Diagnosis of genetic diseases in seriously ill children by rapid whole-genome sequencing and automated phenotyping and interpretation.

By informing timely targeted treatments, rapid whole-genome sequencing can improve the outcomes of seriously ill children with genetic diseases, particularly infants in neonatal and pediatric intensive care units (ICUs). The need for highly qualified professionals to decipher results, however, precludes widespread implementation. We describe a platform for population-scale, provisional diagnosis of genetic diseases with automated phenotyping and interpretation. Genome sequencing was expedited by bead-based genome library preparation directly from blood samples and sequencing of paired 100-nt reads in 15.5 hours. Clinical natural language processing (CNLP) automatically extracted children's deep phenomes from electronic health records with 80% precision and 93% recall. In 101 children with 105 genetic diseases, a mean of 4.3 CNLP-extracted phenotypic features matched the expected phenotypic features of those diseases, compared with a match of 0.9 phenotypic features used in manual interpretation. We automated provisional diagnosis by combining the ranking of the similarity of a patient's CNLP phenome with respect to the expected phenotypic features of all genetic diseases, together with the ranking of the pathogenicity of all of the patient's genomic variants. Automated, retrospective diagnoses concurred well with expert manual interpretation (97% recall and 99% precision in 95 children with 97 genetic diseases). Prospectively, our platform correctly diagnosed three of seven seriously ill ICU infants (100% precision and recall) with a mean time saving of 22:19 hours. In each case, the diagnosis affected treatment. Genome sequencing with automated phenotyping and interpretation in a median of 20:10 hours may increase adoption in ICUs and, thereby, timely implementation of precise treatments.

Early response to antibiotic treatment in European patients hospitalized with complicated skin and soft tissue infections: analysis of the REACH study.

BACKGROUND: The treatment of complicated skin and soft tissue infections (cSSTI) is challenging and many patients do not receive adequate first-line therapy. REACH (REtrospective Study to Assess the Clinical Management of Patients With Moderate-to-Severe cSSTI or Community-Acquired Pneumonia in the Hospital Setting) was a retrospective observational study of cSSTI patients in real-life settings in European hospitals. In this analysis, we review characteristics and outcomes of patients with an early response (≤72 hours) compared with those without an early response to treatment. We also compare the results according to two differing definitions of early response, one of which (Definition 1) requires resolution of fever within 72 hours, in line with previous US FDA guidelines. METHODS: Patients were adults hospitalized with cSSTIs 2010-2011 and requiring treatment with intravenous antibiotics. Clinical management, clinical outcomes and healthcare resource use were assessed using a descriptive analysis approach. RESULTS: The analysis set included 600 patients, of which 363 showed early response with Definition 1 and 417 with Definition 2. Initial treatment modification was frequent, and highest in patients without early response (48.1% with Definition 1). Patients without early response were more likely to have diabetes than those with early response (31.6% vs. 22.9%, respectively) and to suffer from more severe disease (e.g. skin necrosis: 14.8% and 7.7%, respectively), to be infected with difficult-to-treat microorganisms and to have recurrent infections. Furthermore, patients without early response had a higher rate of adverse clinical outcomes (e.g. septic shock) and higher use of healthcare resources. The results obtained with the two definitions for early response were largely similar. CONCLUSIONS: This study highlights the significance of early evaluation of patients in hospitals, in potentially preventing prolonged use of inappropriate or ineffective antibacterial therapy. TRIAL REGISTRATION: NCT01293435 .

Resource use in patients hospitalized with complicated skin and soft tissue infections in Europe and analysis of vulnerable groups: the REACH study.

BACKGROUND: Hospitalized patients with complicated skin and soft tissue infections (cSSTI) present a substantial economic burden, and resource use can vary according to the presence of comorbidities, choice of antibiotic agent, and the requirement for initial treatment modification. REACH (NCT01293435) was a retrospective, observational study aimed at collecting empirical data on current (year 2010-2011) management strategies of cSSTI in 10 European countries. METHODS: Patients (n = 1995) were aged ≥18 years, hospitalized with a cSSTI and receiving intravenous antibiotics. Data, collected via electronic Case Report Forms, detailed patient characteristics, medical history, disease characteristics, microbiological diagnosis, disease course and outcomes, treatments before and during hospitalization, and health resource consumption. RESULTS: For the analysis population, mean length of hospital stay (including duration of hospitalizations for patients with recurrences) was 18.5 days (median 12.0). Increased length of hospital stay was found for patients with comorbidities vs those without (mean = 19.9; [median = 14.0] days vs 13.3 [median = 8.0] days), for patients with methicillin-resistant Staphylococcus aureus compared with patients with methicillin-sensitive S. aureus (mean = 27.7 [median = 19.5] days vs 18.4 [median = 13.0] days) and for patients requiring surgery (mean = 24.4 [median = 16.0] days vs 15.0 [median = 11.0] days). Patients requiring modification of their initial antibiotic treatment had an associated increase in mean length of hospital stay of 10.9 days (median = 6.5) and additional associated hospital resource use. A multivariate analysis confirmed the association of nosocomial infections, comorbidities, directed treatment, recurrent infections, diabetes, recent surgery, and older age (≥65 years), with longer hospital stay. CONCLUSIONS: This study provides real-life data on factors that are expected to impact length of hospital stay, to guide clinical decision-making to improve outcomes, and reduce resource use in patients with cSSTI.

