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\begin{document}

\title{Management of new onset anosmia during the COVID pandemic - BRS
Consensus Guidelines}



\author[1]{Claire Hopkins}%
\author[2]{Mikkel Alanin}%
\author[3,3]{Carl Philpott}%
\author[4]{Philip Harries}%
\author[5]{Katherine Whitcroft}%
\author[6]{Ali Qureishi}%
\author[7]{Shahram Anari}%
\author[8]{Yujay Ramakrishnan}%
\author[8]{Anshul Sama}%
\author[9]{Elgan Davies}%
\author[10]{Benjamin Stew}%
\author[11]{Simon Gane}%
\author[12]{Sean Carrie}%
\author[13]{Iain Hathorn}%
\author[14]{Raj Bhalla}%
\author[15]{Christine Kelly}%
\author[16]{Nina  Hill}%
\author[16]{Duncan Boak}%
\author[17]{B. Nirmal Kumar}%
\affil[1]{Guy's Hospital}%
\affil[2]{Guy's and Saint Thomas' Hospitals NHS Trust}%
\affil[3]{University of East Anglia}%
\affil[4]{University Hospital Southampton NHS Foundation Trust}%
\affil[5]{South Yorkshire Deanery}%
\affil[6]{Oxford University Hospitals NHS Foundation Trust}%
\affil[7]{University Hospitals Birmingham NHS Foundation Trust}%
\affil[8]{Nottingham University Hospitals NHS Trust}%
\affil[9]{Spire Regency Hospital, Macclesfield}%
\affil[10]{University Hospital of Wales Healthcare NHS Trust}%
\affil[11]{Royal National Throat Nose and Ear Hospital}%
\affil[12]{The Freeman Hospital and University of Newcastle}%
\affil[13]{University of Edinburgh}%
\affil[14]{Central Manchester \& Manchester Children's Foundation Trust}%
\affil[15]{AbScent }%
\affil[16]{Fifth Sense}%
\affil[17]{WWL NHS FT}%


\vspace{-1em}



  
  \date{June 16, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Objectives The primary aim of the study is to provide recommendations
for the investigation and management of patients with new onset anosmia
during the COVID-19 pandemic Design After undertaking a literature
review, we used the RAND/UCLA methodology with a multi-step process to
reach consensus about treatment options, onward referral imaging.
Setting and participants An expert panel consistent of 15 members was
assembled. A literature review was undertaken prior to the study and
evidence was summarised for the panellists. Main outcome measures The
panel undertook a process of ranking and classifying appropriateness of
different investigations and treatment options for new onset anosmia
during the COVID-19 pandemic. Using a 9-point Likert scale, panellists
scored whether a treatment was: Not recommended, optional, or
recommended. Consensus was achieved when more than 70\% of responses
fell into the category defined by the mean. Results Consensus was
reached on the majority of statements after 2 rounds of ranking.
Disagreement meant no recommendation was made regarding one treatment,
using Vitamin A Drops. Alpha lipoic acid was not recommended, olfactory
training was recommended for all patients with persistent anosmia of
more than 2 weeks duration, and oral steroids, steroid rinses and omega
3 supplements may be considered on an individual basis. Recommendations
have been made regarding the need for referral and investigation have
been made. Conclusion This study identified the appropriateness of
olfactory training, different medical treatment options, referral
guidelines and imaging for patients with COVID-19 related anosmia. The
guideline may evolve as our experience of COVID-19 develops.%
\end{abstract}%



\sloppy


\textbf{Management of new onset anosmia during the COVID pandemic - BRS
Consensus Guidelines} Running title

BRS Consensus guidelines for COVID anosmia

Abstract Objectives The primary aim of the study is to provide
recommendations for the investigation and management of patients with
new onset anosmia during the COVID-19 pandemic

Design

After undertaking a literature review, we used the RAND/UCLA methodology
with a multi-step process to reach consensus about treatment options,
onward referral

imaging.

