Malaysian COVID-19 Anosmia Study (Phase 2) - A Nationwide Multicentre Case-Control Study

Olfactory and Gustatory Disturbances as a Clinical Presentation of Coronavirus Disease 2019 (COVID-19) Infection in Malaysia - A Nationwide Multicentre Case-Control Study

The Malaysian COVID-19 Anosmia Study is a nationwide multicentre observational study to investigate the prevalence and characteristics of olfactory and gustatory/taste disturbances in COVID-19 infection in Malaysia, and to evaluate the predictive value of screening for these symptoms in COVID-19 infection.

This study consists of two phases: the first phase is a cross-sectional study and the second phase is a case-control study. The case-control study is described here (the cross-sectional study is described in a separate ClinicalTrials.gov record).

Study Overview

• Status: Unknown
• Conditions: COVID-19; Anosmia; SARS-CoV Infection; Dysgeusia
• Intervention / Treatment: Other: Patient-Reported Online Questionnaire on Olfactory & Taste Disturbances

Detailed Description

The world is currently in the midst of the Coronavirus 2019 (COVID-19) pandemic that is caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). According to published cohort studies on COVID-29 infected patients, the most prevalent symptoms consist of fever, dry cough, dyspnoea, sputum production, myalgia, arthralgia, headache, diarrhoea, and sore throat. Recently, there have been concerns of significant viral transmission through asymptomatic, pre-symptomatic or even mildly symptomatic patients.

There is increasing anecdotal evidence from patients and healthcare professionals highlighting isolated loss of sense of smell (anosmia) and taste disturbances (dysgeusia) as atypical symptoms of COVID-19 infection in otherwise asymptomatic patients. In parallel, expert statements from the British Association of Otorhinolaryngology-Head & Neck Surgery (ENT UK), British Rhinological Society, and the American Association of Otolaryngology-Head & Neck Surgery (AAO-HNS) have suggested that olfactory and taste disturbances could be a clinical feature of COVID-19 infection.

Rapidly emerging evidence from Europe, the United Kingdom and the United States have found olfactory and taste disturbances to be highly prevalent in patients diagnosed with COVID-19. In contrast, there is currently limited evidence from Asia on the prevalence of these symptoms in COVID-19 infection. Additionally, there is also limited evidence on the predictive value of screening for olfactory and taste disturbance in COVID-19 patients with subclinical symptoms.

The aim of this case-control study is to study the predictive value of screening for olfactory and taste disturbance in patients with COVID-19 infection in Malaysia. The cases will be selected from the cohort of COVID-19 positive patients recruited from participating Malaysian Ministry of Health-designated COVID-19 treating hospitals across the country (from Phase 1 of the Malaysian COVID-19 Anosmia Study). Controls will be recruited from healthy volunteers who will will answer the an online questionnaire to evaluate and characterise their olfactory and taste symptoms. This is the same questionnaire that is answered by the COVID-19 patients in case cohort.

• Study Type: Observational
• Enrollment (Anticipated): 60

Contacts and Locations

• Study Contact: Name: Siti Sabzah Mohd Hashim, MD MS; Phone Number: +604 740 7335; Email: dr_ctsabzah@yahoo.com
• Study Contact Backup: Name: Shen-Han Lee, MB PhD MRCS; Phone Number: +6016 474 0088; Email: shen-han.lee@cantab.net

