Frequency of IRF5+ dendritic cells is associated with the TLR7-induced inflammatory cytokine response in SARS-CoV-2 infection.

The SARS-CoV-2 infection leads to enhanced inflammation driven by innate immune responses. Upon TLR7 stimulation, dendritic cells (DC) mediate the production of inflammatory cytokines, and in particular of type I interferons (IFN). Especially in DCs, IRF5 is a key transcription factor that regulates pathogen-induced immune responses via activation of the MyD88-dependent TLR signaling pathway. In the current study, the frequencies of IRF5+ DCs and the association with innate cytokine responses in SARS-CoV-2 infected individuals with different disease courses were investigated. In addition to a decreased number of mDC and pDC subsets, we could show reduced relative IRF5+ frequencies in mDCs of SARS-CoV-2 infected individuals compared with healthy donors. Functionally, mDCs of COVID-19 patients produced lower levels of IL-6 in response to in vitro TLR7 stimulation. IRF5+ mDCs more frequently produced IL-6 and TNF-α compared to their IRF5- counterparts upon TLR7 ligation. The correlation of IRF5+ mDCs with the frequencies of IL-6 and TNF-α producing mDCs were indicators for a role of IRF5 in the regulation of cytokine responses in mDCs. In conclusion, our data provide further insights into the underlying mechanisms of TLR7-dependent immune dysfunction and identify IRF5 as a potential immunomodulatory target in SARS-CoV-2 infection.

Short-course versus long-course antibiotic treatment for uncomplicated vancomycin-resistant enterococcal bacteraemia: a retrospective multicentre cohort study.

OBJECTIVES: The optimal treatment duration for vancomycin-resistant enterococcal (VRE) bacteraemia is still a matter of debate. The aim of the present study was to compare short-course (≤9 days) and long-course (≥10 days) antibiotic treatments in hospitalized adult patients with uncomplicated VRE bacteraemia. METHODS: This retrospective study was conducted in four university hospitals in Germany. Adult patients with a positive blood culture for a VRE were screened from 1 January 2016 to 31 December 2018. Only patients who received a VRE-active antibiotic for at least 48 hours were included. The exclusion criteria were a survival of <10 days and a deep-seated source of infection requiring prolonged treatment. To compare the outcome of short-course therapy with that of long-course therapy, 30-day and 90-day overall mortality, relapse within 90 days, duration of hospitalization, and potential antibiotic-related adverse events were analysed by inverse probability of treatment weighting using the propensity score and by additional covariate adjustment. RESULTS: Of the 363 patients screened, 219 (60.3%) patients were included in the final analysis. Among them, 48 (21.9%) patients had underlying haematological diseases. Seventy-eight (35.6%) patients received short-course treatment (median, 7 days; interquartile range, 5-8 days) and 141 (64.4%) patients received long-course treatment (median, 15 days; interquartile range, 12-23.5 days). Thirty-day mortality was similar in both groups (19.2% vs. 22.0%; adjusted OR, 1.15; p 0.773). Duration of hospitalization (in total and after onset of bacteraemia) was significantly shorter (p < 0.05) in the short-course treatment group, whereas other secondary outcome parameters did not differ between both groups. DISCUSSION: Our study suggests that short-course treatment might not be associated with a worse outcome in patients with uncomplicated VRE bacteraemia.

Evidence of surface contamination in hospital rooms occupied by patients infected with monkeypox, Germany, June 2022.

The extent of monkeypox virus environmental contamination of surfaces is unclear. We examined surfaces in rooms occupied by two monkeypox patients on their fourth hospitalisation day. Contamination with up to 105 viral copies/cm2 on inanimate surfaces was estimated by PCR and the virus was successfully isolated from surfaces with more than 106 copies. These data highlight the importance of strict adherence of hospital staff to recommended protective measures. If appropriate, pre-exposure or early post-exposure vaccination should be considered for individuals at risk.

Humoral and Cellular Immune Response After Third and Fourth SARS-CoV-2 mRNA Vaccination in Liver Transplant Recipients.