Setting and participants

An expert panel consistent of 15 members was assembled. A literature
review was undertaken prior to the study and evidence was summarised for
the panellists.

Main outcome measures

The panel undertook a process of ranking and classifying appropriateness
of different investigations and treatment options for new onset anosmia
during the COVID-19 pandemic. Using a 9-point Likert scale, panellists
scored whether a treatment was: Not recommended, optional, or
recommended. Consensus was achieved when more than 70\% of responses
fell into the category defined by the mean.

Results Consensus was reached on the majority of statements after 2
rounds of ranking. Disagreement meant no recommendation was made
regarding one treatment, using Vitamin A Drops. Alpha lipoic acid was
not recommended, olfactory training was recommended for all patients
with persistent anosmia of more than 2 weeks duration, and oral
steroids, steroid rinses and omega 3 supplements may be considered on an
individual basis. Recommendations have been made regarding the need for
referral and investigation have been made.

Conclusion This study identified the appropriateness of olfactory
training, different medical treatment options, referral guidelines and
imaging for patients with COVID-19 related anosmia. The guideline may
evolve as our experience of COVID-19 develops.

Keywords COVID-19, corona virus, anosmia, olfactory training, RAND/UCLA

Five succinct key points.

\begin{enumerate}
\tightlist
\item
  If the COVID status is unknown, serology should be performed for all
  patients with new onset smell loss
\item
  Patients with Isolated loss of smell for less than three months may be
  managed by their GP.
\item
  When ENT referral is necessary, remote ENT consultation may be offered
  instead of a face-to-face consultation depending on duration of
  symptoms and associated nasal symptoms
\item
  An MRI brain is not recommended for patients with COVID infection
  regardless of LOS duration.
\item
  Olfactory training is recommended to patients with LOS more than 2
  weeks.
\end{enumerate}

\textbf{Introduction}

At the time of writing (May 12th 2020), there have been 226,000
confirmed cases of COVID-19 in the UK. Using data available through the
COVID Symptom tracker which is monitoring over 2.5 million members of
the public, it is estimated that there have been in excess of 2 million
cases.

The British Rhinological Society (BRS) and ENTUK were the first to
report that loss of smell or taste may be an important symptom. There
has been a rapid growth in the evidence base supporting the initial
observations made by the BRS/ENTUK that an apparent rise in incidence of
anosmia reflected the onset of the COVID-19 pandemic(1-3).

We have undertaken a systematic review, which suggests a prevalence of
self-reported loss of sense of smell in 50\% of patients. Emerging data
suggests a high rate of early recovery, but at 4-6 weeks after onset
approximately 10\% patients have not experienced any recovery and still
self-report severe loss of sense of smell. Applying the prevalence and
recovery rates to estimated cases in the UK, there are likely already
more than 100,000 new cases of severe loss of sense of smell persisting
beyond the first few weeks of COVID infection. We do not yet know the
potential for long term recovery, but we anticipate that both GPs and
ENT doctors will see an increase in the number of patients presenting
for advice.

As there is a high rate of spontaneous recovery reported across all
studies within 2 weeks of onset of symptoms therefore we will consider
only patients where duration of loss or reduction of sense smell (LOS),
with or without loss of sense of taste, is longer than 14 days or more.
Furthermore, respiratory deterioration typically occurs between day 7 --
12 after onset of symptoms and this period should be allowed to pass
before considering specific treatments, particularly as the safety of
treatments in the setting of severe COVID-19 has yet to be fully
established for any treatments considered.

Many patients report loss of flavour (due to loss of retronasal
olfactory function) as loss of taste. Some reports suggest that true
taste disturbance is also present in COVID-19. However, we will not
attempt to differentiate or address this in this guidance, which will
focus on self-reported loss of sense of smell

The aim of this guidance is to provide evidence-based recommendations
for the management of patients with COVID-19 related anosmia, while at
the same time trying to optimise use of resources but ensuring those
with alternative pathologies are identified in a timely manner. We
therefore considered investigation of patients presenting with loss of
sense of smell during the COVID pandemic and management of post-COVID
loss of sense of smell.



