Histiocitosis / Histiocytosis

Las histiocitosis son un grupo de enfermedades raras que se caracterizan por la inflamación y acúmulo de células derivadas de los monocitos y macrófagos en diferentes tejidos. La clínica es muy variable, desde formas leves con afectación de un solo órgano a formas multisistémicas graves que pueden comprometer la vida. Su diagnóstico se basa en la clínica, hallazgos radiológicos y la anatomía patológica. Se recomienda realizar una biopsia del tejido afecto en todos los casos dado que puede tener implicaciones terapéuticas. En este sentido, durante la última década se han identificado mutaciones en tejido afecto que condicionan activación de la vía de las proteínas cinasas activadas por mitógenos (MAPK/ERK) y fosfatidilinositol 3 kinasa (PI3K/AKT), en proporción variable, en función del tipo de histiocitosis. En esta revisión nos centramos fundamentalmente en la histiocitosis de células de Langerhans, la enfermedad de Erdheim-Chester y la enfermedad de Rosai-Dorfman (AU)

Histiocytosis is a group of rare diseases characterized by inflammation and accumulation of cells derived from monocytes and macrophages in different tissues. The symptoms are highly variable, from mild forms with involvement of a single organ to severe multisystem forms that can be life compromising. The diagnosis of histiocytosis is based on the clinic, radiological findings and pathological anatomy. A biopsy of the affected tissue is recommended in all cases as it may have therapeutic implications. During the last decade, some mutations have been identified in the affected tissue that condition activation of the MAPK/ERK and PI3K/AKT pathway, in a variable proportion depending on the type of histiocytosis. In this review we mainly focus on Langerhans Cell Histiocytosis, Erdheim-Chester Disease and Rosai-Dorfman Disease (AU)

[Histiocytosis]. / Histiocitosis.

Histiocytosis is a group of rare diseases characterized by inflammation and accumulation of cells derived from monocytes and macrophages in different tissues. The symptoms are highly variable, from mild forms with involvement of a single organ to severe multisystem forms that can be life compromising. The diagnosis of histiocytosis is based on the clinic, radiological findings and pathological anatomy. A biopsy of the affected tissue is recommended in all cases as it may have therapeutic implications. During the last decade, some mutations have been identified in the affected tissue that condition activation of the MAPK/ERK and PI3K/AKT pathway, in a variable proportion depending on the type of histiocytosis. In this review we mainly focus on Langerhans Cell Histiocytosis, Erdheim-Chester Disease and Rosai-Dorfman Disease.

Evaluation of Humoral and Cellular Immune Responses to the SARS-CoV-2 Vaccine in Patients With Common Variable Immunodeficiency Phenotype and Patient Receiving B-Cell Depletion Therapy.

Introduction: SARS-CoV-2 vaccines' effectiveness is not yet clearly known in immunocompromised patients. This study aims to assess the humoral and cellular specific immune response to SARS-CoV-2 vaccines and the predictors of poor response in patients with common variable immunodeficiency (CVID) phenotype and in patients treated with B-cell depletion therapies (BCDT), as well as the safety of these vaccines. Methods: From March to September 2021, we performed a prospective study of all adult patients who would receive the SARS-CoV-2 vaccination and were previously diagnosed with (i) a CVID syndrome (CVID phenotype group; n=28) or (ii) multiple sclerosis (MS) treated with B-cell depleting therapies three to six months before vaccination (BCD group; n=24). Participants with prior SARS-CoV-2 infection; or prior SARS-CoV-2 vaccine administration; or use of any immunosuppressant (except BCDT in MS group) were excluded. A group of subjects without any medical condition that confers immunosuppression and who met all study criteria was also assessed (control group; n=14). A chemiluminescence immunoassay was used to determine pre- and post-SARS-CoV-2 vaccine anti-S IgG antibodies. T-cell specific response was assessed by analysis of pre- and post-SARS-CoV-2 vaccination blood samples with an interferon-gamma release assay. The baseline blood sample also included several biochemical, haematological and immunological analyses. Results: SARS-CoV-2 vaccines are safe in immunocompromised patients, although their effectiveness was lower than in healthy individuals. CVID phenotype patients showed impaired humoral (29%) and cellular (29%) response, while BCD patients fundamentally presented humoral failure (54%). Low IgA values, low CD19+ peripheral B cells, low switched memory B cells, and a low CD4+/CD8+ ratio were predictors of inadequate specific antibody response in CVID phenotype patients. No factor was found to predict poor cellular response in CVID phenotype patients, nor a defective humoral or cellular response in BCD patients. Conclusion: The effectiveness of SARS-CoV-2 vaccines in CVID phenotype and BCD patients is lower than in healthy individuals. Knowledge of predictive factors of humoral and cellular response failure in immunocompromised patients could be very useful in clinical practice, and thus, studies in this regard are clearly needed.

