Functional dependence following intensive care unit-treated sepsis: three-year follow-up results from the prospective Mid-German Sepsis Cohort (MSC).

Background: Surviving sepsis can lead to chronic physical, psychological and cognitive impairments, which affect millions of patients worldwide, including survivors after COVID-19 viral sepsis. We aimed to characterize the magnitude and trajectory of functional dependence and new impairments post-sepsis. Methods: We conducted a prospective cohort study including sepsis survivors who had been discharged from five German intensive care units (ICUs), until 36 months post-discharge. Primary outcome was functional dependence, defined as ≥1 impaired activity of daily living (ADL; 10-item ADL score <100), self-reported nursing care dependence or nursing care level. Secondary outcome was post-sepsis morbidity in the physical, psychological or cognitive domain. We used a multistate, competing risk model to address competing events in the course of dependence, and conducted multiple linear regression analyses to identify predictors associated with the ADL score. Findings: Of 3210 sepsis patients screened, 1968 survived the ICU treatment (61.3%). A total of 753 were included in the follow-up assessments of the Mid-German Sepsis cohort. Patients had a median age of 65 (Q1-Q3 56-74) years, 64.8% (488/753) were male and 76.1% (573/753) had a septic shock. Considering competing risk modelling, the probability of still being functional dependent was about 25%, while about 30% regained functional independence and 45% died within the three years post-sepsis. Patients reported a high burden of new and often overlapping impairments until three years post-sepsis. In the subgroup of three-year survivors (n = 330), new physical impairments affected 91.2% (n = 301) while new cognitive and psychological impairments were reported by 57.9% (n = 191) and 40.9% (n = 135), respectively. Patients with pre-existing functional limitations and higher age were at risk for low ADL scores three years after sepsis. Interpretation: Sepsis survivorship was associated with a broad range of new impairments and led to functional dependence in around one quarter of patients. Targeted measures are needed to mitigate the burden of this Post-Sepsis-Syndrome and increase the proportion of patients that achieve functional improvements. Funding: This work was supported by the Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC) at the Jena University Hospital funded by the German Ministry of Education and Research and by the Rudolf Presl GmbH & Co, Kreischa, Germany.

COVID-19 outbreak among employees of a German hospital: risk factor analysis based on a follow-up questionnaire and seroprevalence.

BACKGROUND: The Co-FriSero study describes a COVID-19 outbreak at the Friedrichroda hospital in Thuringia, Germany, with 185 beds and 404 employees, at the onset of the pandemic between March 30th, 2020, and April 13th, 2020. This study aimed to analyze potential sources of SARS-CoV-2 transmission amongst hospital employees. METHODS: After the outbreak, a comprehensive follow-up was conducted through a questionnaire and a seroprevalence study using two different immunoassays for IgG detection and a third for discordant results. RESULTS: PCR screenings confirmed SARS-CoV-2 infection in 25 of 229 employees, with an additional 7 detected through serology. Statistical analysis indicated that direct patient contact, exposure to high flow ventilation in non-isolated rooms, direct contact with colleagues, shared use of recreational rooms, and carpooling were associated with an increased infection risk. Conversely, contact with family and friends, public transportation, public events, and use of locker rooms were not associated with infection. Male gender showed a lower infection likelihood, independent of age and other risk factors. CONCLUSION: This study highlights the role of direct patient care and internal staff interactions in the spread of SARS-CoV-2 in the hospital setting. It suggests that non-traditional transmission routes like carpooling require consideration in pandemic preparedness.

[Tendency to fall and injuries related to the Covid-19 pandemic at a department of emergency medicine]. / Sturzneigung und Verletzungen im Zusammenhang mit der COVID-19-Pandemie in einer Klinik für Notfallmedizin.