BACKGROUND & AIMS: Liver transplant recipients (LTRs) show a decreased immune response after 2 severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) vaccinations compared with healthy controls (HCs). Here, we investigated the immunogenicity of additional vaccinations. METHODS: In this prospective study, humoral (anti-SARS-CoV-2 receptor-binding domain [anti-S RBD]) and cellular (interferon-gamma release assay) immune responses were determined after mRNA-based SARS-CoV-2 vaccination in 106 LTRs after a third vaccination and in 36 LTRs after a fourth vaccination. Patients with anti-S RBD antibody levels >0.8 arbitrary unit (AU)/mL after vaccination were defined as responders. RESULTS: After 3 vaccinations, 92% (97/106) of LTRs compared with 100% (28/28) of HCs were responders. However, the antibody titer of LTRs was lower compared with HCs (1891.0 vs 21,857.0 AU/mL; P < .001). Between a second and third vaccination (n = 75), the median antibody level increased 67-fold in LTRs. In patients seronegative after 2 vaccinations, a third dose induced seroconversion in 76% (19/25), whereas all HCs were already seropositive after 2 vaccinations. A spike-specific T-cell response was detected in 72% (28/39) after a third vaccination compared with 32% (11/34) after a second vaccination. Independent risk factors for a low antibody response (anti-S RBD <100 AU/mL) were first vaccination within the first year after liver transplant (odds ratio [OR], 8.00; P = .023), estimated glomular filtration rate <45 mL/min (OR, 4.72; P = .006), and low lymphocyte counts (OR, 5.02; P = .008). A fourth vaccination induced a 9-fold increase in the median antibody level and seroconversion in 60% (3/5) of previous non-responders. CONCLUSIONS: A third and fourth SARS-CoV-2 vaccination effectively increases the humoral and cellular immune response of LTRs, but to a lesser extent than in HCs. A fourth vaccination should be generally considered in LTRs.

Natural killer cell-mediated ADCC in SARS-CoV-2-infected individuals and vaccine recipients.

COVID-19, caused by SARS-CoV-2, has emerged as a global pandemic. While immune responses of the adaptive immune system have been in the focus of research, the role of NK cells in COVID-19 remains less well understood. Here, we characterized NK cell-mediated SARS-CoV-2 antibody-dependent cellular cytotoxicity (ADCC) against SARS-CoV-2 spike-1 (S1) and nucleocapsid (NC) protein. Serum samples from SARS-CoV-2 resolvers induced significant CD107a-expression by NK cells in response to S1 and NC, while serum samples from SARS-CoV-2-negative individuals did not. Furthermore, serum samples from individuals that received the BNT162b2 vaccine induced strong CD107a expression by NK cells that increased with the second vaccination and was significantly higher than observed in infected individuals. As expected, vaccine-induced responses were only directed against S1 and not against NC protein. S1-specific CD107a responses by NK cells were significantly correlated to NK cell-mediated killing of S1-expressing cells. Interestingly, screening of serum samples collected prior to the COVID-19 pandemic identified two individuals with cross-reactive antibodies against SARS-CoV-2 S1, which also induced degranulation of NK cells. Taken together, these data demonstrate that antibodies induced by SARS-CoV-2 infection and anti-SARS-CoV-2 vaccines can trigger significant NK cell-mediated ADCC activity, and identify some cross-reactive ADCC-activity against SARS-CoV-2 by endemic coronavirus-specific antibodies.

SARS-CoV-2 vaccination response in patients with autoimmune hepatitis and autoimmune cholestatic liver disease.

