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19th January 2023
Dupilumab add-on therapy in severe asthma improves the exacerbation rate and disease control according to the findings of a real-world study.
Dupilumab add-on treatment in patients with severe asthma is associated with significant improvements in the exacerbation rate, asthma control, pulmonary function and quality of life, according to the findings of a real-world study by Dutch researchers.
Severe asthma occurs when adequate control cannot be achieved by high-dose treatment with inhaled corticosteroids and additional agents (i.e. long-acting inhaled beta 2 agonists, montelukast, and/or theophylline) or by oral corticosteroid treatment, for at least six months per year.
Although it is generally considered that 5% and 10% of all asthmatic patients have severe disease, a 2015 Dutch study of asthmatic adults, found that only 3.6% qualified for a diagnosis of severe refractory asthma, representing 10.4 patients per 10,000 inhabitants.
There are currently several biological agents used to treat severe asthma including mepolizumab, benralizumab and dupilumab, with the latter agent binding to the interleukin-4-receptor-α and therefore targeting interleukin-4 and interleukin-13, both of which are key cytokines in type-2 (T2) inflammation.
Moreover, the prevalence of type 2 asthma in severe, uncontrolled disease has been found to be present in the majority (89%) of cases.
Dupilumab add-on therapy is therefore an appropriate treatment option in severe asthma and effective, as shown in randomised, controlled trials.
Nevertheless, while effective in clinical trials, some evidence has shown, especially with mepolizumab, that a large proportion of real-world mepolizumab-treated population with severe asthma, would be excluded from the clinical trial population, raising concerns over the generalisability of trial findings.
In the present study, the Dutch team set out to assess the efficacy and safety of dupilumab add-on therapy for severe asthma in a real-world cohort.
The team retrospectively examined the impact of subcutaneously administered dupilumab, either at hospital or by self-administration at home, at a dose of 200 mg every 14 days, or 300 mg in patients with other type 2 co-morbidities.
The primary endpoint was the annually exacerbation-rate (AER), whereas secondary outcomes included asthma control, pulmonary function and quality of life and the changes were assessed by comparing baseline to 12 month values.
A total of 148 patients with a median age of 52.5 years (57% male) were included in the study, of whom 73% had allergic asthma (which includes the type 2 form).
The AER reduced from 3.00 at baseline to 1.00 at 12 months with dupilumab use (p < 0.001). In fact, after 12 months of treatment, 46% of dupilumab add-on therapy patients remained completely exacerbation-free.
Similarly, asthma-controlled-questionnaire-5 scores reduced over time, from a median of 3.00 at baseline to 1.40 after 12 months of dupilumab use (p < 0.001). Furthermore, lung function (based on FEV1) also improved, increasing from a median of 2.21 at baseline to 2.51 at 12 months (p < 0.001) in the dupilumab group.
The authors concluded that dupilumab add-on therapy in severe asthma was associated with significant improvements in the exacerbation rate, asthma control and pulmonary function, which was in line with findings observed in previous Phase III trials.
Citation
Thelen JC et al. Efficacy and safety of dupilumab as add-on therapy for patients with severe asthma: A real-world Dutch cohort study. Respir Med 2023.
Lebrikizumab in combination with low to mid-potency topical corticosteroids is an effective therapeutic approach for adults with moderate to severe atopic eczema according to the results of a randomised, placebo-controlled trial by an international research group.
Atopic eczema (AE) is a chronic, relapsing and remitting skin disease which, according to one UK-based study, affects up to 16.5% of children aged 2 years and 2.8% of adults aged 30-39. Moderate to severe disease symptoms include intense itch, sleep disturbance together with skin pain, affecting sleep, daily activities and occurs in 28.9% and 11% of adults, respectively. Both emollients and topical corticosteroids (topical steroids) are used to manage mild to moderate disease whereas systemic therapy and or phototherapy is recommended for those with more severe disease. In recent years, biologic therapies such as dupilumab have emerged for the treatment of individuals with moderate to severe disease.
Another recently introduced biologic is the monoclonal antibody lebrikizumab, which targets interleukin (IL)-13, a pro-inflammatory Th2 cytokine central to AE pathogenesis and which is an important driver of the clinical manifestations of AE. Although lebrikizumab has been shown to provide a rapid and dose-dependent efficacy across a broad range of clinical manifestations in adult patients with moderate to severe AE, no studies have examined the value of the drug in combination with topical steroids, which is reflective of real-life practice.
