Improved clinical outcomes for haematological malignancy COVID-19 patients after convalescent plasma therapy

13th April 2022

Haematological malignancy patients infected with COVID-19 appear to achieve improved clinical outcomes after receiving convalescent plasma therapy

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

Convalescent plasma use reduces hospitalisation in unvaccinated COVID-19 patients

12th April 2022

Convalescent plasma use in people unvaccinated against COVID-19 significantly reduced the need for hospitalisation due to disease progression, according to a US study

Convalescent plasma (CP) use in people unvaccinated against COVID-19 within 9 days of symptom onset, led to a significant reduction in the proportion of individuals requiring hospital admission due to disease progression. This was the conclusion of a randomised, double-blind, controlled trial by a multidisciplinary group of researchers from New York, US.

CP use represents a form of passive antibody therapy that relies on the transfer of pathogen-specific antibodies from a recovered patient for the purpose of preventing or treating disease. It has been successfully used in the past for the management of patients with severe acute respiratory syndrome and early indicators suggested that transfusion of convalescent plasma was safe in hospitalised patients with COVID-19.

Furthermore, preliminary results among patients hospitalised with severe COVID-19 were encouraging, with the authors of one study concluding that convalescent plasma is potentially effective against COVID-19.

Nevertheless, in a Cochrane database living systematic review in May 2021, the authors commented on how they had high certainty in the evidence that convalescent plasma for the treatment of individuals with moderate to severe disease does not reduce mortality and has little to no impact on measures of clinical improvement.

Whether CP might help prevent disease worsening in those with less severe disease is uncertain and the available evidence is mixed. For example, one study found that early administration of high-titer convalescent plasma against COVID-19 to mildly ill older adults, reduced the progression of the illness.

By contrast, in a study where the authors set the primary outcome as disease progression within 15 days after randomisation, it was concluded that administration of convalescent plasma to high-risk outpatients within 1 week after the onset of symptoms of COVID-19 did not prevent disease progression.

With some uncertainty over the role of CP in less severe disease, for the present study, the US team examined the value of administering CP within 9 days of COVID-19 symptom onset to determine if the treatment prevented disease progression leading to hospitalisation.

They recruited adults testing positive for the virus and randomised them 1:1 to either CP or control plasma, with both transfused over 1 hour period within 24 hours of enrolment. The primary outcome was COVID-19-related hospitalisation within 28 days after the transfusion.

Convalescent plasma use and disease progression

A total of 1181 individuals with a median age of 43 years (57.2% female) were included with 592 given CP and median time from symptom onset to transfusion was 6 days. Co-morbidities were well matched and among those receiving CP included hypertension (23%) and those with a BMI > 35 (16.4%) with 83.3% of those given CP (and a similar proportion in the control group) unvaccinated against COVID-19.

The primary outcome occurred in 2.9% of those receiving CP and 6.3% of those given control plasma (absolute risk reduction = 3.4% (95% CI 1.0 – 5.8%, p = 0.005). Among those who were hospitalised, virtually all (53 of 54) were unvaccinated against COVID-19.

The authors concluded that giving convalescent plasma within 9 days of COVID-19 symptom onset reduced disease progression leading to hospitalisation.

Citation
Sullivan DJ et al. Early Outpatient Treatment for Covid-19 with Convalescent Plasma N Engl J Med 2022

No benefit from early convalescent plasma in high-risk COVID-19 patients

23rd August 2021

Convalescent plasma has no effect on COVID-19 disease progression when given later in the course of illness but could help if given earlier.

The use of convalescent plasma (CP) in patients with COVID-19 is based on the notion that the administered plasma, by containing therapeutic antibodies to the virus, enables recovery. However, to date, results with this therapy have been disappointing, prompting the RECOVERY trial in the UK to halt recruitment to the CP arm in January 2021. In fact, studies have shown how the use of CP in those with severe COVID-19 infection, did not result in any improvements compared to standard care. Nevertheless, in these studies, CP was administered to patients late in their disease. Furthermore, and there is some evidence from a small study in 80 older patients that when CP was given within 72 hours of the onset of mild COVID-19, it did result in reduced illness progression.

In an attempt to provide more robust evidence for the benefit of early use of CP in those with COVID-19, a team from Michigan State University, US, decided to undertake a randomised, multi-centre, single-blind trial in patients who presented at an emergency department within seven days of developing COVID-19 symptoms. The researchers wanted to examine if the early administration of CP was able to halt disease progression. All participants had PCR confirmed COVID-19 infection and were aged 50 years or older and with one or more known risk factors for disease progression. Individuals were randomised in a 1:1 fashion to either one unit of convalescent plasma or saline (placebo) which was coloured to resemble the plasma. The primary outcome of the study was disease progression within 15 days of randomisation and which was defined by a composite of hospital admission, seeking emergency/urgent care or death without hospitalisation.

