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1.
Infezioni in Medicina ; 30(3):403-411, 2022.
Article in English | EMBASE | ID: covidwho-2033629

ABSTRACT

Cases with SARS-CoV-2 RT-PCR negative pneumonia are an understudied group with uncertainty remain-ing regarding their treatment approach. We aimed to compare the clinical and radiological characteristics of RT-PCR positive and clinically diagnosed RT-PCR negative COVID-19. This was a single-centre retrospective study conducted at a tertiary care hospital in Western India. All patients (age ≥18 years) with suspicion of COVID-19 with SARI (severe acute respiratory infec-tions) who were subjected to RT-PCR testing (nasal/ oropharyngeal swab) were included. Based on RT-PCR results, patients were categorized and compared for demographic, clinical, and biochemical characteristics and outcomes. Out of 500 patients, 339 (67.8%) found RT-PCR positive. Except for the radiological findings, both groups differ in clinical presentation, disease severity (inflammatory markers), and outcome. RT-PCR-positive patients had raised ferritin, NLR (Neutrophil-Lymphocyte ratio), LDH, and high mortality compared to the swab-negative group. In-hospital mortality was also significantly high in RT-PCR positive group (HR=1.9, 95% CI=1.4-2.5, p=0.001). On mul-tivariate analysis, NLR, ferritin, and d-dimer were the independent predictors of mortality in RT-PCR-posi-tive (p=0.038, 0.054, and 0.023). At the same time, raised TLC (total leukocyte count) and procalcitonin were the risk factors for poor outcomes in RT-PCR-negative patients (p=0.041 and 0.038). We found significantly raised ferritin, NLR, and LDH levels and increased mortality in RT-PCR positive patients compared to RT-PCR neg-ative. Incorporating clinical features, radiological, and biochemical parameters could be prudent while managing the RT-PCR-negative patients.

2.
GERMS ; 12(2):298-303, 2022.
Article in English | EMBASE | ID: covidwho-2033515

ABSTRACT

Introduction COVID-19 is an emerging infectious disease that remains to be further investigated. Case report Here, we describe a case of COVID-19 in an octogenarian woman with comorbidities who slowly recovered during hospitalization, but died due to sudden cardiac death after 2 weeks of hospitalization. Her nasopharyngeal and anal swabs returned positive for SARS-CoV-2 by RT-PCR on day 7 of hospitalization. The NGS showed possible intraindividual evolution of virus. The sample from the nasopharyngeal swab yielded a B.1470 variant classified as clade GH. This variant showed mutation in the spike gene D614G;N gene;NS3 gene;NSP2 gene and NSP12 gene. The sample from the anal swab showed similar mutation but with additional point mutation in spike gene S12F and was classified as B.1.465 variant. Conclusions The possibility of the gastrointestinal tract that served as reservoir for virus mutation accumulation should also be considered and the potential impact of viral fecal transmission in the environment should be further investigated.

3.
Pulmonologiya ; 31(6):701-709, 2021.
Article in Russian | EMBASE | ID: covidwho-2033500

ABSTRACT

Although antibiotics (ABs) are ineffective against COVID-19, they are often prescribed to patients with the new coronavirus infection. Many of these prescriptions are uncalled for. The aim of the work is to assess the frequency of prescribing antibiotics to hospitalized patients with confirmed COVID-19, identify the most commonly prescribed ABs, and determine the significance of various biomarkers for the diagnosis of bacterial infection. Methods. A retrospective analysis of 190 inpatient cases with confirmed COVID-19 was carried out. The records of COVID-19 patients who were admitted to the intensive care unit were excluded from the analysis. Two groups were formed: 30 patients (group 1) with COVID-19, emergency or elective surgery, and exacerbation of chronic infectious diseases, and 160 patients (group 2) with manifestations of COVID-19 only. Results. ABs were prescribed to 189 patients upon admission to the hospital. The most frequently prescribed ABs included macrolides (63.5%), respiratory fluoroquinolones (49.7%), and third or fourth-generation cephalosporins (57.1%). ABs were administered starting from the first day of admission and until the discharge. The patients in group 2 were more often prescribed respiratory fluoroquinolones and, less often, III – IV generation cephalosporins. Moreover, macrolides were used in the treatment regimens of both groups. Longer administration of respiratory fluoroquinolones to patients in group 2 than patients in group 1 (p < 0,05) was noted. Group 2 also tended to receive longer therapy with macrolides. On admission, the patients with signs of bacterial infection had more significant leukocytosis with a neutrophilic shift, a more common increase in ESR of more than 20 mm/h and an increase in the level of procalcitonin ≥ 0,5 ng/ml. Conclusion. ABs were administered to the overwhelming majority of hospitalized patients in the absence of clear therapeutic indications. The ABs are likely to have a minimal benefit as empirical treatment of COVID-19 and are associated with unintended consequences, including adverse effects and increased antibiotic resistance. According to our data, the most informative markers of a secondary bacterial infection in patients with COVID-19 are leukocytosis with a neutrophilic shift, an increase in ESR of more than 20 mm/h, and a procalcitonin level of more than 0,5 ng/ml.