\textbf{Material and Methods}

An expert panel of 15 members was assembled, comprising of members of
the BRS Council, members of an ENTUK taskforce charged with developing
guidance for outpatient practice in ENT and representatives of the
Global Consortium of Chemosensory Research.

A comprehensive literature review has been undertaken, by CH and MA,
using Medline, Cochrane databases, and MEdRxIv, and preprint server.
Evidence was summarised for the panellists (Appendix 1), and where a
systematic review had been performed this was circulated in full.
Studies were considered if they included any patients with post-viral
olfactory loss, or idiopathic loss. Some treatments identified by the
literature review were excluded if the evidence base showed that there
were infective, or if the mode of administration could not be supported
during the pandemic (for example, repeated intravenous administration),
or if regularly face to face contact was required for administration or
monitoring (Appendix 2). We used the RAND/UCLA methodology with a
multi-step process. Our expert panel undertook a process of ranking and
classifying appropriateness of different investigations and treatment
options. Using a 9-point -Likert scale, panellists scored whether a
treatment was:

Not recommended: should not be undertaken or prescribed based on current
evidence base as risks outweigh likely benefits (1 -3),

Optional: could be undertaken or prescribed based on discussion with
individual patient based on likely risks versus benefits (4-6),

Recommended: should be undertaken or prescribed in all patients unless
there are contraindications as benefits outweigh likely risks (7-9)

Free text comments were encouraged if greater context was required, if
question were ambiguous or if anything had been overlooked

Specific combinations of treatment were not considered as the evidence
base does not currently have sufficient data to evaluate for any
enhanced effectiveness when used in combination. However multiple
options could be considered and recommended, and none of the treatments
would be considered a contra-indication to use of any others.

Upon receiving the results, the classification of recommendation was
based on the mean ranking scores collated from each clinical scenario
provided that there was consensus.

Consensus was defined as the requirement for more than 70\% of responses
to fall into the category defined by the mean, and when the mean score
sits in `recommended', less than 15\% of responses fall into not
recommended, and vice versa. Where consencus was not reached items were
reconsidered in a further round.

Disagreement was declared if more than 30\% responses fell in both
recommended and not recommended; in this setting no recommendation could
be given.

Panellists were given 72 hours to return their answers. The scores at
the end of round 1 were analysed and represented to the group, with each
individual receiving a copy of their own initial evaluation. The panel
was then asked to repeat the scoring for any items where consensus had
not been reached. After the second round, any remaining items that had
not reached consensus were further reviewed.

\textbf{Results}

Six items reached consensus at the end of round 1. Some questions were
amended for the second round in response to comments from panellists;
for example, many panellists requested information on COVID status and
endoscopy findings in order to make recommendations. Steroid rinses were
identified as a missing treatment and added.

All panellists completed both rounds of the Delphi process.

After the second round, consensus had been achieved on most items. There
was disagreement on the use of Vit A drops and therefore no
recommendations have been made in the guideline.

In 4 areas consensus could not be achieved at the 70\% threshold, but
was met at 60\%. Further discussion lead to consensus regarding imaging.
The remaining items related to treatment using oral corticosteroids,
steroid drops or rinses and omega 3 supplements. The mean score for
these items was 5, and 60 -- 67\% considered these an option, and less
than 15\% would not recommend. They have been included as an option but
the uncertainty regarding the balance of risk and benefit should be
discussed with the patient, and a decision made on an individual basis.