Resource use by patients hospitalized with community-acquired pneumonia in Europe: analysis of the REACH study.

BACKGROUND: Management of community-acquired pneumonia (CAP) places a considerable burden on hospital resources. REACH was a retrospective, observational study (NCT01293435) involving adults ≥18 years old hospitalized with CAP and requiring in-hospital treatment with intravenous antibiotics conducted to collect data on current clinical management patterns and resource use for CAP in hospitals in ten European countries. METHODS: Data were collected via electronic Case Report Forms detailing patient and disease characteristics, microbiological diagnosis, treatments before and during hospitalization, clinical outcomes and health resource consumption. RESULTS: Patients with initial antibiotic treatment modification (n = 589; 28.9%) had a longer mean hospital stay than those without (16.1 [SD: 13.1; median 12.0] versus 11.1 [SD: 8.9; median: 9.0] days) and higher ICU admission rate (18.0% versus 11.9%). Septic shock (6.8% versus 3.0%), mechanical ventilation (22.2% versus 9.7%), blood pressure support (fluid resuscitation: 19.4% versus 11.4%), parenteral nutrition (6.5% versus 3.9%) and renal replacement therapy (4.2% versus 1.4%) were all more common in patients with treatment modification than in those without. Hospital stay was longer in patients with comorbidities than in those without (mean 13.3 [SD: 11.1; median: 10.0] versus 10.0 [SD: 7.5; median: 8.0] days). CONCLUSIONS: Initial antibiotic treatment modification in patients with CAP is common and is associated with considerable additional resource use. Reassessment of optimal management paradigms for patients hospitalized with CAP may be warranted.

Early versus later response to treatment in patients with community-acquired pneumonia: analysis of the REACH study.

BACKGROUND: Key goals in the treatment of CAP include early response to treatment and achievement of clinical stability. The US FDA recommends early response endpoints (72 hours after initiation of treatment) in clinical trials for the treatment of community-acquired bacterial pneumonia. REACH (REtrospective Study to Assess the Clinical Management of Patients With Moderate-to-Severe Complicated Skin and Soft Tissue Infections [cSSTI] or CAP in the Hospital Setting) was a retrospective observational study, providing current data on the clinical management and resource burden of CAP in real-life settings in European hospitals. This analysis reviews the characteristics and outcomes of patients showing early positive response to treatment (time to clinical stability [TCS] ≤4 days, as assessed by Halm's criteria) compared with patients with later positive response (TCS >4 days). METHODS: Patients were adults, hospitalized with CAP (2010-2011) and requiring in-hospital treatment with intravenous antibiotics. RESULTS: Of the 2039 patients included in REACH, 585 (28.7%) had TCS assessed by Halm's criteria: 332 (56.8%) showed early response (median 3.0 days), and 253 (43.2%) showed later response to treatment (median 7.0 days). Use of Halm's criteria varied across participating countries, ranging from 0% (Belgium) to 49.1% (UK). Patient characteristics and relevant medical history were similar between the two groups. There were no notable differences in initial antibiotic therapy between groups, except that more early responders had been treated with amoxicillin-clavulanate and amoxicillin monotherapy (22.6%; 7.5%, respectively) than later responders (5.9%; 1.2%, respectively). Initial treatment modification and re-infection or recurrences were less frequent in early responders compared with later responders (14.2% and 3.3% vs. 34.8% and 5.9%, respectively). Early responders had a shorter duration of hospitalization (mean 9.4 ± SD 7.0; median 8.0 days vs. mean 15.6 ± SD 10.5; median 12.0 days, respectively), lower rate of ICU admission (3.3% vs. 21.3%) and shorter duration of ICU stay (mean 6.2 ± SD 5.7; median 4.0 days vs. mean 10.4 ± SD 10.1; median 8.0 days, respectively) compared with later responders. Mortality was low in both groups. CONCLUSIONS: Achieving early clinical stabilization in CAP (≤4 days) is associated with improved outcomes, lower requirement for initial treatment modification or readmission and lower resource use, compared with a later response. TRIAL REGISTRATION: NCT01293435.

