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BACKGROUND: The modulating effect of vitamin D on cytokine concentrations in severe coronavirus disease 2019 (COVID-19) remains unknown. OBJECTIVES: We aimed to investigate the effect of a single high dose of vitamin D3 on cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19. METHODS: This is a post hoc, ancillary, and exploratory analysis from a multicenter, double-blind, placebo-controlled, randomized clinical trial. Patients with moderate to severe COVID-19 were recruited from 2 hospitals in São Paulo, Brazil. Of 240 randomly assigned patients, 200 were assessed in this study and randomly assigned to receive a single oral dose of 200,000 IU vitamin D3 (n = 101) or placebo (n = 99). The primary outcome was hospital length of stay, which has been published in our previous study. The prespecified secondary outcomes were serum concentrations of IL-1ß, IL-6, IL-10, TNF-α, and 25-hydroxyvitamin D. The post hoc exploratory secondary outcomes were IL-4, IL-12p70, IL-17A, IFN-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-8, IFN-inducible protein-10 (IP-10), macrophage inflammatory protein-1ß (MIP-1ß), monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), and leukocyte count. Generalized estimating equations for repeated measures, with Bonferroni's adjustment, were used for testing all outcomes. RESULTS: The study included 200 patients with a mean ± SD age of 55.5 ± 14.3 y and BMI of 32.2 ± 7.1 kg/m2, of which 109 (54.5%) were male. GM-CSF concentrations showed a significant group-by-time interaction effect (P = 0.04), although the between-group difference at postintervention after Bonferroni's adjustment was not significant. No significant effects were observed for the other outcomes. CONCLUSIONS: The findings do not support the use of a single dose of 200,000 IU vitamin D3, compared with placebo, for the improvement of cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19.This trial was registered at clinicaltrials.gov as NCT04449718.

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Resumen Se analiza, en un estudio descriptivo retrospectivo, las características clínicas y epidemiológicas, la evolución de la enfermedad y su asociación con los marcadores del laboratorio de mal pronóstico, en los primeros 100 pacientes internados en clínica médica con COVID-19 en el Hospital de Clínicas José de San Martín de la Universidad de Buenos Aires. El 31% de los pacientes provenían de geriátricos, las manifestaciones clínicas más comunes fueron fiebre, tos y odinofagia. En relación a las comorbilidades, la obesidad fue la más frecuente y la hipertensión arterial la más prevalente en los pacientes con neumonía. La edad y la presencia de neumonía fueron los predictores más importantes de mortalidad. Los pacientes mayores de 70 años presentaron reactantes de fase aguda más elevados mostrando una respuesta inflamatoria exagerada. La mortalidad fue elevada (13%), en comparación con la mayoría de las comunicaciones (5%), probablemente como consecuencia de la edad avanzada de nuestra población y las condiciones clínicas desfavorables que presentaron a su ingreso.

Abstract This retrospective descriptive study analyzes the clinical and epidemiological characteristics, the disease evolution and its association with laboratory markers of poor prognosis of the first 100 patients with COVID-19 admitted to internal medicine wards at the Hospital de Clínicas José de San Martín, University of Buenos Aires. Thirty-one patients were nursing home residents, the most common clinical manifestations were fever, cough and odynophagia. Regarding comorbidities, obesity was the most frequent one and hypertension was the most prevalent in patients with pneumonia. The most important predictors of mortality were age and pneumonia. Patients older than 70 years had higher acute phase reactants showing an exaggerated inflammatory response. Mortality was high (13%), compared to most reports (5%), probably because of the advanced age of our population and the unfavorable clinical conditions they presented at admission.

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This retrospective descriptive study analyzes the clinical and epidemiological characteristics, the disease evolution and its association with laboratory markers of poor prognosis of the first 100 patients with COVID-19 admitted to internal medicine wards at the Hospital de Clínicas José de San Martín, University of Buenos Aires. Thirty-one patients were nursing home residents, the most common clinical manifestations were fever, cough and odynophagia. Regarding comorbidities, obesity was the most frequent one and hypertension was the most prevalent in patients with pneumonia. The most important predictors of mortality were age and pneumonia. Patients older than 70 years had higher acute phase reactants showing an exaggerated inflammatory response. Mortality was high (13%), compared to most reports (5%), probably because of the advanced age of our population and the unfavorable clinical conditions they presented at admission.

