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16th January 2023
Remdesivir treatment has been shown to produce an improvement in the level of several COVID-19 severity biomarkers which are associated with better clinical outcomes according to an analysis of trial data by researchers at Gilead Sciences.
Laboratory biomarkers act as indicators of the underlying pathogenic process responsible for disease progression and can inform on the risk of disease progression. In COVID-19, several biomarkers have been identified including lymphocyte and neutrophil count, C-reactive protein (CRP), interleukin (IL)-6 and D-dimer as well as angiopoietin-2, which is a relevant predictor for intensive care unit admission. However, what is less clear, is how levels of these biomarkers change in response to treatment. In an attempt to understand the impact of COVID-19 therapy on these biomarkers, researchers focused on the effect of remdesivir treatment. Remdesivir is an anti-viral agent and in a recent study (PINETREE) of symptomatic, non-hospitalised patients with COVID-19, at a high risk for disease progression, a 3-day course of the drug resulted in an 87% lower risk of hospitalisation or death than placebo. The primary outcome of the trial was COVID-19-related hospitalisation or death at day 28. Using data from patients in the PINETREE trial, researchers obtained plasma samples of biomarkers at baseline, day 3 (on-treatment) and day 14 (post-treatment). The biomarkers analysed included soluble angiopoietin 2 (sAng2), interleukin (IL)-6, ferritin, lactate dehydrogenase (LDH), C-reactive protein (CRP), prothrombin time and lymphocyte counts.
Remdesivir treatment and biomarker changes
The PINETREE trial included 312 patients with a mean age of 52 years (47% female) who were randomised 1:1 to remdesivir treatment (168) or placebo and who consented to longitudinal biomarker assessments. Overall, only 6 participants (two given remdesivir and four placebo) met the primary endpoint.
Biomarker values at baseline were compared between patients who either met or did not meet, the primary endpoint. The results show that six of these markers, sAng2, CRP, IL-6, ferritin, LDH and PCT, were significantly elevated (p < 0.05) in those who met the primary endpoint.
Among all of the biomarkers measured, there were no significant difference in values between the two treatment arms at baseline. However, by day 14, there was a significant decrease in biomarker values in remdesivir treated patients compared to placebo for sAng2, ferritin, LDH, D-dimer, the international normalised ratio and prothrombin time. The most prominent difference between the treatment arms was for D-dimer at day 14 (compared to baseline) and which continued to increase in placebo-treated patients but quickly returned to baseline levels in those given remdesivir.
The authors concluded that their findings suggested that remdesivir treatment may accelerate the improvement of multiple biomarkers of COVID-19 severity, leading to better clinical outcomes.
Citation Pan DZ et al. Remdesivir improves biomarkers associated with disease severity in COVID-19 patients treated in an outpatient setting. Commun Med 2023
27th July 2022
Combining an additional magnetic resonance imaging (MRI) and computed tomography (CT) scan in patients presenting with an acute ischaemic stroke, does not lead to better patient outcomes at both discharge and 12 months later, according to the findings from a retrospective study by US researchers.
Data from 2017 show that there were 1.12 million incident strokes in the European Union, 9.53 million stroke survivors, 0.46 million deaths, and 7.06 million disability-adjusted life years lost because of stroke. Patients who present with an acute ischaemic stroke (AIS) are normally initially evaluated with a CT scan to exclude haemorrhage.
Moreover, according the the American Heart Association/American Stroke Association guidelines, in patients who are suspected of having ischaemic stroke, if CT or MRI does not demonstrate symptomatic cerebral infarct, follow-up CT or MRI of the brain is reasonable to confirm diagnosis. In support of this recommendation, there are already some data to indicate that the use of MRI scanning in patients with an AIS is associated with substantial decrease in the rates of inpatient mortality and complications.
However, whether combining a CT scan with an additional MRI improves outcomes for patients is less clear. To date, only a single study has examined the effect of a CT scan and an additional MRI scan on patient outcomes, concluding that the long-term (one-year) patient outcomes may not be influenced by either imaging strategy.