Study Locations

• Malaysia
  • Kuala Lumpur, Malaysia, 50586
    • Recruiting
    • Kuala Lumpur General Hospital
    • Contact: Elang Kumaran Krishnan, MBBS MS
    • Principal Investigator: Elang Kumaran Krishnan, MBBS MS
    • Sub-Investigator: Chee Loon Leong, MBBS MMed
  • Melaka, Malaysia, 75400
    • Recruiting
    • Hospital Melaka
    • Contact: Linda Pei Fang Lim, MD MS
    • Principal Investigator: Linda Pei Fang Lim, MD MS
    • Sub-Investigator: Nor Zaila Zaidan, MD MMed
  • Johor
    • Kluang, Johor, Malaysia, 86000
      • Recruiting
      • Hospital Enche' Besar Hajjah Khalsom
      • Contact: Jothi Shanmuganathan, MBBS MMed
      • Principal Investigator: Jothi Shanmuganathan, MBBS MMed
      • Sub-Investigator: Masliza Zaid, MBBS MMed
      • Principal Investigator: Tengku Mohamed Izam Tengku Kamalden, MD MS FRCS
  • Kedah
    • Alor Setar, Kedah, Malaysia, 05400
      • Recruiting
      • Hospital Sultanah Bahiyah
      • Contact: Siti Sabzah Mohd Hashim, MD MS
      • Contact: Shen-Han Lee, MB PhD MRCS
      • Principal Investigator: Siti Sabzah Mohd Hashim, MD MS
      • Sub-Investigator: Norzi Gazali, MBBS MMed
      • Sub-Investigator: Ida Sadja'ah Sachlin, MBBS MMed
      • Sub-Investigator: Zhi Xiang Yeoh, MBBS MS MRCS
      • Sub-Investigator: Shen-Han Lee, MB PhD MRCS
      • Sub-Investigator: Lee Lee Low, MD MRCP
      • Sub-Investigator: Sharifah Baizura Syed Alwi, MD MRCPI
      • Sub-Investigator: Shahrul Aiman Soelar, B Ind Stats
      • Sub-Investigator: Ibtisam Ismail, BSc
  • Kelantan
    • Kota Bharu, Kelantan, Malaysia, 15200
      • Recruiting
      • Hospital Raja Perempuan Zainab Ii
      • Contact: Zulkiflee Salahuddin, MD MS
      • Principal Investigator: Zulkiflee Salahuddin, MD MS
      • Sub-Investigator: Rosdi Ramli, MBBS MMed
      • Sub-Investigator: Mahiran Mustafa, MBBCh MMed
      • Sub-Investigator: Anilawati Mat Jelani, MD MMed
      • Sub-Investigator: Rosli Mohd Noor, MD MMed
  • Negeri Sembilan
    • Seremban, Negeri Sembilan, Malaysia, 70300
      • Recruiting
      • Hospital Tuanku Jaafar
      • Contact: Jeyasakthy Saniasiaya, MMed FEBORL
      • Principal Investigator: Jeyasakthy Saniasiaya, MMed FEBORL
      • Sub-Investigator: Tiang Koi Ng, MBBS MRCP
  • Pahang
    • Kuantan, Pahang, Malaysia, 25100
      • Recruiting
      • Hospital Tengku Ampuan Afzan
      • Contact: Suhaimi Yusuf, MBBS MMed
      • Principal Investigator: Suhaimi Yusof, MBBS MMed
      • Sub-Investigator: Dzawani Muhamad, MD MMed
  • Penang
    • George Town, Penang, Malaysia, 10990
      • Recruiting
      • Penang Hospital
      • Contact: Chenthilnathan Periasamy, MBBS MMed
      • Principal Investigator: Chenthilnathan Periasamy, MBBS MMed
      • Sub-Investigator: Ting Soo Chow, MD MRCP
  • Perak
    • Ipoh, Perak, Malaysia, 30450
      • Recruiting
      • Hospital Raja Permaisuri Bainun
      • Contact: Philip Rajan Devesahayam, MMed FRCS
      • Principal Investigator: Philip Rajan Devesahayam, MMed FRCS
      • Sub-Investigator: Hong Bee Ker, MD MRCP
  • Perlis
    • Kangar, Perlis, Malaysia, 01000
      • Recruiting
      • Hospital Tuanku Fauziah
      • Contact: Mohd Zambri Ibrahim, MD MMed
      • Principal Investigator: Mohd Zambri Ibrahim, MD MMed
      • Sub-Investigator: Suhaila Abd Wahab, MBBS MMed
  • Sabah
    • Kota Kinabalu, Sabah, Malaysia, 88200
      • Recruiting
      • Hospital Queen Elizabeth
      • Contact: Halimuddin Sawali, MBBS MS
      • Principal Investigator: Halimuddin Sawali, MBBS MS
      • Sub-Investigator: Heng Gee Lee, MBChB MRCP
  • Sarawak
    • Kuching, Sarawak, Malaysia, 93586
      • Recruiting
      • Sarawak General Hospital
      • Contact: Chun Yiing Wong, MBBS MMed
      • Principal Investigator: Chun Yiing Wong, MBBS MMed
      • Sub-Investigator: Hock Hin Chua, MD MRCP
  • Selangor
    • Sungai Buloh, Selangor, Malaysia, 47000
      • Recruiting
      • Hospital Sungai Buloh
      • Contact: Sobani Din, MD MS
      • Principal Investigator: Sobani Din, MD MS
      • Sub-Investigator: Carren Sui Lin Teh, MD MS
      • Sub-Investigator: Kuldip Kaur Prem Kaur, MBBS MPH
      • Sub-Investigator: Nor Arisah Misnan, MBBS MMed
  • Terengganu
    • Kuala Terengganu, Terengganu, Malaysia, 20400
      • Recruiting
      • Hospital Sultanah Nur Zahirah
      • Contact: Amran Mohamad, MD MS
      • Principal Investigator: Amran Mohamad, MD MS
      • Sub-Investigator: Mohd Noor Ismail, MD MRCP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