Findings
A total of 511 patients underwent randomisation, 257 to plasma with a mean age of 54 years (52.5% female). Risk factors included a body mass index greater than 30 (59.1%), hypertension (40.9%) and diabetes (29.6%). In fact, overall, 54.9% of those assigned to convalescent plasma had three or more COVID-19 risk factors. The primary outcome occurred in 30% of those given CP and 31.9% of those given saline. Furthermore, subgroup analysis, i.e., by body mass index, age, ethnicity etc, also showed no important differences. Within 30 days of administration of either treatment, death occurred in 1.9% of those given plasma and 0.4% given saline.
In their discussion, the authors noted that there was a potentially sound rational for giving early convalescent plasma, i.e., that it would boost the level of neutralising antibodies before an individual could develop their own sufficient antibody response. Despite this obvious possible benefit, the authors concluded that even that even among those with a number of risk factors for COVID-19 disease progression, early use of convalescent plasma had no impact on clinical outcomes.

Citation

Korley FK et al. Early Convalescent Plasma for High-Risk Outpatients with Covid-19. New Eng J Med 2021

Higher convalescent plasma antibody titre levels associated with lower risk of death in COVID-19

18th January 2021

Passive antibody transfer (convalescent plasma therapy) has been widely used to treat COVID-19; however, little is known about the effect on mortality of different antibody titre levels.

The use of convalescent plasma (CP) to treat respiratory infections has a long history having been used for over a century. During the current pandemic, interest in this therapeutic modality has picked up although the efficacy signals from this approach are still preliminary and require further study. As a result, a team led by researchers from the Department of Anaesthesiology and Peri-operative Medicine, Rochester, Minnesota, in the US, retrospectively studied the results obtained from an expanded-access programme to CP across a range of hospitals. Eligible patients were 18 years and over, hospitalised with a laboratory confirmed positive COVID-19 test and deemed at high risk for progression to severe or life-threatening COVID-19.

Treatment consisted of CP given intravenously although the corresponding IgG COVID-19 antibody levels within these samples were unknown. The researchers therefore collected and quantitively analysed, remnant aliquots of serum retained from the donation process for IgG antibody levels. These which were divided into low (<4.62), medium (4.62 to 18.45) and high (>18.45) titre levels. The primary outcome for the study was mortality at 30 days after transfusion of CP.

Findings
The patient cohort consisted of 3082 individuals of whom, 61% were male and 69% were younger than 70 years of age. In total, two-thirds received CP prior to mechanical ventilation. Death within 30 days after CP occurred in a 26.9% of all patients. Furthermore, the outcome occurred in 29.6%, 27.4% and 22.3% of those in the low, medium and high, IgG titre ranges respectively. The risk of death among those with higher antibody titre levels was reduced by 46% compared to the lowest antibody titre (relative risk, RR = 0.66, 95% CI 0.48-0.91) in patients who were not mechanically ventilated. However, there was no effect of antibody titre levels on death rates among patients who required mechanical ventilation.

The authors concluded that their data support the notion that the benefits of CP are largely dependent on the levels of antibody present within samples.

Citation
Joyner MJ et al. Convalescent plasma antibody levels and the risk of death from COVID-19. N Engl J Med 2021

Plasma therapy ineffective for COVID-19

23rd October 2020

Given the current limited treatments available for COVID-19, one area of interest has been convalescent or plasma therapy, which represents a form of passive immunity and has been successfully used to treat other viral infections.

To date only two clinical trials have examined the value of convalescent plasma therapy (CP) in patients with COVID-19 though both were stopped early and did not appear to show any significant benefit. For this new study, researchers from the Indian Council of Medical Research have undertaken a randomised trial in over 400 patients but the results also suggest that CP is of limited value. The study recruited 464 adult patients (aged 18 and over) with a median age of 52 years (75% male) from 39 public and private hospitals across India who were admitted to hospital with confirmed moderate COVID-19, based on a positive PCR test. Included patients had a partial pressure of oxygen in arterial blood/fraction of inspired oxygen (Pa02/FiO2) ratio between 200mmHg and 300mmHg, or a respiratory rate of more than 24/minute and an oxygen saturation < 93%. Eligible CP donors were required to have had a PCT positive test for COVID-19 and symptom resolution for 28 consecutive days before donation or a 14-day period which included two negative PCR tests collected 24 hours apart.

Patients were randomised to either CP and best standard of care (intervention group) or care lone (the control group) and intervention patients received two doses of 200ml CP transfused 24 hours apart. The primary outcome as a composite of progression to severe disease Pa02/FiO2 ratio < 100mmHg, anytime within 28 days of enrolment or mortality at 28 days.

Findings
Progression to severe disease occurred in 19% vs 18% (intervention vs control) and 28 day mortality occurred in 15% vs 14% (intervention vs control) of patients. There was a statistically significant higher proportion of patients receiving CP with a resolution of shortness of breath after 7 days (76% vs 66%) and fatigue (73% vs 60%), there was no difference for fever or cough. In addition, significantly more patients (68% vs 55%) had a negative PCR test at day 7. The authors concluded that as a treatment for COVID-19, CP appeared to be of limited value.

Reference
Agarwal A et al. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ 2020;371:m3939.