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7th February 2022
In a human challenge study, which is available as a pre-print, researchers from Imperial College, London, have learnt much about the progression of COVID-19 infection. Human challenge studies involve deliberately infecting individuals with an agent known to cause infection. Such studies would not usually be undertaken during a pandemic but emerging evidence suggests that infection with COVID-19 is generally mild in healthy, young, non-smoking adults aged 18–29 years. Individuals meeting these criteria would therefore serve as low-risk participants for any type of human challenge study.
Human challenge study
With young adults without co-morbidities representing an ideal group for an infection challenge, in the present study, the UK researchers recruited 36 healthy volunteers with a mean age of 21.8 years (72% male) and no specific risk factors for severe COVID-19 infection. As this study was undertaking during the pandemic, participants were admitted to individual negative pressure rooms in an in-patient quarantine unit with 24 hour medical monitoring and access to clinical support if required. Each were given a dose of the wild-type COVID-19 which was administered via nasal drops. The first 10 volunteers were given pre-emptive remdesivir once two consecutive nose and throat swabs showed quantifiable COVID-19 virus after PCR testing. The rational for using the drug was to mitigate any unexpected progression of the infection to more severe disease.
Only 18 (53%) of participants developed a PCR confirmed COVID-19 infection and viral shedding from throat swabs was detectable 40 hours (roughly 1.67 days) post-inoculation and this was significantly earlier (p = 0.022) than from the nose, which was only detectable at 58 hours. Viral particles from the throat peaked 112 hours post-inoculation (roughly 4.7 days) and after 148 hours from the nose. In all of those who became infected, the virus could be detected at high levels for several days and remained present 14 days after inoculation. Following inoculation, self-reported symptoms became apparent 2 – 4 days later and were generally mild-to-moderate in severity, peaking 112 hours after inoculation, which aligned with peak viral load levels. Although anosmia developed in 9 of the infected participants, it persisted for at least 180 days in 5 of them. One of the interesting observations from this human challenge was how after 28 days, 33% of nose and 11% of throat samples remained positive for COVID-19. Serum antibodies were detected among infected participants after 14 days with levels roughly doubling at day 28.
Among the 10 who were given remdesivir, 6 still became infected though there were no apparent differences in viral load between treated and untreated individuals.
With lateral flow antigen testing becoming a recognised strategy for home use, the researchers observed that none of the uninfected individuals tested positive, but that the median time for a positive result was 4 days post-inoculation for those who became infected and viral load was identified as a significant predictor for a positive lateral flow test result.
Summarising the findings of this human challenge study, the authors noted how only just over half of those inoculated became infected, which was something they were unable to explain, and that viral loads increased rapidly within 2 days of inoculation. In addition, while symptoms were present in 89% of infected individuals, despite high viral loads, these symptoms were generally mild-to-moderate in severity. Although symptoms were present after 2 days these peaked between days 4 and 5. They added that high viral shedding occurred irrespective of symptom severity which suggested that the virus was highly transmissible. Finally, given that viable viral was detectable 10 days after inoculation, the authors suggested that these data supported the isolation period of 10 days after symptom onset.
Chiu C et al. Safety, tolerability and viral kinetics during SARS- CoV-2 human challenge Nature portfolio 2022
9th December 2021
Patients with moderate-to-severe atopic eczema prescribed the monoclonal antibody dupilumab experienced less severe COVID-19 symptoms according to the results of a prospective study by researchers from the Department of Dermatology, and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, US.
Atopic eczema is a chronic skin disease and is characterised by T helper 2 (Th2)-driven inflammation due to a Th1/Th2 imbalance. Moreover, cytokines released by Th2 cells including IL-4, IL-5 and IL-13 elevate production of IgE and increased inflammation in the skin and aggravate the skin barrier defect seen in atopic eczema. Interestingly, research suggests that infection with COVID-19 leads to an increased level of various interleukins, including IL-13. Since the mode of action for dupilumab involves blockage of the two interleukins, IL-4 and IL-13, it might be possible that the drug impacts on the severity of symptoms in those with COVID-19.
