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19th December 2022
According to a press release by drug manufacturer Lilly, donanemab provides a greater level of brain amyloid clearance compared to aducanumab at 6 months.
Brain amyloid-β deposition is a hallmark used to define Alzheimer’s disease. Moreover, in March 2022, the Food and Drug administration (FDA) in the US, approved the first in vitro diagnostic test for early detection of amyloid plaques associated with Alzheimer’s disease. The FDA added that a positive test was consistent with the presence of amyloid plaques, similar to what would be seen in a PET scan and that a negative result is consistent with a negative amyloid PET scan result, reducing the likelihood that a patient’s cognitive impairment was due to Alzheimer’s disease, enabling physicians to pursue other causes of cognitive decline and dementia.
The current data announced by Lilly, comes from the TRAILBLAZER-ALZ 4 trial, which was a randomised, open-label phase 3 study designed to compare donanemab (DM) with aducanumab (AM) on amyloid plaque clearance in participants with early, symptomatic Alzheimer’s Disease. In the trial, donanemab and aducanumab were administered via intravenous infusions every four weeks for up to 18 months.
Donanemab efficacy
In the co-primary outcomes, brain amyloid plaque clearance, defined as achieving brain amyloid plaque levels of <24.1 Centiloids, was achieved in 37.9% of DM-treated participants compared with 1.6% of AM-treated patients at 6 months. In the intermediate tau subpopulation, 38.5% of DM-treated participants reached brain amyloid clearance compared with 3.8% of AM-treated participants by 6 months. In a key secondary outcome, DM reduced brain amyloid levels vs. baseline by 65.2% compared with 17.0% for AM at 6 months. In an exploratory outcome, donanemab, but not aducanumab treatment significantly reduced plasma P-tau217 at 6 months compared to baseline.
In terms of safety, amyloid-related imaging abnormalities were the most common treatment emergent adverse event in both groups and occurred with a similar frequency (25.4% vs 26.1%, DM vs AM).
Although only 6-month data is currently, available, the press release describes how TRAILBLAZER-ALZ 4 is an on-going study and results from 12 or 18 months will be presented once available.
The COVID-19 pandemic period was associated with a higher level of advanced colorectal cancer diagnoses compared to pre-pandemic levels.
Italian researchers have found that the COVID-19 pandemic was associated with the diagnosis of more advanced stage colorectal cancer in comparison to pre-pandemic levels.
The World Health Organization describes how globally, colorectal cancer is the third most common cancer with nearly two million cases and almost one million deaths in 2020.
Nevertheless, despite screening programs being widely available, emerging data from, for example, the US, clearly shows how after the national lockdowns imposed because of COVID-19, while stool testing increased by 7%, there was a 16% decrease in colonoscopy between 2018 and 2020.
Consequently, there have been concerns that the pandemic together with a reluctance of patients to seek medical attention, could be associated with a risk of more advanced colorectal cancer at diagnosis.
Moreover, one modelling study estimated 1,176,942 to 2,014,164 fewer colorectal cancer screenings, 8,346 to 12,894 fewer colorectal cancer diagnoses and 6,113 to 9,301 fewer early-stage colorectal cancer diagnoses between 2020 and 2023.
Nevertheless, there has been a lack of real-world evidence on the actual level of advanced colorectal diagnoses because of COVID-19.
In the present study, the Italian team set out to determine if the pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer.
The team undertook a retrospective, multicentre cohort study of all adult patients who underwent surgery for colorectal cancer from 1 March 2020, to 31 December 2021 (pandemic period) in comparison to 1 January 2018, to 29 February 2020 (the pre-pandemic period).
They considered any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections.
The primary outcome was advanced stage of colorectal cancer at diagnosis whereas secondary outcomes included distant metastasis and T4 stage.
A total of 17,938 patients with a mean age of 70.6 years (55.8% male) underwent surgery for colorectal cancer, 43.5% of whom had surgery during the pandemic period.