4.
Pharmacognosy Journal ; 14(4):450-454, 2022.
Article in English | EMBASE | ID: covidwho-2033372

ABSTRACT

A 26-year-old man complained of shortness of breath for 3 days before the hospital admission. The patient had a history of coughing up blood and had consumed alcohol and drugs. Decreased vesicular auscultation and dull percussion in the left lateral pulmo. Laboratory result showed increased neutrophil-lymphocyte ratio C-reactive protein, D-dimer, procalcitonin, ferritin, and decreased albumin level. Pleural fluid analysis indicated the presence of exudate, SARS-CoV-2 PCR positive, and increased ADA level to 43 U/L. Based on the examination results, we suspected that the etiology of the massive pleural effusion was tuberculous pleurisy, particularly due to increased ADA levels. The patient was diagnosed with COVID-19 pneumonia with massive pleural effusion and tuberculous pleurisy. Massive pleural effusion in SARS-CoV-2 infection is rare. Thus, laboratory modalities for massive pleural effusion diagnosis are needed to determine the etiology and effective treatment for the patient. ADA analysis could be considered as an initial examination in patients with pleural effusion during the wait for pleural fluid culture results.

5.
National Journal of Physiology, Pharmacy and Pharmacology ; 12(7):958-961, 2022.
Article in English | EMBASE | ID: covidwho-2033363

ABSTRACT

Background: Coronavirus disease 2019 (COVID-19) has rapidly become a worldwide concern ever since first being reported from Wuhan, China in December 2019. With no known cure, there is widespread fear-provoking interest in studying the factors contributing to mortality. Aim and Objectives: The current study was undertaken with a view to try to understand the cause of morbidity and mortality. Materials and Methods: A retrospective study done in our Institution on COVID-19 patients admitted over a course of 3 months after approval from Institutional Ethics Committee. Results: We had 17 deaths over the period under consideration whereas 73 patients improved (mortality = 19%, n = 90). Most of the patients were in the 41–80 years age group (>70%). No gender preponderance was found with mortality in each being around 20%. A clear correlation between co-morbidities and mortality was found with no person without any comorbidity succumbing to the disease. Respiratory and Heart conditions were found to contribute most to mortality with patients presenting with shortness of breath being most at risk. Similarly, a Neutrophil: Lymphocyte ratio greater than 12 was found to significantly increase the mortality. Conclusion: Patients with comorbidities need to be monitored closely with treatment being directed at improving the respiratory outcome.

6.
Frontiers in Cellular and Infection Microbiology ; 12, 2022.
Article in English | EMBASE | ID: covidwho-2032744

ABSTRACT

Pneumonia is one of the leading causes of morbidity and mortality worldwide and Gram-negative bacteria are a major cause of severe pneumonia. Despite advances in diagnosis and treatment, the rise of multidrug-resistant organisms and hypervirulent strains demonstrates that there will continue to be challenges with traditional treatment strategies using antibiotics. Hence, an alternative approach is to focus on the disease tolerance components that mediate immune resistance and enhance tissue resilience. Adaptive immunity plays a pivotal role in modulating these processes, thus affecting the incidence and severity of pneumonia. In this review, we focus on the adaptive T cell responses to pneumonia induced by Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. We highlight key factors in these responses that have potential for therapeutic targeting, as well as the gaps in current knowledge to be focused on in future work.

7.
HemaSphere ; 6:1395-1396, 2022.
Article in English | EMBASE | ID: covidwho-2032168

ABSTRACT

Background: Persistent cytopenia due to poor graft function (PGF) is a life-threatening complication in patients undergoing allogeneic HSCT (allo-HSCT). Several therapeutic approaches have been tested in this subset of patients with poor clinical results. Aims: The objective of this multicenter open-label interventional prospective phase II Novartis study (ELTION, ClinicalTrials.gov id: NCT03718533), was to analyze efficacy and safety of EPAG in patients with post-allo-HSCT poor graft function. Methods: Adult patients diagnosed with PGF (defined as severe cytopenia after day +30 post-transplant, with two or more of the following: platelets <20000/μL-mandatory-, ANC <1000/μL, hemoglobin< 10 g/dL), and full donor chimerism, were eligible to enter the trial. Study treatment consisted of EPAG. at 150 mg/day administered up to 36 weeks;dose adjustments were contemplated as per protocol on an individual basis. The primary efficacy endpoint was the overall hematologic response (partial and complete), as determined by platelet, hemoglobin and neutrophil counts by 16 weeks after the initiation of EPAG. Results: Although the aim of the study was to include 33 patients, recruitment stopped prematurely due to the difficulties for hospital visits posed during COVID-19 pandemic, and eventually only 10 patients were included. The decision for this premature termination is not related to any safety concern related to the drug. Patient characteristics are shown in the table 1 attached below. At EPAG. initiation, all 10 patients showed thrombocytopenia (<20000/μcL), 5 presented with anemia (Hgb <10 g/dL), and 4 had neutropenia (ANC <1000/μcL). Four patients discontinued EPAG before week 12 due to: disease progression/relapse (2 patients), protocol deviation (1 patient), and CMV infection (1 patient). In none of the cases, the event was related to study drug. At week 16, 4 patients (4/10, 40%) and at week 24, 5 patients, showed improvement in at least one of the 3 hematologic cell lines (partial response), respectively. Counts pre-and post-EPAG and global response in patients who stayed on treatment > 12 weeks are displayed below: Image: Summary/Conclusion: In our experience, EPAG worked well in subjects with PGF, an otherwise life-threatening condition for patients, and its use at 150 mg/day is safe and well tolerated in this setting. Our data suggest that eltrombopag might improve hematologic cell counts in patients with PGF, especially in those patients who remained on treatment at week 24, however further research is warranted to extend its applicability for larger cohorts.