Activación del Código Sepsis en urgencias: rendimiento de la escala q-SOFA respecto los criterios SIRS / Sepsis Code in emergency department: Performance of q-SOFA score compared to SIRS score

Introducción:El diagnóstico y el tratamiento precoces de la sepsis sigue siendo un reto en los servicios de urgencias hospitalarios.Objetivo:El objetivo es evaluar el rendimiento de la escala quick Sequential related Organ Failure Assessment (qSOFA) para la activación de un Código Sepsis en urgencias, respecto la aplicación de los criterios previos basados en los parámetros Systemic Inflammatory Response Syndrome (SIRS).Métodos:Se incluyeron los pacientes ≥18años que consultaron en un servicio de urgencias de un hospital de tercer nivel durante dos períodos de tiempo (mayo-octubre de 2015) mediante criterios SIRS (grupo SIRS), y en los mismos meses de 2017 mediante criterios qSOFA (grupo qSOFA).Resultados:Se analizaron 125 episodios: 70 correspondieron al grupo SIRS y 55 al grupo qSOFA. Los grupos fueron comparables respecto a antecedentes, con mayor presencia de enfermedad neoplásica en el grupo qSOFA. No se evidenciaron diferencias en la forma de presentación, la actuación realizada en urgencias, los ingresos en unidades de críticos, el uso de vasopresores o la estancia media hospitalaria entre los dos grupos. Sí se objetivó una mayor tasa de mortalidad a 30días en el grupo qSOFA (21,81% vs 4,3%; p=0,003). En el estudio multivariado destaca la enfermedad neoplásica como factor independiente de mal pronóstico (OR:5,36; p=0,01), y la activación mediante criterios SIRS como factor de buen pronóstico (OR:0,15; p=0,021).Conclusiones:La activación del Código Sepsis mediante criterios qSOFA comporta una disminución en la detección, con mayor mortalidad asociada. Es necesario buscar otras herramientas complementarias para la detección precoz de la sepsis en urgencias.(AU)

Introduction:The early diagnosis and treatment of sepsis remains a challenge in hospital emergency departments.Objective:The objective was to evaluate the performance of the qSOFA (quick Sequential related Organ Failure Assessment) for activating a Sepsis Code in the emergency department, compared to applying previous criteria based on SIRS (Systemic Inflammatory Response Syndrome).Methods:Patients ≥18years were included who consulted an emergency department of a tertiary hospital over two periods of time (May-October 2015), using SIRS criteria (SIRS Group) and over the same months in 2017 using qSOFA criteria (qSOFA Group).Results:One hundred and five episodes were analysed: 70 corresponded to the SIRS Group and 55 to the qSOFA Group. The groups were comparable in terms of history, with a greater presence of neoplastic disease in the qSOFA Group. No differences were observed in the form of presentation, the action taken in the emergency department, admissions to critical care units, use of vasopressors or mean hospital stay between the two groups. A higher 30-day mortality rate was observed in the qSOFA group (21.81% vs. 4.3%; P=.003). In the multivariate study, neoplastic disease was noteworthy as an independent factor of poor prognosis (OR 5.36; P=.01), and activation using the SIRS criteria as a factor of good prognosis (OR .15; P=.021).Conclusions:The activation of the Sepsis Code using qSOFA criteria results in a reduction in detection, with greater associated mortality. Other complementary tools need to be sought for the early detection of sepsis in the emergency department.