INTRODUCTION: This study investigates whether restrictions associated with the Covid-19 pandemic, in particular the temporary restrictions on social contacts in 2020, affected the number of inpatients admitted by the Department of Emergency Medicine of Jena University Hospital with a documented susceptibility to falls, injury or a susceptibility to falls resulting in at least one injury. METHODS: Using the ICD-10-GM code for susceptibility to falls (R29.6) and the codes for injuries (S00 to T14) from medicare claims data, the incidence rates of inpatient admissions between the years 2019 and 2020 were compared. In addition to all inpatient admissions recorded by the Department of Emergency Medicine, the cases of inpatients aged 65 years or older were considered separately, as they have an increased risk of having a fall. RESULTS: In 2020, the number of inpatient admissions in all age groups with one or more codes for injuries (S00 to T14) was significantly lower than in 2019 (2019: 19.2%, 2020: 17.3%, p<0.001). Regarding the codes for a documented susceptibility to falls (R29.6) or a documented susceptibility to falls (R29.6) with at least one injury (S00-T14), no differences were observed between the two years. In the group of inpatients 65 years or older, there were also no differences between 2019 and 2020 for any of the diagnoses considered. CONCLUSION: In this monocentric study of Jena University Hospital, it could be demonstrated for the first time that the Covid-19 pandemic had little impact on the number of inpatients admitted to the Department of Emergency Medicine with a documented diagnosis of susceptibility to falls (R29.6) and of susceptibility to falls in combination with at least one documented injury (S00-T14). As observed in previous publications, the number of inpatient admissions with documented injury diagnoses (S00 to T14) decreased.

Planning adaptive treatment by longitudinal response assessment implementing MR imaging, liquid biopsy and analysis of microenvironment during neoadjuvant treatment of rectal cancer (PRIMO).

INTRODUCTION: Conducting neoadjuvant chemoradiotherapy (CRT) and additional preoperative consolidating chemotherapy (CTx), that is, total neoadjuvant therapy (TNT), improves local control and complete response (CR) rates in locally advanced rectal cancer (LARC), putting the focus on organ preservation concepts. Therefore, assessing response before surgery is crucial. Some LARC patients would either not benefit from intensification by TNT or may reach CR, making resection not mandatory. Treatment of LARC should therefore be based on patient individual risk and response to avoid overtreatment.The "PRIMO" pilot study aims to determine early response assessment to form a basis for development and validation of a noninvasive response prediction model by a subsequent prospective multicenter trial, which is highly needed for individual, response-driven therapy adaptions. METHODS: PRIMO is a prospective observational cohort study including adult patients with LARC receiving neoadjuvant CRT. At least 4 multiparametric magnetic resonance imaging (MRI) scans (diffusion-weighted imaging [DWI] and hypoxia-sensitive sequences) as well as repeated blood samples in order to analyze circulating tumor cells (CTC) and cell-free tumor DNA (ctDNA) are scheduled. Pelvic radiotherapy (RT, 50.4 Gy) will be performed in combination with a 5-fluorouracil/oxaliplatin regimen in all patients (planned: N = 50), succeeded by consolidation CTx (FOLFOX4) if feasible. Additional (immuno)histochemical markers, such as tumor-infiltrating lymphocytes (TIL) and programmed death ligand 1 (PD-L1) status will be analyzed before and after CRT. Routine resection is scheduled subsequently, nonoperative management is offered alternatively in case of clinical CR (cCR).The primary endpoint is pathological response; secondary endpoints comprise longitudinal changes in MRI as well as in CTCs and TIL. These are evaluated for early response prediction during neoadjuvant therapy, in order to develop a noninvasive response prediction model for subsequent analyses. DISCUSSION: Early response assessment is the key in differentiating "good" and "bad" responders during neoadjuvant CRT, allowing adaption of subsequent therapies (additional consolidating CTx, organ preservation). This study will contribute in this regard, by advancing MR imaging and substantiating new surrogate markers. Adaptive treatment strategies might build on these results in further studies.

Psychometric properties of the Reintegration to Normal Living Index for sepsis survivors.