This study population will draw subjects from the cohort in Phase 1 of the Malaysian COVID-19 Anosmia Study (Nationwide Multicentre Cross-Sectional Study) as cases. These cases will comprise adult patients with laboratory-confirmed COVID-19 infection from participating Malaysian hospital sites in this study, since the arrival of COVID-19 infection in Malaysia (January 2020) until present time.

The control subjects will be age and sex-matched healthy volunteers recruited from participating hospital sites in this study.

Description

Inclusion Criteria:

1. Age at least 18 years old
2. For Cases: Laboratory confirmed COVID-19 infection [Reverse Transcription Polymerase Chain Reaction (RT-PCR)]
3. Patients clinically able to answer the questionnaire

Exclusion Criteria:

1. Patients with olfactory or taste/gustatory disorders before the COVID-19 epidemic
2. For Cases: Patients without a laboratory-confirmed COVID-19 diagnosis
3. For Cases: Patients in intensive care unit at the time of study

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Malaysian COVID-19 Cohort (Cases); A cohort of COVID-19 positive patients will be recruited from participating Malaysian Ministry of Health-designated COVID-19 treating hospitals across the country.	Other: Patient-Reported Online Questionnaire on Olfactory & Taste Disturbances; This is an online patient-reported questionnaire that examines the presence or absence of olfactory and taste disturbances, the onset of olfactory and taste disturbances in relation to other COVID-19 symptoms, and the temporal evolution of the severity of olfactory and taste disturbances. The occurrence of ear symptoms in COVID-19 infection will also be evaluated in this questionnaire as a secondary outcome. The questionnaire will also have questions relating to the patient's underlying health conditions, risk factors for COVID-19 infection, and demographics.
Healthy Volunteers (Controls); A cohort of age and sex-matched healthy volunteers will be recruited from participating Malaysian Ministry of Health-designated COVID-19 treating hospitals across the country.	Other: Patient-Reported Online Questionnaire on Olfactory & Taste Disturbances; This is an online patient-reported questionnaire that examines the presence or absence of olfactory and taste disturbances, the onset of olfactory and taste disturbances in relation to other COVID-19 symptoms, and the temporal evolution of the severity of olfactory and taste disturbances. The occurrence of ear symptoms in COVID-19 infection will also be evaluated in this questionnaire as a secondary outcome. The questionnaire will also have questions relating to the patient's underlying health conditions, risk factors for COVID-19 infection, and demographics.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence or absence of olfactory and taste disturbances in study participants	In the patient-reported online questionnaire, subjects will be asked regarding whether they experienced symptoms of olfactory and/or taste disturbances	2 weeks prior to answering questionnaire/ prior to diagnosis of COVID-19 infection
Adjusted odds ratio of olfactory & taste disturbances in COVID-19 infection	The relationship between case & control status and each exposure variable will be estimated by odds ratios and their 95% confidence intervals using conditional logistic regression models.	2 weeks prior to answering questionnaire/ prior to diagnosis of COVID-19 infection