[Sepsis Code in emergency department: Performance of q-SOFA score compared to SIRS score]. / Activación del Código Sepsis en urgencias: rendimiento de la escala q-SOFA respecto los criterios SIRS.

INTRODUCTION: The early diagnosis and treatment of sepsis remains a challenge in hospital emergency departments. OBJECTIVE: The objective was to evaluate the performance of the qSOFA (quick Sequential related Organ Failure Assessment) for activating a Sepsis Code in the emergency department, compared to applying previous criteria based on SIRS (Systemic Inflammatory Response Syndrome). METHODS: Patients ≥18years were included who consulted an emergency department of a tertiary hospital over two periods of time (May-October 2015), using SIRS criteria (SIRS Group) and over the same months in 2017 using qSOFA criteria (qSOFA Group). RESULTS: One hundred and five episodes were analysed: 70 corresponded to the SIRS Group and 55 to the qSOFA Group. The groups were comparable in terms of history, with a greater presence of neoplastic disease in the qSOFA Group. No differences were observed in the form of presentation, the action taken in the emergency department, admissions to critical care units, use of vasopressors or mean hospital stay between the two groups. A higher 30-day mortality rate was observed in the qSOFA group (21.81% vs. 4.3%; P=.003). In the multivariate study, neoplastic disease was noteworthy as an independent factor of poor prognosis (OR 5.36; P=.01), and activation using the SIRS criteria as a factor of good prognosis (OR .15; P=.021). CONCLUSIONS: The activation of the Sepsis Code using qSOFA criteria results in a reduction in detection, with greater associated mortality. Other complementary tools need to be sought for the early detection of sepsis in the emergency department.

Pre-existing Autoantibodies Neutralizing High Concentrations of Type I Interferons in Almost 10% of COVID-19 Patients Admitted to Intensive Care in Barcelona.

BACKGROUND: It is important to predict which patients infected by SARS-CoV-2 are at higher risk of life-threatening COVID-19. Several studies suggest that neutralizing auto-antibodies (auto-Abs) against type I interferons (IFNs) are predictive of critical COVID-19 pneumonia. OBJECTIVES: We aimed to test for auto-Abs to type I IFN and describe the main characteristics of COVID-19 patients admitted to intensive care depending on whether or not these auto-Abs are present. METHODS: Retrospective analysis of all COVID-19 patients admitted to an intensive care unit (ICU) in whom samples were available, from March 2020 to March 2021, in Barcelona, Spain. RESULTS: A total of 275 (70.5%) out of 390 patients admitted to ICU were tested for type I IFNs auto-antibodies (α2 and/or ω) by ELISA, being positive in 49 (17.8%) of them. Blocking activity of plasma diluted 1/10 for high concentrations (10 ng/mL) of IFNs was proven in 26 (9.5%) patients. Almost all the patients with neutralizing auto-Abs were men (92.3%). ICU patients with positive results for neutralizing IFNs auto-Abs did not show relevant differences in demographic, comorbidities, clinical features, and mortality, when compared with those with negative results. Nevertheless, some laboratory tests (leukocytosis, neutrophilia, thrombocytosis) related with COVID-19 severity, as well as acute kidney injury (17 [65.4%] vs. 100 [40.2%]; p = 0.013) were significantly higher in patients with auto-Abs. CONCLUSION: Auto-Abs neutralizing high concentrations of type I IFNs were found in 9.5% of patients admitted to the ICU for COVID-19 pneumonia in a hospital in Barcelona. These auto-Abs should be tested early upon diagnosis of SARS-CoV-2 infection, as they account for a significant proportion of life-threatening cases.