For the present study, the US researchers examined a disease registry within the department of dermatology at their hospital which included medication prescribed for patients with moderate-to-severe atopic eczema. They enrolled patients 9 years of age and older either at the time of a clinic visit or invited them to participate over the telephone. They included patients prescribed dupilumab, other systemic agents and either limited or no current treatment. Individuals were asked about the presence and duration of COVID-19 symptoms and based on their responses, categorised on a 1 – 5 scale ranging from mild disease (1), severe (3) through to 5 (fatal). The primary outcome was the presence of moderate-to-severe COVID-19 symptoms.
A total of 1237 patients were included, of which 632 with a mean age of 41.2 years (47% male), were prescribed dupilumab, 107 other systemic agents including oral JAK inhibitors, prednisolone, methotrexate and mycophenolate. The remaining 498 patients were on limited treatment or no treatment, with the majority (71%) prescribed only topical agents. In terms of COVID-19 severity, the majority (77%) of all individuals scored 0 on the 1 – 5 scale.
Among non-dupilumab treated patients, there was a nearly four-fold increased risk of experiencing moderate-to-severe COVID-19 symptoms (odds ratio, OR = 3.89, p = 0.01) compared to those prescribed dupilumab. Similarly, this risk was elevated for those with either limited or no treatment (OR = 1.95, p = 0.04).
In addition, when examining the relationship among those with a PCR confirmed COVID-19 diagnosis, non-dupilumab treated patients again had a significantly increased risk of moderate-to-severe COVID-19 symptoms compared to those prescribed dupilumab (OR = 13.79, p = 0.002), as did those with limited or no treatment (OR = 2.44, p = 0.05).
Commenting on their findings, the authors speculated that given the over-expression of Th2 cells in atopic eczema, patients were unable to mount a sufficient Th1 response to viral infections. With the use of dupilumab, which attenuated the Th2 response, the Th1/Th2 imbalance could be redressed allowing individuals to mount a greater Th1 response against the virus.
They concluded by suggesting that future studies should seek to understand the implications of their findings for other specific viral infections.
Ungar B et al. COVID-19 Symptoms Are Attenuated in Moderate-to-Severe Atopic Dermatitis Patients Treated with Dupilumab. J Allergy Clin Immunol Pract 2021
25th November 2021
Using both inhaled and intranasal ciclesonide for symptom resolution appears to be no better than placebo for patients with COVID-19. This was the conclusion of a randomised, placebo-controlled trial by a team from the Centre for Outcomes Research and Evaluation, Montreal, Canada.
With much attention currently, focused on the use of vaccines directed at COVID-19, other work has looked at re-purposing existing treatments against the virus. One potential candidate is the corticosteroid, ciclesonide, used as a preventative therapy, due to its anti-inflammatory action, in patients with asthma. In addition, in vitro work has shown that the drug is able to suppress replication of both MERS and COVID-19 therefore suggesting that they drug might be of value in those with COVID-19 respiratory symptoms although to date, no studies have explored its role as a treatment for the virus.
Based on these findings, the Canadian team hypothesised that ciclesonide could, if administered early in the course of a COVID-19 infection, reduce the respiratory symptom burden. The team recruited patients 18 years and older with a PCR confirmed COVID-19 infection, with at least one of the following symptoms: fever, cough (wet or dry) and chest symptoms including shortness of breath and chest tightness or congestion. They excluded those hospitalised because of COVID-19 and patients with non-respiratory symptoms, or if they had already been prescribed an inhaled corticosteroid. Enrolled patients were randomised, 1:1 to either inhaled ciclesonide, at a dose of 1200 micrograms twice daily combined with an intranasal dose of 200 micrograms daily or matching placebos, for 14 days. The primary outcome was self-reported symptom resolution at day 7 with secondary outcomes including hospital admission or death due to COVID-19.
A total of 203 individuals with a median age of 35 years (54% women) were randomised to either ciclesonide or placebo. The majority (86%) had cough, dyspnoea, shortness of breath, chest tightness or congestion (50%) and less than half (46%) fever. Overall, fever and respiratory symptoms had resolved in 37% of participants by day 7. The proportion of patients who had symptom resolution by day 7 was 40% (ciclesonide) and 35% (placebo) and this difference was not significant. Similarly, by day 14, the proportion of individuals with symptom resolution was not significantly different (66% vs 58%). In addition, 6 and 3 patients using ciclesonide and placebo were admitted to hospital although no deaths occurred.
