Although cytomegalovirus viral load is commonly used to guide pre-emptive therapy in the post-transplantation setting, few data are available correlating viraemia with clinical endpoints. We ...therefore investigated the association between cytomegalovirus viral load and mortality in the first year after haemopoietic stem cell transplantation.
In this retrospective cohort study, we included patients from the Fred Hutchinson Cancer Research Center, WA, USA, who received an allogeneic haemopoietic stem cell transplantation between Jan 1, 2007, and Feb 28, 2013, were cytomegalovirus seropositive or had a seropositive donor, and underwent weekly plasma cytomegalovirus monitoring by PCR through to day 100 post-transplantation. Cox proportional hazards models were used to estimate the association of cytomegalovirus viral load at different thresholds with overall mortality by 1 year post-transplantation, adjusting for the use of pre-emptive therapy and other factors such as neutropenia, and graft-versus-host disease.
Of the 1037 patients initially selected for inclusion in this cohort, 87 (8%) patients were excluded because of missing cytomegalovirus testing and 24 (2%) were excluded because of their participation in cytomegalovirus prophylaxis trials. In the remaining 926 patients included in this study, the cumulative overall mortality was 30·0% (95% CI 26·9-33·0) 1 year after haemopoietic stem cell transplantation. 95 patients developed cytomegalovirus disease; death was directly attributable to cytomegalovirus disease in three (1%) of 263 patients who died in the first year after transplantation. A cytomegalovirus viral load of 250 IU/mL or greater was associated with increased risk of early (day 0-60 post-transplantation) death (adjusted hazard ratio HR 19·8, 95% CI 9·6-41·1). The risk was attenuated after day 60 (adjusted HR 1·8, 95% CI 1·3-2·3). Similar associations were noted for higher cytomegalovirus viral load thresholds.
Cytomegalovirus viraemia is associated with an increased risk of overall mortality in the first year after haemopoietic stem cell transplantation, independent of the use of pre-emptive therapy, and with evidence of a positive dose-response relationship. These data indicate the suitability of viral load as a surrogate clinical endpoint for clinical trials for cytomegalovirus vaccines, biologics, and drugs.
Merck and Co, National Institutes of Health.
Confirmation of respiratory syncytial virus (RSV) in the lower respiratory tract is associated with worse clinical outcomes, including increased supplemental oxygen use, decreased supplemental ...oxygen–free days, and greater mortality rate. Supplemental oxygen–free days as a clinical end point may allow smaller sample sizes for trials evaluating RSV antivirals.
Abstract
Background
Clinically meaningful endpoints for respiratory syncytial virus (RSV) treatment trials are lacking for hematopoietic cell transplant (HCT) recipients. We evaluated supplemental oxygen use among HCT recipients with RSV infection.
Methods
Subjects were grouped according to the presence of upper respiratory tract infection (URTI) without lower respiratory tract infection (LRTI), URTI progressing to LRTI, and LRTI at presentation. LRTI was defined as a positive lower respiratory tract sample with or without radiographic abnormality (defined as proven or probable LRTI, respectively) or a positive upper respiratory tract sample with radiographic abnormality (possible LRTI). Supplemental oxygen–free days were defined as any day while alive after diagnosis of RSV infection during which ≤2 L of supplemental oxygen per minute was received.
Results
Among 230 patients, supplemental oxygen use by day 28 after the first diagnosis of RSV infection was lowest in patients presenting with URTI (31 of 197 16%). Supplemental oxygen use was lower in patients with possible LRTI (12 of 45 27%) than in those with proven/probable LRTI (29 of 42 69%). Patients presenting with proven/probable LRTI had a median of 16 fewer supplemental oxygen–free days than those presenting with URTI (P < .0001). Death only occurred among patients with proven/probable LRTI (11 of 42 26%).
Conclusions
Confirmation of RSV infection in the lower respiratory tract provides prognostic information that may help prioritize therapies. Supplemental oxygen–free days as a clinical endpoint may allow smaller sample sizes for trials evaluating RSV antivirals.
Corona Virus disease 2019 (COVID-19), which is one of the biggest outbreaks in the last century and is caused by a kind of coronavirus, spread to many countries in a short time after being first seen ...in the Wuhan region of China in December 2019. The COVID-19 outbreak, which spread rapidly and caused many deaths, was declared as a pandemic by the World Health Organization on March 11, 2020. The first COVID-19 case in Turkey, coincidentally, was seen on the same day. In this article, the story of the pandemic struggle successfully carried out in a private hospital and the teachings of the process are provided.