PURPOSE: Return to a normal state of living is a key patient-relevant outcome for sepsis survivors. The Reintegration to Normal Living Index (RNLI) assesses self-perceived participation in patients with chronic disease, but its psychometric properties have been analyzed neither for patients after sepsis nor in a German patient cohort. This study aims to analyze the psychometric properties of the German version of the RNLI in sepsis survivors. METHODS: In a prospective multicenter survey study, 287 sepsis survivors were interviewed 6 and 12 months after hospital discharge. Multiple-group categorical confirmatory factor analyses with three competing models were used to explore the factor structure of the RNLI. Concurrent validity was evaluated in relation to the EQ-5D-3L and the Barthel Index of Activities of Daily Living (ADL). RESULTS: Regarding structural validity, all models showed an acceptable model fit. Because of high correlation between the latent variables in the two-factor models (up to r = 0.969) and for reason of parsimony, we opted for the common factor model to analyze the concurrent validity. Our analyses showed moderate positive correlations between RNLI score and ADL score (r ≥ 0.630), EQ-5D-3L visual analogue scale (r ≥ 0.656) and EQ-5D-3L utility score (r ≥ 0.548). The reliability assessed by McDonald's Omega was 0.94. CONCLUSION: We found convincing evidence for good reliability, structural and concurrent validity of the RNLI in German sepsis survivors. We propose to use the RNLI in addition to generic health-related quality of life measures to assess the reintegration to normal living after sepsis.

[Differential Effects of an Internet-Based Cognitive-Behavioral Writing Therapy for Reducing PTSD Symptoms after Intensive Care: Results of a Per-Protocol Analysis]. / Differentielle Wirksamkeit einer internetbasierten kognitiv-behavioralen Schreibtherapie zur Reduktion von PTBS-Symptomen nach intensivmedizinischer Behandlung: Ergebnisse einer Per-Protokoll-Analyse.

OBJECTIVE: To investigate the differential effects of an internet-based cognitive-behavioral writing therapy (iCBT) on post-traumatic stress disorder (PTSD) symptoms after intensive care in patients and their spouses. METHODS: This reanalysis of a randomized controlled trial compared PTSD symptom severity (measured by PCL-5) before and after therapy considering potential influencing factors in the per-protocol population. RESULTS: A significant reduction in post-traumatic symptom severity after iCBT was found. Eleven of the 25 treated participants showed a clinically significant change (PCL-5 difference≥10 points). The number of words written by the participants in the therapy modules had a significant impact on iCBT efficacy. CONCLUSION: iCBT appears to be a promising option to augment therapy for PTSD, particularly for physically impaired patients following critical illness.

Immunomodulator comedication promotes the reversal of anti-drug antibody-mediated loss of response to anti-TNF therapy in inflammatory bowel disease.

PURPOSE: Loss of therapeutic response (LOR) due to anti-drug antibodies (ADA) against tumor necrosis factor (TNF) inhibitors is common in patients with inflammatory bowel disease (IBD). We aimed to investigate whether immunomodulator comedication can reverse the immunogenic LOR to TNF inhibitors in IBD. METHODS: In this real-world retrospective cohort study, 123 IBD patients with neutralizing ADA to infliximab or adalimumab and concomitant subtherapeutic trough levels were screened for clinical LOR. Subsequent ADA and trough level measurements and clinical outcomes were analyzed for patients who received either immunomodulator comedication or dose intensification of infliximab or adalimumab to overcome LOR. RESULTS: Following immunogenic LOR, the initial anti-TNF regimen was optimized in 33 patients. In univariable and multivariable logistic regression analyses, immunomodulator comedication was identified as the crucial factor for regaining clinical remission and ADA clearance. Detectable trough levels (≥ 0.98 or ≥ 1.00 mg/L, respectively) had optimal predictive performance for both endpoints in receiver operating characteristics curves [area under the curve 0.86 (95% confidence interval 0.68-1.00) for regaining clinical remission, 0.87 (0.71-1.00) for ADA clearance]. Furthermore, 11/20 patients (55%) on a comedication with azathioprine or methotrexate and 2/13 patients (15%) receiving anti-TNF dose intensification exclusively (P = 0.032) exhibited ADA elimination, regain of therapeutic trough levels, and clinical remission. Regain of clinical remission alone was achieved in 17/20 (85%) patients receiving comedication and 2/13 (15%) patients receiving anti-TNF dose intensification (P = 1.6 × 10-4). CONCLUSION: Immunogenic LOR to infliximab or adalimumab in IBD can be successfully reversed using immunomodulator comedication.

Non-patient-related SARS-CoV-2 exposure from colleagues and household members poses the highest infection risk for hospital employees in a German university hospital: follow-up of the prospective Co-HCW seroprevalence study.