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical manifestations of study participants	In the patient-reported online questionnaire, subjects will be asked regarding other symptoms they experienced when they were diagnosed with COVID-19/within the past 2 weeks of answering the questionnaire (e.g. headache, nasal congestion, fever, chills, cough, dyspnoea, gastrointestinal symptoms, eye & ear symptoms)	2 weeks prior to answering questionnaire/ prior to diagnosis of COVID-19 infection
Other pre-existing health conditions	In the patient-reported online questionnaire, subjects will be asked regarding their pre-existing health conditions (for example, obesity, diabetes, hypertension, cardiac conditions, previous head trauma, chronic rhinosinusitis, etc.)	Baseline
Positive predictive value (PPV) of olfactory and taste disturbances in predicting diagnosis of COVID-19 infection	PPV reflects the probability that the presence of olfactory and taste disturbances will have a positive diagnosis of COVID-19. This is derived from dividing the number of patients with olfactory & taste disturbances with COVID-19 infection over the total number of patients with olfactory and taste disturbances, and multiplying by 100%	Baseline
Negative predictive value (NPV) of olfactory and taste disturbances in predicting absence of COVID-19 infection	NPV reflects the probability that the absence of olfactory and taste disturbances will have a negative diagnosis of COVID-19. This is derived from dividing the number of patients without olfactory & taste disturbances and without COVID-19 infection over the total number of patients with no olfactory and taste disturbances, and multiplying by 100%	Baseline
Sensitivity of olfactory and taste disturbances in predicting COVID-19 infection	The percentage of true positives, i.e. the proportion of patients with olfactory and taste disorders with COVID-19 infection. This can be calculated by dividing the number of subjects with olfactory & taste disturbances who have COVID-19 infection with the number of patients with olfactory & taste disturbances, and multiplying by 100%	Baseline
Specificity of olfactory and taste disturbances in predicting COVID-19 infection	The percentage of true negatives, i.e. the proportion of patients without olfactory and taste disorders who do not have COVID-19 infection. This can be calculated by dividing the number of subjects without olfactory & taste disturbances who do not have COVID-19 infection with the number of patients without olfactory & taste disturbances, and multiplying by 100%	Baseline

Collaborators and Investigators

• Sponsor: Hospital Sultanah Bahiyah
• Collaborators: Sarawak General Hospital; Penang Hospital, Malaysia; Hospital Queen Elizabeth, Malaysia; Kuala Lumpur General Hospital; Hospital Raja Permaisuri Bainun; Hospital Tuanku Fauziah, Kangar, Perlis; Hospital Sungai Buloh, Selangor; Hospital Tuanku Jaafar, Seremban, Negeri Sembilan; Hospital Melaka, Melaka; Hospital Enche Besar Hajjah Khalsom, Kluang, Johor; Hospital Raja Perempuan Zainab II, Kota Bahru, Kelantan; Hospital Sultanah Nur Zahirah, Kuala Terengganu, Terengganu; Hospital Tengku Ampuan Afzan, Kuantan, Pahang
• Investigators: Study Chair: Siti Sabzah Mohd Hashim, MD MS, Hospital Sultanah Bahiyah

