key: cord-0687690-c5872lio authors: Quadrio, M.; Pipolo, C.; Bulfamante, A. M.; Schillaci, A.; Banchetti, J.; Castellani, L.; Saibene, A. M.; Felisati, G. title: Through The Back Door: Expiratory Accumulation of SARS-Cov-2 in the Olfactory Mucosa as Mechanism for CNS Penetration date: 2020-12-11 journal: nan DOI: 10.1101/2020.12.09.20242396 sha: 85ffa60c5133e58ce1bdd78e49f8b13938922fee doc_id: 687690 cord_uid: c5872lio SARS-CoV-2 is a respiratory virus supposed to enter the organism through aerosol or fomite transmission to the nose, eyes and oropharynx. It is responsible for various clinical symptoms, including hyposmia and other neurological ones. Current literature suggests the olfactory mucosa as a port of entry to the CNS, but how the virus reaches the olfactory groove is still unknown. Because the first neurological symptoms of invasion (hyposmia) do not correspond to first signs of infection, the hypothesis of direct contact through airborne droplets during primary infection and therefore during inspiration is not plausible. The aim of this study is to evaluate if a secondary spread to the olfactory groove in a retrograde manner during expiration could be more probable. Four three-dimensional virtual models were obtained from real CT scans and used to simulate ex-48 piratory droplets. The volume mesh consists of 25 million of cells, the simulated condition is a steady 49 expiration, driving a flow rate of 270 ml/s, for a duration of 0.6 seconds. Droplet diameter is of 5 50 μm. 51 Results 52 The analysis of the simulations shows the virus to have a high probability to be deployed in the 53 rhinopharynx, on the tail of medium and upper turbinates. The possibility for droplets to access the 54 olfactory mucosa during the expiratory phase is lower than other nasal areas, but consistent. 55 56 Discussion 57 The data obtained from these simulations demonstrates that virus can be deployed in the olfactory 58 groove during expiration. Even if the total amount in a single act is very low, it must be considered 59 that it is repeated tens of thousands of times a day, and the source of contamination continuously 60 acts on a timescale of several days. The present results also imply CNS penetration of SARS-CoV-2 61 through olfactory mucosa might be considered a complication and, consequently ,prevention strat-62 egies should be considered in diseased patients. 63 64 Introduction 69 70 SARS-CoV-2 is a respiratory virus, still widely spreading throughout the globe, that is thought to 71 enter the organism through aerosol or fomite transmission to the nose, eyes and oropharynx (1, 2) . 72 Presentation ranges from respiratory symptoms such as cough and fever to neurological symptoms 73 such as headache, dizziness and hyposmia, showing different target organs of the virus (3,4). Current 74 literature has recently started to study access points into the CNS and the anatomical proximity 75 between neurons, nerve fibers and the mucosa within the olfactory groove (5); the reported clinical-76 neurological signs related to alteration in smell suggest that SARS-CoV-2 exploits this neuro-mucosal 77 interface as port of entry. Even though early reports (6) are indeed supporting this hypothesis 78 through autopsy sampling, no literature exists as to how the SARS-CoV-2 reaches the mucosa at the 79 level of the olfactory cleft, and whether the olfactory mucosa involvement is a direct consequence 80 of viral particle deposition or due to a secondary viral invasion of these tissues during the course of 81 the infection. 82 From other respiratory viruses we know that aerosols, which are responsible for the transmission 83 of airborne microorganisms, consist of small droplet nuclei (1-5μm) or droplets (>5μm) (7); these 84 have specific characteristics regarding their distribution inside the nose and respiratory tract. 85 Considering that the first neurological symptoms of invasion (hyposmia) do not correspond to first 86 signs of presentation of infection, the hypothesis of direct contact through airborne at the stage of 87 primary infection and therefore during inspiration is not plausible. 88 The second hypothesis of a secondary spread to the olfactory groove in a retrograde manner during 89 for example expiration in an already challenged organism seems to be more likely. This would make 90 CNS penetration a complication secondary to e.g. pulmonary infection, thus opening the field to so 91 far unconsidered preventative measures. 92 Our group has therefore used computational fluid dynamics to study distribution of airflow and 93 deposition of supposed infectious sub-micron droplets during breathing, to better understand the 94 possible routes of infection and penetration inside the nasal cavities and the olfactory mucosa. 95 96 This study was granted exemption from the Institutional Review Board of the San Paolo Hospital, 98 Milano, Italy, due to its retrospective nature and is based on a set of CFD simulations of breathing, 99 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 11, 2020. ; https://doi.org/10.1101/2020.12.09.20242396 doi: medRxiv preprint reconstructions of nasal anatomies is used. LES is a high-cost and high-fidelity CFD approach, which 101 allows fine control over the modelling error in dealing with complex and possibly turbulent flows. 102 LES numerical simulations were performed starting from a set of four CT scans, whose sinonasal 103 anatomy was defined by consensus by all authors as devoid of any appreciable anatomic anomaly 104 (i.e. a straight septum, normotrophic turbinates with orthodox bending, symmetrical distribution of 105 anatomical features among the two sinonasal emi-systems). The simulations portrait the preferential sites of droplet deposition on the nasal mucosa during 130 expiration. It is clearly visible in Figure 2 , 3 and 4 that, although virus deposition is prevalent in the 131 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 11, 2020. Regardless of the mechanism for viral transmission (direct respiratory, aerosol or fomite), first 149 access to the nose must happen through inspiration. Once the virus has gained entry to the sinonasal 150 cavities, however, many different potential mechanisms concur to further diffusion, among which 151 transport, local replication, and invasion of proximal structures. The ability of SARS-CoV-2 to bind 152 the ACE-2 receptor, enter the respiratory epithelium cells and thereby initiate its replication has 153 been thoroughly demonstrated (17,18). 154 Respiratory droplets containing viral particles are unable to massively reach the olfactory cleft, 155 which should not be therefore considered as a primary target for COVID-19 infection. The droplet 156 ability to deposit on the olfactory cleft is a direct function of the particle size, given that the olfactory 157 cleft is anatomically developed to receive smaller particles such as odorants, while droplets carrying 158 the viral load can be larger (8). Such an ineffective viral deposition on to the olfactory mucosa, 159 coupled with the known defensive mechanisms employed by the olfactory mucosa to protect from 160 environmental noxae (17,19) , make the direct infection of the olfactory cleft by SARS-CoV-2 at the 161 time of primary entry into the organism unlikely at best. On the other hand, cumulative exposure of 162 the olfactory cleft to expiratory droplets from the lower respiratory tract in an already diseased 163 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 11, 2020. The authors have declared that no competing interest exists 193 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 11, 2020. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 11, 2020. ; https://doi.org/10.1101/2020.12.09.20242396 doi: medRxiv preprint 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 P1 P2 P3 P4 Figure 3 : As in figure 1 , but axial projection. All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 11, 2020. ; https://doi.org/10.1101/2020.12.09.20242396 doi: medRxiv preprint P4 P3 P1 P2 Figure 4 : As in figure 1 , but coronal projection. All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 11, 2020. ; https://doi.org/10.1101/2020.12.09.20242396 doi: medRxiv preprint Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1 Face touching: a frequent habit that has implications for hand 200 hygiene Approaching Otolaryngology Patients 202 During the COVID-19 Pandemic. 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