PURPOSE: The Co-HCW study is a prospective, longitudinal, single-center observational study that aims to assess the SARS-CoV-2 seroprevalence and infection status in staff members of Jena University Hospital (JUH) in Jena, Germany. METHODS: This follow-up study covers the observation period from 19th May 2020 to 22nd June 2021. At each of the three voluntary study visits, participants filled out a questionnaire regarding their SARS-CoV-2 exposure and provided serum samples to detect specific SARS-CoV-2 antibodies. Participants who were tested positive for antibodies against nucleocapsid and/or spike protein without previous vaccination and/or reported a positive SARS-CoV-2 PCR test were regarded to have been infected with SARS-CoV-2. Multivariable logistic regression modeling was applied to identify potential risk factors for infected compared to non-infected participants. RESULTS: Out of 660 participants that were included during the first study visit, 406 participants (61.5%) were eligible for the final analysis as their COVID-19 risk area (high-risk n = 76; intermediate-risk n = 198; low-risk n = 132) did not change during the study. Forty-four participants [10.8%, 95% confidence interval (95%CI) 8.0-14.3%] had evidence of a current or past SARS-CoV-2 infection detected by serology (n = 40) and/or PCR (n = 28). No association between SARS-CoV-2 infection and the COVID-19 risk group according to working place was detected. However, exposure to a SARS-CoV-2 positive household member [adjusted OR (AOR) 4.46, 95% CI 2.06-9.65] or colleague (AOR 2.30, 95%CI 1.10-4.79) was found to significantly increase the risk of a SARS-CoV-2 infection. CONCLUSION: Our results demonstrate that non-patient-related SARS-CoV-2 exposure posed the highest infection risk for hospital staff members of JUH.

Internet-based cognitive-behavioural writing therapy for reducing post-traumatic stress after severe sepsis in patients and their spouses (REPAIR): results of a randomised-controlled trial.

OBJECTIVES: To investigate the efficacy, safety and applicability of internet-based, therapist-led partner-assisted cognitive-behavioural writing therapy (iCBT) for post-traumatic stress disorder (PTSD) symptoms after intensive care for sepsis in patients and their spouses compared with a waitlist (WL) control group. DESIGN: Randomised-controlled, parallel group, open-label, superiority trial with concealed allocation. SETTING: Internet-based intervention in Germany; location-independent via web-portal. PARTICIPANTS: Patients after intensive care for sepsis and their spouses of whom at least one had a presumptive PTSD diagnosis (PTSD-Checklist (PCL-5)≥33). Initially planned sample size: 98 dyads. INTERVENTIONS: ICBT group: 10 writing assignments over a 5-week period; WL control group: 5-week waiting period. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome: pre-post change in PTSD symptom severity (PCL-5). SECONDARY OUTCOMES: remission of PTSD, depression, anxiety and somatisation, relationship satisfaction, health-related quality of life, premature termination of treatment. Outcomes measures were applied pre and post treatment and at 3, 6 and 12 months follow-up. RESULTS: Twenty-five dyads representing 34 participants with a presumptive PTSD diagnosis were randomised and analysed (ITT principle). There was no evidence for a difference in PCL-5 pre-post change for iCBT compared with WL (mean difference -0.96, 95% CI (-5.88 to 3.97), p=0.703). No adverse events were reported. Participants confirmed the applicability of iCBT. CONCLUSIONS: ICBT was applied to reduce PTSD symptoms after intensive care for sepsis, for the first time addressing both patients and their spouses. It was applicable and safe in the given population. There was no evidence for the efficacy of iCBT on PTSD symptom severity. Due to the small sample size our findings remain preliminary but can guide further research, which is needed to determine if modified approaches to post-intensive care PTSD may be more effective. TRIAL REGISTRATION NUMBER: DRKS00010676.

Comparison of fatigue, cognitive dysfunction and psychological disorders in post-COVID patients and patients after sepsis: is there a specific constellation?