Consequently, in the current study, researchers randomised eligible patients, i.e., with a diagnosis of moderate-to-severe AE, 2:1 to lebrikizumab and topical steroids or placebo and topical steroids. An initial lebrikizumab loading dose of 500 mg was administered subcutaneously, at baseline and week 2, followed by 250 mg once every two weeks. The primary efficacy endpoint was the percentage of patients with an investigator’s Global Assessment scale (IGA) score of 0 or 1 (i.e., clear or almost clear) and a 2 or more point improvement from baseline at week 16. A key secondary objective was the percentage of patients achieving 75% improvement in EASI (EASI-75) at week 16.
Lebrikizumab and atopic eczema outcomes
A total of 211 patients with mean age of 37.2 years (48.8% female) were randomised to lebrikizumab and topical steroids (145) or placebo and steroids.
After 16 weeks of treatment, an IGA score of 0 or 1 with a 2-point or more reduction from baseline was achieved by 41.2% of those receiving lebrikizumab compared to 22.1% on placebo (p = 0.01), although a statistically significant difference was observed as early as week 8.
There was also a significantly higher proportion of lebrikizumab patients achieving an EASI75 (69.5% vs 42.2%, p < 0.01) and this time, a statistically significant difference was achieved and maintained from as early as week 4 and maintained through week 16.
The authors concluded on how lebrikizumab in combination with topical steroids was superior to topical steroids alone, adding how safety data was consistent with previously reported AE trials.
Citation
Simpson EL et al. Efficacy and Safety of Lebrikizumab in Combination With Topical Corticosteroids in Adolescents and Adults With Moderate-to-Severe Atopic DermatitisA Randomized Clinical Trial (ADhere). JAMA Dermatol 2023
The gestational age can be more accurately estimated with AI than by standard foetal biometry-based methods used by expert sonographers.
The gestational age is more accurately determined using artificial intelligence (AI) based models compared to the standard foetal biometry-based estimates used by sonographers according to the findings of a retrospective study by US researchers.
Foetal ultrasonography is used during pregnancy to check the health of unborn babies. In addition, ultrasonography allows for an estimation of the gestational age and which is particularly important for women unable remember the date of their last menstrual period or to confirm estimated delivery dates.
Estimates of the age are based on measurement of several parameters such as biparietal diameter, head and abdominal circumference, femur or crown-rump length. However, these estimates rely to some extent on the skill and experience of the sonographer and machine-based learning methods have been shown good accuracy. In fact, a 2022 study found that an AI model was non-inferior to standard estimates of gestational age.
In the present study, the US researchers developed three AI models to estimate gestational age (GA). The first model used foetal ultrasound images captured by sonographers using biometry measurements, the second made use of five to 10 seconds of video before image capture and the final model incorporated data from both the image and video models, which was referred to as the ensemble model.
All data was collected retrospectively and during all three trimesters. The models were assessed using the mean difference in absolute error between the GA model estimate and the clinical standard estimate. Moreover, evaluation of the AI models was undertaken on an independent test set, i.e., a different set to that used for development of the models.
The test set consisted of 407 women with a mean age of 28.8 years.
The overall mean absolute error (MAE) for both the video and ensemble model were significantly lower than the standard foetal biometry. The MAE mean difference for the ensemble model was lowest at -1.51 days (95% CI -1.90 to -1.10) followed by the video model, -1.48 days (95% CI 1.90. to -1.10). The researchers also found that each of the models outperformed standard estimates (i.e., Hadlock-based) of suspected foetal growth restriction.
The authors concluded that their diagnostic study demonstrated how AI models were superior for gestational age estimation when compared against the clinical standard of foetal biometry. They added that since the models utilised information collected during routine ultrasound examinations, it should be possible to incorporate such models into routine clinical care, enabling sonographers to estimate gestational age with a higher accuracy.
Citation
Lee C et al. Development of a Machine Learning Model for Sonographic Assessment of Gestational Age. JAMA Netw Open 2023.
18th January 2023
Heart failure risk has been found to be significantly elevated within 9 months of an acute COVID-19 infection and directly related to both age and a previous history of hypertension, according to a systematic review and meta-analysis by Italian researchers.