Se analiza, en un estudio descriptivo retrospectivo, las características clínicas y epidemiológicas, la evolución de la enfermedad y su asociación con los marcadores del laboratorio de mal pronóstico, en los primeros 100 pacientes internados en clínica médica con COVID-19 en el Hospital de Clínicas José de San Martín de la Universidad de Buenos Aires. El 31% de los pacientes provenían de geriátricos, las manifestaciones clínicas más comunes fueron fiebre, tos y odinofagia. En relación a las comorbilidades, la obesidad fue la más frecuente y la hipertensión arterial la más prevalente en los pacientes con neumonía. La edad y la presencia de neumonía fueron los predictores más importantes de mortalidad. Los pacientes mayores de 70 años presentaron reactantes de fase aguda más elevados mostrando una respuesta inflamatoria exagerada. La mortalidad fue elevada (13%), en comparación con la mayoría de las comunicaciones (5%), probablemente como consecuencia de la edad avanzada de nuestra población y las condiciones clínicas desfavorables que presentaron a su ingreso.

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Resumen Introducción: Una velocidad de eritrosedimentación (VHS) extremadamente elevada, definida como mayor o igual a 100 mm/h, se ha asociado a condiciones graves subyacentes como enfermedades infecciosas, enfermedades del colágeno u oncológicas. Objetivo: Analizar un grupo de pacientes para determinar los diagnósticos de base y las características que se asocian con valores de VHS mayores a 100 mm/h en nuestro medio. Pacientes y Métodos: Estudio tipo observacional de corte transversal, con recolección retrospectiva de datos de pacientes adultos con al menos un valor de VHS mayor o igual a 100 mm/h, registrado en el laboratorio entre enero de 2002 y agosto de 2014 en el Hospital Italiano de Buenos Aires. Resultados: Durante el período evaluado se analizaron 879 pacientes mayores de 18 años. La mediana de los valores de VHS fue 111 mm/h (Rango intercuartil 105-120). La etiología prevalente de VHS elevada fueron las enfermedades infecciosas (41,6%), seguida de malignidad (21,6%) y de autoinmune/inflamatoria (12,9%). El diagnóstico individual más frecuente fue el de neumonía (11,4%), seguido por causa indeterminada (5,9%). Conclusión: En pacientes internados, la causa más frecuente de VHS ≥ 100 mm/h fue las enfermedades infecciosas, mientras que en pacientes ambulatorios la causa más frecuente fue la malignidad.

Background: An extremely elevated erythrosedimentation rate (ESR), defined as equal or higher than 100 mm/h, has been linked to serious underlying conditions, such as infections, connective tissue and oncologic disease. Aim: To analyze a group of patients in order to determine the underlying diagnosis and the characteristics associated with extremely elevated ESR in our environment. Methods: Cross-sectional study of adult patients, who presented with at least one ESR equal or higher than 100 mm/h at Hospital Italiano, in Buenos Aires (Buenos Aires, Argentina) between January 2002 and August 2014. Results: During the previously stated period of time, we analyzed the results of 879 patients. All patients were over 18 years of age. The median for the ESR results was 111 mm/h (interquartile range 105-120). The most prevalent etiology of an elevated ESR was infectious (41.64%), followed by malignancies (21.62%) and autoimmune / inflammatory diseases (12.97%). The most frequent individual diagnosis found was pneumonia (11.49%), followed by undetermined causes (5.92%). Conclusion: When comparing inpatient versus outpatient populations, the most frequent cause was infectious in the former group, while malignancies were the most frequent diagnosis in the latter.