Genetic Screening for TLR7 Variants in Young and Previously Healthy Men With Severe COVID-19.

Introduction: Loss-of-function TLR7 variants have been recently reported in a small number of males to underlie strong predisposition to severe COVID-19. We aimed to determine the presence of these rare variants in young men with severe COVID-19. Methods: We prospectively studied males between 18 and 50 years-old without predisposing comorbidities that required at least high-flow nasal oxygen to treat COVID-19. The coding region of TLR7 was sequenced to assess the presence of potentially deleterious variants. Results: TLR7 missense variants were identified in two out of 14 patients (14.3%). Overall, the median age was 38 (IQR 30-45) years. Both variants were not previously reported in population control databases and were predicted to be damaging by in silico predictors. In a 30-year-old patient a maternally inherited variant [c.644A>G; p.(Asn215Ser)] was identified, co-segregating in his 27-year-old brother who also contracted severe COVID-19. A second variant [c.2797T>C; p.(Trp933Arg)] was found in a 28-year-old patient, co-segregating in his 24-year-old brother who developed mild COVID-19. Functional testing of this variant revealed decreased type I and II interferon responses in peripheral mononuclear blood cells upon stimulation with the TLR7 agonist imiquimod, confirming a loss-of-function effect. Conclusions: This study supports a rationale for the genetic screening for TLR7 variants in young men with severe COVID-19 in the absence of other relevant risk factors. A diagnosis of TLR7 deficiency could not only inform on treatment options for the patient, but also enables pre-symptomatic testing of at-risk male relatives with the possibility of instituting early preventive and therapeutic interventions.

Methylprednisolone Pulses Plus Tacrolimus in Addition to Standard of Care vs. Standard of Care Alone in Patients With Severe COVID-19. A Randomized Controlled Trial.

Introduction: Severe lung injury is triggered by both the SARS-CoV-2 infection and the subsequent host-immune response in some COVID-19 patients. Methods: We conducted a randomized, single-center, open-label, phase II trial with the aim to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus plus standard of care (SoC) vs. SoC alone, in hospitalized patients with severe COVID-19. The primary outcome was time to clinical stability within 56 days after randomization. Results: From April 1 to May 2, 2020, 55 patients were prospectively included for subsequent randomization; 27 were assigned to the experimental group and 28 to the control group. The experimental treatment was not associated with a difference in time to clinical stability (hazard ratio 0.73 [95% CI 0.39-1.37]) nor most secondary outcomes. Median methylprednisolone cumulative doses were significantly lower (360 mg [IQR 360-842] vs. 870 mg [IQR 364-1451]; p = 0.007), and administered for a shorter time (median of 4.00 days [3.00-17.5] vs. 18.5 days [3.00-53.2]; p = 0.011) in the experimental group than in the control group. Although not statistically significant, those receiving the experimental therapy showed a numerically lower all-cause mortality than those receiving SoC, especially at day 10 [2 (7.41%) vs. 5 (17.9%); OR 0.39 (95% CI 0.05-2.1); p = 0.282]. The total number of non-serious adverse events was 42 in each the two groups. Those receiving experimental treatment had a numerically higher rate of non-serious infectious adverse events [16 (38%) vs. 10 (24%)] and serious infectious adverse events [7 (35%) vs. 3 (23%)] than those receiving SoC. Conclusions: The combined use of methylprednisolone pulses plus tacrolimus, in addition to the SoC, did not significantly improve the time to clinical stability or other secondary outcomes compared with the SoC alone in severe COVID-19. Although not statistically significant, patients receiving the experimental therapy had numerically lower all-cause mortality than those receiving SoC, supporting recent non-randomized studies with calcineurin inhibitors. It is noteworthy that the present trial had a limited sample size and several other limitations. Therefore, further RCTs should be done to assess the efficacy and safety of tacrolimus to tackle the inflammatory stages of COVID-19. Clinical Trial Registration: Identifier [NCT04341038/EudraCT: 2020-001445-39].