Although COVID-19 is primarily a respiratory infection, myocardial injury is a significant pathogenic feature and associated with worse in-hospital outcomes. In fact, it has become recognised that in addition to acute COVID-19-related cardiac complications such as myocarditis or pericarditis, follow-up studies also suggest an increased incidence of arrhythmia, acute coronary syndrome, right ventricular dysfunction, myocardial fibrosis, hypertension and diabetes mellitus. One condition which has not fully explored, although identified as a potential adverse sequelae following infection with COVID-19, is incident heart failure (HF) risk. In the present study, the Italian team undertook a systematic review and meta-analysis of all studies, either retrospective or prospective, published at any time up to September 1, 2022 and which reported on the mid/long-term risk (defined as > 4 months) of incident HF in COVID-19 recovered patients. The researchers set the pooled incidence of HF in recovered patients as the primary outcome and the secondary outcome was the risk of incident HF compared to contemporary control group patients, i.e., those without COVID-19 infection.
Heart failure risk following COVID-19 infection
The analysis identified only 5 relevant and retrospective studies. These studies involved 21,463,173 patients with mean age 54.5 years (58.7% males), of whom, 1,628,424 had confirmed COVID-19 infection while the remaining 19,834,749 represented the controls.
A random effect model revealed a pooled incidence of post COVID-19 HF in 1.1% of cases (95% CI 0.7 – 1.6). After a mean follow-up of 9.2 months, recovered COVID-19 patients had a significantly elevated incident heart failure risk (Hazard ratio, HR = 1.90, 95% CI 1.54 –3.24, p < 0.0001) in comparison to non-infected controls.
In addition, a meta-regression analysis showed a significant and direct relationship for the risk of incident HF using age (p = 0.001) and a previous history of hypertension (p = 0.02) as moderators. Interestingly, there was an indirect association observed when the follow-up length was adopted as moderating variable (p = 0.01), suggesting that this risk was higher in the early post-acute phase of the infection.
The authors concluded that COVID-19 survivors had an additional 90% risk of developing HF following infection, especially in the early post-acute phase of the infection.
Citation
Zuin M et al. Risk of incident heart failure after COVID-19 recovery: a systematic review and meta-analysis. Heart Fail Rev 2022
17th January 2023
Low procalcitonin levels in patients with a non-pneumonia lower respiratory tract infection, fails to identify those who might benefit from azithromycin therapy according to the findings of a randomised trial by US researchers.
Antibiotics are commonly prescribed for acute respiratory infections, although most of these infections are viral in nature and for which antibiotics are ineffective. It is therefore necessary to implement strategies that are able to identify those patients unlikely to benefit from antibiotics, thus mitigating the development and spread of resistant pathogens. Procalcitonin is a peptide for which serum levels are believed to increase during bacterial, but not during viral, infections. In fact, procalcitonin levels have been shown to improve the accuracy of currently recommended approaches for the diagnosis of community-acquired pneumonia, thereby complementing clinical signs and symptoms. Normal human procalcitonin serum levels are less than 0.1 ng/ml, whereas if levels increase above 0.25 ng/ml, this may indicate the presence of a bacterial infection.
In the present study, US researchers hypothesised that in patients with a procalcitonin concentration of 0·25 ng/mL or less, a placebo would be just as good, i.e., non-inferior (in terms of clinical efficacy) to antibiotics such as azithromycin, in adults with suspected lower respiratory tract infection. The team recruited adults aged 18 years or older, with clinically suspected non-pneumonia lower respiratory tract infection and a low procalcitonin level (i.e., 0·25 ng/mL or less). These individuals were randomised 1:1 to either oral azithromycin 250 mg or matching placebo (two capsules on day 1 followed by one capsule daily for 4 days). The primary outcome was the efficacy of azithromycin versus placebo in terms of clinical improvement at day 5 (assessed with several different measures) and the non-inferiority margin (to placebo) was set as a lower confidence interval of -12·5%.
Low procalcitonin and azithromycin outcomes
A total of 499 participants with a mean age of 52.3 years (35% female), all of whom had procalcitonin levels below 250 ng/ml, were included and randomised to azithromycin (249) or placebo.