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OBJECTIVE: Clinical and genetic findings of familial Mediterranean fever (FMF) may vary in different populations. Environmental factors may also affect phenotypic features of FMF. In this study, we investigated demographic, clinical and mutational features of FMF patients treated in a single reference hospital in Turkey. SUBJECTS AND METHODS: One hundred and ninety-seven patients were included. The 11 mutations most frequently seen in FMF were investigated in these patients. Patients were assessed as homozygous, heterozygous, compound heterozygous or non-mutation bearing. Clinical and laboratory examinations in the attack and attack-free periods were recorded. A disease severity score was calculated for each patient. RESULTS: One hundred patients were female and 97 male. The most commonly seen mutations in our region was M694V (51.7%). The most frequent clinical findings in our patients was gastric pain (90.1%), followed by fever (82.2%). The highest disease severity score was determined in patients with homozygous M694V. Sedimentation values were significantly high in patients with homozygous M694V mutation, while no statistically significant difference was determined among other acute phase reactants and haemoglobin and leukocyte values. CONCLUSION: Changes in acute phase reactants in attack and attack-free periods are used as diagnostic tools in FMF. Severity and frequency of attacks are clearly correlated with mutations. However, the fact that the clinical course can differ even in individuals with mutations reveals the importance of environmental factors.

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BACKGROUND: Pro-inflammatory cytokines play an important role in diabetic retinopathy. There is conflicting evidence about their serum elevation in this condition and that they also may be possible serum inflammatory biomarkers of diabetic retinopathy. OBJECTIVE: To evaluate the presence of serum pro-inflammatory cytokines and acute phase reactants in the serum of patients with and without diabetic retinopathy. MATERIAL AND METHODS: Comparative case series with 36 patients divided into three groups were included: 12 patients with diabetes mellitus and diabetic retinopathy (group 1), 12 diabetic patients without diabetic retinopathy (group 2), and 12 healthy patients as a control group. Serum levels of the following pro-inflammatory cytokines were measured in all patients: TNF-α, IL-1ß and IL-6. Pro-inflammatory biomarkers measurements were also performed, such as erythrocyte sedimentation rate and C-reactive protein. RESULTS: The levels of TNF-α and IL-6 were higher in group 1 (TNF-α: 19.4 ± 10.9 pg/ml, IL-6: 5.75 ± 7 pg/ml) compared to the other two groups, although the difference was statistically significant only in the case of TNF-α (group 1: 19.4 ± 10.9 pg/ml, group 2: 14 ± 4.3 pg/ml and control: 8.49 ± 3.69 pg/ml, p = 0.001). There were no differences among pro-inflammatory biomarkers such as erythrocyte sedimentation rate and C reactive protein. among the three groups (p > 0.05). CONCLUSIONS: Pro-- inflammatory serum cytokine levels were higher in the diabetes mellitus with diabetic retinopathy group. Larger studies are warranted to establish the real impact of this finding.

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Low levels of 25-hydroxyvitamin D, or 25(OH)D, are commonly associated with inflammatory diseases. These associations could be due to an increased prevalence of inflammatory diseases in hypovitaminosis D, although reverse causality cannot be excluded. We aimed to systematically review the longitudinal studies that reported serum 25(OH)D during an acute inflammatory response in humans. Using Ovid MEDLINE, EMBASE, and the Cochrane Library, an electronic search of the literature was conducted from database inception until January 2014 by combining the MeSH terms: vitamin D and acute-phase reactants. Other sources for obtaining articles were used as cross-referencing texts. Based on 670 titles and abstracts, 40 articles were selected for full-text review, and 8 of these studies met the final inclusion criteria. In 6 of the reviewed studies, 25(OH)D dropped after the inflammatory insult; this decrease was abrupt in the studies that measured 25(OH)D early after the insult. In 2 studies, there was no change of 25(OH)D during the course of the disease, but baseline levels were measured in both after days of symptoms onset. One study suggested that hemodilution decreased 25(OH)D, with no effect on inflammation. Serum C-reactive protein concentrations were used as inflammatory markers in almost all studies. The metabolic meaning and the functional importance of these changes are unknown. In light of the current evidence, the 25(OH)D measured during acute-phase response should be interpreted with care. Future research, including other markers of vitamin D adequacy, could help to clarify if hypovitaminosis D might be the cause or the consequence of inflammatory diseases.

