Is loss of smell an early predictor of COVID-19 severity: a systematic review and meta-analysis

Abstract

Anecdotal evidence suggests that the severity of coronavirus disease of 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is likely to be distinguished by variations in loss of smell (LOS). Thus, we conducted a meta-analysis of 45 articles that include a total of 42,120 COVID-19 patients from 17 different countries to demonstrate that severely ill or hospitalized COVID-19 patients have a lesser chance of experiencing LOS than non-severely ill or non-hospitalized COVID-19 patients (odds ratio = 0.527 [95% CI 0.373-0.744; p < 0.001] and 0.283 [95% CI 0.173-0.462; p < 0.001], respectively). We also proposed a possible mechanism underlying the association of COVID-19 severity with anosmia, which may explain why patients without sense of smell develop severe COVID-19. Variations in LOS according to the severity of COVID-19 is a global phenomenon, with few exceptions. Since severely ill patients have a lower rate of anosmia, patients without anosmia should be monitored more closely in the early stages of COVID-19, for early diagnosis of severity of illness. An understanding of how the severity of COVID-19 infection and LOS are associated has profound implications for the clinical management and mitigation strategies for the disease.

Keywords: Anosmia; COVID-19; COVID-19 hospitalization; COVID-19 severity; SARS-CoV-2.

Fig. 1

Flowchart of study selection in accordance with PRISMA guidelines. In total, first and second comprehensive search of databases provided 45 studies involving confirmed cases according to severity and hospitalization status with respect to anosmia

Fig. 2

Funnel plots representing effect estimates and standard errors of each report in the meta-analysis. Funnel plots for estimated a odds ratio for the association between COVID-19 severity and smell disorder and b odds ratio for the association between hospitalization of patients with COVID-19 and smell disorder. The white circle represents values for reports included in each analysis. The sides of the triangle illustrate the expected inverted funnel shape

Fig. 3

Severely ill patients with COVID-19 are associated with a significantly lower risk of smell disorder. The table summarizes the number of patients with loss of smell (LOS) and the total number of confirmed COVID-19 cases who were either severe or non-severe from 34 reports. For each analysis (grey boxes), the forest plot shows the estimated odds ratio (OR) for the association of LOS with severe COVID-19 cases, with a 95% confidence interval (CI; horizontal black lines). The estimated pooled OR (grey diamond) was 0.527 (95% CI 0.373–0.744), which was significantly different from 1 (p < 0.001), according to a two-sided test. A random-effects model was used to calculate effects and summaries

Fig. 4

Patients hospitalized with COVID-19 are associated with a significantly lower risk of smell disorder. The table summarizes the number of patients with loss of smell (LOS) and the total number of confirmed COVID-19 cases who were either hospitalized or non-hospitalized from 11 reports. The forest plot demonstrates the estimated odds ratio (OR) for the correlation of LOS with hospitalized COVID-19 cases for each analysis (grey boxes), with a 95% confidence interval (CI; horizontal black lines). The pooled OR (grey diamond) was estimated to be 0.283 (95% CI 0.173–0.462). A two-sided test confirmed that the estimated pooled OR was significantly different from 1 (p < 0.001). Effects and summaries were calculated using a random-effects model weighted by the study population

Fig. 5

The possible mechanism underlying the association of COVID-19 severity with anosmia. SARS-CoV-2 can invade the central nervous system (CNS) via the olfactory pathway (straight purple line leading up towards the brain) or spread to the lower respiratory tract via inhalation after entering the nasal cavity (straight purple line pointing downward). However, viral invasion activates the host immune system and recruits inflammatory mediators, which can cause damage to the olfactory epithelium (red spot), leading to anosmia. This process can prevent viral entry into the CNS by blocking its transmission to the olfactory bulb (green dotted line pointing towards the brain), thereby prevents the infection of respiratory centres in the brain. When this innate immune response is triggered, it can destroy the virus and limit viral propagation to the lower respiratory tract (green dotted line pointing towards the lower respiratory tract). Mucociliary clearance is another nasal defence mechanism that clears the particles that enter the lower respiratory tract by expelling them into the oropharynx from where they are either expectorated or swallowed (straight purple lines pointing toward the oral cavity and oesophagus). However, individuals with risk factors may have compromised nasal defences mechanism, allowing the virus to enter the lower respiratory tract through aspiration into the lungs, resulting in lower respiratory tract infection (dotted purple lines)