Commenting on their findings, the authors discussed how the study participants were generally in good health but with a high COVID-19 symptom burden and that treatment was initiated early in the course of the infection (median time of three days). Despite the high dose of ciclesonide, it proved to be no better than placebo which was in contrast to data using budesonide, which has shown a benefit in terms of a shorter duration to symptom recovery.
They concluded that further research is required to demonstrate the value of intranasal corticosteroids in the treatment of COVID-19.
7th October 2021
In systemic inflammatory conditions such as sepsis, low serum albumin levels are associated with an increased risk of death in patients with severe disease. However, whether serum albumin (SA) levels can used predictively to identify those at risk of both severe disease and mortality in COVID-19 remains unclear. This was the question addressed in a retrospective study by a team from the Emergency Department, Alto Adige, Italy. The team considered consecutive patients with COVID-19 seen at the emergency department (ED) of three hospitals during March to April 2020. Serum albumin levels were added to the panel of blood samples routinely performed on those with suspected COVID-19 upon arrival at the ED. The primary outcome of the study was the presence of severe COVID-19 infection. In addition, the team explored 30-day mortality after the initial ED assessment as a secondary outcome. The researchers categorised SA levels upon ED admission as < 3 g/dL, 3 – 3.49 g/dL and greater than 3.5 g/dL.
There were 296 patients with COVID-19 for whom the overall mean SA value was 3.7 g/dL. Serum albumin levels were higher for patients aged under 75 years of age (3.9 vs 3.4, under 75 years vs over 75 years, p < 0.001) although there were no gender differences. Most patients (59.8%) had SA levels above 3.5 g/dL with only 10.1% having levels below 3 g/dL. Nearly two thirds (63.2%) of patients had severe COVID-19 infection and 18.2% of all patients died within 30 days of their arrival at the ED.
In their analysis, the authors calculated that SA levels < 3.5 g/dL was an independent risk factor for both severe infection (adjusted odds ratio, aOR = 2.92, 95% CI 1.51 – 5.66) and 30-day mortality (aOR – 2.62, 95% CI 1.13 – 6.1).
In their conclusion, the authors stated that their preliminary data suggested that “serum albumin level in the ED may play a role in the assessment of the severity of SARS-CoV-2 infection and the risk of death at 30 days.” They also called for more prospective evaluations to confirm whether albumin levels was an important prognostic factor in patients with COVID-19.
16th August 2021
Pregnant women have been deemed to be at a higher risk of severe illness from COVID-19. Moreover, in a systematic review in May 2020, it was concluded that mothers infected with COVID-19 were at an increased risk of pre-term birth although the authors urged caution, as their data were derived from a small number of cases and also included the SARS and MERS viruses. In order to provide as much information as possible on the pregnancy outcomes associated with COVID-19 infection, a team from the Department of Obstetrics and Gynaecology, St George’s University Hospitals NHS Foundation Trust, London, UK, undertook a systematic review of all available literature on COVID-19 and pregnancy in order to provide comprehensive data and to direct the course of ongoing research and studies. They searched all major databases and included a wide range of studies e.g., case reports, case series, and randomised trials, provided that studies reported on women with a PCR-confirmed diagnosis of COVID-19. Extracted information on maternal outcomes including clinical symptoms, laboratory findings, any obstetric complications and perinatal outcomes including death and vertical transmission were also collected.
A total of 86 studies were identified which included 2567 pregnancies. Nearly a third of mothers (30.6%) were older than 35 years and half of the cohort (50.8%) were of Black, Asian or other ethnic minority groups. Overall, antiviral therapy was given to a fifth (21.1%) of women though a much higher proportion (51.15%) received anticoagulation and 18.2% required nasal or non-invasive oxygen support.
