Fatigue in Mastocytosis: A Case Series.

PURPOSE: Accumulating evidence suggests that fatigue in chronic inflammatory diseases is generated in the brain by mechanisms involving proinflammatory cytokines. We recently reported a high prevalence of fatigue in patients with mastocytosis, a condition with a constant activation of mast cells and release of a variety of bioactive substances. This observation indicates that mast cells somehow could be involved in the biological mechanisms that generate fatigue. In this case series, we aim to describe how typical triggering factors of mastocytosis attacks, as reported by patients, are accompanied by increased fatigue. Possible mechanisms by which mast cells may contribute to the pathophysiology of fatigue are discussed. METHODS: Seven patients with mastocytosis were interviewed regarding triggers and clinical symptoms and signs of mastocytosis, including the presence and severity of fatigue. Fatigue severity during and between attacks was assessed using the fatigue Visual Analog Scale (fVAS). FINDINGS: The most important reported triggers were heat and/or cold, exercise, food, alcohol, and psychological stress. The median fatigue Visual Analog Scale scores were 80 (range 40-91) during attacks and 40 (range 30-72) between attacks Fatigue reportedly impaired social and recreational activities in all 7 patients, and influenced occupational activities in 6. IMPLICATIONS: This case series illustrates that fatigue is common and severe among patients with mastocytosis. Fatigue increases during attacks, which may indicate that mast cell-derived substances are directly involved in the pathophysiology of fatigue. Mast cells could be an underestimated cellular actor in fatigue and other conditions and thus may represent a potential therapeutic target.