BACKGROUND: Sequelae of COVID-19 can be severe and longlasting. We compared frequencies of fatigue, depression and cognitive dysfunction in survivors of SARS-CoV-2-infection and sepsis. METHODS: We performed a prospective cohort study of 355 symptomatic post-COVID patients who visited our out-patient clinic for post-COVID-19 care. We compared them with 272 symptomatic patients from the Mid-German Sepsis Cohort, which investigates the long-term courses of sepsis survivors. Possible predictors for frequent clinical findings (fatigue, signs of depression, cognitive dysfunction) in post-COVID were investigated with multivariable logistic regression. RESULTS: Median age of the post-COVID patients was 51 years (range 17-86), 60.0% were female, and 31.8% required hospitalization during acute COVID-19. In the post-COVID patients (median follow-up time: 163 days) and the post-sepsis patients (180 days), fatigue was found in 93.2% and 67.8%, signs of depression were found in 81.3% and 10.9%, and cognitive dysfunction was found in 23.5% and 21.3%, respectively. In post-COVID, we did not observe an association between fatigue or depression and the severity of acute COVID-19. In contrast, cognitive dysfunction was associated with hospitalization (out-patient versus in-patient) and more frequent in post-COVID patients treated on an ICU compared to the MSC patients. CONCLUSION: In post-COVID patients, fatigue and signs of depression are more common than in sepsis survivors, independent from the acute SARS-CoV-2-infection. In contrast, cognitive dysfunction is associated with hospitalization. Despite the differences in frequencies, owing to the similarity of post-COVID and post-sepsis sequelae, this knowledge may help in implementing follow-up approaches after SARS-CoV-2 infection.

Prospective surveillance study in a 1,400-bed university hospital: COVID-19 exposure at home was the main risk factor for SARS-CoV-2 point seroprevalence among hospital staff.

The Co-HCW study is a prospective cohort study among hospital staff, including healthcare workers (HCWs) and administration staff, at the Jena University Hospital (JUH), Germany. The objectives of this study were to assess SARS-CoV-2 IgG seroprevalence, individual exposure risk factors and compliance of HCWs to wear personal protective equipment (PPE). After the first nosocomial COVID-19 outbreak at JUH, mandatory masking was implemented on 20th March 2020. We evaluated point seroprevalence using two IgG detecting immunoassays and issued a questionnaire to assess COVID-19 exposure, clinical symptoms and compliance to wear PPE. Antibody retesting was offered to participants with a divergent result of both immunoassays 5-10 weeks after the first test. Between 19th May and 19th June 2020, we analysed 660 participants [out of 3,228; 20.4%]. Among them, 212 participants (32.1%) had received a previous COVID-19 test. Four of them (1.9%) reported a positive test result. After recruitment, 18 participants (2.7%) had SARS-CoV-2 antibodies in at least one immunoassay. Overall, 21 participants (3.2%) had any evidence of a past or current SARS-CoV-2 infection. Among them, 13 (61.9%) were not aware of direct COVID-19 exposure and 9 (42.9%) did not report any clinical symptoms. COVID-19 exposure at home (adjusted OR (aOR) with 95% CI: 47.82 (5.49, 416.62)) was associated with SARS-CoV-2 seroprevalence. We observed no evidence for an association between seroprevalence and exposure at work (aOR 0.48 (0.13, 1.70)) or with COVID-19 risk area according to the working place (aOR for intermediate-risk vs. high-risk: 1.97 (0.42, 9.22), aOR for low-risk versus high-risk: 2.10 (0.40, 11.06); p = .655). Reported compliance of HCWs to wear PPE differed (p < .001) between working in high-risk (98.3%) and in intermediate-risk areas (69.8%). In conclusion, compared to administration staff, we observed no additional risk to acquire SARS-CoV-2 infections by patient care, probably due to high compliance to wear PPE.

Mid-German Sepsis Cohort (MSC): a prospective observational study of sepsis survivorship.

