We retrospectively studied outcomes for HIV-infected patients admitted to the intensive care unit (ICU) between January 1999 and June 2009. Patient demographics, receipt of highly active antiretroviral therapy (HAART), reason for ICU admission and survival to ICU and hospital discharge were recorded. Comparison was made against outcomes for general medical patients contemporaneously admitted to the same ICU. One hundred and ninety-two HIV-infected patients had 222 ICU admissions; 116 patients required mechanical ventilation (MV) and 43 required renal replacement therapy. ICU admission was due to an HIV-associated diagnosis in 113 patients; 37 had Pneumocystis pneumonia. Survival to ICU discharge and hospital discharge for HIV-infected patients was 78% and 70%, respectively, and was 75% and 68% among 2065 general medical patients with 2274 ICU admissions; P = 0.452 and P = 0.458, respectively. HIV infection was newly diagnosed in 42 patients; their ICU and hospital survival was 69% and 57%, respectively. From multivariable analysis, factors associated with ICU survival were patient's age (odds ratio [OR] = 0.74 [95% confidence interval (CI) = 0.53-1.02] per 10-year increase), albumin (OR = 1.05 [1.00-1.09] per 1 g/dL increase), Acute Physiology and Chronic Health Evaluation (APACHE) II score (OR = 0.55 [0.35-0.87] per 10 unit increase), receipt of HAART (OR = 2.44 [1.01-4.94]) and need for MV (OR = 0.14 [0.06-0.36]). In the era of HAART, HIV-infected patients should be offered ICU admission if it is likely to be of benefit.

Objectives: Despite improvements in survival of people with HIV admitted to the intensive care unit (ICU), late diagnosis continues to contribute to in-ICU mortality. We quantify the population attributable fraction (PAF) of in-ICU mortality for recent late diagnosis among people with HIV admitted to a London ICU. Methods: Index ICU admissions among people with HIV were considered from 2000 to 2019. Recent late diagnosis was a CD4 T-cell count < 350 cells/μL and/or AIDS-defining illness at/within 6 months prior to ICU admission.Univariate comparisons were conducted using Wilcoxon rank-sum/Cochran-Armitage/χ 2 /Fisher's exact tests. We used Poisson regression (robust standard errors) to estimate unadjusted/adjusted (age, sex, calendar year of ICU admission) risk ratios (RRs) and regression standardization to estimate the PAF. Results: In all, 207 index admissions were included [median (interquartile range) age: 46 (38-53) years; 72% male]; 58 (28%) had a recent late diagnosis, all of whom had a CD4 count < 350 cells/μL, and 95% had advanced HIV (CD4 count < 200 cells/μL and/or AIDS at admission) as compared with 57% of those who did not have a recent late diagnosis (p < 0.001). In-ICU mortality was 27% (55/207); 38% versus 22% in those who did and did not have a recent late diagnosis, respectively (p = 0.02). Recent late diagnosis was independently associated with increased in-ICU mortality risk (adjusted RR = 1.75) (95% confidence interval: 1.05-2.91), with 17.08% (16.04-18.12%) of deaths being attributable to this.Conclusions: There is a need for improved public health efforts focused on HIV testing and reporting of late diagnosis to better understand potentially missed opportunities for earlier HIV diagnosis in healthcare services.

BackgroundLung transplant recipients on calcineurin inhibitor immunosuppression have increased susceptibility to, and increased mortality from, invasive aspergillosis. Tacrolimus (FK506) diminishes the innate immune response to Aspergillus fumigatus infection partly by inhibition of the calcineurin-NFAT axis. We investigated the effects of FK506 on transcriptional regulation in dendritic cells (DC’s), and assessed interferon-gamma as a treatment, with a combination of RNA-Seq and histone modification ChIP-seq.MethodsHealthy volunteer monocytes were negatively isolated from gradient-centrifugation-selected PBMC’s and differentiated into DC’s with GM-CSF and IL-4. DC’s were treated with FK506, interferon-gamma and/or inoculated with swollen conidia of A.fumigatus (MOI 1:1). For RNA-Seq, extracted mRNA was poly-A purified and reverse-transcribed to ds-DNA, and for ChIP-seq, DNA was cross-linked, sonicated, then immunoprecipitated with antibodies against histone marks H3k4me1 and H3k27ac. Resultant DNA was PCR-amplified to generate libraries for next generation sequencing on the Illumina HiSeq 2500. Computational sequencing analysis pipelines used open-source C++ and R-based packages (Bowtie, Kallisto, edgeR and MACS).Results A.fumigatus infection in DC’s elicited upregulation of genes belonging to two key groups of early-phase response transcription factors – the early growth response family (EGR1 – log fold-change 4.90, FDR p-value = 0.0003) and the nuclear receptor family (NR4A2 – logFC 6.96, p = 1.56 × 10–6). FK506 treatment ablated significant differential expression of these genes whilst subsequent interferon-gamma treatment restored their upregulation (EGR1 – logFC 4.43, p = 0.00093; NR4A2 – logFC 5.56, p = 0.00034).Active gene enhancers regions were identified by presence of significant peaks of H3k4me1 and H3k27ac antibody binding. Motif analysis of enhancers within regulatory domains around differentially-expressed genes identified enrichment of core binding motifs of NFAT (p = 7.8 × 10-9) and FOXF2 (p = 8.6 × 10–10) transcription factors, which was lost after FK506 treatment.ConclusionsTranscriptome analysis has revealed the key genes involved in early dendritic cell responses to A.fumigatus infection, and their ablation by FK-506 treatment suggests a deleterious genome-level effect of calcineurin inhibitors in this context. Furthermore, interferon-gamma treatment restores a more favourable transcriptomic response to infection in FK506-treated DC’s. The condition-dependent differential enrichment of enhancer motifs suggests a role for both suspected (NFAT) and previously unidentified (FOXF2) transcription factors in the DC response to A.fumigatus infection.