Deep immunophenotyping reveals biomarkers of multisystemic inflammatory syndrome in children in a Latin American cohort.

BACKGROUND: Multisystemic inflammatory syndrome in children (MIS-C) is a life-threatening disease that occurs 2-5 weeks after severe acute respiratory syndrome coronavirus 2 exposure and is characterized by severe multisystemic inflammation. Early recognition of MIS-C is key to prognosis; therefore, establishing clinical and laboratory biomarkers that predict complications is urgently needed. OBJECTIVE: We characterized the immune response and clinical features of patients with acute MIS-C and determined biomarkers of disease in a cohort of 42 Latin American patients. METHODS: Immune characterization was performed using flow cytometry from peripheral mononuclear cells and severe acute respiratory syndrome coronavirus 2-specific humoral and cellular response was performed using flow cytometry, enzyme-linked immunospot, enzyme-linked immunosorbent assay, and neutralizing antibody assays. RESULTS: MIS-C is characterized by robust T-cell activation and cytokine storm. We uncovered that while C-X-C motif chemokine ligand (CXCL) 9, IL-10, CXCL8, CXCL10, IL-6, and IL-18 are significantly elevated in patients with shock, while CCL5 was increased in milder disease. Monocyte dysregulation was specifically associated with KD-like MIS-C. Interestingly, MIS-C patients show a natural killer cell degranulation defect that is persistent after 6 months of disease presentation, suggesting it could underlie disease susceptibility. Most MIS-C had gastrointestinal involvement, and higher levels of neopterin were identified in their stools, potentially representing a biomarker of intestinal inflammation in MIS-C. Severe acute respiratory syndrome coronavirus 2-specific cellular response and neutralizing antibodies were identifiable in convalescent MIS-C patients, suggesting sustained immunity. CONCLUSION: Clinical characterization and comprehensive immunophenotyping of Chilean MIS-C cohort provide valuable insights in understanding immune dysregulation in MIS-C and identify relevant biomarkers of disease that could be used to predict severity and organ involvement.

Coronavirus disease 2019 in patients with inborn errors of immunity: An international study.

BACKGROUND: There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense. OBJECTIVE: We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2. METHODS: An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI. RESULTS: We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died. CONCLUSIONS: This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2.

Genomic Loads and Genotypes of Respiratory Syncytial Virus: Viral Factors during Lower Respiratory Tract Infection in Chilean Hospitalized Infants.

The clinical impact of viral factors (types and viral loads) during respiratory syncytial virus (RSV) infection is still controversial, especially regarding newly described genotypes. In this study, infants with RSV bronchiolitis were recruited to describe the association of these viral factors with severity of infection. RSV antigenic types, genotypes, and viral loads were determined from hospitalized patients at Hospital Roberto del Río, Santiago, Chile. Cases were characterized by demographic and clinical information, including days of lower respiratory symptoms and severity. A total of 86 patients were included: 49 moderate and 37 severe cases. During 2013, RSV-A was dominant (86%). RSV-B predominated in 2014 (92%). Phylogenetic analyses revealed circulation of GA2, Buenos Aires (BA), and Ontario (ON) genotypes. No association was observed between severity of infection and RSV group (p = 0.69) or genotype (p = 0.87). After a clinical categorization of duration of illness, higher RSV genomic loads were detected in infants evaluated earlier in their disease (p < 0.001) and also in infants evaluated later, but coursing a more severe infection (p = 0.04). Although types and genotypes did not associate with severity in our children, higher RSV genomic loads and delayed viral clearance in severe patients define a group that might benefit from new antiviral therapies.

Autoantibodies Against Proteins Previously Associated With Autoimmunity in Adult and Pediatric Patients With COVID-19 and Children With MIS-C.

The antibody profile against autoantigens previously associated with autoimmune diseases and other human proteins in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that 30% of adults with COVID-19 had autoantibodies against the lung antigen KCNRG, and 34% had antibodies to the SLE-associated Smith-D3 protein. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute onset of insulin-dependent diabetes. While autoantibodies associated with SLE/Sjögren's syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring in vivo decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Further testing of IgG and/or IgA antibodies against a subset of potential targets identified by published autoantigen array studies of MIS-C failed to detect autoantibodies against most (16/18) of these proteins in patients with MIS-C who had not received IVIG. However, Troponin C2 and KLHL12 autoantibodies were detected in 2 of 20 and 1 of 20 patients with MIS-C, respectively. Overall, these results suggest that IVIG therapy may be a confounding factor in autoantibody measurements in MIS-C and that antibodies against antigens associated with autoimmune diseases or other human proteins are uncommon in MIS-C.

Cerebral blood flow changes associated with experimental pain stimulation in patients with major depression.

