The authors have declared that no competing interests exist.
To understand lung damages caused by COVID-19, we deduced two phases lung damage mechanisms. After the lungs are infected with COVID-19, the affected lung tissue swells and surface properties of pulmonary capillaries change, both contributing to an increased flow resistance of the capillaries. The initial damages are mainly fluid leakage in a limited number of involved alveoli.
The increased vascular resistance results in retaining more white blood cells (“WBCs”) in pulmonary capillaries. Some of the WBCs may get into interstitial spaces. When more and more WBCs are dynamically retained, the vascular resistance of pulmonary capillaries further rises; and thus the overall vascular resistance of the lungs rises and pulmonary pressure rises. The rise in the pulmonary pressure in turn results in elevated capillary pressures. When pulmonary capillary pressures around the alveoli are sufficiently high, the elevated pressure causes interstitial pressures to change from normally negative values to positive values. The positive pressures cause fluid leakage to the alvoeli and thus degrade lung function. Tissue swelling, and occupation of WBCs in interstitial spaces and occupation of alvoelar spaces by leaked water result in reduced deformable and compressible spaces, and thus causes a further rise of the vascular resistance of the lungs. When the pulmonary pressure has reached a critical point as in the second phase, the blood breaks capillary walls and squeezes through interstitial spaces to reach alveolar spaces, resulting in irreversible lung damages. Among potential influencing factors, the available space in the thorax cage, temperature, and humid are expected to have great impacts. The free space in the thorax cage, lung usable capacity, and other organ usable capacities are the major factors that determine the arrival time of last- phase irreversible damage. The mechanisms imply that the top priority for protecting lungs is maintaining pulmonary micro-circulation and preserving organ functions in the entire disease course while controlling viral reproduction should be stressed in the earliest time possible. The mechanisms also explain how leukecytes are “recruited and migrated” into inflamed tissues by dynamic retention.
The pathological features of lung damages caused by SARS has been described
The lungs showed bilateral diffuse alveolar damage with cellular fibromyxoid exudates. The left lung tissue displayed pulmonary oedema with hyaline membrane formation. Interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes, were seen in both lungs. To find best treatments for the COVID- 19 disease, it is essential to understand the mechanisms by which the lungs are damaged by the COVID-19 virus. Yoo et al. have conducted a review on viral infection of lungs and host innate and adaptive responses
In this theoretical study, we found and used well known data related to the COVID- 19 diseases, lung structure, lung physiology, physiological data, blood composition, viral replication, physical factors, environmental factors, etc to predict micro-circulation condition in lungs, change in blood pressure, and changes in lung and other organs. We conducted several simulations to see how the retention of WBCs at various rates can take up free deformable and compressible volume in the thorax cage. Our suspect is that when the free space is occupied by leaked blood fluid and exudates, the vascular resistance in lungs rapidly goes up and results in heart arrest or irreversible damages to the lungs.
We then propose two-phase mechanisms and use the mechanisms to predict how each of those well known factors affect the course of lung damages.
White blood cells (“WBCs”) pass through pulmonary capillaries by deforming themselves and squeezing through
The endothelium actively participates in controlling blood flow, and affect permeability, leukocyte infiltration, and tissue edema
Diagram (a) in
Early phase Infection leads to swelling and changes in epithelial cells, which in turn raise the vascular resistance of pulmonary capillaries, raise local capillary pressures and increase interstitial pressures. Normal capillary pressure at a middle point is about 7 mm Hg. If the capillary is blocked in the venous side, the pressure is same as the arterial pressure (about 15 mm Hg mean). This results in an increase in the interstitial pressure. The reversal of the interstitial pressure leads to fluid leakage to the alveoli, and, if the capillary pressure is too high, the blood raptures epithelium of alveoli and reach alveoli inner spaces in a limited number of alveoli. In the early phase, lung injury is caused by damages to a limited number of alveoli as sporadic incidences.
Lungs are a highly expandable and deformable organ. A healthy adult can have 3000 ml inspiration volume while the normal breathing takes about only 500 ml volume
However, if the blood circulation is partially or severely jammed, both water and blood cells are nearly non-compressible. Thus, leaked blood reduces available space for capillaries to expand, and has an equivalent effect of reducing capillary deformability or elasticity. Affected tissue has an increased vascular resistance to blood circulation, which further promotes the retention of WBCs at higher rates.
If the inflammation is of a limited degree, the slower traveling speed of WBCs has an effect of extending the WBCs’ dwell times so that they can have more time to contact infected cells and foreign matters. However, on a long term basis, the body must maintain balance that the number of entering WBCs must substantially be equal to the number of exiting WBCs. We refer this requirement as WBCs transport balance for convenience. This balance is absolutely vital and determine lungs health and the host person’s life.