\textbf{Recommendations}

\emph{ENT REFERRAL}

\textbf{Isolated loss of smell (LOS)}

Patients with COVID infection

\begin{enumerate}
\tightlist
\item
  LOS less than three months:
\item
  The patient may be managed by their GP.
\item
  Anosmia advice sheets provided and treatment discussed (smell training
  and optional treatments outlined below)
\item
  LOS more than three months:
\item
  ENT referral.
\item
  Remote ENT consultation should be offered initially instead of a
  face-to-face consultation.
\end{enumerate}

Patients with no COVID infection

\begin{enumerate}
\tightlist
\item
  LOS more than 4-6 weeks:
\item
  ENT referral.
\item
  Remote ENT consultation may be offered instead of a face-to-face
  consultation.
\item
  LOS more than 3 months:
\item
  ENT referral.
\item
  A face-to-face ENT consultation should be considered to exclude other
  pathologies.
\end{enumerate}

Patients with unknown COVID status

If the COVID status is unknown, serology should be performed for all
patients with new onset smell loss. If results unavailable, treat the
patient as COVID positive if sudden onset loss of sense of smell

\textbf{Loss of smell (LOS) associated with nasal symptoms}

All patients with LOS more than 4-6 weeks associated with nasal symptoms
should be referred to ENT for consideration of a face-to-face
consultation +/- nasendoscopy to exclude other pathologies.

Endoscopy findings should direct decisions regarding further imaging if
possible.

\emph{}

\emph{INVESTIGATONS}

COVID status should be established through history/PCR/serology in
patients if possible.

\textbf{Isolated loss of smell (LOS)}

A) Patients with COVID infection (regardless of LOS duration)

An MRI scan of brain is not recommended

B) Patients with no COVID infection (LOS more than 3 months)

An MRI scan of brain is recommended if endoscopy is normal

C) Patients with unknown COVID status (LOS more than 3 months)

An MRI scan of brain is recommended if endoscopy is normal

\textbf{Loss of smell (LOS) associated with nasal symptoms} (regardless
of COVID status)

Nasal endoscopy should be performed prior to imaging. However given the
risks surrounding endoscopy and limited availability, imaging may be
requested first in selected cases.

If endoscopy is normal, further imaging is recommended (either MRI or
CT).

Unilateral lesions or suspicion of malignancy on endoscopy needs urgent
investigation with MRI/CT.

Benign findings (eg nasal polyps) should be treated medically before
considering imaging.

\textbf{Loss of smell (LOS) associated with neurological symptoms
(excluding gustatory dysfunction)}

All patients with LOS more than 6 weeks with additional neurological
symptoms should have an MRI scan of brain regardless of COVID-19 status.

\emph{}

\emph{MANAGEMENT}

COVID status should be established through history/PCR/serology in
patients if possible.

The recommendation is divided into:

1) Recommended, 2) Not Recommended, and 3) Optional*.

\textbf{Olfactory training and support}

Olfactory training is \emph{recommended} to patients with LOS more than
2 weeks.

It is \emph{recommended} that anosmia advice is provided to the
patients.

It is \emph{recommended} that patients are directed to AbScent and Fifth
Sense for further support.

\textbf{Intranasal corticosteroid sprays}

It is \emph{recommended} in patients with LOS more than 2 weeks
associated with nasal symptoms.

\textbf{Intranasal corticosteroid drops or rinses}

It is \emph{optional} to recommend intranasal steroid drops or rinses in
patients with LOS more than 2 weeks associated with nasal symptoms.

\textbf{Oral corticosteroids}

It is \emph{not recommended} to prescribe oral corticosteroids for a
patient with LOS more than 2 weeks with persistent COVID symptoms.

It is \emph{optional} to recommend oral corticosteroids for a patient
with LOS more than 2 weeks as an isolated symptom or following
resolution of any other COVID symptoms.

\textbf{Vitamin A Drops}

Due to disagreement within the group, it was not possible to make a
recommendation regarding the use of Vitamin A drops.

\textbf{Alpha Lipoic Acid}

It is \emph{not recommended} for a patient with LOS more than 2 weeks as
an isolated symptom or following resolution of any other COVID symptoms.