A clinical improvement at day 5 was observed in 63% in the placebo group and 69%, in the azithromycin group (between-group difference -6%, 95% CI -15 to 2). As the lower confidence interval for this difference was numerically greater than –12·5%, it was not possible to conclude that there was non-inferiority for the placebo compared with azithromycin. This was despite there being no significant difference in the rates of any of the individual parameters comprising the primary outcome for clinical improvement. However, at day 11, clinical improvement was observed in 76% of the placebo group and 81% in the azithromycin group (between-group difference –4%, 95% CI –12 to 3). This time, since the lower confidence interval value was less than -12.5, non-inferiority for the placebo and azithromycin was demonstrated.
The authors concluded that it was not possible to confirm non-inferiority for a placebo and azithromycin in terms of clinical improvement at day 5 in adults with a lower respiratory tract infection and a low procalcitonin concentration. Consequently, it remained unclear whether antibiotics would be of benefit to such patients.
Citation
Tsalik EL et al. Efficacy and safety of azithromycin versus placebo to treat lower respiratory tract infections associated with low procalcitonin: a randomised, placebo-controlled, double-blind, non-inferiority trial. Lancet Infect Dis 2022
16th January 2023
A diagnostic aid based on polymerase chain reactions (PCR) that uses a 52-pathogen custom array card, has been found to provide both rapid (compared to blood culture) and reliable information on respiratory infections in critically ill, mechanically ventilated children, according to a study by UK researchers.
Respiratory tract infections are responsible for a large number of admissions to paediatric intensive care units. Moreover, an intensive care unit is unique environment and for which clinicians often make decisions to use antibiotics with some degree of diagnostic uncertainty.
This was clearly illustrated in one study of paediatric intensive care unit children, where despite most critically children receiving antimicrobial therapy, infection was often not microbiologically confirmed.
While in many cases respiratory infections are viral in nature, it is necessary to utilise methods such as quantitative PCR, as a diagnostic aid to identify the presenting pathogens.
In fact, a recent study in adults found that multiplex bacterial PCR examination of bronchoalveolar lavage, reduced the duration of inappropriate antibiotic therapy of patients admitted to hospital with pneumonia and who were at risk of Gram-negative infection.
In the current study, researchers made use of the TaqMan Array Card (TAC) as a diagnostic aid, which is a microfluidic quantitative PCR system comprising of 384 wells containing pre-aliquoted customised primer and probe combinations.
The aid has been previously shown to be of value in supporting ventilator-associated pneumonia (VAP) diagnosis in adults. Nevertheless, it has not been examined in critically ill children and therefore, the aim of the present study was to assess the utility of TAC to identify bacterial and fungal respiratory pathogens in critically ill children with suspected community acquired pneumonia or VAP.
The study recruited children ≤ 18 years of age who were mechanically ventilated and had commenced or were commencing antimicrobial therapy for a lower respiratory tract infection.
The researchers determined the sensitivity and specificity of TAC to detect bacterial and fungal pathogens causing lower respiratory tract infections and the time to a result provided by TAC compared to standard microbiology cultures.
Secondary objectives included a description of the micro-organisms detected by TAC but not by microbiology culture as well as the impact of TAC on antimicrobial decision-making.
A total of 100 children with a median age of 1.2 years (58% male) were included in the study, of whom 80 had suspected community acquired pneumonia and the remainder had hospital acquired pneumonia.
Bacteria were detected more frequently on TAC compared to microbiology cultures (57% vs 18%, p < 0.001)) and In addition, TAC also identified more fungi (17% vs 2%, p < 0.001).
For the detection of bacterial and fungal species, TAC had a sensitivity of 89.5% (95% CI 66.9 – 98.7) and a specificity of 97.9% (95% CI 97.2 – 98.5).
The median time to obtain a result for the diagnostic aid was 25.8 hours compared to 110.4 hours for microbiological cultures and overall, TAC was significantly quicker for both positive and negative results (p < 0.001).
Finally, consultants reported a change of prescription in 47% of cases based upon TAC results. Antimicrobial therapy duration was reduced or stopped in 26% of children, extended in 16% and the spectrum of treatment was broadened in 17% of cases and reduced in 17%.
The authors concluded that as a diagnostic aid, TAC can be used to reliably detect pathogens quicker than routine culture in critically ill children with suspected lower respiratory tract infections. They also called for future studies to incorporate antimicrobial decision support and economic analysis.