Clinical Significance of Indeterminate QuantiFERON-TB Gold Plus Assay Results in Hospitalized COVID-19 Patients with Severe Hyperinflammatory Syndrome.

Performance of the QuantiFERON-TB Gold Plus (QFT-Plus) assay could be affected by conditions of immune dysregulation. Little is known about the reliability of QTF-Plus in COVID-19 patients. Our aim was to determine the prevalence and the factors related to an indeterminate QFT-Plus test in COVID-19 hospitalized patients, and to analyze its relationship with in-hospital mortality. A retrospective analysis of all hospitalized COVID-19 patients on whom a QTF-Plus assay was performed in a tertiary care public hospital during the first epidemic wave in Spain (March-April 2020). Out of a total of 96 patients included, 34 (35.4%) had an indeterminate result, in all cases due to a lack of response in the mitogen control. Factors related to COVID-19 severity, such as higher lactate dehydrogenase (LDH) (odds ratio [OR] 1.005 [95% confidence interval [CI] 1.002-1.008]) and previous administration of corticosteroids (OR 4.477 [95% CI 1.397-14.345]), were independent predictors for indeterminate QFT-Plus assay. Furthermore, indeterminate results were more frequent among COVID-19 patients who died during hospitalization (29.1% vs. 64.7%; p = 0.005). We conclude that QFT-Plus assay yielded an unexpected, high prevalence of indeterminate results in severe COVID-19 patients. Factors related to worse COVID-19 outcome, such as LDH, as well as corticosteroid use before the QFT-Plus assay, seem to be predictors for an indeterminate result. The role of an indeterminate QFT-Plus result in predicting COVID-19 severity and mortality should be evaluated.

La activación de un código sepsis en urgencias se asocia a una menor mortalidad / Activation of a code sepsis in the emergency department is associated with a decrease in mortality

Objetivos: Evaluar el impacto de la implantación de un código sepsis (CS) en la evolución de pacientes con sepsis grave (SG)/shock séptico (SS). Determinar los factores independientes asociados a mortalidad. Método: Estudio de cohortes de pacientes con diagnóstico de SG/SS que consultaron en urgencias de un hospital terciario durante 6 meses. Se analiza el cumplimiento de las recomendaciones de la Surviving Sepsis Campaign, la estancia media, el ingreso en críticos y la mortalidad a 30 días. Se comparan 2 grupos: activación CS (A) y no activación (NA). Resultados: Se detectaron 114 episodios, 61,4% del grupo A y 38,6% del NA. El grupo A presenta con mayor frecuencia presión arterial sistólica<90mmHg (61,5% vs 34,4%; p=0,005) y el NA mayor elevación del lactato>3mmol/l (48,3% vs 80%; p=0,01) y foco abdominal (34,3% vs 13%; p=0,01). En el grupo A más frecuentemente se cursaron hemocultivos en la primera hora (95% vs 41,7%; p<0,001), se inició antibiótico precoz (76,9% vs 25%; p=0,005), se hizo reposición hídrica inicial (54,5% vs 18,2%; p=0,01) y se cumplieron globalmente los objetivos (31,4% vs 9,1%; p=0,006). El grupo NA tuvo mayor necesidad de ingreso en críticos (10% vs 36,4%; p<0,001), estancia hospitalaria (10,2días; desviación estándar 6,9 vs 14,4días; desviación estándar 5,8; p<0,001) y mortalidad (4,3% vs 34,1%; p<0,001). Una determinación de proteína C reactiva>200mg/l (odds ratio 33,7; p<0,001) y la no activación del código (odds ratio 13,3; p=0,001) resultaron factores independientes asociados a mortalidad. Conclusiones: La implantación de un CS mejora el cumplimiento de las recomendaciones y se asocia a una reducción de los ingresos en unidades de críticos, estancia media y mortalidad. La elevación de la proteína C reactiva y la no activación del código son factores independientes asociados a mortalidad. Existe un gran margen de mejora en la detección de los pacientes con SG/SS, así como en la optimización del tratamiento inicial en urgencias