\textbf{Omega 3 supplements}

It is \emph{optional} for a patient with LOS more than 2 weeks as an
isolated symptom or following resolution of any other COVID symptoms.
The flow chart (Figure 1) summarizes key points in relation to
treatment, investigations and management of new onset anosmia during the
COVID 19 pandemic.

*Denotes items where consensus was achieved at 60\% and not the 70\%
threshold, highlighting ongoing uncertainty regarding usage. We
therefore suggest that decisions regarding usage should be made at an
individual patient level, considering the risks in view of comorbidities
and individual patient preferences



\textbf{Discussion}

Postviral olfactory loss (PVOL) is one of the most common causes of
olfactory dysfunction. Pathogens include those viruses causing the
common cold comprising influenza-, parainfluenza-, rhino- and
coronavirus(4). Olfactory dysfunction can have a significant negative
impact on quality of life(5). COVID-19 has been shown to be associated
with a high prevalence of loss of sense of smell and taste, and early
reports on recovery suggest that while this may be transient in many
cases, resolving in 7-14 days, at least 10\% will have severe deficits
lasting beyond the first 4 -- 6 weeks(6). Longer term data is not yet
available. Historical reports of spontaneous recovery following
post-viral loss likely exclude patients with transient loss due to
under-reporting, but instead capture those with loss persisting at least
in beyond the first few weeks. Nevertheless, two retrospective studies,
including 791 and 262 patients respectively, indicate that between one
third to two thirds of patients with PVOL will experience a clinically
relevant improvement(5, 7, 8). However, recovery can sometimes take
several years. Given the high incidence of COVID-19 it is anticipated
that both primary care and ENT specialists will see a surge in patients
seeking advice.

The applied RAND/UCLA methodology allowed for timely development of
appropriateness criteria for the medical management, referral
guidelines, endoscopy and strategies for imaging of patients with new
onset anosmia. Indeed, time was the essence in this study as many
doctors including general practitioners and ENT surgeons are expected to
meet a significant number of patients with post-COVID loss of sense of
smell in the near future (8). The flow chart created should assist with
overview and appropriate management. This methodology combined the best
available evidence with the cooperative judgment of experts in the
field. There exists solid evidence for the use of olfactory training in
the treatment of PVOL (5--7). Smell training is also recommended by the
expert panel in this study for the management of new onset anosmia
during the COVID-19 pandemic. Many different medications have been
proposed to treat PVOL, including oral corticosteroids, topical
corticosteroids, zinc sulfate, alpha lipoic acid, theophylline,
caroverine, vitamin A, Ginkgo biloba, sodium citrate and minocycline.
However, the evidence to support use of these medical treatments for
PVOL is limited and no large randomized controlled trials (RCT) exist.
The expert panel only recommended use of INCS in patients with anosmia
and concomitant nasal symptoms and made recommendations against the use
of alpha lipoic acid.

We were unable to reach consensus at the 70\% threshold determined a
priori but did achieve consensus at a 60\% threshold for 3 treatments;
topical steroid rinses, omega-3 supplements and oral corticosteroids
(but only if no symptoms of COVID or after full resolution of symptoms).
We did agree that these could be considered as optional medical
treatments, but after discussion with patients regarding the uncertainty
surrounding usage and assessment of risks at an individual level.

Delivery of ENT care will be challenging as we undertake a graduated
return to elective practice. In particular, use of nasal endoscopy needs
to be carefully considered due to its potential to be an aerosol
generating procedure. Waiting times for ENT care will likely
significantly increase. For many patients with confirmed COVID-19
infection and anosmia, specialist review and further investigation will
not be required; however, serology testing will be required for those
who had been unable to access testing at the time of active infection.
We have identified those who will benefit from specialist review, and
also provided supporting material to assist primary care doctors, who
may have had quite limited experience in this area. We plan to develop
further educational material for both GP's and ENT surgeons. Patient
groups including AbScent and Fifth Sense will play an important role in
patient support, we are delighted to be partnering with both groups to
provide patient information leaflets (Appendix 3) and further support
through a variety of different media.