COVID-19 infection or other lungs infection disturbs the normal WBCs transport balance. As a result, some WBCs may stay in the capillary for too long while certain large WBCs may being caught indefinitely. The infected tissue keeps retaining WBCs. By perpetual accumulative effects, the occupation of WBCs in interstitial spaces and slow-travel of WBCs in capillary pores result in higher vascular resistance. The retention of WBCs results in a reduction of WBC concentration in blood. A reduction of the WBCs concentration in the blood causes bone marrows to generate more WBCs
When newly arrived WBCs travel through the lungs, they are again caught and retained dynamically. Eventually, accumulated WBCs occupy too much of interstitial spaces, and leaked fluid and blood exudates fill more alveolar spaces. The pulmonary vascular resistance reaches the maximum and shuts down pulmonary circulation as heart arrest or multiple organs failure. The most obvious damages are found on alveoli. Alveoli are filled with viscous materials and WBCs
Healthy lungs are highly elastic and have ample room for alveoli and capillaries to expand during breathing cycles. While the WBCs are accumulated in interstitial spaces and alveolar air spaces, blood circulation in affected locations becomes worse and worse. In the affected locations, normal blood circulation is increasingly replaced by extremely-slow diffusion process. As a result, some lung cells die from lack of energy and oxygen. To replace dead tissues, lungs generate fibroblastic cells.
The total volume of compressible alveolar spaces is estimated to be 2000- 3000 mL. Since part of this compressible space is attributed to reduced lung blood volume, we use 2000 ml. The heart of an adult person pumps blood at 5 liters per min, The pulmonary flow is essentially same as the cardiac output. WBCs make up approximately 1% of the total blood volume. Assuming that only 0.1%of the WBCs are retained for any time increment, the retention rate would be equivalent to 0.05 ml volume of WBCs per minute. The retention of WBCs in interstitial spaces has the same effect of reducing the volume of alveolar spaces because the total volume of the lungs is substantially fixed. The fluid in alvoelar spaces is not compressible. Free volume occupied by retained WBCs are shown in
The filled volume can also be estimated by computing the WBC volume. In a normal adult, there are 4.3-10.8 ⨯10(9) WBCs per liter of blood. Assuming 0.1% of the largest WBCs are retained in any given time, we got a similar trend (
Retention Vol rate.(ml/min) | Time (min) | Time (various) | Exudate Vol. (ml) | Percent of CompressibleVol. (%) |
0.05 | 1 | 1 min | 0.05 | 0.0025 |
0.05 | 60 | 1 hour | 3 | 0.15 |
0.05 | 1440 | 1 day | 72 | 3.6 |
0.05 | 7200 | 5 days | 360 | 18 |
0.05 | 14400 | 10 days | 720 | 36 |
0.05 | 28800 | 20 days | 1440 | 72 |
0.05 | 43200 | 30 days | 2160 | Over-limited |
Lung compressible volume: 2000 ml; blood flow rate: 5 liter/min; WBC: 1% of blood volume; and WBCs retention rate: 0.1%.
WBC No | Each Cell Vol.(cu.µm) | Vol. Retention Rate (mL/min) | Time (min) | Time (various) | Exudate Vol. (ml) | Percent of Lung Compressible Vol. (%) |
4E+07 | 1000 | 0.035 | 1 | 1 min | 0.035 | 0.0018 |
4E+07 | 1000 | 0.035 | 60 | 1 hour | 2.1 | 0.105 |
4E+07 | 1000 | 0.035 | 1440 | 1 day | 50.4 | 2.52 |
4E+07 | 1000 | 0.035 | 7200 | 5 days | 252 | 12.6 |
4E+07 | 1000 | 0.035 | 14400 | 10 days | 504 | 25.2 |
4E+07 | 1000 | 0.035 | 28800 | 20 days | 1008 | 50.4 |
4E+07 | 1000 | 0.035 | 43200 | 30 days | 1512 | 75.6 |
The discrepancy between the two methods may be attributed to the approximate volume of WBC cells and estimated mean WBC cell volume. The exact numbers are not important because all of those parameters can vary considerable anyway. What is important is that WBCs retention is a parameter that can control the lung performance and the volume token by retained WBCs can progressively impair the lungs in a time window similar to observed disease time window. In those computations, the lungs have considerable compressible space (for a healthy person). The situation would be much worse for people who even experience shortness of breath in their daily lives.
When the lungs cannot maintain WBCs transport balance, the lungs may fail within five to ten days. If the retention rate of WBCs increases to 1%, the patient may die in one to two days. This happens when a big part of alveolar spaces are filled by extruded blood and leaked fluid.
We found there is a critical point for the lungs to experience irreversible damage. The systolic pulmonary pressure is about 25 mm Hg and diastolic pulmonary pressure is about 8 mm Hg, with the mean pulmonary arterial pressure being about 15 mm Hg. The negative pressures in interstitial spaces is maintained by the flow caused by lymphatic pumping, and net osmotic pressure. Extra fluid that has been on alveoli is sucked back to the lung interstitium through the small openings between epithelial cells. Damage to the capillary membrane causes leakage of fluid and plasma proteins and thus result in an increase in the interstitial pressure. The edema of the interstitium results in a raised interstitial pressure, which can cause immediate rapture of the epithelium.