The proportion of patients with stage 1 disease was significantly lower during the pandemic period compared to the pre-pandemic phase (20.7% vs 23.3%, p < 0.001). In addition, there was a significantly higher proportion of stage 4 disease during the pandemic (15% vs 13.9%, p = 0.03).
Using regression analysis, the pandemic period was found to be significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio, OR = 1.07, 95% CI 1.01 – 1.13, p = 0.03), an aggressive biology (OR = 1.32, p < 0.01) and stenotic lesions (OR = 1.15, p = 0.03).
The authors concluded that the COVID-19 pandemic was significantly associated with a risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer. They added that these results may indicate a potential reduced survival for these patients.
Citation
Rottoli M et al. Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy. JAMA Netw Open 2022.
16th December 2022
Non-steroidal anti-inflammatory drugs (NSAIDs) used for the management of osteoarthritis appear to worsen inflammation in the knee joint over time, according to a study presented at the Radiological Society of North America (RSNA) conference 2022.
NSAIDs such as ibuprofen and naproxen are widely recommended and prescribed to treat pain in osteoarthritis yet are also known to elicit adverse events affecting the gastrointestinal, cardiovascular, and renal systems. In fact, one US study of patients with knee osteoarthritis (OA) revealed how non-prescription non-steroidal anti-inflammatory drugs were the most frequently reported medications (26.8%), even in those more than 75-years old. In recent years attention has focused on the role of the synovium in OA and how the presence of synovitis is associated with more severe pain and joint dysfunction and may be predictive of faster rates of cartilage loss in certain patient populations. However, whether NSAIDs are beneficial to patients with OA in the longer term remains uncertain, though some data suggests that there may not be long-term benefits given how a majority of patients had persistent pain and disability despite therapy.
In the study presented at RSNA, researchers set out to analyse the association between NSAID use and synovitis in patients with osteoarthritis of the knee and to assess how treatment with NSAIDs affects joint structure over time. The team used data derived from participants from the Osteoarthritis Initiative (OAI) cohort who had moderate to severe OA and sustained NSAID treatment for at least 12 months between baseline and 4-year follow-up. The outcomes for these participants were then compared with non-NSAID treated participants. All participants underwent a 3T MRI of the knee at baseline and after 4 years. and images were semi-quantitatively scored for MR biomarkers of synovial inflammation (effusion-synovitis, size and signal intensity of infra-patellar fat pad (IFP) and the synovial proliferation score (SPS). Cartilage thickness and T2-relaxation time measurements served as non-invasive biomarkers for evaluating OA progression. The associations between baseline and findings after 4 years were investigated with linear regression models (including adjustment for sex, BMI, age, pain, K/L grade).
NSAIDs and arthritic markers over time
A total of 721 participants (129 with and 592 participants without regular usage of NSAID) were included in the analysis. At baseline, there was a significantly higher signal intensity in the IFP among NSAID users as compared to controls (adjusted difference in score = 0.26, 95% CI -0.5 – 0.129, p = 0.039). Additionally, when assessed over time, there was a significantly higher increase in the signal intensity of IFP (0.46, 95% CI 0.2 – 0.72, p < 0.001) and a higher increase in effusion synovitis (0.27, 95% CI 0.06 – 0.47, p = 0.01) in NSAID users compared to controls. The size of IFP and SPS did not show a significant difference between groups at baseline and no significant change over time. NSAID users showed more degenerative changes regarding T2-relaxation time and cartilage thickness over time, but this did not reach statistical significance.
Based on these findings, the authors suggested that among those using NSAIDs, there was a higher signal intensity in IFP and more effusion/ synovitis than controls, indicating that long-term NSAID usage is associated with more synovitis.
Commenting on these findings in a press release, lead author, Johanna Luitjens, a postdoctoral scholar in the Department of Radiology and Biomedical Imaging at the University of California, San Francisco, said ‘in this large group of participants, we were able to show that there were no protective mechanisms from NSAIDs in reducing inflammation or slowing down progression of osteoarthritis of the knee joint.’ She added that ‘the anti-inflammatory effect that normally comes from NSAIDs may not effectively prevent synovitis, with progressive degenerative change resulting in worsening of synovitis over time.’