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Background: Late cytomegalovirus (CMV) disease is a well-established complication in patients undergoing HCT and extended surveillance and preemptive therapy in high-risk patients is recommended by ...international guidelines. The objectives of this study were to describe the incidence, clinical characteristics and outcome of, and risk factors for the development of late CMV disease in day 100 survivors of allogeneic HCT who did and did not undergo viral load-guided preemptive therapy based on a pre-defined risk algorithm.
Methods: We retrospectively analyzed medical records of 1526 HCT patients (donor or recipients seropositive), who received their first allogeneic HCT at FHCRC between 2001 and 2011 and survived to day 100. PCR-based surveillance was recommended for patients who had CMV viremia or disease before day 100 or had GVHD that required systemic treatment. Preemptive therapy was recommended for CMV DNA levels of >1000 copies per mL of plasma. We evaluated all CMV disease events occurring between day 100 and 2 years. Patients were categorized by their recommended surveillance status and, among those who were in the surveillance category, adherence to the testing schedule was examined. Cox proportional hazards models were used to evaluate the risk of late CMV disease and overall mortality. Candidate variables included risk status for PCR surveillance, CMV reactivation (before day 100 and after day 100 as time dependent variable), steroid use (≥ 1mg/kg/day) as well as other patient/donor and transplantation related factors; for mortality late CMV disease was also analyzed as a variable.
Results: Among 1526 patients there were 118 cases of late CMV disease by 2 years (cumulative incidence 8% 95% CI- 7-9%). The first manifestation of late CMV disease was pneumonia in 57 cases (48%), gastrointestinal disease (GI) in 54 cases (46%), and retinitis in 7 cases (6%). Fifteen percent of patients with late CMV disease (1% of cohort) had a subsequent event. Among first cases of late CMV disease 97 (82%) occurred between day 100 and 1 year and 21 (18%) occurred between 1 and 2 years after HCT. The median time to first late CMV disease was 192 days for pneumonia, 196 days for GI, and 230 days for retinitis.
Extended CMV surveillance after day 100 was recommended for 1246 (82%) of patients. Late CMV disease occurred in 8.7% of patients for whom continued surveillance was recommended, compared to 2.9% of patients who were considered at low risk and were not advised to continue CMV testing. The median time to first late CMV disease event was 192 days post-transplant for the high risk group and 292 days for the low risk group. Among the 8 disease cases in patients in the low risk group, 4 cases (2 pneumonia, 2 GI) occurred in the first year and 4 (1 pneumonia, 3 GI) in the second year after HCT.
In a multivariable Cox model steroid treatment after day 100 (HR=6.49; 95% CI 3.4-12.3, p<0.001), CMV reactivation after day 100 (HR=3.78; 95% CI 2.5-5.7, p<0.001), and CMV reactivation before day 100 (HR=2.07; 95% CI 1.3-3.4, p=0.003) were all strongly associated with the risk of late CMV disease. The development of CMV disease and acute GVHD (grade 3-4) before day 100 were not significantly associated with late CMV disease.
Late CMV disease (HR=2.2; 95% CI 1.6-3, p<0.001) and late CMV reactivation (HR=1.63; 95% CI 1.3-2, p<0.001) were associated with increased risk of death between day 100 and 2 years after HCT.
An analysis of the adherence to PCR surveillance and viral load levels among breakthrough cases will be presented at the conference.
Conclusions: Late CMV disease remains an important complication after HCT. Currently recommended risk stratification parameters for extended surveillance identify most patients at risk for late CMV disease, however, occasionally late CMV disease can occur in patients that were deemed at low risk at 3 months after HCT. Also, late CMV disease can occur beyond 1 year after HCT and disease recurrence is about 15%. Overall, both late CMV infection and disease continue to be independently associated with overall mortality in the preemptive therapy era. Refined strategies are needed to further reduce the late-occurring complications of CMV infection among HCT recipients.
Boeckh:Chimerix Inc.: Consultancy, Research Funding; Viropharma Inc.: Research Funding; Genentech/Roche: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Clinigen: Consultancy.
Tigecycline is a semi-synthetic tetracycline with activity against most multidrug-resistant (MDR) bacteria.
We studied in vitro activity of tigecycline by agar dilution (AD) and Etest methods to ...evaluate their correlation. The study included 206 isolates of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli, Klebsiella pneumoniae and MDR Acinetobacter baumannii recovered from blood cultures of patients of Baskent University between 2008 and 2010.
