Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19). Little is known about the interplay between preexisting immunity to endemic seasonal coronaviruses and the development of a SARS-CoV-2–specific IgG response. We investigated the kinetics, breadth, magnitude, and level of cross-reactivity of IgG antibodies against SARS-CoV-2 and heterologous seasonal and epidemic coronaviruses at the clonal level in patients with mild or severe COVID-19 as well as in disease control patients. We assessed antibody reactivity to nucleocapsid and spike antigens and correlated this IgG response to SARS-CoV-2 neutralization. Patients with COVID-19 mounted a mostly type-specific SARS-CoV-2 response. Additionally, IgG clones directed against a seasonal coronavirus were boosted in patients with severe COVID-19. These boosted clones showed limited cross-reactivity and did not neutralize SARS-CoV-2. These findings indicate a boost of poorly protective CoV-specific antibodies in patients with COVID-19 that correlated with disease severity, revealing “original antigenic sin.”

The purpose of this study was to determine the one-year mortality rate and its predictors regarding long-term intensive care-treated patients together with their health-related quality of life (HRQL), place of living, healthcare use and long-term complication characteristics after intensive care unit (ICU) discharge. A retrospective cohort study was performed in a 20-bed mixed ICU. The patients that were treated for more than 72 h between 2007 and 2012 were included in this study. The one-year mortality rate was calculated, and the characteristics of the ICU survivors that died within one year after ICU discharge were further analysed. For all patients, the Dutch version of the SF-36 questionnaire was used to assess their current HRQL. The results were compared with a normal population. Additionally, patients were questioned about their place of living, and their general practitioners (GPs) were questioned about the patients’ possible long-term complications. Seven hundred and forty patients were included in this study, and their one-year mortality rate was 28 %, of which half died within the first week after ICU discharge. The one-year mortality rate predictors included age at the time of ICU admission, APACHE IV-predicted mortality score, number of comorbidities and ICU re-admissions. The ICU survivor HRQL was significantly lower compared with the normal population. Half of the patients did not return to their pre-hospital place of living, and numerous possible long-term complications were reported, particularly decreased tolerance, chronic fatigue and processing problems of relatives. One-year mortality rate of long-term ICU-treated patient was 28 %, and this was predicted by age, disease severity, comorbidities and ICU re-admissions. The ICU survivors reported a lower HRQL, and a minority of these patients returned home directly after hospital discharge; however, GPs reported numerous possible long-term complications.

Background: The level of inflammation alters drug pharmacokinetics (PK) in critically ill patients. This might compromise treatment efficacy. Understanding the specific effects of inflammation, measured by biomarkers, on drug absorption, distribution, metabolism, and excretion is might help in optimizing dosing strategies. Objectives: This review investigates the relationship between inflammatory biomarkers and PK parameters absorption, distribution, metabolism and excretion (ADME) in critically ill patients, providing insight in the complexity of dosing drugs in critically ill patients. Method: Following PRISMA guidelines, we conducted a comprehensive search of Medline, Embase, Web of Science, and Cochrane databases (January 1946–November 2023). Studies examining inflammatory biomarkers, PK parameters, or drug exposure in critically ill patients were included. Records were screened by title, abstract, and full text, with any discrepancies resolved through discussion or consultation with a third reviewer. Results: Of the 4479 records screened, 31 met our inclusion criteria: 2 on absorption, 7 on distribution, 17 on metabolism, and 6 on excretion. In general, results are only available for a limited number of drugs, and most studies are done only looking at one of the components of ADME. Higher levels of inflammatory biomarkers may increase or decrease drug absorption depending on whether the drug undergoes hepatic first-pass elimination. For drug distribution, inflammation is negatively correlated with drug protein binding capacity, positively correlated with cerebrospinal fluid penetration, and negatively correlated with peritoneal penetration. Metabolizing capacity of most drugs was inversely correlated with inflammatory biomarkers. Regarding excretion, inflammation can lead to reduced drug clearance, except in the neonatal population. Conclusion: Inflammatory biomarkers can offer valuable information regarding altered PK in critically ill patients. Our findings emphasize the need to consider inflammation-driven PK variability when individualizing drug therapy in this setting, at the same time research is limited to certain drugs and needs further research, also including pharmacodynamics.