8.
HemaSphere ; 6:882-883, 2022.
Article in English | EMBASE | ID: covidwho-2032138

ABSTRACT

Background: The end of the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease-19 (COVID-19), is not foreseen. Vaccination using two subtypes of mRNA-based vaccines, BNT162b2 or mRNA-1273, is an effective public health measure to reduce the risk of infection and severe complications from COVID-19. However, COVID-19 vaccine response data for patients with myeloid malignancy, who are at severe risk in case of infection, has not emerged. Aims: We investigated the antibody titers of COVID-19 in patients with myeloid malignancies who received two doses of mRNA-based COVID-19 vaccine. Methods: Previously treated, currently treated, and newly diagnosed 46 patients with acute myeloid leukemia (AML) and 23 patients with myelodysplastic syndrome (MDS) were included in this study. Anti-spike SARS-CoV-2 antibody titers were measured at 3 months after the second vaccination and compared them to those in healthy controls. Results: Seroconversion rates for AML and MDS were 94.7% and 100%, without significant difference from healthy controls (100%). In AML patients, the median antibody titers of patients in complete remission (CR) (816.5 [interquartile range (IQR): 250.0-2063.5] U/ml vs 1023.0 [640.0-1535.0] U/ml, P=0.668), especially those who were under treatment-free observation in CR (1630.0 [806.0-2454.0] U/ml vs 1023.0 [640.0-1535.0] U/ml, P=0.1220), were comparable to those in healthy controls. On the other hand, even in CR, the antibody titer in AML patients under maintenance therapy was significantly lower than that in patients under treatment-free observation (154.0 [126.0-289.0] U/ml vs 1630.0 [806.0-2454.0] U/ml, P=0.0003). Among the AML patients in CR, patients receiving maintenance treatment had a significantly lower median absolute lymphocyte count (0.81 [0.71-1.46] x 109/l vs 1.58 [1.29-1.93] x 109/l, P=0.0094) and a significantly lower median absolute neutrophil count (1.45 [1.15-1.64] x 109/l vs 3.45 [2.68-4.28] x 109/l, P<0.0001) than that in patients under treatment-free observation. Significantly lower antibody titers were associated with current active treatment (92.2 [37.5-216.3] U/ml vs 1630.0 [806.0-2454.0] U/ml, P<0.0001), AML with myelodysplasia-related changes (50.8 U/ml [39.9-109.1] vs 816.5 [283.0-1935.3] U/ml, P=0.0022), advanced age more than the median age of 68 years (195.0 [43.3-743.0] U/ml vs 1630.0 [806.0-3391.0] U/ml, P=0.0002), and vaccine subtypes of BNT162b2 (285.0 [127.8-1045.3] U/ml vs 3037.0 [2198.50-4537.0] U/ml, P=0.0002) in AML patients and with current active treatment (41.0 [10.7-227.5] U/ml vs 623.5 [173.8-1613.3] U/ml, P=0.0233), subtypes of excess blasts (11.1 [4.8-34.1] U/ml vs 212.0 [81.7-600.0] U/ml, P=0.0293), and high and very high risk of the revised international prognostic scoring system in MDS patients (9.0 [3.4-41.0] U/ml vs 169.0 [48.5-327.0] U/ml, P=0.0380). Summary/Conclusion: This is one of the first studies on the effect of COVID-19 vaccines focusing on patients with AML and MDS, and there are many new findings. The response to COVID-19 vaccine appears to be related to disease and treatment status. Myeloid malignancies may have less impact than lymphoid malignancies on the vaccine response. AML patients under treatment-free observation in CR could be expected to have a vaccine effect that is comparable to that in healthy individuals. In contrast, since the response to vaccination might be insufficient in AML patients undergoing maintenance therapy, maintenance therapy should be continued with strict measures for prevention of infection even after vaccination.