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Hypoferremia observed during systemic inflammatory disorders is regulated by hepcidin. Hepcidin up-regulation is particularly important during acute inflammation, as it restricts the availability of iron, which is necessary for pathogenic microorganism growth before adaptive immunity occurs. The aim of this study was to evaluate the clinical findings and hepatic hepcidin mRNA expression in horses using a Freund's complete adjuvant (FCA) model of inflammation. The expression of hepcidin mRNA in the liver was determined in healthy horses following two intramuscular injections of FCA at 0 h and 12 h. Plasma iron and fibrinogen concentrations were measured at multiple time points between 0 h and 240 h post-FCA injection (PI). Hepcidin mRNA expression was determined by RT-qPCR using liver biopsy samples performed at 0 h (control), 6 h and 18 h PI. The mean plasma fibrinogen level was significantly different from the control values only between 120 and 216 h PI. The mean plasma iron level was significantly lower than the control between 16 and 72 h PI, reaching the lowest levels at 30 h PI (33 % of the initial value), and returned to the reference value from 96 h PI to the end of the experiment. Hepcidin mRNA expression increased at 6 h PI and remained high at 18 h PI. The iron plasma concentration was an earlier indicator of inflammatory processes in horses when compared with fibrinogen and might be useful for the early detection of inflammation in the horse. FCA administration caused the rapid onset of hypoferremia, and this effect was likely the result of up-regulated hepatic hepcidin gene expression. This study emphasizes the importance of hepcidin and iron metabolism during inflammation in horses.(AU)

A hipoferremia observada durante os processos inflamatórios sistêmicos é mediada pela hepcidina. O aumento da expressão da hepcidina é particularmente importante durante a inflamação aguda, por restringir a disponibilidade de ferro necessária para o crescimento de microrganismos patogênicos antes que a imunidade adaptativa ocorra. O objetivo deste estudo foi avaliar os achados clínicos e a expressão hepática do RNA mensageiro (RNAm) da hepcidina em cavalos após a indução da inflamação com Adjuvante completo de Freund (FCA). A expressão hepática do RNAm da hepcidina foi determinada em cavalos sadios após duas administrações intramusculares de FCA às 0 h (M0) e 12 h (M12). As concentrações plasmáticas de ferro e fibrinogênio foram mensuradas em múltiplos momentos entre 0 h e 240 h (M240) após a primeira administração de FCA (PI). A expressão do RNAm da hepcidina foi determinada por RT-qPCR usando amostras de biopsias hepáticas colhidas as 0 h (controle), 6 h (M6) e 18 h (M18) PI. A concentração plasmática média de fibrinogênio foi estatisticamente diferente do M0 entre 120 h e 216 h PI. A concentração plasmática média de ferro foi significantemente menor que o controle entre 16 h e 72 h PI, alcançou o nível mais baixo às 30 h PI (33% do valor inicial) e retornou aos valores de referência entre 96 h PI e até o final do experimento. A expressão do RNAm da hepcidina aumentou no M6 e permaneceu alta no M18. A concentração plasmática de ferro foi um indicador precoce da inflamação quando comparada com o fibrinogênio e pode ser útil na detecção precoce da inflamação em cavalos. A administração do FCA causou um rápido início da hipoferremia, e isto foi resultante do aumento da expressão hepática da hepcidina. Estes resultados enfatizam a importância da hepcidina e do metabolismo do ferro durante a inflamação em cavalos.(AU)