Citation
Clark JA et al. The rapid detection of respiratory pathogens in critically ill children. Crit Care, 2023.
Data presented by US researchers at the American Society of Haematology (ASH) conference in New Orleans, showed that talquetamab demonstrated robust efficacy and manageable safety in patients wit heavily pre-treated relapsed/refractory multiple myeloma.
Multiple myeloma is a malignancy of terminally differentiated plasma cells that typically presents with bone marrow infiltration of clonal plasma cells and monoclonal protein in the serum and/or urine. Multiple myeloma accounts for 10% of all haematological malignancies and the global incidence was found to be 160,000 in 2020 and with a mortality of 106,000. Although treatments have improved in recent years, a proportion of patients experience relapse as shown in a 2016 study of 511 patients, which found that 16.0% experienced early relapse, with median time to relapse of 8.0 months.
Talquetamab is a bispecific IgG4 antibody which binds to both the the G protein–coupled receptor, family C, group 5, member D (which is highly expressed on multiple myeloma (MM) cells plasma cells) as well as to CD38 receptors that are also highly and uniformly expressed on MM cells. In preclinical studies, talquetamab was found to be a promising novel anti-myeloma agent in relapsed/refractory MM. In MonumenTAL-1, a phase 1/2 trial, researchers collected safety, efficacy, pharmacokinetic and pharmacodynamic data and which was used to select two appropriate doses of talquetamab: 0.405 mg/kg subcutaneous (SC) weekly and 0.8 mg/kg SC every other week. In the data presented at ASH, researchers used both doses and recruited patients with relapsed/refractory disease with ≥3 prior lines of therapy. A step-up dosing schedule was used to mitigate the risk of severe cytokine release syndrome (CRS) and the primary endpoint was the overall response rate (ORR) based on independent committee review. Several secondary endpoints were used including the duration of response (DOR), the rate of complete response or better (≥CR) and progression-free survival (PFS) as well as the incidence of adverse events.
Talquetamab outcomes in relapsed/remitted disease
A total of 288 with median age was 67 years were included and of whom, 143, received the 0.405 mg/kg dose. Overall, patients had received a median of 5 prior therapies.
Among those receiving the 0.405 mg dose, the ORR was 73% and the median time to response was 1.2 months, the median time to complete response (CR) was 2.1 months and the median DOR was 9.3 months, with a median PFS of 7.5 months. The most common adverse events (AEs) were CRS (79%), dysgeusia (48%), anaemia (45%) and skin-related AEs (56%). Data for the 0.8 mg/kg patients was not given in the abstract.
The authors concluded that talquetamab demonstrated robust efficacy, adding that further phase 1 studies were in place to evaluate the drug in combination with other agents in patients with relapsed/refractory MM.
Citation
Chari A et al. Talquetamab, a G Protein-Coupled Receptor Family C Group 5 Member D x CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Phase 1/2 Results from MonumenTAL-1. Abstract 157, ASH, 2022
Skeletal muscle loss among critical care patients during the first week of admission to an intensive care unit (ICU) approaches 2 per cent according to the findings of a systematic review and meta-analysis by UK and German researchers.
Critical illness is defined as a state of ill health with vital organ dysfunction and a high risk of imminent death if care is not provided and the potential for reversibility. Moreover, among critically ill patients with sepsis, a considerable number will show signs of severe skeletal muscle wasting and/or ICU-acquired weakness (ICUAW). While the pathophysiology of ICU-AW is incompletely understood, the condition appears to be triggered by critical illness and there is some evidence that skeletal muscle loss is associated with an increased mortality risk. Despite the recognition that skeletal muscle losses occur among critically ill patients, there have been no attempts to summarised the published data on the daily amount of muscle that is lost in ICU patients, which methods are used to monitor muscle size in such patients and on the prevalence of ICU-AW in critically ill patients.
The researchers therefore undertook a systematic review of the topic and searched for studies in which there were at least 20 adult critically ill patients and where the investigators had measured a muscle mass-related variable at two time points during the ICU stay.
Skeletal muscle loss among ICU patients
The literature search identified 52 relevant studies that included 3251 patients in which 1773 patients had data on on muscle wasting and 1478 on ICU-acquired weakness. Muscle mass was assessed by ultrasound in 85% of studies and the remainder by computed tomography.
