Decoding the mechanophysiology for inhaled onset of smallpox with model-based implications for mpox spread

Abstract

Orthopoxviruses can transmit via inhalation of virus-laden airborne particulates, with the initial infection triggered along the respiratory pathway. Understanding the flow physics of inhaled aerosols and droplets within the respiratory tract is crucial for improving transmission mitigation strategies and elucidating disease pathology. Here, we introduce an experimentally-validated physiological fluid dynamics model simulating inhaled onset of smallpox caused by the variola virus of Orthopoxvirus genus. Using high-fidelity Large Eddy Simulations, we modeled airflow and particulate motion within anatomical airway domains reconstructed from medical imaging. By integrating these simulations with viral concentration and individual immune factors, we estimated critical exposure durations for infection onset to be between 1-19 hours, aligning with existing smallpox literature. To formalize the broader applicability of this framework, we extended our analysis to mpox virus, a circulating pathogen from same genus. For mpox, the mechanophysiological computations indicate a critical exposure window of 24-40 hours; however, this can vary significantly-from as short as 8 hours to as long as 127 hours-depending on virion concentration fluctuations within inhaled particulates, assuming happenstance of viral evolution. Predictably longer than the critical exposure durations for smallpox, the mpox findings still strongly suggest the possibility for airborne inhaled transmission during prolonged proximity.

Keywords: Computational physiology; Critical exposure duration; Inhaled virus transmission; Mpox; Orthopoxviruses; Respiratory fluid dynamics; Smallpox.

Figure 1.. Mechanophysiological domain:

Panel A depicts a cartoon illustration of a smallpox patient with pustules; the inset close-up shows the variola virus structure with outer membrane. Similar skin lesions can also be found in currently circulating viruses from the Poxviridae family, such as the mpox virus, which bears a similar virion morphology. The visual is adopted with a perpetual license agreement from the Getty Images^®. Panels B and C respectively show the anatomical test airway domains (respectively labeled anatomical geometry 1 or ${\mathrm{A}\mathrm{G}}_1$ and anatomical geometry 2 or ${\mathrm{A}\mathrm{G}}_2$, built from high-resolution medical-grade computed tomography imaging). The red regions mark the initial infection trigger sites along the upper respiratory tract; downwind particulate penetration across the tracheal outlet to the lower airway is also tracked to account for bronchial infection expression. Panels D and E zoom on the orange box in B, demonstrating the mid cross-section for the mesh with 6.0 million tetrahedral cells, along with the four prismatic layers along airway walls. Panel F shows the 3D-printable digital model (derived from the ${\mathrm{A}\mathrm{G}}_1$ reconstruction), with a scaled-up view of the separable glottic plug included in G. Panel H demonstrates the experimental setup for mimicking particulate transport using a nebulizer. The location where the glottic plug is inserted in the main 3D-printed structure is indicated within the black rectangle. Panels I and J compare the simulated (in blue) and experimental (in red) measurements for localized deposition fractions at the glottis. The colored area coverages are proportional to the inhaled glottic deposition fraction (with respect to the total number of particulates administered to the numerical space) for 9.5-μm particulates. See Methods for details on the experimental benchmarking and validation. Note: the length scale for the anatomical domains is included between panels B, C.

Figure 2.. Simulated inhaled transport trend:

Panels A and B respectively show the numerically simulated deposition and penetration percentage ${\eta }_k$, summing the percentage of inhaled particulates that: (i) directly deposit at the infective tissue regions along the upper airway; (ii) penetrate downwind through the tracheal outlet into the infective bronchial airspace. The four rows in the heatmaps correspond to ${\mathrm{A}\mathrm{G}}_1$ and ${\mathrm{A}\mathrm{G}}_2$ (as marked), for inhalation rates 15 and 30 L/min. Considering all four geometry-flow combinations, ${\eta }_k\gtrsim 30\mathrm{\%}$ for $d\lesssim 9\mu \mathrm{m}$. The corresponding heatmap regions are highlighted within red boxes. Panel C shows 50 representative simulated airflow velocity magnitude streamlines (with 25 streamlines initiating from each nostril plane) during 15 L/min inhalation. Panel D depicts the simulated trajectories for 10 representative 1.5-μm particulates; with 5 starting from each nostril plane. Panel E includes the Q-Q plots for the deposition and penetration trends as a function of the particulate sizes. Therein, the horizontal axis shows theoretical quantiles from a fitted normal distribution, the vertical axis shows sorted sample quantiles, and the red dashed line marks perfect normality. Panel F demonstrates the mean deposition and penetration rate $\eta$ (in %), averaged across the test geometries and breathing rates. The red square marks the point when $\eta$ first exceeds 30%. Based on the reported particulate size distribution in respiratory ejecta, panel G shows the number of environmentally dehydrated particulates of each test size assumed to be inhaled per minute by an exposed subject.

Figure 3.. Exposure duration for infection onset (with Panels A–C for VARV; Panel D for MPXV):

Panel A reports the critical exposure duration ${\tau }_c$ (in hours) for infectious dose $I_D\in [10,100]$ pfu and infectious virion potency $p\in \left[\mathrm{60,100}\right]\mathrm{\%}$. The top trend lines are for lower $p$, implying longer time needed for infection onset (hence ${\tau }_c$ elevates). Panel B depicts the same data, but with $p$ placed along the horizontal axis. Therein, each of the trend lines accounts for the entirety of the assumed $I_D$ range, with the bottom-most point corresponding to $I_D$ = 10 pfu and the top-most point corresponding to $I_D$ = 100 pfu. In both A and B, the red curves are for $p=63\%$. Panel C records the sample frequency for $\beta$, where ${10}^{\beta }$ pfu/mL is the measured viral concentration in throat swabs, adopted from. The data comprises 147 samples, collected from 32 patients, with a mortality rate of 34.38% . Explained on the right of panel C, the color code points to the day number during illness when the corresponding sample was collected. From this representation, the averaged index ${\beta }_{\text{mean}}=2.952$ is used for calculating $V_L={10}^{{\beta }_{\text{mean}}}$ (in pfu/mL) while extracting the model projections. Panel D (in light yellow) highlights the mpox results on critical exposure duration (${{\tau }_c}^{\prime }$). Curve I comprises findings with previously measured $V_L$; II shows the state if ${\mathrm{l}\mathrm{o}\mathrm{g}}_{10}{V}_L$ reduces by 0.5; III shows the state if ${\mathrm{l}\mathrm{o}\mathrm{g}}_{10}{V}_L$ increases by 0.5. The underlying blue region depicts the comprehensive ${{\tau }_c}^{\prime }$ domain from viral concentration evolution, with perturbations on $V_L$ following $\mathrm{\Delta }{\mathrm{l}\mathrm{o}\mathrm{g}}_{10}{V}_L\in [-0.5,0.5]$.