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Hypoferremia observed during systemic inflammatory disorders is regulated by hepcidin. Hepcidin up-regulation is particularly important during acute inflammation, as it restricts the availability of iron, which is necessary for pathogenic microorganism growth before adaptive immunity occurs. The aim of this study was to evaluate the clinical findings and hepatic hepcidin mRNA expression in horses using a Freund's complete adjuvant (FCA) model of inflammation. The expression of hepcidin mRNA in the liver was determined in healthy horses following two intramuscular injections of FCA at 0 h and 12 h. Plasma iron and fibrinogen concentrations were measured at multiple time points between 0 h and 240 h post-FCA injection (PI). Hepcidin mRNA expression was determined by RT-qPCR using liver biopsy samples performed at 0 h (control), 6 h and 18 h PI. The mean plasma fibrinogen level was significantly different from the control values only between 120 and 216 h PI. The mean plasma iron level was significantly lower than the control between 16 and 72 h PI, reaching the lowest levels at 30 h PI (33 % of the initial value), and returned to the reference value from 96 h PI to the end of the experiment. Hepcidin mRNA expression increased at 6 h PI and remained high at 18 h PI. The iron plasma concentration was an earlier indicator of inflammatory processes in horses when compared with fibrinogen and might be useful for the early detection of inflammation in the horse. FCA administration caused the rapid onset of hypoferremia, and this effect was likely the result of up-regulated hepatic hepcidin gene expression. This study emphasizes the importance of hepcidin and iron metabolism during inflammation in horses.

A hipoferremia observada durante os processos inflamatórios sistêmicos é mediada pela hepcidina. O aumento da expressão da hepcidina é particularmente importante durante a inflamação aguda, por restringir a disponibilidade de ferro necessária para o crescimento de microrganismos patogênicos antes que a imunidade adaptativa ocorra. O objetivo deste estudo foi avaliar os achados clínicos e a expressão hepática do RNA mensageiro (RNAm) da hepcidina em cavalos após a indução da inflamação com Adjuvante completo de Freund (FCA). A expressão hepática do RNAm da hepcidina foi determinada em cavalos sadios após duas administrações intramusculares de FCA às 0 h (M0) e 12 h (M12). As concentrações plasmáticas de ferro e fibrinogênio foram mensuradas em múltiplos momentos entre 0 h e 240 h (M240) após a primeira administração de FCA (PI). A expressão do RNAm da hepcidina foi determinada por RT-qPCR usando amostras de biopsias hepáticas colhidas as 0 h (controle), 6 h (M6) e 18 h (M18) PI. A concentração plasmática média de fibrinogênio foi estatisticamente diferente do M0 entre 120 h e 216 h PI. A concentração plasmática média de ferro foi significantemente menor que o controle entre 16 h e 72 h PI, alcançou o nível mais baixo às 30 h PI (33% do valor inicial) e retornou aos valores de referência entre 96 h PI e até o final do experimento. A expressão do RNAm da hepcidina aumentou no M6 e permaneceu alta no M18. A concentração plasmática de ferro foi um indicador precoce da inflamação quando comparada com o fibrinogênio e pode ser útil na detecção precoce da inflamação em cavalos. A administração do FCA causou um rápido início da hipoferremia, e isto foi resultante do aumento da expressão hepática da hepcidina. Estes resultados enfatizam a importância da hepcidina e do metabolismo do ferro durante a inflamação em cavalos.

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Familial Mediterranean fever (FMF) is a periodic autoinflammatory disease characterized by chronic inflammation. This study investigated the relationship between acute-phase reactants and gene mutations in attack-free periods of childhood FMF. Patients diagnosed with FMF were divided into four groups based on genetic features: no mutation, homozygous, heterozygous, and compound heterozygous. These groups were monitored for 2 years, and blood samples were collected every 6 months during attack-free periods. Erythrocyte sedimentation rate, C-reactive protein, fibrinogen, and white blood cell count were measured. A disease severity score was determined for each patient. Mean values for erythrocyte sedimentation rate and fibrinogen were significantly different in the homozygous group. White blood cell count and C-reactive protein were similar between the groups. Disease severity score was higher in patients with the M694V mutation than in individuals without the mutation, as well as in those with other mutation groups. Periodic follow-up of patients with FMF MEFV mutations in subjects with acute-phase reactants may be useful in the prevention of morbidity.