9.
HemaSphere ; 6:1149-1150, 2022.
Article in English | EMBASE | ID: covidwho-2032119

ABSTRACT

Background: In pts with CML, the BCR::ABL1 T315I mutation is associated with poor clinical outcomes and confers resistance to previously approved ATP-competitive tyrosine kinase inhibitors (TKIs). Until recently, ponatinib (PON) was the only TKI available for these pts, but its use may be limited by associated cardiovascular events. In the primary analysis of the phase I trial X2101, asciminib-the 1st BCR::ABL1 inhibitor to Specifically Target the ABL Myristoyl Pocket (STAMP)-demonstrated efficacy and a favorable safety profile in heavily pretreated pts with CML with T315I. These results supported the FDA approval of asciminib as a new treatment option for pts with CML-CP with T315I (NCCN 2021). We report updated efficacy and safety data in these pts (data cutoff: January 6, 2021). Aims: Provide updated safety and efficacy data for pts with CML-CP with T315I treated with asciminib monotherapy 200 mg twice daily (BID) after added exposure. Methods: Pts with CML-CP with T315I were enrolled if treated with ≥1 prior TKI and no other effective therapy was available, provided informed consent, and received asciminib 200 mg BID. Results: 48 pts with T315I were included;2 (4.2%) pts had additional BCR::ABL1 mutations at baseline. Eight (16.7%), 15 (31.3%) and 25 (52.1%) pts received 1,2, and ≥3 prior TKIs, respectively. At data cutoff, treatment was ongoing in more than half (27 [56.3%]) of pts;the predominant reason for treatment discontinuation was physician's decision (11 [22.9%]), mainly due to lack of efficacy. Of the 48 pts, 45 were evaluable (BCR::ABL1IS >0.1% at baseline) for major molecular response (MMR);3 were excluded for BCR::ABL1 atypical transcripts. Among evaluable pts, 19 (42.2%) achieved MMR by wk 24 and 22 (48.9%) by wk 96;19 were still in MMR at the cutoff date. Evaluable pts included 26 PON-pretreated and 19 PONnaive pts;34.6% and 68.4%, respectively, achieved MMR by the cutoff date (Table). The probability of pts maintaining MMR for ≥96 wks was 84% (95% CI, 68.1-100.0). Thirteen (28.9%) and 11 (24.4%) pts achieved MR4 and MR4.5, respectively. Twenty (54.1%) and 23 (62.2%) of 37 pts with BCR::ABL1IS >1% at baseline achieved BCR::ABL1IS ≤1% by wk 48 and 96, respectively. The median duration of exposure was 2.08 (range, 0.04-4.13) yrs with more than half (27 [56.3%]) of pts receiving treatment for ≥96 wks;the median daily dose intensity was 398.3 (range, 179-400) mg/day. The safety/tolerability profile of asciminib remained favorable after ≈9 months of added follow-up (Table). The most common (≥5%) grade ≥3 adverse events (AEs) were lipase increase (18.8%, all asymptomatic elevations), thrombocytopenia (14.6%), and vomiting, ALT increase, abdominal pain, hypertension, anemia, neutropenia, and neutrophil count decrease (6.3% each). Arterial occlusive events occurred in 4 (8.3%) pts;none led to dose adjustment/interruption/discontinuation. AEs leading to discontinuation were reported in 2 new pts since the previous data cutoff;both pts discontinued and died due to COVID-19. These were the only study deaths reported in this pt population. Image: Summary/Conclusion: Asciminib monotherapy 200 mg BID exhibited a sustained, favorable safety profile after added exposure with no new safety signals in pts with CML-CP with T315I-a population with high unmet medical need. The clinical efficacy of asciminib is demonstrated by the high proportion of pts achieving durable MMR and BCR::ABL1IS ≤ 1%. The updated analysis confirms asciminib as a treatment option for pts with CML-CP with T315I, including those for whom treatment with PON has failed.

10.
HemaSphere ; 6:1914-1915, 2022.
Article in English | EMBASE | ID: covidwho-2032116

ABSTRACT

Background: Patients (pts) with follicular lymphoma (FL) generally respond well to first-line CD20-targeted therapies, such as obinutuzumab or rituximab-based regimens. However, many pts relapse and studies suggest that each subsequent relapse is associated with shorter durations of response to the next treatment. Parsaclisib is a potent and highly selective next generation PI3Kδ inhibitor. The combination of bendamustine + obinutuzumab is approved for pts with relapsed/refractory (R/R) FL. We hypothesized that adding parsaclisib may improve clinical benefit with a manageable safety profile in this pt population. Aims: CITADEL-102 (NCT03039114) is an open-label, phase 1, dose-finding study that investigated safety and efficacy of parsaclisib in combination with bendamustine + obinutuzumab in pts with R/R FL following rituximabcontaining regimens. Methods: Pts enrolled were ≥18 years with histologically confirmed CD20-positive FL, R/R to any prior rituximabcontaining regimen, ECOG PS 0-2, ≥1 measurable lesion, and ≤4 prior therapies. Pts received parsaclisib 20 mg orally once daily (QD) for 8 weeks then 20 mg once weekly (QW);bendamustine 90 mg/m2 infusion on days 1 and 2 of cycles 1-6;and obinutuzumab 1000 mg infusion on days 1, 8, and 15 of cycle 1, and day 1 of cycles 2-6, and on every second cycle of cycles 8-30 in pts having complete response/complete metabolic response (CR/CMR), partial response/partial metabolic response (PR/PMR), or stable disease/no metabolic response. Part 1 (safety run-in) used a 3+3 design with dose de-escalation to identify the maximum tolerated dose (MTD) of parsaclisib in combination with bendamustine + obinutuzumab. In Part 2 (dose expansion), the safety and efficacy of this combination were further evaluated. The primary study endpoint was safety and tolerability;secondary endpoints included efficacy outcomes (ORR, DOR, PFS, and OS). Results: A total of 26 pts were enrolled and treated;median (range) age was 65.0 (44-80) years, 25 (96.2%) had ECOG PS ≤1, 11 (42.3%) had ≥2 prior systemic therapies, and 6 (23.1%) had received prior bendamustine. Median (range) parsaclisib exposure was 10.6 (0.4-32.8) months. Main reasons for treatment discontinuation included adverse events (AEs) (8 pts, 30.8%) and progressive disease (6 pts, 23.1%). All pts experienced treatment-emergent AEs (TEAEs);most common any-grade TEAEs (≥10 pts) were pyrexia (53.8%), neutropenia (50%), diarrhea (46.2%), thrombocytopenia, and nausea (each 38.5%). Grade ≥3 TEAEs were experienced by 88.5% of pts;most common grade ≥3 TEAEs (≥2 pts) were neutropenia (34.6%), febrile neutropenia (23.1%), thrombocytopenia (19.2%), ALT and AST increase (each 11.5%), and diarrhea, neutrophil count decreased, and rash maculopapular (each 7.7%). One of 6 evaluable pts in Part 1 had a DLT of grade 4 QTc elongation. The MTD was not reached, and parsaclisib 20 mg QD for 8 weeks then 20 mg QW was the selected dosage for dose expansion in Part 2. Treatment discontinuation due to TEAEs was 30.8%, 7.7%, and 15.4% for parsaclisib, bendamustine, and obinutuzumab, respectively. One fatal TEAE (COVID-19 pneumonia) occurred. ORR (95% CI) as reported by the investigator was 76.9% (56.4-91.0), with 17 pts (65.4%) achieving CR/CMR and 3 pts (11.5%) achieving PR/PMR as the best overall response. Median DOR, PFS, and OS were not reached. Summary/Conclusion: Parsaclisib in combination with bendamustine + obinutuzumab appears to have a manageable safety profile and demonstrated promising efficacy in pts with R/R FL.