COVID-19 symptoms were predominately cough (71.4%), fever (63.3%), dyspnoea (34.4%) and loss of taste or smell (22.9%). The most common laboratory abnormality was a raised D-dimer (84.6%), followed by a raised C-reactive protein or procalcitonin (54%). Fortunately, only 7% of women needed admission to an intensive care unit. Pre-term birth which was primarily iatrogenic was found to be common (21.8%) though this was medically indicated in 18.4% of all cases. The incidence of neonatal COVID-19 infection was low at 1.2%.
Commenting on their findings, the authors noted that generally, pregnancy outcomes were good. The incidence of admission to maternal intensive care was low and likely to be similar to the rates for other non-infected women. Furthermore, there was a very low incidence of maternal mortality. The authors did note how their analysis had several limitations including the retrospective nature of most studies and a lack of standardisation of care, given that studies came from several different countries. While the incidence of vertical transmission appeared to be low, the authors felt that more evidence was needed to confirm whether this represents a significant problem. However, there was a higher-than-average increase in pre-term births which was consistent with findings from other studies.
Khalil A et al. SARS-CoV-2 infection in pregnancy: A systematic review and meta- analysis of clinical features and pregnancy outcomes. EClinicalMedicine 2021
12th August 2021
The presence of gastrointestinal (GI) symptoms among those infected with COVID-19, occurs in around 17.6% of patients. Whether or not the presence of GI symptoms is prognostic for more severe disease, however, remains unclear except perhaps for abdominal pain. In contrast, other studies have indicated that the development of GI symptoms could even attenuate any COVID-19 associated inflammation. The term inflammatory bowel disease (IBD) is essential an umbrella term which covers both Crohn’s disease and ulcerative colitis although typically, both groups of patients will experience symptoms of diarrhoea, abdominal pain, fatigue, rectal bleeding and weight loss. Some evidence indicates that among those with IBD infected with COVID-19, there is a higher incidence of both diarrhoea and abdominal pain, compared to non-IBD patients. In fact, in a review of 1028 patients with IBD infected with COVID-19, 20% experienced diarrhoea. Given that infection with COVID-19 can lead to gastrointestinal symptoms in nearly a fifth of patients without IBD, researchers from the Henry D Janowitz Division of Gastroenterology, Icahn School of Medicine, New York, US, decided to examine the extent of symptoms experienced by IBD patients using data held within a global disease registry. The Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) is an international registry, created to monitor the outcomes of COVID-19 in both adults and children with IBD. Clinicians are advised to the voluntarily report all cases of PCR-confirmed infections in all their IBD patients onto the registry to enable the capture of data related to those with IBD. Using this registry, the team sought to determine the association between any new GI symptoms with the odds of death due to COVID-19.
Data were available for 2917 IBD patients who had COVID-19, of whom, 26.4%, with a mean age of 43 years (55.5% female) developed new GI symptoms when infected with the virus. There was no significant difference in the incidence of new GI symptoms in those with Crohn’s disease or ulcerative colitis. Moreover, new gastrointestinal symptoms occurred more frequently in those with active disease compared to those in remission (29.4% vs 23.3%, p < 0.01). The pattern of symptoms however, was broadly similar apart from abdominal pain. For instance, diarrhoea occurred in 83% vs 76% (active disease vs remission) and nausea in 24% vs 25% (active disease vs remission). The greatest disparity was in abdominal pain (44% vs 26%, active disease vs remission). In addition, patients with IBD experiencing new GI symptoms were more likely to be hospitalised because of COVID-19 (31.4% vs 19.2%, p < 0.01) although the development of new symptoms was not associated with a higher risk of death.
The authors discussed how the development of new gastrointestinal symptoms were unlikely to represent a disease flare, because a large number of those in remission also experienced new symptoms after becoming infected. They concluded that the presence of new gastrointestinal symptoms in a patient with IBD should clinicians to consider infection with COVID-19 although the team also felt that further studies were needed to determine if infection could trigger an IBD flare or even alter the subsequent course of the disease.