When a sufficient number of capillaries are “blocked” by slow-moving or retained WBCs, the overall vascular resistance rises; and slow-moving WBCs in capillaries reduce the “expandable” volume of the blood vessels in the lungs. An elevated pulmonary pressure in turn raises capillary pressures for all alvoeli. The interstitial pressures are directly related to capillary pressures, and become positive when venous pressure is elevated
In the above computations, we did not consider two self-aggravating factors. We predicted that lung function degrades potentially by a doubly exponential curve for the following reasons. First, retained WBCs and lung swelling are expected to make pulmonary vascular circulation progressively worse. The expected failure to maintain energy metabolism further aggravates inflammation and diminishes the heart ability to maintain required pulmonary vascular circulation. Thus, the speed of lung damage at a later time intervals is faster than that at previous time intervals. Moreover, the lungs have a fixed total volume and all expandable spaces including the “compressible” volume of blood vessels are required for normal breathing. When some compressible spaces are filled by incompressible fluid and WBCs, their adverse impacts cannot be linear. There is a point at which BWCs cannot pass through.
When more of the lung voids are filled by fluid and WBCs, the pulmonary vascular resistance rises rapidly. The elevated pulmonary pressure forces blood to squeeze into and through any spaces in the entire lungs. It may take a short time, possibly in a matter of less than an hour to complete the final stage of irreversible damages. When substantially all elastic spaces are occupied by WBCs and fluid, the pulmonary vascular resistance approaches the maximum, pulmonary flow reaches zero, and lung function approaches zero. There is no way to stop or reverse.
Considering the potentially doubly exponential damaging process, we estimate that dynamic retention rates of WBCs could be 0.01%-0.1% initially, increase to 0.1% to 1% when the lungs lose most function; the blood rapidly fills the voids in the lungs finally. Our ballpark prediction is consistent with the rapid disease course from shortness of breath to death
Low temperature is known to affect flu
Since the mechanisms tell only how the lungs are damaged reversibly or irreversibly, such mechanisms are not enough for predicting the severity of lung damages or death. Thus, we must focus on lung structures and personal health. It is well known that a person’s ability to survive depends on their vital functional reserves
If the lungs are unable to perform required functions, expected degraded energy metabolism leads to a diminished lung function and leads to failure of major organs such as heart, kidneys, and liver. Those processes are shown in
The human ability to survive depends on vital usable functional capacities of heart, kidneys and liver
Severe lung damages could be caused by viral damages before the start of adaptive immune responses. This may happen because low temperature causes blood vessels and capillaries to constrict and raises blood viscosity
Our proposed lung damage mechanisms add more variables to classic leukocytes recruitment theory. Unlike motility in bacterial chemotaxis, mechanism by which leukocytes physically move is unclear. T and B cell homing and transendothelial migration have been extensively studied
It is believed that leukocytes take the “path of least resistance” across the endothelium
Some studies have investigated hydrodynamic properties for leukocytes migration. Models they used involve cancer cell culture media
Erratic and uncontrolled leukocyte migration and accumulation were seen in diseased tissues such as atherosclerotic plaque
Maintaining pulmonary vascular circulation is the top priority in the entire disease course for COVID-19 as well as other lung infection. Maintaining the mobility of WBCs is vitally important to both innate immunity and acquired immune response
Our mechanisms imply that temperature is very important factor. Temperature may regulate immunity by multiple ways
Our mechanisms imply that raising body temperature can help improve pulmonary micro-circulation and keep WBCs transport balance. Patients should be advised to avoid exposure to low temperature and high humidity in the entire disease course. Other measures should be taken to reduce blood viscosity. We question the measure of using drugs to lower body temperature as the standard of care simply because patients demand comfort. Excessive fever can cause damage to the Central Nervous System. A better strategy is maintaining the body at a higher temperature but lowering the head’s temperature by using a cooling bath only if necessary. If cooling is necessary, it should be used only to the extent to avoid fever damages to the brain, but should never overdo.
The mechanisms also imply that antiviral drugs or alternative measures should be taken as early as possible. When the virus has infected the whole lungs and the patient’s lung function has approached a disability level, such a drug treatment may burden the lungs by its side effects. A sound strategy is to reduce tissue inflammation
The mechanisms imply that age, obesity, and organ usable functions are the most important factors. Age is related to organ reserve
Medicine should explore safe drugs that can dilate blood vessels that can be used to relieve WBC retention.
The author(s) declared that no grant was used in support of this research project.
This subject of this article was initially disclosed in part in preprint.org on 6 February 2020, and was later rewritten and posted in substantially current form on preprints.org server on 8 September 2020.