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ABSTRACT.Purpose: To evaluate clinical outcomes of first-line immunomodulatory therapy (IMT) and prednisone alone or late IMT in Vogt-Koyanagi-Harada disease. Methods: Retrospective cohort study of 152 patients with Vogt-KoyanagiHarada disease evaluated in a referral uveitis clinic in Chile from 1985 to 2011. Medical records of these patients were reviewed. Demographic data, clinical evaluation, type of treatment, functional outcomes, glucocorticoid (GC) dose and complications were recorded. Multivariate logistic regression was used to identify prognostic factors of poor response to GC. Results: There were no significant differences between first-line IMT group and prednisone alone/late IMT group in terms of visual acuity (VA) improvement, complications and GC sparing effect. There was a trend for a higher frequency of systemic adverse effects leading to discontinuation of treatment in patients receiving IMT than in those receiving prednisone (14.6% and 6.5%, respectively). The subgroup of patients with poor response to GC who showed functional improvement had a significantly earlier time to IMT initiation than the patients who had no improvement. We identified following prognostic factors of poor response to GC: VA ≤20/200, fundus depigmentation, chronic disease and tinnitus at diagnosis. Patients with a prognostic factor (excluding tinnitus) and VA improvement had an earlier IMT initiation than those who had worse functional outcome. Conclusion: There were no differences in outcomes between first-line IMT and prednisone alone/late IMT in the entire VKH group. However, in a subset of patients, there was a significant better functional outcome with earlier IMT initiation.

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BackgroundA protective role for glucocorticoid therapy in animal models of sepsis was shown many decades ago. In human sepsis, there is new interest in glucocorticoid therapy at a physiological dose after reports of improved response to vasopressor drugs and decreased mortality in a selected group of patients. However, other reports have not confirmed these results. Cellular glucocorticoid resistance could explain a possible cause of that. To evaluate this hypothesis, we evaluated the expression of glucocorticoid receptor beta, the dominant negative isoform of glucocorticoid receptor, in peripheral mononuclear cells of septic patients and the effect of serum septic patients over glucocorticoid receptor expression and glucocorticoid sensitivity in immune cells culture.MethodsA prospective cohort study and an in vitro experimental study with matched controls were developed. Nine patients with septic shock and nine healthy controls were prospectively enrolled. Mononuclear cells and serum samples were obtained from the patients with sepsis on admission to the Intensive Care Unit and on the day of discharge from hospital, and from healthy volunteers matched by age and sex with the patients. Glucocorticoid receptor alpha and beta expression from patients and from immune cell lines cultured in the presence of serum from septic patients were studied by western blot. Glucocorticoid sensitivity was studied in control mononuclear cells cultured in the presence of serum from normal or septic patients. A statistical analysis was performed using a Mann-Whitney test for non-parametric data and analysis of variance for multiple comparison; P < 0.05 was considered significant.ResultsThe patients' glucocorticoid receptor beta expression was significantly higher on admission than on discharge, whereas the alpha receptor was not significantly different. In vitro, septic serum induced increased expression of both receptors in T and B cells in culture, with a greater effect on receptor beta than the control serum. Septic serum induced glucocorticoid resistance in control mononuclear cells.ConclusionThere is a transient increased expression of glucocorticoid receptor beta in mononuclear cells from septic patients. Serum from septic patients induces cell glucocorticoid resistance in vitro. Our findings support a possible cell glucocorticoid resistance in sepsis.

Respiratory syncytial virus (RSV) and human rhinovirus (HRV) respiratory infection in children induce production of inflammatory interleukins (ILs) in the respiratory epithelium. As IL(s) determine the severity of illness, the purpose of this study was to identify the pro-inflammatory IL(s) that could be predictor(s) of clinical severity.One hundred and fifteen patients <2 years old with bronchiolitis due to RSV and /or HRV and 38 controls were selected from a hospital and an outpatient clinic. Clinical data of all patients were recorded. Severity was defined by the number of days with oxygen need. Nasopharyngeal aspirates (NPA) were collected to perform viral diagnosis by quantitative reverse transcription and polymerase chain reaction (qRT-PCR) and to quantify ILs: TNF-α, IL-10, IL-6, IL-1β, and IL-8, by flow cytometry. Simple and multiple regression and receiver operating characteristic (ROC) curves were used for statistical analysis.Of the patients selected 60 were single RSV, 28 RSV associated to HRV, and 27 single HRV. All patients (115) showed significantly higher IL levels when compared with controls. Levels of IL-6, IL-1β, and IL-8 detected in NPA from RSV single and associated to HRV were significantly higher than HRV infected and positively associated with days requiring O2.Levels of IL-6, IL-1β, and IL-8 detected in NPA from patients infected with RSV only or with both RSV and HRV are increased, and any of those 3 cytokines may have a predictive value for the number of days with need of supplemental oxygen.

Mutations in the dihydropteroate synthase (DHPS) gene of Pneumocystis jirovecii are associated with the failure of sulfa prophylaxis. They can develop by selection in patients receiving sulfa drugs or be acquired via person-to-person transmission. DHPS mutations raise concern about the decreasing efficacy of sulfa drugs, the main available therapeutic tool for Pneumocystis pneumonia (PCP). The prevalence of Pneumocystis DHPS mutations was examined in Pneumocystis isolates from 56 sulfa-prophylaxis-naive adults with a first episode of PCP from 2002 to 2010 in Santiago, Chile. Their clinical history was reviewed to analyze the effect of these mutations on response to trimethoprim-sulfamethoxazole (TMP-SMX) therapy and outcome. Mutant genotypes occurred in 22 (48%) of 46 HIV-infected patients and in 5 (50%) of 10 HIV-uninfected patients. Compared to patients with a wild-type genotype, those with mutant genotypes were more likely to experience sulfa treatmentlimiting adverse reactions and to have a twice-longer duration of mechanical ventilation if mechanically ventilated. Specific genotypes did not associate with death, which occurred in none of the HIV-infected patients and in 50% of the non-HIVinfected patients. Chile has a high prevalence of DHPS mutations, which were presumably acquired through interhuman transmission because patients were not on sulfa prophylaxis. These results contrast with the low prevalence observed in other Latin American countries with similar usage of sulfa drugs, suggesting that additional sources of resistant genotypes may be possible. The twice-longer duration of mechanical ventilation in patients with mutant DHPS genotypes suggests a decreased efficacy of TMP-SMX and warrants collaborative studies to assess the relevance of DHPS mutations and further research to increase therapeutic options for PCP.

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The decrease of the α:β GR ratio by an increase of β receptors expression is related to illness severity and may partly explain the insensitivity to corticoid treatment in RSV-infected infants. The increased expression of β GR could be a marker of disease severity.