Ungaro RC et al. New Gastrointestinal Symptoms Are Common in Inflammatory Bowel Disease Patients With COVID-19: Data from an International Registry. Inflamm Bowel Dis 2021
4th August 2021
The timely detection of COVID-19 infections through PCR testing is vital to contain the spread of the virus. However, while PCR testing has become the most widely used analytical technique to detect the virus, the result is highly dependent on the timing of sample collection, the type of specimen and the quality of the sample. An alternative means of identifying infected individuals is through a combination of symptoms and then ensuring that only those with appropriate symptoms are tested. This approach was used in an Italian study of nearly 3000 subjects and with the aid of a short diagnostic scale, was able to correctly identify the symptoms associated with infection. This same methodology is utilised in the COVID-19 Symptom Study App which is a longitudinal, self-reported study of the symptom profile of patients with COVID-19. Through the use of machine learning models, the study has been able to develop models to identify the main symptoms of infection and their correlation with outcomes. Nevertheless, current models are not conducive to the early detection of infection. This prompted the COVID-19 Symptom Study team to create a machine learning model that captured self-reported symptoms for only the first three days and used this information to predict an individual’s likelihood of being COVID-19 positive.
The team used three different machine learning models to analyse self-reported symptoms. The first model was based on the NHS algorithm which uses the presence of cough, fever or loss of smell between days 1 and 3 as potentially representative of COVID-19 infection. The second logistic regression model, is based on an algorithm which incorporates loss of smell, persistent cough, fatigue and skipped meals and which has been previously validated and found to correlate well with COVID-19 infection. For the third algorithm, the team used 18 self-reported symptoms combined with co-morbidities as well as demographic data and referred to this as a hierarchical Gaussian process model. All three models were compared in terms of sensitivities, specificities and area under the receiver operating characteristics curve (AUC) and evaluated with a training set, for patients self-reporting symptoms between April and October 2020 and a test set for self-reported symptoms between October and November 2020.
There were data from 182,991 participants in the training set and 15,049 in the test set with a similar symptom distribution. The predictive power of the three model was different. For example, the hierarchical Gaussian process model showed the highest predictive value (AUC = 0.80, 95% CI 0.80–0.81) using three days of symptoms compared to the logistic regression model (AUC = 0.74) and the NHS model (AUC = 0.67). The hierarchical Gaussian process model for prediction of COVID-19 infection had a sensitivity of 73% and a specificity 72%. This was higher than either the logistic regression model (59%, 76%, sensitivity, specificity, respectively) and the NHS model (60%, 75%, sensitivity, specificity, respectively). Interestingly, the key symptoms predictive of early COVID-19 were loss of smell, chest pain, persistent cough, abdominal pain, feet blisters, eye soreness and unusual pain.
The authors concluded that the hierarchical Gaussian process model was successfully able to predict the early signs of infection and could be used to enable referral for testing and self-isolation when these symptoms were present.
Canas LS et al. Early detection of COVID-19 in the UK using self-reported symptoms: a large-scale, prospective, epidemiological surveillance study. Lancet Digit Health 2021
19th July 2021
Olfactory dysfunction has been defined as the best predictor of infection with COVID-19. Moreover, in a study of 60 patients, 59 exhibited some dysfunction during a smell identification test. The study also revealed how only 58% of those tested had anosmia indicating in imperfect relationship between olfactory dysfunction and anosmia. It is possible therefore that the use of an inexpensive, rapid and sensitive method, based on olfactory dysfunction would be of potential value in identifying those with COVID-19. Based on this assumption, a team from the Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California, US, sought to evaluate the prognostic value of a smell test for identifying those with COVID-19. The team enrolled healthy adults (18 years and over) from a single university campus screening site. Each of the participants were tested for olfactory dysfunction using a novel scent card (SAFER Diagnostics) and immediately followed up with a PCR test for COVID-19. The card itself contained several different scents under a scratch-off and sniff label and participants had eight options: grape, floral, blueberry, banana, mint, unsure or no scent. Using a QR code, the answers were processed electronically and an incorrect choice was labelled as olfactory dysfunction. The team collected participant demographics, medical history, any COVID-19 symptoms and a subjective smell test on a binary (yes/no) and a 10-point visual analogue scale, where 0 indicated no sense of smell and 10 was a normal sense of smell. Using regression analysis, the team assessed the association between the SAFER card and PCR test results, controlling for the presence of any other COVID-19-related symptoms such as fever, fatigue and cough.