In trying to better understand the value of a strategy that combined a CT scan with an additional MRI scan, in the present study, the researchers undertook a retrospective, propensity score matched study of the clinical outcomes at both discharge and one year later, for patients hospitalised with an AIS.
For the outcomes of interest, the researchers used either death or dependence at discharge, based on the Modified Rankin scale (mRS) which assesses disability in patients who have suffered a stroke. The scale ranges from 0 (no disability) through 5 (requiring constant care) to 6 (death) and the researchers set a non-inferiority margin of -7.5%, for the percentage of patients discharged with a mRS score of 3 to 6. For death, the researchers set a relative risk, RR of 0.725 as the margin for non-inferiority.
Additional MRI and clinical outcomes
A total of 246 patients (123 with and without an MRI scan) and a median age of 68 years (53% male) were included in the study. Among those who had an additional MRI scan, this was ordered by the attending vascular neurologists in 42.3% of cases, 33.3% by emergency physicians and 24.4% by nurse practitioners. In 111 cases of the 123 MRIs ordered, there was no specific indication other than either a stroke or neurological symptoms.
For the primary endpoint of a mRS score 3 – 6 at discharge, there was no significant difference between the two groups (relative risk, RR = 1.50, 95% CI 0.86 – 1.05, p = 0.44), with an absolute difference of 5.7%, thus meeting the -7.5% difference criteria for inferiority.
Stoke or death at one year after discharge occurred in more patients receiving the additional MRI compared to those who only had a CT scan (19.5% vs 12.5%), giving a RR of 1.14 (95% CI 0.86 – 1.50) thus again meeting the RR of 0.725 criteria for non-inferiority.
The authors concluded that the value of an additional MRI to a CT scan in patients with AIS should not be presumed and called for future studies to identify which patients hospitalised with an AIS may benefit from an MRI scan.
Citation
Frade HC et al. Comparison of Outcomes of Ischemic Stroke Initially Imaged With Cranial Computed Tomography Alone vs Computed Tomography Plus Magnetic Resonance Imaging JAMA Netw Open 2022
13th April 2022
Haematological malignancy patients infected with COVID-19 can expect better clinical outcomes after receipt of convalescent plasma according to the results of a pre-print systematic review by researchers from the Department of Biomedical Science, Qatar University, Doha, Qatar.
Patients with any form of cancer have been deemed particularly vulnerable to infection with COVID‐19 given how immunodeficiency is a secondary consequence of their cancer treatment. Convalescent plasma (CP) therapy is a type of passive immunity whereby plasma enriched with specific antibodies generated by patients who have recovered from a specific infection, is transfused into other patients.
The possible value of CP in those with cancers such as a haematological malignancy, the the authors of one study conclude that convalescent plasma may be a promising therapy in cancer patients with COVID-19. Despite these potentially promising results, the use of convalescent plasma therapy among patients with cancer, especially those with a haematological malignancy has not been systematically reviewed.
For the present study, the Qatarian team focused on haematological malignancies and searched for studies that included patients infected with COVID-19, based on a PCR confirmed result and who were treated with convalescent plasma. Included studies were those reported in English and either randomised trials or prospective and retrospective comparative cohort studies.
The authors extracted malignancy data and set several primary outcome measure of clinical improvement including mortality, viral clearance and recovery one month post-treatment. The main secondary outcome was adverse events after use of convalescent therapy.
Haematological malignancy outcomes and convalescent plasma
A total of 17 studies with 1103 patients of whom 258 had one or more haematological malignancies were included in the analysis. Among these studies, 13 were case reports or case series, two were retrospective in nature and two were observational studies.
The main haematological malignancies were follicular lymphoma, chronic lymphocytic leukaemia, non-Hodgkin’s lymphoma, diffused large B-cell lymphoma and B-cell lymphoma.
The dose of convalescent plasma ranged from 200 – 300 ml per transfusion and in many cases this therapy was used as the last option.
Mortality was the main clinical outcome reported in 21.7% of patients receiving CP and 25.2% in control patients. The use of CP was associated with an improved overall survival (odds ratio, OR = 1.41, 95% CI 0.99 – 1.99), viral clearance (OR = 2, 95% CI 1.04 – 2.08), detection of COVID-19 antibodies in the recipient’s plasma (OR = 6.33) and recovery one month after the use of CP (OR = 1.74, 95% CI 1.1 – 2.8).