11.
HemaSphere ; 6:1922-1923, 2022.
Article in English | EMBASE | ID: covidwho-2032111

ABSTRACT

Background: Patients with relapsed/refractory follicular lymphoma (R/R FL) often experience multiple relapses and require various lines of therapy. The ELARA and ZUMA-5 trials demonstrated high response rates along with acceptable safety profiles. We perform a phase 1b/2 single-center clinical trial of autologous point-of-care (POC) academic anti-CD19 chimeric antigen receptor (CAR) T-cells for patients with R/R FL treated with at least 2 lines of systemic therapy (NCT02772198). Aims: To report outcomes of POC CAR T-cell therapy in patients with R/R FL. Methods: Adults with R/R FL underwent a single leukapheresis procedure. Fresh peripheral blood mononuclear cells were isolated, activated, and transduced with a gammaretrovirus encoding for a CD19 CAR (based on an FMC63-derived ScFv, a CD28 costimulatory domain, and a CD3-ζ signaling domain). Lymphodepletion included fludarabine 25 mg/m2 over 3 days (days-4 to-2) and cyclophosphamide 900 mg/m2 once (day-2), followed by infusion of 1×106/kg CAR T-cells in the inpatient setting. Primary endpoints were response (by PET-CT, per Lugano criteria) at day 28, best response, and safety. Secondary endpoints included overall survival, progression-free survival (PFS), and production feasibility. Last follow-up was as of 02/2022. Results: All 19 patients enrolled received CAR T-cell infusion in a median of 11 days (IQR 10-11) after leukapheresis. The median age was 61 years (IQR 52-66). Five (26%) patients had Karnofsky performance status < 90%. Disease stage at enrollment was III-IV in 16 (84%) patients. Two (11%) patients had bulky disease;8 (42%) had LDH > upper limit of normal;and 16 (84%) had Follicular Lymphoma International Prognostic Index ≥ 3. Disease status at enrollment was progressive disease (n=14, 74%), stable disease (n=3, 16%), or partial response (PR;n=2, 11%). Twelve patients (64%) were refractory to last treatment. Disease grade at most recent lymph node biopsy was 1 (n=3, 16%), 2 (n=11, 58%), or 3a (n=5, 26%). The median time from FL diagnosis was 3.9 years (IQR 2.5-4.6). Sixteen (84%) patients had progression of disease within 24 months of initial therapy. The number of prior therapies was ≥ 4 in 6 (32%) patients;and 5 (26%) patients underwent prior autologous transplantation. Grade III-IV cytokine release and immune effector cell-associated neurotoxicity syndromes occurred in 1 (5%) and 4 (21%) patients, respectively. One patient was infected with COVID-19 on the 5th day following cell infusion and was admitted to the intensive care unit. One patient had grade 3 atrial fibrillation. Severe neutropenia (absolute neutrophil count <500/μL), thrombocytopenia (platelets <50K/μL) and anemia (hemoglobin <10g/dl) occurred in 15 (79%), 5 (26%), and 7 (37%) patients, respectively. No bleeding events or death were recorded following cell infusion. Response was evaluated in all patients. Overall response rate on day 28 was 84% (79% complete response [CR]). One patient with PR on day 28 achieved a CR after a year of follow-up. Three patients (16%) continued to progress following CAR infusion. All patients were alive at the last follow-up (median follow-up, 11.5 months [IQR 4-21]). One-year PFS was 74% (95% CI, 53-100). The median duration of response (DOR) was not reached (95% CI, 12.5-not reached). Estimated DOR at 1-year was 89% (95% CI, 71-100). Image: Summary/Conclusion: Point-of-Care anti-CD19 CAR T-cell therapy, performed following a very short production time, induced high CR rate with an acceptable safety profile in a cohort of patients with high-risk R/R FL.