BACKGROUND/AIMS: In this observational study, we explored the humoral and cellular immune response to SARS-CoV-2 vaccination in patients with autoimmune hepatitis (AIH) and patients with cholestatic autoimmune liver disease (primary sclerosing cholangitis [PSC] and primary biliary cholangitis [PBC]). METHODS: Anti-SARS-CoV-2 antibody titers were determined using the DiaSorin LIAISON and Roche immunoassays in 103 AIH, 64 PSC, and 61 PBC patients and 95 healthy controls >14 days after the second COVID-19 vaccination. The spike-specific T-cell response was assessed using an activation-induced marker assay (AIM) in a subset of individuals. RESULTS: Previous SARS-CoV-2 infection was frequently detected in AIH but not in PBC/PSC (10/112 (9%), versus 4/144 (2.7%), p = 0.03). In the remaining patients, seroconversion was measurable in 97% of AIH and 99% of PBC/PSC patients, respectively. However, in 13/94 AIH patients antibody levels were lower than in any healthy control, which contributed to lower antibody levels of the total AIH cohort when compared to PBC/PSC or controls (641 vs. 1020 vs. 1200 BAU/ml, respectively). Notably, antibody levels were comparably low in AIH patients with (n = 85) and without immunosuppression (n = 9). Also, antibody titers significantly declined within 7 months after the second vaccination. In the AIM assay of 20 AIH patients, a spike-specific T-cell response was undetectable in 45% despite a positive serology, while 87% (13/15) of the PBC/PSC demonstrated a spike-specific T-cell response. CONCLUSION: Patients with AIH show an increased SARS-CoV-2 infection rate as well as an impaired B- and T-cell response to SARS-CoV-2 vaccine compared to PBC and PSC patients, even in the absence of immunosuppression. Thus, antibody responses to vaccination in AIH patients need to be monitored and early booster immunizations considered in low responders.

SARS-CoV2-specific Humoral and T-cell Immune Response After Second Vaccination in Liver Cirrhosis and Transplant Patients.

BACKGROUND & AIMS: Detailed information on the immune response after second vaccination of cirrhotic patients and liver transplant (LT) recipients against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is largely missing. We aimed at comparing the vaccine-induced humoral and T-cell responses of these vulnerable patient groups. METHODS: In this prospective cohort study, anti-SARS-CoV-2 spike-protein titers were determined using the DiaSorin LIAISON (anti-S trimer) and Roche Elecsys (anti-S RBD) immunoassays in 194 patients (141 LT, 53 cirrhosis Child-Pugh A-C) and 56 healthy controls before and 10 to 84 days after second vaccination. The spike-specific T-cell response was assessed using an interferon-gamma release assay (EUROIMMUN). A logistic regression analysis was performed to identify predictors of low response. RESULTS: After the second vaccination, seroconversion was achieved in 63% of LT recipients and 100% of cirrhotic patients and controls using the anti-S trimer assay. Median anti-SARS-CoV-2 titers of responding LT recipients were lower compared with cirrhotic patients and controls (P < .001). Spike-specific T-cell response rates were 36.6%, 65.4%, and 100% in LT, cirrhosis, and controls, respectively. Altogether, 28% of LT recipients did neither develop a humoral nor a T-cell response after second vaccination. In LT recipients, significant predictors of absent or low humoral response were age >65 years (odds ratio [OR], 4.57; 95% confidence interval [CI], 1.48-14.05) and arterial hypertension (OR, 2.50; 95% CI, 1.10-5.68), whereas vaccination failure was less likely with calcineurin inhibitor monotherapy than with other immunosuppressive regimens (OR, 0.36; 95% CI, 0.13-0.99). CONCLUSION: Routine serological testing of the vaccination response and a third vaccination in patients with low or absent response seem advisable. These vulnerable cohorts need further research on the effects of heterologous vaccination and intermittent reduction of immunosuppression before booster vaccinations.

Low incidence of COVID-19 in a prospective cohort of patients with liver cirrhosis and hepatocellular carcinoma treated at a tertiary medical center during the 2020 pandemic.