Objectives: To evaluate the impact of a code sepsis (CS) activation, complying with recommendations, the evolution of patients with severe sepsis in the emergency room and determine independent factors associated to mortality. Method: All patients attending the emergency room with severe sepsis during a 6-month period were included. Complying with Surviving Sepsis Campaign recommendations, patients’ average stay, intensive care admissions and 30-day mortality were assessed. Two groups were compared: CS activation (A) and no activation (NA). Results: A total of 114 episodes were found, 61.4% belonging to group A and 38.6% to NA. Patients in group A presented hypotension more frequently (61.5% vs 34.4%; P=.005). Patients in group NA more frequently had lactate levels of >3mmol/L (48.3% vs 80%; P=.01), and abdominal focus of sepsis (34.3% vs 13%; P=.01). In group A, blood cultures were more frequently drawn in the first hour (95% vs 41.7%; P<.001), early antibiotic was administered (76.9% vs 25%; p=.005) and fluid replacement carried out (54.5% vs 18.2%; P=.01). Global achievement of CS objectives was higher in group A (31.4% vs 9.1%; P=.006). In group NA more patients were admitted to the intensive care unit (10% vs 36.4%; P<.001), had longer average stays (10.2 days SD 6.9 vs 14.4 days SD 5.8; P<.001) and a higher mortality rate (4.3% vs 34.1%; P<.001). CRP>200mg/l (OR 33.7; P<.001) and the no activation of CS (OR 13.3; p=.001) resulted in being independent factors associated with mortality. Conclusions: The implementation of a CS improves compliance with SSC recommendations and decreases intensive care admissions, average stays and mortality

Activation of a code sepsis in the emergency department is associated with a decrease in mortality. / La activación de un código sepsis en urgencias se asocia a una menor mortalidad.

OBJECTIVES: To evaluate the impact of a code sepsis (CS) activation, complying with recommendations, the evolution of patients with severe sepsis in the emergency room and determine independent factors associated to mortality. METHOD: All patients attending the emergency room with severe sepsis during a 6-month period were included. Complying with Surviving Sepsis Campaign recommendations, patients' average stay, intensive care admissions and 30-day mortality were assessed. Two groups were compared: CS activation (A) and no activation (NA). RESULTS: A total of 114 episodes were found, 61.4% belonging to group A and 38.6% to NA. Patients in group A presented hypotension more frequently (61.5% vs 34.4%; P=.005). Patients in group NA more frequently had lactate levels of >3mmol/L (48.3% vs 80%; P=.01), and abdominal focus of sepsis (34.3% vs 13%; P=.01). In group A, blood cultures were more frequently drawn in the first hour (95% vs 41.7%; P<.001), early antibiotic was administered (76.9% vs 25%; p=.005) and fluid replacement carried out (54.5% vs 18.2%; P=.01). Global achievement of CS objectives was higher in group A (31.4% vs 9.1%; P=.006). In group NA more patients were admitted to the intensive care unit (10% vs 36.4%; P<.001), had longer average stays (10.2 days SD 6.9 vs 14.4 days SD 5.8; P<.001) and a higher mortality rate (4.3% vs 34.1%; P<.001). CRP>200mg/l (OR 33.7; P<.001) and the no activation of CS (OR 13.3; p=.001) resulted in being independent factors associated with mortality. CONCLUSIONS: The implementation of a CS improves compliance with SSC recommendations and decreases intensive care admissions, average stays and mortality.