Citation
Luitjens J et al. Impact of Non-steroidal Anti-inflammatory Drugs (NSAIDs) on Synovitis and the Progression of Osteoarthritis: Data from the Osteoarthritis Initiative (OAI). RSNA conference 2022.
12th December 2022
Deferiprone, which is an iron chelating agent, failed to delay the progression of symptoms in patients diagnosed with Parkinson’s disease prior to treatment with levodopa according to a recent randomised trial by French researchers.
Globally, Parkinson’s disease is estimated to affect around 10 million people. It is a neurodegenerative disorder that mostly presents in later life, with generalised slowing of movements (bradykinesia) and at least one other symptom of resting tremor or rigidity, due to the loss of dopaminergic activity in the substantia nigra. Within the central nervous system, iron is present in several proteins involved in important processes such as oxygen transportation, oxidative phosphorylation and the synthesis and metabolism of neurotransmitters. However, during ageing, different iron complexes accumulate in brain regions and changes in iron homoeostasis result in altered cellular iron distribution and accumulation in diseases such as Alzheimer’s and Parkinson’s disease. It has therefore been proposed that a moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality for Parkinson’s disease. Deferiprone is the only orally active iron-chelating drug to be used therapeutically in conditions of trans fusional iron overload. Moreover, early data suggests that deferiprone use in early Parkinson’s disease, did lead to a reduction in substantia nigra iron levels in a small number of patients. As a result, in the current trial, the French team undertook, a phase 2, randomised, double-blind trial involving participants with newly diagnosed Parkinson’s disease who had never received levodopa. Participant were randomised 1:1 to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. The team set the primary outcome as the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and which ranges from 0 to 260, with higher scores indicating more severe impairment, at 36 weeks.
Deferiprone and outcomes in early Parkinson’s disease
A total of 372 participants with a mean age of 62.5 years (37% female) were randomised to deferiprone (186) or placebo. The mean MDS-UPDRS baseline score was 34.3 and 33.2 in the deferiprone and placebo groups respectively.
At week 36, the MDS-UPDRS score increased by 15.6 points (i.e., worsened) in the deferiprone group and by 6.3 points with placebo. (mean difference = 9.3, 95% CI 6.3 – 12.2, p < 0.001).
When the researchers looked at iron levels in the brain among a subgroup of 148 patients (70 in the placebo arm), there was a greater decrease among those assigned to deferiprone (-0.65 vs -0.17).
Based on these findings, the authors concluded that despite reducing iron brain levels, deferiprone use was associated with worse scores in measures of Parkinsonism than in those with placebo over a period of 36 weeks.
Citation
Devos D et al. Trial of Deferiprone in Parkinson’s Disease. N Engl J Med 2022
Tisagenlecleucel in paediatric and young adults with relapsed/refractory acute lymphoblastic leukaemia retains durable efficacy over three years.
Tisagenlecleucel appears to remain effective for more than three years in paediatric and young adults who had relapsed or refractory acute lymphoblastic leukaemia according to the results of a follow-up study by an international research group.
B-cell acute lymphoblastic leukaemia (ALL) is a clonal malignant disease originated in a single cell and characterised by the accumulation of blast cells that are phenotypically reminiscent of normal stages of B-cell differentiation.
Moreover, ALL is the most common childhood cancer and has a high survival rate when properly managed.
Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy and in the ELIANA trial, after a single infusion, the drug provided durable remission with long-term (12-month) persistence in paediatric and young adult patients with relapsed or refractory B-cell ALL.
Moreover, the trial reported an overall remission rate within three months of 81% and improvements in patient-reported quality-of-life scores were observed for all measures at month three after the infusion.
However, what remains uncertain is the durability of the response to treatment observed in the ELIANA trial and in the present study, researchers provided an update on the efficacy of the drug.
In the follow-up arm, 79 patients with a median age of 11 years (57% male), 92% of whom had experienced a treatment relapse, provided on-going data for a median follow-up of 38.8 months. Overall, participants had received a median of three previous lines of therapy.