Current management of patients hospitalized with community-acquired pneumonia across Europe: outcomes from REACH.

BACKGROUND: Data describing real-life management and treatment of community-acquired pneumonia (CAP) in Europe are limited. REACH (http://NCT01293435) was a retrospective, observational study collecting data on the management of EU patients hospitalized with CAP. METHODS: Patients were aged ≥18 years, hospitalized with CAP between March 2010 and February 2011, and requiring in-hospital treatment with intravenous antibiotics. An electronic Case Report Form was used to collect patient, disease and treatment variables, including type of CAP, medical history, treatment setting, antibiotics administered and clinical outcomes. RESULTS: Patients (N = 2,039) were recruited from 128 centres in ten EU countries (Belgium, France, Germany, Greece, Italy, the Netherlands, Portugal, Spain, Turkey, UK). The majority of patients were aged ≥65 years (56.4%) and had CAP only (78.8%). Initial antibiotic treatment modification occurred in 28.9% of patients and was more likely in certain groups (patients with comorbidities; more severely ill patients; patients with healthcare-associated pneumonia, immunosuppression or recurrent episodes of CAP). Streamlining (de-escalation) of therapy occurred in 5.1% of patients. Mean length of hospital stay was 12.6 days and overall mortality was 7.2%. CONCLUSION: These data provide a current overview of clinical practice in patients with CAP in EU hospitals, revealing high rates of initial antibiotic treatment modification. The findings may precipitate reassessment of optimal management regimens for hospitalized CAP patients.

Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma with a poor prognosis following first relapse. We present a subgroup analysis of an open-label phase II trial investigating the efficacy and safety of lenalidomide in patients with relapsed or refractory MCL. Oral lenalidomide 25 mg was self-administered once daily on days 1-21 every 28 d for up to 52 weeks, according to tolerability or until disease progression. The primary endpoint was overall response rate (ORR) and secondary endpoints were duration of response, progression-free survival (PFS) and safety. Among 15 patients with MCL with a median disease duration of 5.1 years and a median of four prior treatments, the ORR was 53%. Three patients (20%) had a complete response and 5 (33%) had a partial response. The median duration of response was 13.7 months and median PFS was 5.6 months. Four of five patients who relapsed after transplantation and two of five patients who previously received bortezomib responded to lenalidomide. The most common grade 4 adverse event was thrombocytopenia (13%) and the most common grade 3 adverse events were neutropenia (40%), leucopenia (27%) and thrombocytopenia (20%). In conclusion, oral lenalidomide monotherapy is well tolerated and active in relapsed or refractory MCL.

Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin's lymphoma.

PURPOSE: The major cause of death in aggressive lymphoma is relapse or nonresponse to initial therapy. Lenalidomide has activity in a variety of hematologic malignancies, including non-Hodgkin's lymphoma (NHL). We report the results of a phase II, single-arm, multicenter trial evaluating the safety and efficacy of lenalidomide oral monotherapy in patients with relapsed or refractory aggressive NHL. PATIENTS AND METHODS: Patients were treated with oral lenalidomide 25 mg once daily on days 1 to 21, every 28 days, for 52 weeks, until disease progression or intolerance. The primary end point was response; secondary end points included duration of response, progression-free survival (PFS), and safety. RESULTS: Forty-nine patients with a median age of 65 years received lenalidomide in this study. The most common histology was diffuse large B-cell lymphoma (53%), and patients had received a median of four prior treatment regimens for NHL. An objective response rate of 35% was observed in 49 treated patients, including a 12% rate of complete response/unconfirmed complete response. Responses were observed in each aggressive histologic subtype tested (diffuse large B-cell, follicular center grade 3, mantle cell, and transformed lymphomas). Of patients with stable disease or partial response at first assessment, 25% improved with continued treatment. Estimated median duration of response was 6.2 months, and median PFS was 4.0 months. The most common grade 4 adverse events were neutropenia (8.2%) and thrombocytopenia (8.2%); the most common grade 3 adverse events were neutropenia (24.5%), leukopenia (14.3%), and thrombocytopenia (12.2%). CONCLUSION: Oral lenalidomide monotherapy is active in relapsed or refractory aggressive NHL, with manageable side effects.