PURPOSE: The Mid-German Sepsis Cohort (MSC) aims to investigate mid-term and long-term functional disabilities in sepsis survivors from intensive care unit (ICU) discharge until 1 year after. Secondary, post-acute mortality and morbidity, health-related quality of life and healthcare utilisation will be investigated. PARTICIPANTS: The MSC comprises adult (aged ≥18 years) patients who were treated for (severe) sepsis or septic shock on ICU. The participants were recruited between 15 April 2016 and 30 November 2018 from five German centres. Three thousand two hundred and ten patients with sepsis were identified, of which 1968 survived their ICU stay and were eligible for enrolment in the follow-up cohort. Informed consent for follow-up assessment was provided by 907 patients (46.1% of eligible patients). FINDINGS TO DATE: The recruitment of the participants for follow-up assessments and the baseline data collection is completed. Incidence of sepsis was 116.7 patients per 1000 ICU patients. In this cohort profile, we provide an overview of the demographics and the clinical characteristics of both the overall sepsis cohort and the ICU survivors who provided informed consent for follow-up assessment (907 out of 1968 ICU survivors (46.1%)). FUTURE PLANS: The follow-ups are conducted 3, 6 and 12 months after ICU discharge. Another yearly follow-up up to 5 years after ICU discharge is pursued. Several cooperation and satellite projects were initiated. This prospective cohort offers a unique resource for research on long-term sequelae of sepsis survivors. TRIAL REGISTRATION NUMBER: German Clinical Trials Registry (DRKS00010050).

Validation of the qSOFA score compared to the CRB-65 score for risk prediction in community-acquired pneumonia.

OBJECTIVE: The qSOFA (quick sepsis-related organ failure assessment) score shows similarities to the CRB-65 pneumonia score, but its prognostic accuracy in patients with community-acquired pneumonia (CAP) has not been extensively evaluated. Our aim was to validate the qSOFA (-65) score in a large cohort of CAP patients. METHODS: We conducted a retrospective population-based cohort study including all CAP cases hospitalized between 1st January 2014 and 31st December 2018 from the German nationwide mandatory quality assurance programme. We excluded cases transferred from another hospital, with mechanical ventilation present on admission, and without documented respiratory rate. Predefined outcomes were hospital mortality and need for mechanical ventilation. RESULTS: Among the 1,262,250 included cases, hospital mortality was 12.4% and the mechanical ventilation rate was 7.1%. All CRB and qSOFA criteria were associated with both outcomes, but the qSOFA had inferior sensitivity compared to the CRB-65 for mortality prediction. Including the age criterion ≥65 years, qSOFA-65 and CRB-65 performed similarly (AUC 0.69, 95%CI 0.69-0.69 versus 0.68, 95%CI 0.68-0.68). A qSOFA-65 of 0 was associated with fewer missed deaths (3328, 2.0%) compared to a CRB-65 of 0 (5480, 2.4%). The sensitivity of the suggested qSOFA cut-off of ≥2 for sepsis was low (mortality 25.8%, 95%CI 25.6-26.0%; mechanical ventilation 24.1%, 95%CI 23.8-24.4%). Results were similar when frail and palliative patients were excluded. CONCLUSIONS: The qSOFA parameters show prognostic accuracy similar to the CRB parameters in CAP, but the sepsis cut-off of ≥2 lacked sensitivity. For sensitive mortality prediction, the age criterion ≥65 years should be added to the qSOFA.

Clinical evaluation of two different (1,3)-ß-d-glucan assays for diagnosis of invasive fungal diseases: A retrospective cohort study.

BACKGROUND: Early diagnosis of invasive fungal diseases (IFDs) remains a major challenge in routine clinical practice. OBJECTIVES: The aim of this retrospective cohort study was to evaluate the diagnostic performance of the fungal biomarker (1,3)-ß-d-glucan (BDG) using the ß-Glucan test (GT) and the well-established Fungitell assay® (FA) in real-life clinical practice. PATIENTS/METHODS: We included 109 patients with clinical suspicion of IFD who were treated at Jena University Hospital, Germany, between November 2018 and March 2019. The patients were classified according to the latest update of the EORTC/MSG consensus definitions of IFD. The first serum sample of every patient was analysed for BDG using the FA and the GT, respectively. RESULTS: Fifty-six patients (51.4%) had at least one host factor for IFD. In patients with proven (n = 11) or probable IFDs (n = 20), median BDG concentrations were 145.0 pg/ml for the FA and 5.1 pg/ml for the GT, respectively. A positive test result of both BDG assays at manufacturer's cut-offs predicted 89.5%-98.3% of proven or probable IFD, but the sensitivity of both assays was limited: The FA identified 60.7% of IFDs (cut-off: 80 pg/ml). Reducing the GT cut-off value from 11.0 to 4.1 pg/ml increased the detection rate of IFDs from 35.5% to 54.8%. CONCLUSIONS: A positive test result of both BDG assays at manufacturer's cut-off was highly predictive for IFD, but except for Pneumocystis jirovecii pneumonia sensitivities were limited. Adjustment of the GT cut-off value equalised sensitivities of GT and FA.