In the updated analysis, the overall remission rate was 82% and the median event-free survival was 24 months. In addition, event-free survival was 44% (95% CI 31 – 57) and overall survival was 63% (95% CI 51 – 73) at three years with most events having occurred with the first two years.
Researchers estimated the three-year relapse-free survival with and without censoring for subsequent therapy to be 52% and 48% respectively. The estimated overall survival rate was 63% (95% CI 51 – 73%).
A total of 24 relapses were recorded and of which six had occurred 12 months after the Tisagenlecleucel infusion.
Interestingly, there were no new or unexpected long-term adverse events reported although grade 3/4 adverse events were seen in 29% of patients more than 12 months after the infusion. However, grade 3/4 infection rates did not increase longer than one year after infusion. Patients also reported improvements in quality-of-life up to 36 months after infusion.
The authors concluded that these data demonstrated favourable long-term safety and suggested that tisagenlecleucel is a potentially curative treatment option for heavily pretreated paediatric and young adult patients with either relapsed or refractory acute lymphoblastic leukaemia.
Citation
Laetsch TW et al. Three-Year Update of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial J Clin Oncol 2022.
Increased acetylcholinesterase activity in critically ill patients is associated with an increased risk of being delirious but this does lead to subsequent cognitive impairment following discharge from hospital according to the findings of a prospective study by US researchers.
Delirium is defined as a disturbance of consciousness and cognition that develops over a short period of time (hours to days) and fluctuates over time. Furthermore, it is a common manifestation of acute brain dysfunction in critically ill patients with prevalence as high as 75%. However, more troublesome is the finding from a meta-analysis of 24 studies, which showed how delirium was significantly associated with long-term cognitive decline in both surgical and nonsurgical patients. The causes of delirium remain uncertain although several pro-inflammatory markers have been found to be elevated in critical ill patients with delirium. A widely held hypothesis has proposed that this inflammatory response seen in critically ill patients is regulated by the cholinergic system, resulting from a deficit of acetylcholine (ACh). The cholinesterase enzyme, acetylcholinesterase (AChE), is found primarily found in synapses and red blood cell membranes and cleaves ACh in the synaptic cleft, terminating the transmission of a stimulus. Although the primary neurotransmitter of the cholinergic system is acetylcholine, this cannot be measured directly in clinical settings but the activity of two enzymes, AChE and butyrylcholinesterase (BChE) can be assessed with a decreased activity of the latter, seen in patients with systemic inflammation.
Researchers therefore set out to establish whether there was an association between acute brain dysfunction (i.e., delirium and coma) during critical illness and the activity of these two enzymes as well as if enzyme activity levels were predictive of long-term cognitive impairment, disability, and health-related quality of life in survivors of critical illness. Blood samples were taken on days 1 (study enrolment), 3, 5 and 7 while in the hospital to measure the activity of both enzymes. In addition, patients were assessed for delirium and/or coma twice daily until discharged from the intensive care unit IICU) and then once daily after ICU discharge.
Cholinesterase activity, delirium and cognitive impairment
A total of 272 patients with a median age of 56 (56% male) and a median Sequential Organ Failure Assessment score at enrolment of 8, were included in the analysis. Overall, 15% of the cohort died within the hospital and 23% within 90 days of enrolment.
Measurement showed that a higher AChE enzyme activity level was associated with a higher odd of delirious status on the same day (p = 0.045), but not comatose mental status (p = 0.13). When examining delirium, patients with AChE activity at the 75th percentile compared to those with values at the 25th percentile example, had 64% increased odds of developing delirium (odds ratio, OR = 1.64, 95% CI 1.11 – 2.43, p = 0.045). However, when AChE levels were normalised per gram of haemoglobin (since AChE is found in synapses and on red blood cell membranes), this relationship was no longer significant (OR = 1.20, 95% CI 0.95 – 1.52, P = 0.21).
