Molecular mechanisms and treatment responses of pulmonary fibrosis in severe COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) patients can develop pulmonary fibrosis (PF), which is associated with impaired outcome. We assessed specific leukocytic transcriptome profiles associated with PF and the influence of early dexamethasone (DEXA) treatment on the clinical course of PF in critically ill COVID-19 patients. METHODS: We performed a pre-post design study in 191 COVID-19 patients admitted to the Intensive Care Unit (ICU) spanning two treatment cohorts: the pre-DEXA- (n = 67) and the DEXA-cohort (n = 124). PF was identified based on radiological findings, worsening of ventilatory parameters and elevated circulating PIIINP levels. Longitudinal transcriptome profiles of 52 pre-DEXA patients were determined using RNA sequencing. Effects of prednisone treatment on clinical fibrosis parameters and outcomes were analyzed between PF- and no-PF-patients within both cohorts. RESULTS: Transcriptome analyses revealed upregulation of inflammatory, coagulation and neutrophil extracellular trap-related pathways in PF-patients compared to no-PF patients. Key genes involved included PADI4, PDE4D, MMP8, CRISP3, and BCL2L15. Enrichment of several identified pathways was associated with impaired survival in a external cohort of patients with idiopathic pulmonary fibrosis. Following prednisone treatment, PF-related profiles reverted towards those observed in the no-PF-group. Likewise, PIIINP levels decreased significantly following prednisone treatment. PF incidence was 28% and 25% in the pre-DEXA- and DEXA-cohort, respectively (p = 0.61). ICU length-of-stay (pre-DEXA: 42 [29-49] vs. 18 [13-27] days, p < 0.001; DEXA: 42 [28-57] vs. 13 [7-24] days, p < 0.001) and mortality (pre-DEXA: 47% vs. 15%, p = 0.009; DEXA: 61% vs. 19%, p < 0.001) were higher in the PF-groups compared to the no-PF-groups within both cohorts. Early dexamethasone therapy did not influence these outcomes. CONCLUSIONS: ICU patients with COVID-19 who develop PF exhibit upregulated coagulation, inflammation, and neutrophil extracellular trap-related pathways as well as prolonged ICU length-of-stay and mortality. This study indicates that early dexamethasone treatment neither influences the incidence or clinical course of PF, nor clinical outcomes.

Dexamethasone and tocilizumab treatment considerably reduces the value of C-reactive protein and procalcitonin to detect secondary bacterial infections in COVID-19 patients.

BACKGROUND: Procalcitonin (PCT) and C-reactive protein (CRP) were previously shown to have value for the detection of secondary infections in critically ill COVID-19 patients. However, since the introduction of immunomodulatory therapy, the value of these biomarkers is unclear. We investigated PCT and CRP kinetics in critically ill COVID-19 patients treated with dexamethasone with or without tocilizumab, and assessed the value of these biomarkers to detect secondary bacterial infections. METHODS: In this prospective study, 190 critically ill COVID-19 patients were divided into three treatment groups: no dexamethasone, no tocilizumab (D-T-), dexamethasone, no tocilizumab (D+T-), and dexamethasone and tocilizumab (D+T+). Serial data of PCT and CRP were aligned on the last day of dexamethasone treatment, and kinetics of these biomarkers were analyzed between 6 days prior to cessation of dexamethasone and 10 days afterwards. Furthermore, the D+T- and D+T+ groups were subdivided into secondary infection and no-secondary infection groups to analyze differences in PCT and CRP kinetics and calculate detection accuracy of these biomarkers for the occurrence of a secondary infection. RESULTS: Following cessation of dexamethasone, there was a rebound in PCT and CRP levels, most pronounced in the D+T- group. Upon occurrence of a secondary infection, no significant increase in PCT and CRP levels was observed in the D+T- group (p = 0.052 and p = 0.08, respectively). Although PCT levels increased significantly in patients of the D+T+ group who developed a secondary infection (p = 0.0003), this rise was only apparent from day 2 post-infection onwards. CRP levels remained suppressed in the D+T+ group. Receiver operating curve analysis of PCT and CRP levels yielded area under the curves of 0.52 and 0.55, respectively, which are both markedly lower than those found in the group of COVID-19 patients not treated with immunomodulatory drugs (0.80 and 0.76, respectively, with p values for differences between groups of 0.001 and 0.02, respectively). CONCLUSIONS: Cessation of dexamethasone in critically ill COVID-19 patients results in a rebound increase in PCT and CRP levels unrelated to the occurrence of secondary bacterial infections. Furthermore, immunomodulatory treatment with dexamethasone and tocilizumab considerably reduces the value of PCT and CRP for detection of secondary infections in COVID-19 patients.

Successful treatment of severe, treatment resistant GHB withdrawal through thiopental-coma.

BACKGROUND: In patients with gamma-hydroxybutyrate (GHB) use disorder (GUD), withdrawal can have a fulminant course with rapid progression of severe, potentially life-threatening complications. Case: We present a 45-year old man with severe GHB withdrawal, resistant to conventional treatment with pharmaceutical GHB, high doses of benzodiazepines and baclofen. GHB withdrawal finally responded to thiopental-induced coma therapy, with burst suppression pattern on electroencephalography (EEG). The patient fully recovered, without withdrawal or residual neuropsychiatric symptoms. Discussion: To our knowledge, this is the first case report in which barbiturates were used to induce a coma to treat severe, treatment resistant GHB withdrawal. This case suggests barbiturate coma therapy might be considered in severe GHB withdrawal which does not respond to conventional treatment.

[Autointoxication with 'suicide powder']. / Auto-intoxicatie met 'zelfmoordpoeder'.

We present two patients who were treated for an intentional overdose of sodium nitrite. When ingested sodium nitrite leads to severe methaemoglobinaemia, resulting in severe hypoxia (as methaemoglobin does not transport oxygen), vasodilation and hypotension. Symptoms include cyanosis, headache, nausea, convulsions, coma and death. When measured by pulse oximetry, patients with a sodium nitrite intoxication and severe methaemoglobinaemia generally have an oxygen saturation of around 85%. This value is unreliable as the oxygen content of the blood is often extremely low - this can be confirmed by arterial blood gas analysis. Treatment of sodium nitrite intoxication consists of intravenous administration of methylthioninium chloride 1-2 mg/kg. Methylthioninium chloride converts the methaemoglobin back to haemoglobin. Due to the pharmacokinetics of methylthioninium chloride and sodium nitrite, a rebound effect is not to be expected. The only contra-indication for methylthioninium chloride is glucose-6-phosphate dehydrogenase deficiency, which is extremely rare in the Netherlands.