Publications and helpful links

General Publications

• Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24. Erratum In: Lancet. 2020 Jan 30;:
• Spinato G, Fabbris C, Polesel J, Cazzador D, Borsetto D, Hopkins C, Boscolo-Rizzo P. Alterations in Smell or Taste in Mildly Symptomatic Outpatients With SARS-CoV-2 Infection. JAMA. 2020 May 26;323(20):2089-2090. doi: 10.1001/jama.2020.6771.
• Giacomelli A, Pezzati L, Conti F, Bernacchia D, Siano M, Oreni L, Rusconi S, Gervasoni C, Ridolfo AL, Rizzardini G, Antinori S, Galli M. Self-reported Olfactory and Taste Disorders in Patients With Severe Acute Respiratory Coronavirus 2 Infection: A Cross-sectional Study. Clin Infect Dis. 2020 Jul 28;71(15):889-890. doi: 10.1093/cid/ciaa330. No abstract available.
• Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Chang J, Hong C, Zhou Y, Wang D, Miao X, Li Y, Hu B. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020 Jun 1;77(6):683-690. doi: 10.1001/jamaneurol.2020.1127.
• Lechien JR, Chiesa-Estomba CM, De Siati DR, Horoi M, Le Bon SD, Rodriguez A, Dequanter D, Blecic S, El Afia F, Distinguin L, Chekkoury-Idrissi Y, Hans S, Delgado IL, Calvo-Henriquez C, Lavigne P, Falanga C, Barillari MR, Cammaroto G, Khalife M, Leich P, Souchay C, Rossi C, Journe F, Hsieh J, Edjlali M, Carlier R, Ris L, Lovato A, De Filippis C, Coppee F, Fakhry N, Ayad T, Saussez S. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur Arch Otorhinolaryngol. 2020 Aug;277(8):2251-2261. doi: 10.1007/s00405-020-05965-1. Epub 2020 Apr 6.
• Kaye R, Chang CWD, Kazahaya K, Brereton J, Denneny JC 3rd. COVID-19 Anosmia Reporting Tool: Initial Findings. Otolaryngol Head Neck Surg. 2020 Jul;163(1):132-134. doi: 10.1177/0194599820922992. Epub 2020 Apr 28.
• Yan CH, Faraji F, Prajapati DP, Boone CE, DeConde AS. Association of chemosensory dysfunction and COVID-19 in patients presenting with influenza-like symptoms. Int Forum Allergy Rhinol. 2020 Jul;10(7):806-813. doi: 10.1002/alr.22579. Epub 2020 Jun 1.

Helpful Links

• AAO-HNS: Anosmia, Hyposmia, and Dysgeusia Symptoms of Coronavirus Disease | American Academy of Otolaryngology-Head and Neck Surgery

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 6, 2020
• Primary Completion (ANTICIPATED): March 31, 2021
• Study Completion (ANTICIPATED): March 31, 2021

Study Registration Dates

• First Submitted: May 10, 2020
• First Submitted That Met QC Criteria: May 10, 2020
• First Posted (ACTUAL): May 12, 2020

Study Record Updates

• Last Update Posted (ACTUAL): February 25, 2021
• Last Update Submitted That Met QC Criteria: February 23, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: SARS-CoV-2; Prevalence; COVID-19; Infectious Diseases; Otorhinolaryngology; Cross-sectional study; Anosmia; Coronavirus 2019; Dysgeusia; Olfactory Disorders; Taste Disorders
• Additional Relevant MeSH Terms: Nervous System Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Neurologic Manifestations; Sensation Disorders; Olfaction Disorders; Taste Disorders; Severe Acute Respiratory Syndrome; COVID-19; Infections; Dysgeusia; Anosmia
• Other Study ID Numbers: MCO-002; NMRR-20-934-54803 (OTHER: National Medical Research Register (NMRR), Malaysia)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No