ESBL-producing E. coli had MIC50/MIC90 values of 0.5/0.5 µg/ml by AD and 0.25/0.5 µg/ml by Etest. ESBL-producing K. pneumoniae had MIC50/MIC90 values of 1/2 µg/ml by AD and 0.75/2 µg/ml by Etest, whereas MDR A. baumannii had MIC50/MIC90 values of 4/4 µg/ml by AD and 2/4 µg/ml by Etest. The correlation between AD and Etest was weak for ESBL-producing E. coli and strong for ESBL-producing K. pneumoniae and MDR A. baumannii. Tigecycline MIC values for ESBL-producing E. coli were lower than the tigecycline concentration, while they were higher than the concentrations attainable by treatment doses for A. baumannii.
Tigecycline is an appropriate agent in the treatment of E. coli bacteremia, but it is not for treating A. baumannii bacteremia. Tigecycline could be used for K. pneumoniae bacteremia treatment after determining its MIC value. Determining the MIC value by gold-standard methods is more appropriate due to the correlation between Etest and AD at high MIC values.
•Delayed-onset clinically significant CMV infection is a persistent challenge with new transplantation techniques and anti-CMV drugs.•Dynamic risk stratification with restart of virologic monitoring ...when immunosuppression increases should be applied after day 100.
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Preemptive therapy (PET) and letermovir prophylaxis are effective in preventing cytomegalovirus (CMV) disease within the first 100 days after allogeneic hematopoietic cell transplantation (HCT) but are associated with late-onset CMV disease. We retrospectively examined the clinical manifestations, risk factors, prevention algorithm, and outcome of late CMV disease in CMV seropositive day 100 survivors transplanted between 2001-2017 (PET cohort) and 2018-2021 (letermovir cohort). There were 203 episodes of late CMV disease among 2469 day 100 survivors, and the estimated cumulative incidence of first late CMV disease was 7.2% (95% confidence interval CI, 6.2-8.3) with no difference between the PET (7.4%; 95% CI, 6.4-8.6) and the letermovir group (5.4%; 95% CI, 3.2-8.3). Thirty-seven patients (1.5%) had a second episode of CMV disease. In multivariable Cox regression models, posttransplant cyclophosphamide was associated with an increased risk of gastrointestinal CMV disease. CMV viremia or disease detected before day 100, corticosteroid treatment after day 100 at dose ≥1 mg/kg, acute and chronic graft-versus-host disease, lymphopenia, HLA-mismatched related donor status, were also associated with late CMV disease. HLA-mismatched donor status and late use of corticosteroids (≥1 mg/kg) were risk factors for late CMV disease recurrence. Late CMV disease occurred most frequently in a setting of prolonged low-level untreated viremia and was independently associated with death by 2 years after HCT. In summary, late CMV disease continues to occur in the present era. Improved prevention strategies for late CMV disease are needed.
An association between IL-6 levels and cytokine storm syndrome in COVID-19 patients has been suggested. Cases with higher IL-6 levels have more rapid progression and a higher complication rate. On ...the other hand, COVID-19 cases with anosmia have a milder course of the disease.
We aimed to investigate whether there is a relationship between serum IL-6 levels and presence of anosmia in COVID-19 patients.
Patients with a confirmed diagnosis of COVID-19 based on laboratory (PCR) were stratified into two groups based on presence of olfactory dysfunction (OD). In all cases with and without anosmia; psychophysical test (Sniffin' Sticks test) and a survey on olfactory symptoms were obtained. Threshold (t) – discrimination (d) – identification (i), and total (TDI) scores reflecting olfactory function were calculated. Clinical symptoms, serum IL-6 levels, other laboratory parameters, and chest computed tomography (CT) findings were recorded.
A total of 59 patients were included, comprising 23 patients with anosmia and 36 patients without OD based on TDI scores. Patients with anosmia (41.39 ± 15.04) were significantly younger compared to cases without anosmia (52.19 ± 18.50). There was no significant difference between the groups in terms of comorbidities, smoking history, and symptoms including nasal congestion and rhinorrhea. Although serum IL-6 levels of all patients were above normal values (7 pg/mL), patients with anosmia had significantly lower serum IL-6 levels (16.72 ± 14.28 pg/mL) compared to patients without OD (60.95 ± 89.33 pg/mL) (p = 0.026).
Patients with COVID-19 related anosmia tend to have significantly lower serum levels of IL-6 compared to patients without OD, and the lower IL-6 levels is related to milder course of the disease. With the effect of low cytokine storm and IL-6 level, it may be said that anosmic cases have a milder disease in COVID-19.
•Cytokine storm syndrome in COVID-19 is associated with poor prognosis and mortality.•IL-6 is one of the most important mediators of cytokine storm syndrome.•Patients with COVID-19-related anosmia usually have a mild disease.•Serum IL-6 level of patients with COVID-19-related anosmia is higher than normal, it is lower than patients without anosmia.
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