A further finding was how patients in the 75th percentile of BChE activity, had 44% higher odds of having more days alive without delirium or coma, i.e., indicating less brain dysfunction (OR = 1.44, 95% CI 1.06 – 1.94, p = 0.05). Finally, there was no significant association between any of the cholinesterase enzymes with cognitive impairment, disability, or quality of life after discharge.
The authors concluded that plasma cholinesterase activity was predictive of acute brain dysfunction during critical illness but not long-term impairments. They suggested that future studies need to examine whether cholinergic modulation in selected patients identified by plasma cholinesterase activity, could reduce acute brain dysfunction.
Citation
Hughes CG et al. Association between cholinesterase activity and critical illness brain dysfunction. Crit Care 202
A higher mean arterial pressure (MAP) in shock or perioperative patients does not appear to be superior to normotension for the prevention or progression of acute kidney injury (AKI) and the need for renal replacement therapy according to a systematic review by Taiwanese researchers.
Globally, acute kidney injury (AKI) is associated with poor patient outcomes and the available data suggests that the pooled incidence rate of AKI is 21.6% in adults with a 23.9% AKI-related mortality. An acute circulatory failure is the major cause of renal failure in intensive care unit (ICU) patients, since the low cardiac output and/or low mean arterial pressure (MAP) leads to renal hypo-perfusion and AKI. It is necessary therefore to maintain an adequate mean arterial pressure but the level of MAP to adequately protect against worsening of renal function is unknown. However, it is known that hypotensive episodes, i.e., where the MAP is less than 73 mmHg, are associated with progression of AKI in critically ill patients with severe sepsis. Furthermore, other work suggests that mean arterial pressure levels of 70 mmHg or higher do not appear to be associated with improved survival in septic shock. and that elevating above 70 mmHg may increase mortality.
In the present study the Taiwanese researchers conducted a systematic review and meta-analysis of available randomised clinical trial (RCT) results to try and determine whether a higher MAP might be better than normotension for the prevention and worsening AKI. They searched all of the major databases for studies to comparing higher BP target versus normotension in haemodynamically unstable patients, i.e., those with shock, post-cardiac arrest, or surgery patients. They set the two outcomes of interest as the post-intervention AKI and renal replacement therapy rates.
Mean arterial pressure and AKI
A total of 12 eligible trials with 5759 participants, with shock (57%), non-cardiac (29.3%) and cardiac surgery (13.7%) patients were included in the analysis.
The normotensive target varied depending on the patient cohort. For example, in shock patients the normotensive range was 65 – 70 mmHg, 40 – 60 in cardiac surgery and 60 – 75 in non-cardiac surgery.
When compared against the lower mean arterial blood pressure (i.e., normotension), targeting a higher MAP demonstrated no significant effect on AKI rates in shock (risk ratio, RR = 1.10, 95% CI 0.93 – 1.29), cardiac-surgery (RR = 0.87, 95% CI 0.73 – 1.03) or non-cardiac surgery patients (RR = 1.25, 95% CI 0.98 – 1.60]). Similarly, there was no effect on renal replacement therapy in shock patients from targeting a higher MAP (RR = 1.10, 95% CI 0.93 – 1.03) or for either for cardiac and non-cardiac patients.
Interestingly, among shock patients with premorbid hypertension, targeting MAP above 70 mmHg significantly lowered the risk of renal replacement therapy (RR = 1.20, 955 CI 1.03 – 1.41, p < 0.05).
The authors concluded that targeting a higher MAP in shock or perioperative patients may not be superior to normotension, except in shock patients with premorbid hypertension but called for future studies to assess the effects of a high MAP target to preventing AKI in hypertensive patients across common settings of haemodynamic instability.
Citation
Tran PNT et al. Higher blood pressure versus normotension targets to prevent acute kidney injury: a systematic review and meta-regression of randomized controlled trials. Crit Care 2022
An amino acids supplement administered to critically ill patients improved twitch airway pressure and anterior quadriceps volume as well as gut functionality, according to the findings of a randomised, proof-of-concept trial by French researchers.
