Prognosis and persistence of smell and taste dysfunction in patients with covid-19: meta-analysis with parametric cure modelling of recovery curves

Abstract

Objective: To clarify in patients with covid-19 the recovery rate of smell and taste, proportion with persistent dysfunction of smell and taste, and prognostic factors associated with recovery of smell and taste.

Design: Systematic review and meta-analysis.

Data sources: PubMed, Embase, Scopus, Cochrane Library, and medRxiv from inception to 3 October 2021.

Review methods: Two blinded reviewers selected observational studies of adults (≥18 years) with covid-19 related dysfunction of smell or taste. Descriptive prognosis studies with time-to-event curves and prognostic association studies of any prognostic factor were included.

Data extraction and synthesis: Two reviewers extracted data, evaluated study bias using QUIPS, and appraised evidence quality using GRADE, following PRISMA and MOOSE reporting guidelines. Using iterative numerical algorithms, time-to-event individual patient data (IPD) were reconstructed and pooled to retrieve distribution-free summary survival curves, with recovery rates reported at 30 day intervals for participants who remained alive. To estimate the proportion with persistent smell and taste dysfunction, cure fractions from Weibull non-mixture cure models of plateaued survival curves were logit transformed and pooled in a two stage meta-analysis. Conventional aggregate data meta-analysis was performed to explore unadjusted associations of prognostic factors with recovery.

Main outcome measures: The primary outcomes were the proportions of patients remaining with smell or taste dysfunction. Secondary outcomes were the odds ratios of prognostic variables associated with recovery of smell and taste.

Results: 18 studies (3699 patients) from 4180 records were included in reconstructed IPD meta-analyses. Risk of bias was low to moderate; conclusions remained unaltered after exclusion of four high risk studies. Evidence quality was moderate to high. Based on parametric cure modelling, persistent self-reported smell and taste dysfunction could develop in an estimated 5.6% (95% confidence interval 2.7% to 11.0%, I²=70%, τ²=0.756, 95% prediction interval 0.7% to 33.5%) and 4.4% (1.2% to 14.6%, I²=67%, τ²=0.684, 95% prediction interval 0.0% to 49.0%) of patients, respectively. Sensitivity analyses suggest these could be underestimates. At 30, 60, 90, and 180 days, respectively, 74.1% (95% confidence interval 64.0% to 81.3%), 85.8% (77.6% to 90.9%), 90.0% (83.3% to 94.0%), and 95.7% (89.5% to 98.3%) of patients recovered their sense of smell (I²=0.0-77.2%, τ²=0.006-0.050) and 78.8% (70.5% to 84.7%), 87.7% (82.0% to 91.6%), 90.3% (83.5% to 94.3%), and 98.0% (92.2% to 95.5%) recovered their sense of taste (range of I²=0.0-72.1%, τ²=0.000-0.015). Women were less likely to recover their sense of smell (odds ratio 0.52, 95% confidence interval 0.37 to 0.72, seven studies, I²=20%, τ²=0.0224) and taste (0.31, 0.13 to 0.72, seven studies, I²=78%, τ²=0.5121) than men, and patients with greater initial severity of dysfunction (0.48, 0.31 to 0.73, five studies, I²=10%, τ²<0.001) or nasal congestion (0.42, 0.18 to 0.97, three studies, I²=0%, τ²<0.001) were less likely to recover their sense of smell.

Conclusions: A substantial proportion of patients with covid-19 might develop long lasting change in their sense of smell or taste. This could contribute to the growing burden of long covid.

Systematic review registration: PROSPERO CRD42021283922.

Fig 1

PRISMA flow diagram of study selection process. Supplementary table S2 shows the 18 studies included in reconstructed individual patient data meta-analyses, and supplementary tables S7 and S8. show the 72 studies included in conventional aggregate data systemic review (inclusive of 22 studies further used for conventional aggregate data meta-analyses)

Fig 2

Non-parametric random effects summary survival curve from reconstructed time-to-event individual patient data for recovery of sense of smell and taste after covid-19. 1 corresponds to 100%. Blue dashed line represents the summary survival curve; purple lines represent individual studies; filled in circles represent the last follow-up time within the study; translucent blue band represents 95% confidence intervals (CIs) obtained by extension of Greenwood’s formula with the delta method; solid pink and dashed pink lines represent the pooled proportion and the accompanying 95% CIs of patients with persistent dysfunction, derived from figure 3

Fig 3

Random effects meta-analysis of Weibull non-mixture cure fraction for individual studies of persistent smell and persistent taste dysfunction after covid-19. 1 corresponds to 100%. Stretched purple diamonds are the pooled proportion with confidence intervals (CIs) for each random effects meta-analysis; symmetrical purple diamonds with horizontal lines are the study estimate with CIs, where diamond sizes reflect the relative weight apportioned to studies in the meta-analysis. The restricted maximum likelihood estimator was used to estimate τ2, and the Hartung-Knapp adjustment was applied to test statistics and CIs

Fig 4

Conventional aggregate data two stage meta-analysis of various prognostic factors in association with the odds of smell recovery. Stretched purple diamonds are the pooled proportion with confidence intervals (CIs) for each random effects meta-analysis; symmetrical purple diamonds with horizontal lines are the study estimate with CIs, where diamond sizes reflect the relative weight apportioned to studies in the meta-analysis. Supplementary tables S7 and S8 show these studies, with complete references. The restricted maximum likelihood estimator was used to estimate τ2, and the Hartung-Knapp adjustment was applied to test statistics and CIs

Fig 5

Conventional aggregate data two stage meta-analysis of various prognostic factors in association with the odds of recovery. Stretched purple diamonds are the pooled proportion with confidence intervals (CIs) for each random effects meta-analysis; symmetrical purple diamonds with horizontal lines are the study estimate with CIs, where diamond sizes reflect the relative weight apportioned to studies in the meta-analysis. Supplementary tables S7 and S8 show these studies, with complete references. The restricted maximum likelihood estimator was used to estimate τ2, and the Hartung-Knapp adjustment was applied to test statistics and CIs