Introduction: Tobramycin is one of the components used for selective decontamination of the digestive tract (SDD), applied to prevent colonization and subsequent infections in critically ill patients. Tobramycin is administered in the oropharynx and gastrointestinal tract and is normally not absorbed. However, critical illness may convey gut barrier failure. The aim of the study was to assess the prevalence and amount of tobramycin leakage from the gut into the blood, to quantify tobramycin excretion in urine, and to determine the association of tobramycin leakage with markers of circulation, kidney function and other organ failure. Methods: This was a prospective observational cohort study. The setting was the 20-bed closed format-mixed ICU of a teaching hospital. The study population was critically ill patients with an expected stay of more than two days, receiving SDD with tobramycin, polymyxin-E and amphotericin-B four times daily in the oropharynx and stomach. Tobramycin concentration was measured in serum (sensitive high performance liquid chromatography - mass spectrometry/mass spectrometry (HLPC-MS/MS) assay) and 24-hour urine (conventional immunoassay), in 34 patients, 24 hours after ICU admission, and in 71 patients, once daily for 7 days. Tobramycin leakage was defined as tobramycin detected in serum at least once (> 0.05 mg/L). Ototoxicity was not monitored. Results: Of the 100 patients with available blood samples, 83 had tobramycin leakage. Median highest serum concentration for each patient was 0.12 mg/L; 99% of the patients had at least one positive urinary sample (> 0.5 mg/L), 49% had a urinary concentration ≥ 1 mg/L. The highest tobramycin serum concentration was significantly associated with vasopressor support, renal and hepatic dysfunction, and C-reactive protein. At binary logistic regression analysis, high dopamine dose and low urinary output on Day 1 were the significant predictors of tobramycin leakage. Nephrotoxicity could not be shown. Conclusions: The majority of acute critically ill patients treated with enteral tobramycin as a component of SDD had traces of tobramycin in the blood, especially those with severe shock, inflammation and subsequent acute kidney injury, suggesting loss of gut barrier and decreased renal removal. Unexpectedly, urinary tobramycin was above the therapeutic trough level in half of the patients. Nephrotoxicity could not be demonstrated.

Mitochondrial dysfunction has been linked to disease progression in COVID-19 patients. This observational pilot study aimed to assess mitochondrial function in COVID-19 patients at intensive care unit (ICU) admission (T1), seven days thereafter (T2), and in healthy controls and a general anesthesia group. Measurements consisted of in vivo mitochondrial oxygenation and oxygen consumption, in vitro assessment of mitochondrial respiration in platelet-rich plasma (PRP) and peripheral blood mononuclear cells (PBMCs), and the ex vivo quantity of circulating cell-free mitochondrial DNA (mtDNA). The median mitoVO₂ of COVID-19 patients on T1 and T2 was similar and tended to be lower than the mitoVO₂ in the healthy controls, whilst the mitoVO₂ in the general anesthesia group was significantly lower than that of all other groups. Basal platelet (PLT) respiration did not differ substantially between the measurements. PBMC basal respiration was increased by approximately 80% in the T1 group when contrasted to T2 and the healthy controls. Cell-free mtDNA was eight times higher in the COVID-T1 samples when compared to the healthy controls samples. In the COVID-T2 samples, mtDNA was twofold lower when compared to the COVID-T1 samples. mtDNA levels were increased in COVID-19 patients but were not associated with decreased mitochondrial O₂ consumption in vivo in the skin, and ex vivo in PLT or PBMC. This suggests the presence of increased metabolism and mitochondrial damage.

Severe acquired respiratory syndrome coronavirus-2 (SARS-CoV-2) is the cause of coronavirus disease (COVID-19). In severe COVID-19 cases, higher antibody titers against seasonal coronaviruses have been observed than in mild cases. To investigate antibody cross-reactivity as potential explanation for severe disease, we determined the kinetics, breadth, magnitude and level of cross-reactivity of IgG against SARS-CoV-2 and seasonal CoV nucleocapsid and spike from 17 severe COVID-19 cases at the clonal level. Although patients mounted a mostly type-specific SARS-CoV-2 response, B-cell clones directed against seasonal CoV dominated and strongly increased over time. Seasonal CoV IgG responses that did not neutralize SARS-CoV-2 were boosted well beyond detectable cross-reactivity, particularly for HCoV-OC43 spike. These findings support a back-boost of poorly protective coronavirus-specific antibodies in severe COVID-19 patients that may negatively impact de novo SARS-CoV-2 immunity, reminiscent of original antigenic sin.