Critically ill patients such as those with sepsis, undergo dramatic depletion of lean body mass, particularly skeletal muscle, despite aggressive nutritional support. Moreover, this muscle wasting has clear and obvious implications for the patient’s recovery and rehabilitation, particularly in weaning them from the ventilator and their ability to resume normal life. In fact, critically ill patients show a signalling pathway activity directed towards stimulation of muscle protein synthesis and inhibited proteolysis. Other work has shown how this muscle wasting occurred early and rapidly during the first week and was more severe among those with multi-organ failure compared with single organ failure. Animal models of sepsis indicate that an amino acids (AAs) supplement is able to support the synthesis of vital proteins and to spare body protein catabolism during infection. However, evidence for the benefit of this approach in critically ill patients is sparse. For the present study, French researchers performed a randomised, double-blind, placebo-controlled study that included patients with sepsis or acute respiratory distress syndrome. These patients were given a specific combination of five amino acids (threonine, cysteine, proline, serine and leucine) or placebo mixed with enteral feeding for 21 days. Although there was no specific primary outcome set, researchers examined markers of renal function, gut barrier structure and functionality at baseline and 1, 2, 3 and 8 weeks after randomisation. Muscle structure and function were assessed through MRI measurements of the anterior quadriceps volume and by twitch airway pressure.
Amino acids supplement and muscle function
A total of 35 patients (mean age 71 years, 60.3% male) were included and randomised to either the amino acids (18) or placebo. For the amino acid group, all patients had sepsis, and this was also present the majority (88%) of placebo patients.
Use of the amino acids supplement did not impair urine output, blood creatinine levels or creatinine clearance. In addition, plasma citrulline levels (a measure of enterocyte functional mass and thus gut functionality) increased significantly in the amino acid group (mean difference, MD = 5.86, 95% CI 1.72 – 10, p = 0.007).
The mean difference (MD) in the anterior compartment of the quadriceps was significantly greater in the amino acid group (MD = 3.12, 95% CI 0.5 – 5.73, p = 0.0022). Similarly, the twitch airway pressure also increased in this group (MD = 10.6, 95% CI 0.99 – 20.20, p = 0.035). Taken together, the authors suggested that these data indicated that the extent of muscle catabolism was reduced when sufficient amino acids were provided.
The researchers concluded that enteral administration of AAs to critically ill patients increased plasma citrulline levels and improved twitch airway pressure and anterior quadriceps volume. They added that these results provided a rationale for further clinical investigation.
Citation
Heming N et al. Effect of an enteral amino acid blend on muscle and gut functionality in critically ill patients: a proof-of-concept randomized controlled trial. Crit Care 2022
The combination of nirmatrelvir and ritonavir appear to be safe and well tolerated when used in pregnancy among mothers infected with COVID-19.
The nirmatrelvir and ritonavir (Paxlovid) can be used safely in pregnant women infected with COVID-19 according to a case series study by researchers from Johns Hopkins University School of Medicine, Baltimore, US.
COVID-19 leads to a consistent and substantial increase in severe maternal morbidity and mortality and neonatal complications in pregnant women.
In fact, available data suggests that severe acute respiratory syndrome caused by COVID-19 during pregnancy leads to placental inflammation and a reduced antiviral antibody response, which could impact upon the efficacy of treatment in pregnancy.
The combination of nirmatrelvir and ritonavir has been authorised by the European Medicine’s Agency for the treatment of COVID-19 in adults who do not require supplemental oxygen and who are at increased risk for progression to severe COVID-19.
However, the summary of product characteristics states that ‘there are no data from the use of paxlovid in pregnant women’ and that ‘paxlovid is not recommended during pregnancy.’
Despite the lack of human data, animal studies of nirmatrelvir and ritonavir reported no clinically relevant risks associated with administration during pregnancy or in males and females of reproductive age.
In the present study, the US researchers reported on a case series that included pregnant patients who were diagnosed with COVID-19 and who received nirmatrelvir and ritonavir. The team recorded the clinical characteristics and pregnancy outcomes through a manual review of medical records.