During the first week of critical illness, patients were found to have lost an average of -1.75% (95% CI −2.05 −1.45) of their rectus femoris thickness and −2.10% (95% CI −3.17 −1.02) of their rectus femoris cross-sectional area, respectively, every day. In addition, quadriceps muscle thickness decreased by −1.82% (95% CI −2.97 − 0.66) each day and the daily loss in biceps brachii muscle cross-sectional area was −2.23% (95% CI −2.60 − 1.80) and −1.64% (95% CI −3.09, 0.19) for biceps brachii thickness.
Furthermore, the overall prevalence of ICU-acquired weakness was 48% (95% CI 39% – 56%).
The authors concluded that critically ill patients suffer from early and marked muscle wasting, which is about 2% per day but does vary between muscles and depends upon the measurement taken.
Citation
Fazzini B et al. The rate and assessment of muscle wasting during critical illness: a systematic review and meta-analysis. Crit Care 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
Anti-CD20 therapy use in patients with haematological cancers, despite triple vaccination, still poses an increased risk for adverse outcomes following a breakthrough COVID-19 infection, according to the findings of a retrospective population-based cohort study by Canadian researchers.
Although patients with cancer were excluded from the initial clinical trials of COVID-19 vaccines, emerging evidence suggested that adult patients with haematological malignancies, infected with the virus, especially those who were hospitalised and over 60 years of age, were at an increased risk of death. Moreover, once vaccinated, it became clear that patients with haematological cancers displayed an impaired humoral response and the recognition that breakthrough infections were possible and that these infections were correlated with the level of neutralising antibody titers during the peri-infection period, researchers hypothesised that haematological malignancy patients and even those with other types of cancer, might experience a more severe outcomes if infected with COVID-19.
In the present study, the Canadian team set out to examine the relative risk of COVID-19 breakthrough infections and COVID-19-related outcomes in vaccinated patients with cancer (including haematological and solid tumours) compared to matched non-cancer controls. In addition, they considered whether current treatment of cancer, with for example, anti-CD20 therapy, impacted on the risk of COVID-related outcomes. Using a retrospective design, researchers matched patients with haematologic cancer to non-cancer controls (1:4), based on age, sex, type of vaccine, date of vaccine. The primary outcome was COVID-19 breakthrough infection, whereas secondary outcomes were emergency department visits, hospitalisation and death within 4 weeks of infection and the outcomes adjusted for gender, age socioeconomic status and vital status.
Anti-CD20 therapy and COVID-19 outcomes
A total of 289,400 vaccinated cancer patients with a mean age of 66.05 years (65.4% female) were matched with 1,157,600 non-cancer controls. During the period of the study, there were 3118 and 12 150 breakthrough infections in the cancer and non-cancer groups, respectively.
Overall, the risk of a COVID-19 breakthrough infection was significantly higher among cancer patients compared to non-cancer controls (adjusted Hazard ratio, aHR = 1.05, 95% CI, 1.01 – 1.09, p = 0.02). However, the risk was significantly greater among patients with haematologic cancers (aHR = 1.33, 95% CI 1.20 – 1.46, p < 0.01) compared to controls. There were also significantly elevated risks for haematological cancer patients (compared to controls) for emergency department visits, hospitalisation and death. However, when researchers looked at patients who had received a third COVID-19 vaccine dose, this was associated with lower risk of breakthrough infection for blood cancer patients (aHR = 0.61, 95% CI 0.54. – 0.69, p < 0.01).
Among haematological cancer patients in receipt of anti-CD20 therapy, there remained an elevated risk of breakthrough infection (aHR = 1.88, 95% CI 1.27 – 2.78, p =0.02) as well as for emergency department visits, hospitalisation and death. Although a third vaccine dose was associated with a lower risk of infection and COVID-19 complications for all cancer patients, this did not significantly reduce the risk among haematological cancer patients receiving anti-CD20 therapy. For example, the adjusted hazard ratio for death was 0.49 (p = 0.24) and 1.19 (p = 0.46) for severe outcomes.
The authors concluded that patients with haematological cancer had the highest risk for breakthrough infections and adverse COVID-19 outcomes, particularly for those who received anti-CD20 therapy.
Citation
Gong IY et al. Association of COVID-19 Vaccination With Breakthrough Infections and Complications in Patients With Cancer. JAMA Oncol 2022.
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