12.
HemaSphere ; 6:3284-3285, 2022.
Article in English | EMBASE | ID: covidwho-2032098

ABSTRACT

Background: The Bruton's tyrosine kinase (BTK) inhibitor acalabrutinib is approved for treatment of chronic lymphocytic leukemia(CLL). Acalabrutinib induces durable remissions in most CLL patients, which mostly are partial remissions (PR), and therefore treatment typically is given as long-term monotherapy. As a potential alternative we developed a time-limited regimen, combining acalabrutinib with obinutuzumab. Aims: Here, we report early results from 14 treatment-naïve patients with CLL who enrolled in this ongoing phase 2 trial (NCT04505254) since September, 2020 at MD Anderson Cancer Center. Methods: Patients and Study Design: Treatment-naïve CLL patients requiring therapy as per iwCLL criteria receive acalabrutinib 100 mg orally twice a day for 24 cycles, combined with monthly obinotuzumab for 6 doses, starting in cycle 3. The first dose of obinutuzumab is divided into 100 mg on day 1 and 900 mg on day 2 of cycle 3;1000 mg are given during subsequent cycles (cycles 4-8). Patients who do not achieve a complete remission (CR) after cycle 8 can receive an additional 6 monthly doses of obinotuzumab during cycles 9 -14. Treatment is discontinued after 24 cycles, and patients will be monitored. The primary objective is to determine the durability of remissions after treatment discontinuation, secondary objectives are to determine clinical and laboratory characteristics that predict for early versus late relapse after time-limited therapy. Results: The median age of the patients is 70 yrs (range, 40 -83 yrs), 14% had del17p or TP53 mutation, 43% had an unmutated IgHV and 71% advance stage disease (RAI stage III and IV). The median baseline absolute lymphocyte count (ALC) and b2 microglobulin at start of therapy were 39.2x109/L (range: 7.1 - 188.4 x 109/L) and 4.2 mg/L (range: 2.2 - 7.9 mg/L), respectively. After a median follow-up of 7 months (2 - 16 months), 13 (93%) of patients remain on study;one patient died (7%) due from complications from a presumed bacterial (COVID19-negative) pneumonia after 2 months on therapy. The estimated one-year PFS and OS for the cohort is 92.8 %. Seven patients were evaluable for response assessment after 8 months of therapy. No patient has yet discontinued therapy. All patients achieved a PR (one patient with undetectable minimal residual disease/U-MRD in the bone marrow), accounting for an overall responsonse rate of 100%. The median levels of bone marrow infiltration by CLL cells, quantified by flow cytometry, declined from 83.6% (range: 54.3 - 94.0 %) at baseline to 4.1% (range, 0.0 - 63.3%, n=7, p<0.05, see figure) after 6 cycles of combination treatment. Sixty-four percent of patients completed all doses of obinotuzumab, 50% requiered a dose reduction of acalabrutinib to 100 mg per day due to adverse events (AE). Grade 33 AE were observed in 4 patients (29%), which included decreased neutrophil counts (n=2), syncope (n=1), and grade 5 lung infection (COVID19 not detected, n=1). The most frequently reported non-serious related AE (3 2 patients) were anemia (n=5 [36%]), decreased platelets counts (n=3 [21%]), bruising (n=3 [21%]), limbs edema (n=2 [15%]) and headache (n=2 [15%]). All these events were grade 1. Importantly, no bleeding or atrial fibrillation events were observed. 3285 (Figure Presented ) Summary/Conclusion: Our preliminary data indicate that combination therapy of acalabrutinib plus obinotuzumab induces remissions with a major reduction in bone marrow disease after 6 months of combination therapy. Longer treatment and follow-up is warranted to determine the durability of responses after therapy discontinuation.

13.
Journal of Thoracic Oncology ; 17(9):S283, 2022.
Article in English | EMBASE | ID: covidwho-2031519

ABSTRACT

Introduction: Durvalumab received EMA approval as consolidation therapy (CT) for unresectable stage III NSCLC with PD-L1 ≥1% and who did not have progression after CRT. Our objective was to analyze in real clinical practice the effectiveness of durvalumab and explore the clinical factors that may be associated with the benefit from CT. Methods: Retrospective study was made at Hospital of Leon (Spain), including 37 patients with locally advanced NSCLC treated with durvalumab after CRT treatment between March 2018 and october 2021 (40.5% patients were included in the durvalumab early access program). The neutrophil-to-lymphocyte ratio (NLR) could identified after CRT as a factor that may be benefit from durvalumab. Results: Median age was 67 years (range 46-82 years). 40.5% of patients were ≥70 years old. 78.4% were male and 51.4% smokers. 54% had non-squamous histology. PD-L1 expression was <1% in 5% and not available in 8% patients. 2.7% ROS1 rearrangements, 5.4% KRAS mutations and not available in 43.2% patients. Stage IIIA, IIIB, IIIC disease were 24.3%, 54.1% and 21.6%, respectively. Median time from end of CRT to onset durvalumab was 44 days (range 13-120 days). Overall median CT duration was 214.8 days (range 69-399 days) with a median of 14 infusions (range 6-27 infusions). With a median follow up of 19.7 months (range 1.4-34.9 months);67.6% had stopped CT: 37.8% due to completing treatment, 16.2% disease progression, 10.8% adverse event and 2.7% due to COVID19 infection. Median real-world progression-free survival (rwPFS) was 17 months (95% CI, 11-23). Median real-world overall survival (rwOS) was 29.9 months (95% CI, 23.3-36.6). %rwOS at 6, 18 and 24 months were 100%, 86.9% and 74.5%, respectively. For patients with post-CRT NLR not exceeding the cohort median value of 6, receipt of durvalumab was associated with an improvement in rwOS (median not reached vs 25.7 months;p=0.025). 56.8% patients had any grade of radiation pneumonitis (median time from CRT start: 119 days [range 36-241 days]). Of these, 19% patients developed worsening of radiation pneumonitis with durvalumab. 54,1% developed immune-mediated toxicity, mostly G1-2 (85.1%). Conclusions: Our results demonstrate the effectiveness of durvalumab consolidation in this patients population in a real-life setting. We identified low NLR after CRT as a potentially predictive factor for the benefit of CT in locally advanced NSCLC. Keywords: DURVALUMAB, PACIFIC, REAL WORLD DATA