Effect of antiviral therapy on the outcomes of mechanically ventilated patients with herpes simplex virus detected in the respiratory tract: a systematic review and meta-analysis.

BACKGROUND: Herpes simplex virus (HSV) is frequently detected in the respiratory tract of mechanically ventilated patients. The aim of this study was to assess current evidence to determine whether antiviral therapy is associated with better outcomes in these patients. METHODS: MEDLINE, ISI Web of Science, Cochrane Database and ClinicalTrials.gov were searched from inception to 25 May 2020. All clinical studies investigating the effects of antiviral therapy on the outcome of mechanically ventilated ICU patients in whom HSV was detected in the respiratory tract were eligible for inclusion, regardless of study design, publication status or language. Titles and abstracts were reviewed independently by two authors. If the articles seemed eligible, full-text articles were reviewed and data extracted. We performed a random-effects meta-analysis to estimate relative risks (RRs) with corresponding 95% confidence intervals (CIs). The primary endpoint was hospital all-cause mortality. RESULTS: Nine studies were included in the meta-analysis (one randomized controlled trial, eight cohort studies). Antiviral treatment was associated with lower hospital mortality (with antiviral treatment, 40.6% (189 out of 465 patients); without, 52.7% (193 out of 366 patients); RR 0.74 [0.64, 0.85]; eight studies, low quality of evidence). Furthermore, antiviral treatment was associated with lower 30-day mortality (RR 0.75 [0.59, 0.94]; three studies, very low quality of evidence). We did not observe evidence for differences in ICU mortality (RR 0.73 [0.51, 1.05]; three studies, very low quality of evidence). CONCLUSIONS: This meta-analysis of the available data shows that antiviral therapy might result in lower hospital and 30-day all-cause mortality in mechanically ventilated ICU patients who are positive for HSV in the respiratory tract. However, this result must be interpreted with great caution due to the high risk of bias and limited number of patients. Large, well-designed randomized controlled clinical trials are urgently needed. TRIAL REGISTRATION: The study was registered in advance on International Prospective Register of Systematic Reviews (CRD42020180053) .

Effect size estimates from umbrella designs: Handling patients with a positive test result for multiple biomarkers using random or pragmatic subtrial allocation.

Umbrella trials have been suggested to increase trial conduct efficiency when investigating different biomarker-driven experimental therapies. An overarching platform is used for patient screening and subsequent subtrial allocation according to patients' biomarker status. Two subtrial allocation schemes for patients with a positive test result for multiple biomarkers are (i) the pragmatic allocation to the eligible subtrial with the currently fewest included patients and (ii) the random allocation to one of the eligible subtrials. Obviously, the subtrials compete for such patients which are consequently underrepresented in the subtrials. To address questions of the impact of an umbrella design in general as well as with respect to subtrial allocation and analysis method, we investigate an umbrella trial with two parallel group subtrials and discuss generalisations. First, we analytically quantify the impact of the umbrella design with random allocation on the number of patients needed to be screened, the biomarker status distribution and treatment effect estimates compared to the corresponding gold standard of an independent parallel group design. Using simulations and real data, we subsequently compare both allocation schemes and investigate weighted linear regression modelling as possible analysis method for the umbrella design. Our results show that umbrella designs are more efficient than the gold standard. However, depending on the biomarker status distribution in the disease population, an umbrella design can introduce differences in estimated treatment effects in the presence of an interaction between treatment and biomarker status. In principle, weighted linear regression together with the random allocation scheme can address this difference though it is difficult to assess if such an approach is applicable in practice. In any case, caution is required when using treatment effect estimates derived from umbrella designs for e.g. future trial planning or meta-analyses.

