A Double Blinded Randomised Controlled Trial of Vitamin a Drops to Treat Post-viral Olfactory Loss: Study Protocol for a Proof-of-concept Study for Vitamin a Nasal Drops in Post-viral Olfactory Loss (Apollo) (preprint)

Background: Loss of smell or olfactory dysfunction (OD)s a common yet under- addressed problem with an estimated 5% of the general population having no functioning sense of smell. OD secondary to viral infections (eg: Covid-19) is one of the leading causes. Isolation, depression, anxiety, risk of danger from hazards such as toxic gas and spoiled food, weight loss/ gain secondary to loss of appetite are all prevalent negative impacts associated with OD. Various treatment options have been tried to treat smell loss after viral infection. Smell training has been tried with good results in the immediate post-viral phase. Evidence behind treatment with steroids has not shown to have proven effectiveness. With this, a key problem for patients and their clinicians is the lack of proven an effective therapeutic treatment option. Based on previous studies, there is some evidence supporting the regenerative potential of retinoic acid, the metabolically active form of Vitamin A in regeneration of olfactory receptor neurons. It is based on this concept that we have chosen Vitamin A as our study comparator in this two-arm randomised trial to determine proof of conceptMethods/Design: The study will compare 10,000 IU once daily Vitamin A self-administered intranasal drops versus peanut oil drops (placebo) delivered over 12 weeks in patients with post viral olfactory loss. Eligible patients will be recruited from the Smell & Taste Clinic and randomised to receive vitamin A drops or placebo in a 2:1 ratio. They will then be invited to attend the Brain Imaging Centre at the University of East Anglia on two occasions, 3 months apart, Serial MRI scanning will enable volumetric measurement of the OB and ROS; fMRI will then be conducted using an olfactometer to deliver pulsed odours – phenethylalcohol (rose-like) and hydrogen sulphide (rotten eggs). Participants will also undergo a standard smell test at both visits as well as complete a quality-of-life questionnaire. Change in OB volume on MRI will be the primary outcome measure.Discussion: We expect the outputs of this study to enable a subsequent randomised controlled trial of Vitamin A versus placebo. With PPI input we will make the outputs publicly available using journals, conferences and social media via Fifth Sense. We have already prepared a draft RCT proposal in partnership with the Norwich Clinical Trials Unit and would plan to develop this further considering the findings.Trial registration: ISRCTN registry 39523. Date of registration in primary registry: 23rd February 2021

Organisms causing secondary pneumonias in COVID-19 patients at 5 UK ICUs as detected with the FilmArray test (preprint)

ABSTRACT Introduction. Several viral respiratory infections - notably influenza - are associated with secondary bacterial infection and additional pathology. The extent to which this applies for COVID-19 is unknown. Accordingly, we aimed to define the bacteria causing secondary pneumonias in COVID-19 ICU patients using the FilmArray Pneumonia Panel, and to determine this tests potential in COVID-19 management. Methods. COVID-19 ICU patients with clinically-suspected secondary infection at 5 UK hospitals were tested with the FilmArray at point of care. We collected patient demographic data and compared FilmArray results with routine culture. Results. We report results of 110 FilmArray tests on 94 patients (16 had 2 tests): 69 patients (73%) were male, the median age was 59 yrs; 92 were ventilated. Median hospital stay before testing was 14 days (range 1-38). Fifty-nine (54%) tests were positive, with 141 bacteria detected. Most were Enterobacterales (n=55, including Klebsiella spp. [n= 35]) or Staphylococcus aureus (n=13), as is typical of hospital and ventilator pneumonia. Community pathogens, including Haemophilus influenzae (n=8) and Streptococcus pneumoniae (n=1), were rarer. FilmArray detected one additional virus (Rhinovirus/Enterovirus) and no atypical bacteria. Fewer samples (28 % vs. 54%) were positive by routine culture, and fewer species were reported per sample; Klebsiella species remained the most prevalent pathogens. Conclusion. FilmArray had a higher diagnostic yield than culture for ICU COVID-19 patients with suspected secondary pneumonias. The bacteria found mostly were Enterobacterales, S. aureus and P. aeruginosa, as in typical HAP/VAP, but with Klebsiella spp. more prominent. We found almost no viral co-infection. Turnaround from sample to results is around 1h 15 min compared with the usual 72h for culture, giving prescribers earlier data to inform antimicrobial decisions.