BACKGROUND AND AIMS: Patients with liver cirrhosis (LC) are considered to be at increased risk for mortality when acquiring SARS-CoV-2 infection and subsequently developing Corona Virus Disease 2019 (COVID-19). During the COVID-19 pandemic, hospitals are regarded as sites with increased risk of infection. Therefore, patient contacts are often limited to urgent indications, which could negatively affect disease monitoring. However, data regarding actual infection rates in cirrhotic patients is limited. The aim of this prospective study was to assess the incidence of COVID-19 in patients with LC with/without hepatocellular carcinoma (HCC) with physical presentation at our University Medical Center. METHODS: Patients were enrolled between 1st April and 30th June 2020 at the University Medical Center Hamburg-Eppendorf, Germany. Symptoms of upper airway infection at baseline and presence of SARS-CoV-2 antibodies (IgG/IgM/IgA) were assessed at baseline and follow-up (FU) using an Electro-chemiluminescence immunoassay (Roche Elecsys). FU visits, including liver function test, clinical assessment and symptom questionnaire, were conducted after 6-8 weeks (FU-1) and 6 months (FU-2). Prior to inclusion of the first patient, obligatory face masks and personal distance were implemented as protective measures. RESULTS: A total of 150 patients were enrolled, 23% (n = 35) also had diagnosis of HCC (median age: 64 years, range: 19-86), 69% were male. Liver function according to Child-Pugh score (CPS) was: CPS A: 46% (n = 62); CPS B: 37% (n = 50); CPS C: 17% (n = 23). Clinical symptoms indicating upper airway infection were present in 53% (n = 77): shortness of breath (n = 40) and coughing (n = 28) were the most frequent. For the 150 patients enrolled, 284 outpatient visits were registered and 33 patients were admitted to the University Medical Center during the follow-up period. After a median of 52 days, n = 110 patients completed FU-1 and n = 72 completed FU-2 after a median of 6.1 months. Only in one patient, an 80-year-old man with stable liver function (CPS A) and advanced HCC, SARS-CoV-2 antibodies were detected at baseline and FU-1, while antibody testing was negative in the remaining patients at baseline, FU-1 and FU-2. CONCLUSION: The incidence of COVID-19 at our tertiary medical center during the pandemic was low in LC and HCC patients, when simple protective measures were implemented. Therefore, a routine care for patients with chronic liver diseases does not increase the risk of SARS-CoV-2 infection and should be maintained with protective measures.

Multi-dimensional and longitudinal systems profiling reveals predictive pattern of severe COVID-19.

COVID-19 is a respiratory tract infection that can affect multiple organ systems. Predicting the severity and clinical outcome of individual patients is a major unmet clinical need that remains challenging due to intra- and inter-patient variability. Here, we longitudinally profiled and integrated more than 150 clinical, laboratory, and immunological parameters of 173 patients with mild to fatal COVID-19. Using systems biology, we detected progressive dysregulation of multiple parameters indicative of organ damage that correlated with disease severity, particularly affecting kidneys, hepatobiliary system, and immune landscape. By performing unsupervised clustering and trajectory analysis, we identified T and B cell depletion as early indicators of a complicated disease course. In addition, markers of hepatobiliary damage emerged as robust predictor of lethal outcome in critically ill patients. This allowed us to propose a novel clinical COVID-19 SeveriTy (COST) score that distinguishes complicated disease trajectories and predicts lethal outcome in critically ill patients.

Brain magnetic resonance imaging in imported malaria.

BACKGROUND: Previous studies have documented a spectrum of brain magnetic resonance imaging (MRI) abnormalities in patients with cerebral malaria, but little is known about the prevalence of such abnormalities in patients with non-cerebral malaria. The aim of this study was to assess the frequency of brain MRI findings in returning travellers with non-cerebral malaria. METHODS: A total of 17 inpatients with microscopically confirmed Plasmodium falciparum non-cerebral malaria underwent structural brain MRI at 3.0 Tesla, including susceptibility-weighted imaging (SWI). Presence of imaging findings was recorded and correlated with clinical findings and parasitaemia. RESULTS: Structural brain abnormalities included a hyperintense lesion of the splenium on T2-weighted imaging (n = 3) accompanied by visible diffusion restriction (n = 2). Isolated brain microhaemorrhage was detected in 3 patients. T2-hyperintense signal abnormalities of the white matter ranged from absent to diffuse (n = 10 had 0-5 lesions, n = 5 had 5-20 lesions and 2 patients had more than 50 lesions). Imaging findings were not associated with parasitaemia or HRP2 levels. CONCLUSION: Brain MRI reveals a considerable frequency of T2-hyperintense splenial lesions in returning travellers with non-cerebral malaria, which appears to be independent of parasitaemia.