A total of 47 women with a median age of 34 years were included and who received the drugs during pregnancy, 57.4% during the third trimester and 34% during the second trimester.
In addition, 85.1% of women had received some level of COVID-19 vaccination, with 44.7% having received the initial series and one booster. Co-morbidities included a mental health disorder (44.7%), obesity (25.5%) and diabetes (10.6%).
A total of 53.2% of mothers delivered after treatment with nirmatrelvir and ritonavir and of whom, 12 (48%) underwent a caesarean delivery, although three quarters of these were scheduled. Only two patients discontinued the drugs due to adverse effects.
Based on these findings, the authors concluded that pregnant patients treated with nirmatrelvir and ritonavir tolerated the treatment although there was an unexpectedly high rate of caesarean deliveries.
They added that the lack of serious adverse effects affecting pregnant patients or offspring suggests that the drug combination is suitable for the treatment of infected, pregnant women.
Citation
Garneau WM et al. Analysis of Clinical Outcomes of Pregnant Patients Treated With Nirmatrelvir and Ritonavir for Acute SARS-CoV-2 Infection. JAMA Netw Open 2022.
There appears to be no clear temperature threshold which can be used to identify infections among hypothermic young.
It is difficult to identify a suitable temperature threshold to reliably allow emergency care clinicians to identify hypothermic young infants at risk of a serious bacterial infection according to a retrospective study by US researchers.
Fever in young children is a common emergency department (ED) presentation and there are recognised sequential approaches to young febrile infants on the basis of clinical and laboratory parameters, to identify those at risk of an invasive bacterial infection.
In contrast, hypothermia is also recognised as an important factor in very young children who subsequently develop a serious bacterial infection (SBI).
In fact, one study of children less than 60 days old, detected the presence of a SBI in 9% of evaluated infants, prompting the authors to concluded that hypothermia can be a presenting sign of SBI.
Another study found that neonates presenting with hypothermia had a substantial risk for SBI or other significant pathology.
Despite the growing recognition that hypothermia represents a risk factor for a SBI, what remains uncertain is the specific temperature threshold that should be used to identify at-risk young children.
In the present study, researchers undertook a retrospective cross-sectional study of infants less than 90 days old who presented at an ED and with a rectal temperature < 36.4oC.
The team set the primary outcome as SBI defined as either a urinary tract infection, bacteraemia and/or bacterial meningitis and invasive bacterial infections (IBI) with the latter limited to bacteraemia and/or bacterial meningitis.
The team constructed receiver operating characteristic (ROC) curves for the two outcomes and calculated the area under the ROC curve (AUC) to evaluate an optimally derived cut-off point for the minimum ED temperature and the presence of SBI or IBI.
They defined accuracy using the AUC as poor where the AUC was < 70%, 70 – 80% as fair, 80 – 90% as good and > 90% as excellent.
The study included 3,376 infants with a median age of 22 days (53.1% male) with the overall median minimum temperature being 36.2oC.
Overall, 1.8% of infants had an SBI and 0.5% an IBI and the most common infection identified was Escherichia coli UTI (74.2% of all SBIs).
Infants with both an SBI and IBI had lower median temperatures, 35.8°C and 35.4°C respectively, compared with those without corresponding infections and this difference was statistically significant (both p<0.05).
In their analysis, when evaluating the performance of temperature with an outcome of SBI, the AUC was 61% (95% CI 54.1 – 67.9%).
Using a cut-off of 36.2°C, the sensitivity was 59.7% and the specificity 59.2%. Similarly, for IBI, the AUC was 65.9% (95% CI 51.1 – 80.6%) and with a cut-off of 36.1°C, the sensitivity was 68.8% and the specificity 60.1%.
The authors concluded that although young infants with SBI and IBI presented with lower temperatures, there was no temperature threshold to reliably identify SBI or IBI.
Citation
Lo YHJ et al. Temperature threshold in the screening of bacterial infections in young infants with hypothermia. Emerg Med J 2022.
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