14.
Colloids and Surfaces B: Biointerfaces ; 219, 2022.
Article in English | EMBASE | ID: covidwho-2031218

ABSTRACT

Cell membrane cloaking is an important biomimetic approach for improving drug residence time in the body due to its distinctive concealment ability, making it highly biocompatible and efficient for targeted drug delivery. Leukocytes are considered a fundamental part of the immune system. Leukocyte membrane cloaked nanoparticles offer site-specificity and can escape the opsonization process besides enhanced systemic circulation time. This review emphasizes the anatomical and physiological features of different leukocytes in addition to the preparation and characterization of leukocyte membrane cloaked nanoparticles. It also covers the recent advancements of this biointerfacing platform in cancer therapy, inflammatory disorders, multifunctional targeted therapy and hybrid membrane-coated nanoparticles. However, leukocytes are complex, nucleated cell structures and isolating their membranes poses a greater difficulty. Leukocyte membrane cloaking is an upcoming strategy in the infancy stage;nevertheless, there is immense scope to explore this biomimetic delivery system in terms of clinical transition, particularly for inflammatory diseases and cancer.

15.
European Journal of Molecular and Clinical Medicine ; 9(4):3045-3051, 2022.
Article in English | EMBASE | ID: covidwho-2030716

ABSTRACT

Background:COVID 19caused by severe acute respiratory syndrome corona virus2(SARS Cov2) involves respiratory and other systems. Patient with Covid 19 presents with wide range of hematological and coagulation abnormalities. Hemostatic abnormalities in Covid 19 are related with disease progression, severity and mortality. The objective of our study is to evaluate the role of hematological and coagulation parameters in determination of Covid 19 severity.Materials and methods: Total 70 cases were enrolled in the study, conducted in department of pathology at Bangalore Medical college and research institute, Bangalore. Hematological and coagulation parameters were compared with mild, moderate, severe and critical. Appropriate statistical analysis is applied.Result: Parameters like WBC, Neutrophils, HCT,NLR were higher in patients with severe disease when compared to mild and moderate cases.PT, D-Dimer did not show statistically significant association with severity of disease.Conclusion: The study concluded that leukocytosis, neutrophilia,elevated NLR are associated with severity of the disease

16.
Indian Journal of Critical Care Medicine ; 26(9):1031-1035, 2022.
Article in English | Scopus | ID: covidwho-2030240

ABSTRACT

Background: Biomarkers have been extensively studied and used in the diagnosis and management of various diseases. The trend of biomarkers helps in prognosticating and managing critically ill patients. In resource-limited settings, the availability and feasibility of using these biomarkers are challenging. Our study aimed to see the trend of biomarkers and their effect on intensive care unit (ICU) mortality in coronavirus disease-2019 (COVID-19) patients. Methods: A retrospective observational study was done from 1 April 2020 to 30 September 2020. The primary objective was to evaluate the trend of biomarkers in patients with COVID-19 pneumonia and their effect on ICU mortality. The secondary objectives were the duration of mechanical ventilation and length of ICU stay. Results: A total of 380 patients were included. The mean age was 54.9 (SD = 11.1) and 67% were males. The mean age, acute physiology and chronic health evaluation II (APACHE II) score was 29.54 (5.8). Among the biomarkers, total count (TC), ferritin, and procalcitonin (PCT) were higher in non-survivors than in survivors in bivariate analysis. The final multivariable logistic regression model showed age, APACHE II score, length of ICU stay, neutrophil:lymphocyte (NL) ratio, and ferritin as covariates. Among these variables, ferritin was the only biomarker [odds ratio (OR): 1.80, 95% confidence interval (CI) 1.17–2.77] with the APACHE II score (OR: 1.15, 95% CI 1.01–1.30) found to be significant. Conclusion: Ferritin was the only significant biomarker with higher values in non-survivors than in survivors. The trend of biomarkers was not found to be useful in predicting outcome of the patients. © The Author(s). 2022.

17.
Frontiers in Medicine ; 9, 2022.
Article in English | Web of Science | ID: covidwho-2022767

ABSTRACT

Background: Systemic inflammation indices, including neutrophil/lymphocyte ratio (NLR), nnonocyte/lymphocyte ratio (MLR), platelet/lymphocyte ratio (PLR), derived neutrophil/lymphocyte ratio (dNLR), neutrophil/lymphocyte*platelet ratio (NLPR), aggregate index of systemic inflammation (AISI), systemic inflammation response index (SIR-I), and systemic inflammation index (SII) are well-expressed inflammatory indices that have been used to predict the severity and mortality of various inflammatory diseases. This study aimed to investigate the rote of systemic inflammatory markers in predicting mortality in non-elderly and elderly COVID-19 patients. Methods: In a retrospective study, laboratory parameters were examined for 1,792 COVID-19 patients (elderly = 710 and non-elderly = 1,082). The ability of inflammatory markers to distinguish the severity of COVID-19 was determined by receiver operating characteristic (ROC) analysis, and survival probability was determined by the mean of Kaplan-Meier curves, with the endpoint being death. Results: In the non-survivor non-elderly and elderly patients, the parameters PLR, MLR, dNLR, NLPR, AISI, SIR-I, and SII were significantly higher than in the surviving patients. WBC count (HR = 4.668, 95% CI = 1.624 to 13.413, P < 0.01), neutrophil count (HR = 6.395, 95% CI = 2.070 to 19.760, P < 0.01), dNLR (HR = 0.390, 95% CI = 0.182 to 0.835, P < 0.05), and SII (HR = 10.725, 95% CI = 1.076 to 106.826, P < 0.05) were significantly associated with survival. On the other hand, in elderly patients, it was found that WBC count (HR = 4.076, 95% CI = 2.176 to 7.637, P < 0.001) and neutrophil count (HR = 2.412, 95% CI = 1.252 to 4.647, P < 0.01) were significantly associated with survival. Conclusion: WBC count and neutrophil count in non-elderly and elderly patients, were reliable predictors of mortality.