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La neutropenia febril constituye una de las principales causas de morbiletalidad en los pacientes con hemopatías malignas; sin embargo, la presentación clínica y evolución de esta complicación varía considerablemente de un paciente a otro. El primer modelo de estratificación de riesgo fue desarrollado por Talcot a partir de elementos clínicos y diferenciaba a los pacientes según el riesgo de presentar complicaciones letales. No obstante, cerca del 10 % de los pacientes catalogados como de bajo riesgo de complicaciones graves requieren tratamiento intrahospitalario. La determinación de algunos reactantes de fase aguda como la proteína C reactiva, las interleucinas 6 y 8 y la procalcitonina, aumentan notablemente la sensibilidad y especificidad de los modelos pronósticos. Las nuevas técnicas imagenológicas y de biología molecular facilitarán el diagnóstico precoz y certero de las infecciones en un futuro cercano. Sin embargo, es necesario desarrollar modelos pronósticos que combinen elementos clínicos y humorales adaptados a las condiciones epidemiológicas de cada centro, para optimizar el tratamiento diferenciado de los enfermos con neutropenia febril.

Febrile neutropenia is one of the main causes of mortality in patients presenting with malignant hemopathic disorders; however the clinical and course presentation of this condition differ notably between patients. The first risk stratification model was developed by Talcot from clinical elements and differentiated the patients according the risk of lethal complications. However, around the 10% of patients classed as low risk of severe complications required intrahospital treatment. The determination of some acute phase reactants e.g. reactive C protein, 6 and 8 interleukins, and procalcitonin, increases remarkably the sensitivity and specificity of prognostic model. The new imaging techniques and of molecular biology allow an early and accurate diagnosis of infections in a near future. However, it is necessary to develop prognostic models combining clinical and humoral elements suited to epidemiological conditions of each institution to optimize the differentiated treatment of patients presenting with febrile neutropenia.

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OBJETIVO:Analisar a relação entre as provas de fase aguda e a atividade clínica da artrite idiopática juvenil e avaliar a concordância entre velocidade de hemossedimentação e proteína C reativa (VHS e PCR) na fase aguda da doença. MÉTODOS: Foi realizado estudo retrospectivo tipo coorte a partir da análise de prontuários de 30 crianças e adolescentes que preenchiam os critérios diagnósticos para artrite idiopática juvenil, estavam em atendimento em ambulatório de Reumatologia Pediátrica e haviam realizado as provas de fase aguda (VHS e PCR). RESULTADOS: Dos 30 pacientes, 21 (70 por cento) eram do sexo feminino e 19 (63,3 por cento) apresentavam o subtipo oligoarticular da doença. A média de idade de início dos sintomas foi 65,6 meses, a idade de diagnóstico de 85,3 e o tempo de evolução, 57,2 meses. As provas de fase aguda mostraram associação positiva com a atividade de doença. A anemia não teve relação com a atividade de doença. A concordância entre as duas provas de fase aguda foi superior a 80 por cento. CONCLUSÕES: As provas de fase aguda mantêm relação positiva com a atividade da doença e o seu uso concomitante aumenta a especificidade.

OBJECTIVE:To analyze the relationship between the acute phase reactants and the disease activity of Juvenile Idiopathic Arthritis (JIA) and to evaluate the agreement between erythrocyte sedimentation rate and C-reactive protein during the acute phase of the disease. METHODS: a cohort retrospective study has been conducted based on the analysis of 30 children and adolescents who fulfilled the diagnostic criteria of JIA. All of them were in current follow-up at the pediatric rheumatology outpatient clinic and had acute phase reactants blood tests performed. RESULTS: Studied population comprised 30 patients: 21 (70 percent) of them were females and 19 (63.3 percent) presented oligoarticular subtype. The mean age at disease onset was 65.6 months; the age at diagnosis was 85.3 months and the follow-up had 57.2 months of duration. The acute phase reactants showed positive association with the disease activity. Anemia was not associated with disease activity. During the acute phase of the disease, agreement between erythrocyte sedimentation rate and C-reactive protein was greater than 80 percent. CONCLUSIONS: The acute phase reactants have a positive association with the activity of the disease and using both tests simultaneously increases their specificity.

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