BACKGROUND: The clinical relationship between pain and depression has been extensively reported. The purpose of this study was to compare the cerebral blood flow (CBF) of patients with major depressive disorder (MDD) during stimulation with experimental pain tolerance or sham stimulation, before and after 2 weeks of at least partially effective antidepressant treatment (ADT), in order to determine the cerebral regions associated with pain processing in the two clinical states. METHODS: Twenty-four antidepressant-free outpatients diagnosed with MDD (DSM-IV), without any pain complaints and a basal score>or=20 points on the Hamilton Rating Scale for Depression were included. Cerebral SPECTs were performed before and after ADT. Patients were stimulated with pain pressure tolerance (PT) or sham stimulation during the radiotracer cerebral uptake time. RESULTS: The comparison between PT and sham stimulation before ADT showed an increase of CBF of PT stimulated patients in right temporal gyrus, left amygdale, right anterior cingulated cortex, bilateral medial frontal gyrus, bilateral insula, lingual gyrus, right precentral gyrus and left postcentral gyrus. Equal comparison after ADT showed an increase of CBF of PT stimulated patients only in left middle frontal gyrus. LIMITATIONS: The sample includes exclusively outpatients with mild-moderate depression. CONCLUSION: CBF before ADT increases in brain areas related with the affective and cognitive components of pain; in contrast, after ADT increases only in cognitive pain related areas. These results offer new avenues to investigate the cerebral substrate of the common relationship between pain and depression.

Correlation between cerebral blood flow and items of the Hamilton Rating Scale for Depression in antidepressant-naive patients.

BACKGROUND: The purpose of this study was to correlate the basal cerebral blood flow (CBF) in patients with major depressive disorder (MDD) with the score for each of the 21 questions in the Hamilton Rating Scale for Depression (HRSD), in order to determine the cerebral regions associated with each item. METHODS: Fourteen antidepressant-naive patients with unipolar depression (DSM-IV criteria for MDD) participated in this study with a HRSD score of >/=20 points. CBF images obtained by SPECT were analyzed by SPM99 software. The significant correlation threshold for a priori regions (frontocortical and limbic regions) was a Z value of at least 2.25 and clusters formed by more than 10 voxels. RESULTS: Items 1, 6, 11 and 20 were positively correlated with right medial frontal gyrus; item 7 was negatively correlated with bilateral medial frontal gyrus. Items 2 and 10 were positively correlated with right anterior and medial cingulate, respectively. Item 5 was negatively correlated with the left amygdala. Item 9 was negatively correlated with bilateral insula, and item 16 with right insula. Items 12 and 14 were positively correlated with right and left precentral frontal gyrus, respectively. LIMITATIONS: The small sample size and only out-patients included in the study. CONCLUSIONS: The frontal cortex plays an important role in the expression of MDD symptoms. Not all the symptoms evaluated correlated with one single structure, which may explain the diverse results reported in the literature. These preliminary results support the necessity of further analyses by symptoms that could provide more specific information on the pathophysiology of MDD.

A gravidez da analista: criação e destruição de um espaço para sonhar / The analyst’s pregnancy: Creation and destruction of a space to dream

Neste trabalho são mostradas três situações clínicas nas quais pacientes com um funcionamento predominantemente psicótico detectam, durante as primeiras semanas, a gravidez de sua analista e expressam-no através de um sonho ou de sonhos diurnos. Observa-se que em seus sonhos, as pacientes tentam simbolizar um ponto muito importante e doloroso de suas próprias histórias, o momento ambivalente de sua concepção (Feder, 1980). Conclui-se que a gravidez da analista revive emoções muito primitivas, principalmente de rejeição, vivenciadas por estas pacientes durante sua gestação e nascimento, e que as pacientes conseguem sonhá-las por estarem contidas na situação analítica, que fornece um espaço para sonhar. No entanto, estas experiências nem sempre podem ser elaboradas em profundidade na situação analítica, razão pela qual suas possíveis causas são discutidas.

In this article, three clinical situations are shown in which patients with a predominant psychotic functioning, detect, during the first weeks, their analyst’s pregnancy and they express it through a dream or through daydreaming. It is observed that in their dreams, patients try to represent a very important and painful point of their own stories, the ambivalent moment of their conception (Feder, 1980). It has been concluded that the analyst’s pregnancy, revive very primitive emotions, mainly of rejection, lived by these patients during their own gestation and birth, and that this patients are able to dream them by being contained in the analytical situation, which provides a space to dream. However, these experiences cannot always be profoundly performed in the analytical situation, reason why, its possible causes are being brought to discussion.

En este trabajo se muestran tres situaciones clínicas en las que pacientes con un funcionamiento predominantemente psicótico detectan durante las primeras semanas el embarazo de su analista y lo expresan a través de un sueño o de los sueños diurnos. Se observa que, en sus sueños, las pacientes intentan simbolizar un punto muy importante y doloroso de sus propias historias: el momento ambivalente de su concepción (Feder, 1980). Se concluye que el embarazo de la analista revive emociones muy primitivas, sobre todo de rechazo, que estos pacientes experimentaron durante su gestación y nacimiento y que se logran soñar gracias a que las pacientes están contenidas en la situación analítica que provee un espacio para soñar. Sin embargo, estas experiencias no siempre pueden ser elaboradas a profundidad en la situación analítica, por lo que se discuten las posibles causas de ello.