18.
Front Immunol ; 13:958418, 2022.
Article in English | PubMed | ID: covidwho-2022743

ABSTRACT

PURPOSE: To investigate the clinical predictors of in-hospital mortality in hospitalized patients with Coronavirus disease 2019 (COVID-19) infection during the Omicron period. METHODS: All consecutive hospitalized laboratory-confirmed COVID-19 patients between January and May 2022 were retrospectively analyzed. All patients underwent accurate physical, laboratory, radiographic and echocardiographic examination. Primary endpoint was in-hospital mortality. RESULTS: 74 consecutive COVID-19 patients (80.0 ± 12.6 yrs, 45.9% males) were included. Patients who died during hospitalization (27%) and those who were discharged alive (73%) were separately analyzed. Compared to patients discharged alive, those who died were significantly older, with higher comorbidity burden and greater prevalence of laboratory, radiographic and echographic signs of pulmonary and systemic congestion. Charlson comorbidity index (CCI) (OR 1.76, 95%CI 1.07-2.92), neutrophil-to-lymphocyte ratio (NLR) (OR 1.24, 95%CI 1.10-1.39) and absence of angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor blockers (ARBs) therapy (OR 0.01, 95%CI 0.00-0.22) independently predicted the primary endpoint. CCI ≥7 and NLR ≥9 were the best cut-off values for predicting mortality. The mortality risk for patients with CCI ≥7, NLR ≥9 and not in ACEI/ARBs therapy was high (86%);for patients with CCI <7, NLR ≥9, with (16.6%) or without (25%) ACEI/ARBs therapy was intermediate;for patients with CCI <7, NLR <9 and in ACEI/ARBs therapy was of 0%. CONCLUSIONS: High comorbidity burden, high levels of NLR and the undertreatment with ACEI/ARBs were the main prognostic indicators of in-hospital mortality. The risk stratification of COVID-19 patients at hospital admission would help the clinicians to take care of the high-risk patients and reduce the mortality.

19.
Frontiers in Cellular and Infection Microbiology ; 12, 2022.
Article in English | Web of Science | ID: covidwho-2022656

ABSTRACT

Coronavirus disease 2019 (COVID-19) pandemic has killed huge populations throughout the world and acts as a high-risk factor for elderly and young immune-suppressed patients. There is a critical need to build up secure, reliable, and efficient drugs against to the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Bioactive compounds of Ashwagandha [Withania somnifera (L.) Dunal] may implicate as herbal medicine for the management and treatment of patients infected by SARS-CoV-2 infection. The aim of the current work is to update the knowledge of SARS-CoV-2 infection and information about the implication of various compounds of medicinal plant Withania somnifera with minimum side effects on the patients' organs. The herbal medicine Withania somnifera has an excellent antiviral activity that could be implicated in the management and treatment of flu and flu-like diseases connected with SARS-CoV-2. The analysis was performed by systematically re-evaluating the published articles related to the infection of SARS-CoV-2 and the herbal medicine Withania somnifera. In the current review, we have provided the important information and data of various bioactive compounds of Withania somnifera such as Withanoside V, Withanone, Somniferine, and some other compounds, which can possibly help in the management and treatment of SARS-CoV-2 infection. Withania somnifera has proved its potential for maintaining immune homeostasis of the body, inflammation regulation, pro-inflammatory cytokines suppression, protection of multiple organs, anti-viral, anti-stress, and anti-hypertensive properties. Withanoside V has the potential to inhibit the main proteases (Mpro) of SARS-CoV-2. At present, synthetic adjuvant vaccines are used against COVID-19. Available information showed the antiviral activity in Withanoside V of Withania somnifera, which may explore as herbal medicine against to SARS-CoV-2 infection after standardization of parameters of drug development and formulation in near future.

20.
Curr Alzheimer Res ; 2022.
Article in English | PubMed | ID: covidwho-2022271

ABSTRACT

The COVID-19 pandemic is caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2), a respiratory pathogen with neuroinvasive potential. Neurological COVID-19 manifestations include loss of smell and taste, headache, dizziness, stroke, and potentially fatal encephalitis. Several studies found elevated proinflammatory cytokines such as TNF-α, IFN-γ, IL-6 IL-8, IL-10 IL-16, IL-17A, and IL-18 in severely and critically ill COVID-19 patients, which may persist even after apparent recovery from infection. Biomarker studies on CSF and plasma and serum from COVID-19 patients have also shown a high level of IL-6, intrathecal IgG, neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP), and tau protein. Emerging evidence on the matter has established the concept of COVID-19 associated neuroinflammation, in the context of COVID-19 associated cytokine storm. While the short-term implications of this condition are extensively documented, its long-term implications are yet to be understood. The association of the aforementioned cytokines with the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington disease, and amyotrophic lateral sclerosis, may increase COVID-19 patients' risk to develop neurodegenerative diseases. Analysis of proinflammatory cytokines and CSF biomarkers in patients with COVID-19 can contribute to the early detection of the disease's exacerbation, monitoring the neurological implications of the disease and devising risk scales, and identifying treatment targets.

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