The hidden dangers of drug–drug interactions

Antiretroviral medications have the potential to produce serious drug interactions by interfering with the hepatic cytochrome P450 cascade. Ritonavir, a protease inhibitor, is a known CYP450 inhibitor that is commonly used in the treatment of HIV infection. Iatrogenic Cushing’s syndrome is caused by exposure to glucocorticoids and may be promoted by interaction with additional drugs that result in hypothalamic-pituitary-adrenal axis suppression. It is well documented in HIV-infected patients receiving inhaled steroids in combination with a ritonavir-containing antiretroviral regimen. This case describes a 45-year-old man with HIV who suffered an unintentional severe reaction between his HIV treatment and fluticasone while participating in an asthma research trial. He presented with classical Cushing’s features, as well as a decline in his respiratory health. Biochemical tests confirmed iatrogenic Cushing’s syndrome and clinical symptoms resolved after stopping ritonavir and tapering down the levels of corticosteroid with eventual discontinuation. Poor outcomes in these cases can be attributed to miscommunication and a lack of clear medical guidelines, as well as the fear of disclosure among patients with sensitive diagnoses. This case highlights the importance of taking a full and thorough drug history, and the risks associated with polypharmacy in patients. </p

Kicking up a cytokine storm: an unusual presentation of Castleman’s disease

Castleman’s disease (CD) is a rare lymphoproliferative disorder that can be separated into localised disease and multicentric Castleman’s disease (MCD). Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8 (HHV-8) is the causal agent for Kaposi’s sarcoma (KS) and MCD in human immunodeficiency virus (HIV)-infected patients. This virus encodes a homologue of interleukin 6 (vIL-6), which may mediate some systemic features of MCD. A 58-year-old man presented to the infectious disease department with a three-day history of dyspnoea, fever, and cough. He had a history of HIV and had been on antiretroviral treatment for the previous year. Despite compliance, his CD4 count had dropped and he was found to have widespread lymphadenopathy and pancytopaenia on admission. Biopsy showed the presence of KS and it was decided to treat him for an ‘MCD-like’ syndrome based on his clinical presentation. The patient responded well to treatment with rituximab, an agent used for MCD, and his haematological profile improved. This case lends support to the theory that some patients with HIV and HHV-8 co-infection, but without MCD, can develop severe systemic inflammatory symptoms associated with elevated levels of HHV-8 vIL-6, IL-6 and HHV-8 viral loads. It additionally illustrates the challenges faced in the diagnosis of this unusual form of MCD in patients with HIV. Most importantly, this case highlights the importance of a thorough history and examination in eliciting the clues to diagnosis in the face of these challenges. </p

Dysregulated early transcriptional signatures linked to mast cell and interferon responses are implicated in COVID-19 severity

BackgroundDysregulated immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are thought to underlie the progression of coronavirus disease 2019 (COVID-19) to severe disease. We sought to determine whether early host immune-related gene expression could predict clinical progression to severe disease.MethodsWe analysed the expression of 579 immunological genes in peripheral blood mononuclear cells taken early after symptom onset using the NanoString nCounter and compared SARS-CoV-2 negative controls with SARS-CoV-2 positive subjects with mild (SARS+ Mild) and Moderate/Severe disease to evaluate disease outcomes. Biobanked plasma samples were also assessed for type I (IFN-α2a and IFN-β), type II (IFN-γ) and type III (IFN-λ1) interferons (IFNs) as well as 10 additional cytokines using multiplex immunoassays.ResultsWe identified 19 significantly deregulated genes in 62 SARS-CoV-2 positive subject samples within 5 days of symptom onset and 58 SARS-CoV-2 negative controls and found that type I interferon (IFN) signalling (MX1, IRF7, IFITM1, IFI35, STAT2, IRF4, PML, BST2, STAT1) and genes encoding proinflammatory cytokines (TNF, TNFSF4, PTGS2 and IL1B) were upregulated in both SARS+ groups. Moreover, we found that FCER1, involved in mast cell activation, was upregulated in the SARS+ Mild group but significantly downregulated in the SARS+ Moderate/Severe group. In both SARS+ groups we discovered elevated interferon type I IFN-α2a, type II IFN and type III IFN λ1 plasma levels together with higher IL-10 and IL-6. These results indicate that those with moderate or severe disease are characterised by deficiencies in a mast cell response together with IFN hyper-responsiveness, suggesting that early host antiviral immune responses could be a cause and not a consequence of severe COVID-19.ConclusionsThis study suggests that early host immune responses linking defects in mast cell activation with host interferon responses correlates with more severe outcomes in COVID-19. Further characterisation of this pathway could help inform better treatment for vulnerable individuals