Effect of Antiviral Therapy on the Outcome of Mechanically Ventilated Patients With Herpes Simplex Virus Type 1 in BAL Fluid: A Retrospective Cohort Study.

BACKGROUND: Herpes simplex virus type 1 (HSV-1) is frequently detected in the BAL fluid of patients on mechanical ventilation. RESEARCH QUESTION: The aim of the study was to investigate whether antiviral therapy is associated with improved overall survival within 30 days. STUDY DESIGN AND METHODS: This was a retrospective cohort study in four ICUs between January 2011 and December 2017. All adult patients on mechanical ventilation with a respiratory tract infection with positive polymerase chain reaction testing for HSV-1 in the BAL were included. Patients already receiving antiviral agents on the day BAL was performed were excluded. We performed uni- and multivariable Cox and logistic regression modeling. RESULTS: Overall, 306 patients were included in the analysis. Among them, 177 patients (57.8%) received antiviral therapy (90.9% acyclovir, 6.2% ganciclovir, 2.9% both). The overall 30-day mortality rate was 42.4% (n = 75) in the antiviral treatment group and 50.4% (n = 65) in the control group. The adjusted hazard ratio (HR) for the primary outcome was 0.62 (95% CI, 0.44-0.87; P = .005), indicating better overall survival within 30 days for the antiviral-treated group than for the untreated group. This benefit was also present in the subgroup of patients without immunosuppression (n = 246; adjusted HR, 0.53; 95% CI, 0.36-0.78; P = .001). Overall, the median lengths of hospital stay (31 vs 24 days, P = .002) and ICU stay (24 vs 17 days, P < .001), and the duration of mechanical ventilation (18 vs 11 days, P < .001), were longer for patients with therapy. No evidence for the treatment-related deterioration of renal function was observed. INTERPRETATION: These data suggest that detection of HSV-1 in the BAL of patients on mechanical ventilation may be of clinical significance and that specific antiviral treatment may improve clinical outcomes. However, this needs to be proven in multicenter randomized controlled trials before implementation into the clinical routine.

Pneumococcal conjugate serotype distribution and predominating role of serotype 3 in German adults with community-acquired pneumonia.

INTRODUCTION: Implementation of the 7-valent pneumococcal conjugate vaccine (PCV7) in infant vaccination programs has substantially reduced the burden of PCV7 serotypes also in adult community-acquired pneumonia (CAP). Currently, it is unclear, if this extensive herd protection effect can be extrapolated to the additional 6 serotypes included in the 13-valent pneumococcal conjugate vaccine (PCV13), which replaced PCV7 in Germany in 2010. OBJECTIVES: We investigated changing trends for PCV13 serotypes in adult CAP patients between three to seven years after implementation of PCV13 infant immunization in Germany. METHODS: Between December 2012 and January 2017, urine samples from German adult patients with radiologically confirmed CAP were prospectively collected by the multi-center cohort study CAPNETZ and analyzed by the serotype-specific multiplex urinary antigen detection assay (SSUAD) allowing for the detection of PCV13 serotypes. RESULTS: PCV13 serotypes were found in 59 of 796 (7.4%) patients with all-cause CAP, most prevalent was serotype 3 (30 of 59 patients, 50.8%). All patients with serotype 3-CAP were admitted to hospital and the majority required oxygen at admission (83.3% of patients with serotype 3-CAP versus 50.9% of patients with pneumococcal CAP by other serotypes, p = 0.005). Compared to SSUAD testing, conventional microbiological workup missed 27 of 30 (90.0%) serotype 3-CAP cases. We could not observe a time trend in the proportions of PCV13 serotypes and serotype 3 in all-cause CAP between 2013 and 2016 (OR trend per year 0.84, 95% CI 0.64-1.11 for PCV13 serotypes and OR trend per year 0.95, 95% CI 0.70-1.28 for serotype 3). CONCLUSIONS: Conventional methods underestimate serotype 3-CAP that can cause severe disease. Changes in overall PCV13 coverage were not detected during the years 2013 to 2016, mostly driven by a high proportion of serotype 3.