A total of 163 participants were enrolled with a mean age of 31.6 years (56.3% male) with the majority (62.5%) of white ethnicity. There were 16 participants who tested positive for COVID-19 and 7 (4.8%) who tested negative. From the 16 who were PCR positive, 12 (75%) also failed the olfactory dysfunction test. A failed scent card screen was found to be the greatest predictor for COVID-19 positivity (odds ratio, OR = 80.24, 95% CI 14.77–435.90). The authors calculated that the smell test had a sensitivity for detecting COVID-19 of 75% and a specificity of 95.2%. When adding the presence of fatigue as an associated symptom, the sensitivity of the olfactory dysfunction test increased to 93.8% and the specificity to 89.8%. However, when either fever or cough were included, there was no increase in sensitivity. Interestingly, only 6 of the 16 who tested positive for COVID-19 presented with subjective anosmia.
In a discussion of their findings, the authors noted how their rapid olfactory dysfunction test was a valuable screening tool for COVID-19. Nevertheless, they recognised that not all patients experience olfactory dysfunction but that in the presence of fatigue, the test became more sensitive. The authors concluded by calling for future studies to include a larger participant cohort to better account for other olfactory dysfunction risk factors.
Said M et al. A Rapid Olfactory Test as a Potential Screening Tool for COVID-19. JAMA Otolaryngol Head Neck Surg.
20th April 2021
The dual action chemical entity, PNB001, has shown promise as a treatment for those hospitalised with COVID-19. The drug acts as both a cholecystokinin-A (CCK-A) agonist and CCK-B antagonist. Cholecystokinin is a peptide hormone originally identified in the gastrointestinal tract where it serves to mediate pancreatic secretion and contraction of the gall bladder. However, later work has revealed how there are two different types of CCK receptors, and PNB001 has been shown to have both analgesic and anti-inflammatory actions through binding with the different receptors termed A and B. It is the anti-inflammatory effect that is thought to be of greater relevance in COVID-19 and while human safety data on the drug proved to be satisfactory, to date, no trials had been undertaken with COVID-19 patients. In the present study, a team from PNB Vesper Life Science, Kerala, India (the manufacturer of PNB001), examined the impact of their new drug on disease severity scores among those hospitalised with COVID-19. Included patients had pneumonia but not severe disease (defined by an oxygen saturation of < 94%) on room air and with at least two recognised COVID-19 symptoms (e.g., fever, cough, dyspnoea). Excluded patients included those requiring mechanical ventilation. Individuals were randomised to receive either PNB001 (100mg three times daily) along with standard care (SC) or standard care alone which was consistent with India’s current clinical management protocol. Treatment with PNB001 was continued for 14 days and the primary outcome was the change in the 8-point WHO ordinal scale score for disease severity from baseline to day 14 and mortality at day 28.
A total of 40 patients (20 per arm) were recruited into the study with a mean age (in the PBN001 group) of 52.1 years (30% female). At baseline, both groups had an equal number of patients with a WHO scale score of 4 (i.e., oxygen by mask or nasal prongs). By day 14, the PNB001 group experienced a greater mean reduction in ordinal scale values (0.22 vs 1.12, PNB001 vs SC, p = 0.042) from baseline. For instance, at day 14, 17 (94.4%) vs 12 (70.6%) patients (PNB001 vs SC), had achieved a WHO scale score of 0 (no clinical or virological evidence of infection) and 1 vs 4 patients, maintained a WHO scale score of 4. However, day 28 mortality was similar in both groups although a higher proportion of patients given PNB001 were discharged from hospital by day 14 (19 vs 15, p = 0.048).
In their conclusion, the authors noted that PNB001 was well tolerated and that it showed significant clinical improvements when added to standard care in patients with moderate COVID-19. However, they also recognised the limitations of the study, i.e., a small sample size and the fact that while randomised, it was not blinded.
Lattmann E et al. Randomised, Comparative, Clinical Trial to Evaluate Efficacy and Safety of PNB001 in Moderate COVID-19 Patients. MedRxiv 2021