Robust cross-cohort gut microbiome associations with COVID-19 severity

ABSTRACTAlthough many recent studies have examined associations between the gut microbiome and COVID-19 disease severity in individual patient cohorts, questions remain on the robustness across international cohorts of the biomarkers they reported. Here, we performed a meta-analysis of eight shotgun metagenomic studies of COVID-19 patients (comprising 1,023 stool samples) and 23 > 16S rRNA gene amplicon sequencing (16S) cohorts (2,415 total stool samples). We found that disease severity (as defined by the WHO clinical progression scale) was associated with taxonomic and functional microbiome differences. This alteration in gut microbiome configuration peaks at days 7–30 post diagnosis, after which the gut microbiome returns to a configuration that becomes more similar to that of healthy controls over time. Furthermore, we identified a core set of species that were consistently associated with disease severity across shotgun metagenomic and 16S cohorts, and whose abundance can accurately predict disease severity category of SARS-CoV-2 infected subjects, with Actinomyces oris abundance predicting population-level mortality rate of COVID-19. Additionally, we used relational diet-microbiome databases constructed from cohort studies to predict microbiota-targeted diet patterns that would modulate gut microbiota composition toward that of healthy controls. Finally, we demonstrated the association of disease severity with the composition of intestinal archaeal, fungal, viral, and parasitic communities. Collectively, this study has identified robust COVID-19 microbiome biomarkers, established accurate predictive models as a basis for clinical prognostic tests for disease severity, and proposed biomarker-targeted diets for managing COVID-19 infection

Associations between host microbiome and inflammation suggest role for host microbiome in driving COVID-19 disease severity

Systemic inflammation and innate immune activation are associated with COVID-19 disease severity. Knowledge gaps remain in the relationships between microbiome, inflammation and COVID-19 disease severity. To better characterise these associations, we performed 16SrDNA analysis of stool samples in COVID-19 subjects to explore diversity and taxanomic composition. We correlated these to host inflammatory profiles, derived from soluble plasma biomarkers measured by bead-based fluorescence and electrochemiluminescence immunoassays. Associations of microbial diversity and inflammatory biomarkers on maximal COVID-19 severity (mild, moderate v severe/critical) was explored using logistic regression and weighted gene correlation network analysis (WGCNA). Of 79 subjects, 58% were male and 88% were Caucasian with 36% experiencing mild disease, 22% moderate disease and 40% critical/severe COVID-19. Hierarchical clustering and principal component analysis (PCo) revealed distinct inflammatory clusters that were found to correlate with 4 modules of microbiome profiles. Modules 3 and 4 were associated with both older age and severe/critical disease outcomes. These modules were enriched in pathogenic and inflammatory bacteria that mapped to a pro-inflammatory biomarker cluster. In contrast, module 1 exhibited enrichment of anti-inflammatory bacteria, was associated with younger age and mild/moderate disease outcomes and mapped to a less-inflamed biomarker cluster. This study provides further insights into links between host microbiome, inflammatory responses to SARS-CoV-2 infection and clinical COVID-19 disease severity, suggesting a role for the microbiome in shaping distinct host inflammatory responses to infection. </p

Associations between host microbiome and inflammation suggest role for host microbiome in driving COVID-19 disease severity

Systemic inflammation and innate immune activation are associated with COVID-19 disease severity. Knowledge gaps remain in the relationships between microbiome, inflammation and COVID-19 disease severity. To better characterise these associations, we performed 16SrDNA analysis of stool samples in COVID-19 subjects to explore diversity and taxanomic composition. We correlated these to host inflammatory profiles, derived from soluble plasma biomarkers measured by bead-based fluorescence and electrochemiluminescence immunoassays. Associations of microbial diversity and inflammatory biomarkers on maximal COVID-19 severity (mild, moderate v severe/critical) was explored using logistic regression and weighted gene correlation network analysis (WGCNA). Of 79 subjects, 58% were male and 88% were Caucasian with 36% experiencing mild disease, 22% moderate disease and 40% critical/severe COVID-19. Hierarchical clustering and principal component analysis (PCo) revealed distinct inflammatory clusters that were found to correlate with 4 modules of microbiome profiles. Modules 3 and 4 were associated with both older age and severe/critical disease outcomes. These modules were enriched in pathogenic and inflammatory bacteria that mapped to a pro-inflammatory biomarker cluster. In contrast, module 1 exhibited enrichment of anti-inflammatory bacteria, was associated with younger age and mild/moderate disease outcomes and mapped to a less-inflamed biomarker cluster. This study provides further insights into links between host microbiome, inflammatory responses to SARS-CoV-2 infection and clinical COVID-19 disease severity, suggesting a role for the microbiome in shaping distinct host inflammatory responses to infection. </p