The probability of developing an adverse effect in haematological malignancy patients was significantly reduced in those given CP compared to controls (OR = 0.24, 95% CI 0.14 – 0.40).
The authors concluded that CP was an effective and safe treatment for patients with haematological malignancies infected with COVID-19, adding that there was a need for further studies to provide a better understanding of the value of this intervention in cancer patients.
Citation
Shibeeb S et al. Effectiveness of convalescent plasma therapy in COVID-19 patients with haematological malignancies MedRxiv 2022
1st February 2022
Relevant vital sign cut off values used for the risk stratification and hence prognosis for patients attending an emergency department do not exist for some signs which has important implications for their use and interpretation. This was the conclusion of a large study by a team from the Emergency Department, Maxima Medical Centre, Veldhoven, The Netherlands.
An emergency department encounters a large number of sick patients who require quick evaluation to detect those who have serious medical problems and which might require hospital admission.
This has led to the introduction of various triage tools such as the modified early warning score (MEWS) which serves as a rapid, simple triage method to identify medical patients in need of hospital admission and those at increased risk of in-hospital death.
Other tools commonly used such as the quick sequential organ failure assessment (qSOFA) rely on the use of vital sign measurements and specify a cut-off for each vital sign to discriminate between a better or worse prognosis.
However, the use of disease severity assessment tools may not be appropriate, particularly for elderly patients as revealed in one study of sepsis, which concluded that ‘prognostic and discriminative performance of the five most commonly used disease severity scores was poor and less useful for risk stratification of older ED sepsis patients.’
For the present study, the Dutch team looked to assess the association between vital signs and relevant clinical outcomes such as mortality and admission to an intensive care unit. In addition, they wanted to determine whether a single cut-off or threshold existed for each vital sign and the extent to which these were influenced by advancing age.
They undertook an observational study at three EDs in the Netherlands and examined consecutive adult patients (18 years and older) where one or more of the following vital signs were measured: respiratory rate (RR), peripheral oxygen saturation (SpO2), systolic (SBP) and diastolic (DBP) blood pressure, mean arterial blood pressure (MAP), heart rate (HR) and temperature.
Patients were stratified by age into three categories; 18 – 65, 66 – 80 and > 80 years and the primary outcome was whether there was a vital sign category that could be used as a cut-off to predict the outcome of in-hospital mortality or ICU admission.
Findings
A total of 101,416 patients with a mean age of 59.6 years (49.6% female) were included in their analysis. In many cases the vital sign values were outside of the usual range. For example, 23.4%, 79.1% and 14.2% of the total cohort had a RR, SBP and SP02 respectively, outside of the normal range. This proportion was also higher in older patients as seen for example with SBP for which 83.3% of patients aged > 80 had a reading outside of the normal range compared to 76.3% of those aged 18 to 65 years.
Among the cohort, a total of 2374 (2.3%) patients died. The adjusted odds ratios (aOR) for predicted mortality increased gradually with worsening values of SBP and SpO2 although there was no clear cut-off point for SBP, DBP, Sp02 and HR and mortality. In addition, for all vital signs, older adults had a larger increase in absolute mortality. For ICU admission, SBP had a relevant cut-off at 70mmHg and for MAP there was a threshold of < 60 mmHg.
In summarising their findings, the authors noted how in-hospital mortality increased gradually with decreasing SBP and SpO2 and there was no evidence of a specific cut-off for either vital sign. For DPB, MAP and HR, there was a quasi-U-shaped association with in-hospital mortality and while there was a single cut-off for MAP, RR and temperature, the authors argued that using a single cut-off value would ignore further increase of risk with more extreme values for these vital signs.
They concluded that the use of a single cut-off for each vital sign in acute care deserves scrutiny and that age-adjusted numerical scores would improve risk stratification since older patients have a larger increase in mortality with changing vital signs even after adjustment for confounds.
Citation
Candel BGJ et al. The association between vital signs and clinical outcomes in emergency department patients of different age categories Emerg Med J 2022
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