The D614G Virus Mutation Enhances Anosmia in COVID-19 Patients: Evidence from a Systematic Review and Meta-analysis of Studies from South Asia

Abstract

The prevalence of chemosensory dysfunction in patients with COVID-19 varies greatly between populations. It is unclear whether such differences are due to factors at the level of the human host, or at the level of the coronavirus, or both. At the host level, the entry proteins which allow virus binding and entry have variants with distinct properties, and the frequency of such variants differs between ethnicities. At the level of the virus, the D614G mutation enhances virus entry to the host cell. Since the two virus strains (D614 and G614) coexisted in the first six months of the pandemic in most populations, it has been difficult to distinguish between contributions of the virus and contributions of the host for anosmia. To answer this question, we conducted a systematic review and meta-analysis of studies in South Asian populations when either the D614 or the G614 virus was dominant. We show that populations infected predominantly with the G614 virus had a much higher prevalence of anosmia (pooled prevalence of 31.8%) compared with the same ethnic populations infected mostly with the D614 virus strain (pooled anosmia prevalence of 5.3%). We conclude that the D614G mutation is a major contributing factor that increases the prevalence of anosmia in COVID-19, and that this enhanced effect on olfaction constitutes a previously unrecognized phenotype of the D614G mutation. The new virus strains that have additional mutations on the background of the D614G mutation can be expected to cause a similarly increased prevalence of chemosensory dysfunctions.

Keywords: COVID-19; D614G virus mutation; SARS-CoV-2; South Asia; anosmia prevalence; olfactory dysfunction.

Fig. 1A-F.. Map of South Asia showing contributions of D614 and G614 virus to COVID-19 in February to July of the year 2020.

Virus strain dominance according to relevant references. ^,–,–,– The large circle in the center of India shows the overall contributions of D614 and G614, regardless of region; the small circles represent regional contributions of D614 and G614 during the indicated months of 2020.

Fig. 2:

Flow chart of literature search and systematic review of studies reporting on COVID-19 related olfactory dysfunction in South Asians through July 22, 2021.

Fig. 3A, B.. Location of studies reporting the prevalence of olfactory dysfunction among South Asians with D614 virus predominance (A), and G614 virus predominance (B).

The cohort size is indicated by the size of the blue dots, the prevalence of olfactory dysfunction is indicated by the heat map, increasing from yellow to red. Note that mostly D614 infections lead rarely to a more than 10% anosmia prevalence, while almost all of the mostly G614 infections lead to a prevalence of 10–90%, in the same ethnicity (South Asians).

Fig. 4A-D.. Comparison of the prevalence of olfactory dysfunction in populations infected with D614 or G614 virus predominance.

A. Forest plots of olfactory dysfunction prevalence in South Asians infected mostly with D614 vs G614 virus. B. Forest plots of olfactory dysfunction prevalence in Caucasians vs. South Asians infected mostly with the G614 virus. C. Bar graph comparing the pooled anosmia prevalence with 95% confidence intervals and p-value between D614 and G614 cohorts. D. Bar graph showing the pooled prevalence of anosmia in Caucasians vs. mostly G614 virus-infected South Asians (Caucasian cohorts from von Bartheld et al., 2020). Numbers of cohorts are indicated in white on the bars.

Fig. 5A. B.. Illustration of the cell types infected in the olfactory epithelium (OE) (panel A) and the concept that the cell entry efficiency of the coronavirus determines the extent of damage that causes hyposmia or anosmia (panel B).

This would explain the varying prevalence of olfactory dysfunction in patients with COVID-19 between populations and dominance of human coronaviruses NL63, SARS-1, SARS-2, and its strains D614, G614 or the G614 Alpha variant. Efficiency of cell entry includes differences in binding affinities, fusion efficiency via the novel furin cleavage site, and neuropilin-1 binding as a co-host. For details, see Butowt et al., 2020. ACE2, angiotensin converting enzyme 2; BG, Bowman gland; SUS, sustentacular cell.