A strength of the method was to give each panellist an equal voice in
the Delphi process, and maintaining anonymity throughout the scoring
process. The methodology is also ideally suited to the social distancing
requirements of the current pandemic in place of nominal group
techniques where face-to-face discussion is required. A limitation is
that the guidelines are based on the panellist's interpretation of the
best available evidence and may be influenced by their own training and
clinical experience. Another limitation may be the group composition as
it is generally recommended that the group is multidisciplinary(9); it
would have benefited from the inclusion of both primary care doctors and
patient representatives.

We look forward to a time when the COVID pandemic will pass -- and these
guidelines no longer be needed. They have been developed for a time when
the prevalence of COVID-19 related loss of smell is high, but they will
need to be reconsidered when the relative likelihood of differential
diagnoses increase -- particularly with regard to indications for
further imaging. Although considered with regard to COVID-19 related
anosmia, the recommendations on treatments may be applied to all
post-viral anosmia, although the risk -- benefit analysis may need to be
modified. Finally, it should be noted that as our experience of COVID-19
grows, our guideline will likely need to evolve. We hope that the
newfound spotlight on loss of sense of smell and taste will drive
clinical research and lead to the development of novel treatment options
for patients with post-viral loss, and that greater understanding exists
for those who do not recover.

References

1. Spinato G, Fabbris C, Polesel J, Cazzador D, Borsetto D, Hopkins C,
et al. Alterations in Smell or Taste in Mildly Symptomatic Outpatients
With SARS-CoV-2 Infection. Jama. 2020.

2. Lechien JR, Chiesa-Estomba CM, Place S, Van Laethem Y, Cabaraux P,
Mat Q, et al. Clinical and Epidemiological Characteristics of 1,420
European Patients with mild-to-moderate Coronavirus Disease 2019. J
Intern Med. 2020.

3. Menni C, Valdes AM, Freidin MB, Sudre CH, Nguyen LH, Drew DA, et al.
Real-time tracking of self-reported symptoms to predict potential
COVID-19. Nat Med. 2020.

4. Hummel T, Whitcroft KL, Andrews P, Altundag A, Cinghi C, Costanzo RM,
et al. Position paper on olfactory dysfunction. Rhinology.
2016;56(1):1-30.

5. Cavazzana A, Larsson M, Munch M, Hahner A, Hummel T. Postinfectious
olfactory loss: A retrospective study on 791 patients. Laryngoscope.
2018;128(1):10-5.

6. Hopkins C, Surda P, Whitehead E, Kumar BN. Early recovery following
new onset anosmia during the COVID-19 pandemic - an observational cohort
study. Journal of otolaryngology - head \& neck surgery = Le Journal
d'oto-rhino-laryngologie et de chirurgie cervico-faciale. 2020;49(1):26.

7. Reden J, Mueller A, Mueller C, Konstantinidis I, Frasnelli J, Landis
BN, et al. Recovery of olfactory function following closed head injury
or infections of the upper respiratory tract. Arch Otolaryngol Head Neck
Surg. 2006;132(3):265-9.

8. Duncan HJ, Seiden AM. Long-term follow-up of olfactory loss secondary
to head trauma and upper respiratory tract infection. Arch Otolaryngol
Head Neck Surg. 1995;121(10):1183-7.

9. Fraser GM, Pilpel D, Kosecoff J, Brook RH. Effect of panel
composition on appropriateness ratings. Int J Qual Health Care.
1994;6(3):251-5.

Data Availability Statement

The data that support the findings of this study are available from the
corresponding author upon reasonable request.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig1-COVID/Fig1-COVID}

\end{center}
\end{figure}

\selectlanguage{english}
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