key: cord-0858257-t9rawsyl authors: Sun, Sam-Shajing title: Pathogen Infection Recovery Probability (PIRP) Versus Proinflammatory Anti-Pathogen Species (PIAPS) Levels: Modelling and Therapeutic Strategies date: 2020-03-11 journal: nan DOI: 10.21203/rs.3.rs-17318/v1 sha: 85686cea3f102a2ee1994f6e0dc156b8467031f1 doc_id: 858257 cord_uid: t9rawsyl Current new COVID-19 viruses have already spread in multiple countries and have resulted in over one hundred thousand human infections and over three thousand human deaths worldwide. World Health Organization (WHO) has already declared a global pandemic warning. It appears most of the infection resulted deaths are mainly due to dysfunctions or failures of the lung or multiple organs that could be attributed to host s immunodysfunction or related disorders. In this work, a model is proposed to correlate the Pathogen Infection Recovery Probability (PIRP) versus Proinflammatory Anti-Pathogen Species (PIAPS) levels within a host unit, where a maximum PIRP is exhibited when the PIAPS levels are equal to or around PIAPS equilibrium levels at the pathogen elimination or clearance onset. Based on this model, rational or effective therapeutic strategies at right stages or timing, with right type of agents (immunostimulators or immunosuppressors) and right dosages, can be designed and implemented that are expected to effectively achieve maximum PIRP or reduce the mortality. Current COVID-19 viruses have already spread in multiple countries around the globe and have resulted in over one hundred thousand human infections and over three thousand human deaths [1] [2] . In addition to loss of human life, social and economic losses or effects could be significant. A number of earlier global pandemics occurred in human history can be attributed to pathogen infections [3] . Though there are differences among different pathogen induced infections, there were certain similarities among all pathogen infections. The pathogens here include viruses (such as the new COVID-19 virus), bacteria, or certain substances that can trigger or initiate a host immune system responses resulting in the production (clonal expansion) of antipathogen species (APS), including both anti-inflammatory and proinflammatory anti-pathogen species (PIAPS). PIAPS here include "double-edged sword" species such as certain white blood cells or related species [4] [5] , antibodies [6] , cytokines [7] [8] [9] [10] [11] [12] [18] [19] [20] , etc. "Double-edged sword" refers to certain PIAPS that not only attack the pathogens but also attack host healthy cells or tissues [4] [5] [6] [7] [8] [9] [10] [11] [12] [18] [19] [20] . Pathogen infection modeling could be very useful for understanding the infection mechanisms and processes, and for preventive or therapeutic strategies. However, most of the existing modeling works are mainly focusing on multiple host infection and transmittance statistics on time domain [13] [14] [15] [16] [17] , very few modeling work provide insights on pathogen infection recovery probability (PIRP) over anti-pathogens species (APS), particularly over proinflammatory antipathogen species (PIAPS) that is the focus of this work. A pathogen infection in a host could result in pathogen un-controlled growth if the host immune system is deficient (immunoparalysis, like in immune deficiency related syndromes) that could result in sepsis or septic shock [20] . In a normal or healthy host, as illustrated in Figure 1 , the pathogen infection at time t0 (end of incubation period) should trigger a normal and efficient growth (clonal expansion) of immune system generated anti-pathogen species (APS, including PIAPS, at an initial level x0) and ideally shall result in pathogen being eliminated/cleared at te (Figure 1 ) [13] . Once the pathogen is eliminated by the APS/PIAPS at te, the APS/PIAPS growth should cease and remain at their equilibrium or saturation level xe. Certain APS/PIAPS (such as antibodies) are expected to remain at their equilibrium levels for certain period of time so the same pathogen infection can be prevented or inhibited (principle of vaacination), though antibody equilibrium level slow decay in long period of time are expected [13] [14] [15] [16] [17] . However, in certain immunodysfunction disorders, such as in cytokine release syndromes (CRS) or cytokine storm (CS) [4] [5] [6] [7] [8] [9] [10] [11] [12] , macrophage activation syndromes (MAS) or macrophagecytokine self-amplifying loop (MCSAL) [11] , certain PIAPS can grow out of control even after te where the pathogen has been eliminated. It has been known that a number of PIAPS attack or damage healthy cells resulting in tissue death (gangrene) and multiple organ dysfunctions or failures [2, [4] [5] [6] [7] [8] [9] [10] [11] [12] [18] [19] [20] . For this reason, a Gaussian type bell shaped normal distribution function Y is proposed here to model the Pathogen Infection Recovery Probability (PIRP, or the survivability, counter to the mortality) versus the PIAPS levels x (shown in Figure 2 ) and is exhibited with equation (1): where α parameter is proportional to the PIRP distribution peak full width at half maximum (FWHM) that affects the PIAPS level range width around PIRP maximum. During this range, PIAPS levels can significantly elevate PIRP as compared to other PIAPS range where PIRP remains relatively low. β parameter represents a coupling factor of PIRP versus PIAPS levels, reflecting how significant or effective PIAPS level affects PIRP. Time ( Based on this model, the PIRP-PIAPS curve are divided into two stages or phases: 1) Stage I or the PIRP rising stage corresponds to pathogen/APS evolution time period between t0 to te ( Figure 1 ): The PIRP of the pathogen infected host starts to rise as the normal immune response generated APS/PIAPS are growing efficiently from initial levels of x0 and eventually approaching and maintaining at their equilibrium or saturation levels xe (blue solid line) where the pathogens are being eliminated or cleared. 2) Stage II or the PIRP descending stage: The PIAPS level further increases beyond their equilibrium/saturation levels xe as represented by the long dashed blue line (representing immunodysregulation or immunodysfunction) [2, [4] [5] [6] [7] [8] [9] [10] [11] [12] [18] [19] [20] , the PIRP descends presumably due to excessive PIAPS start to attack or damage the healthy tissues or organs. Eventually the PIRP could descend to a very low level due to heavy damages of tissues and multiple organ dysfunctions [2, [7] [8] [9] [10] [11] [12] [18] [19] [20] . Based on this model, the general therapeutic strategies for minimizing mortality is to achieve and/or sustain maximum PIRP via a two-stage protocol of APS/PIAPS acceleration or stimulation followed by a deceleration or suppression as following: 1) In the stage I or the PIRP rising stage between t0 and te, if the host has a normal immune response to the pathogen infection, the APS/PIAPS should grow efficiently toward an equilibrium (or saturation) level xe where the pathogens are eliminated or cleared. In this stage and situation, viral targeted therapies appear unnecessary except supportive therapies may be needed for the following two situations: a) If the host exhibits breath difficulty or low blood oxygen level due to the liquids or mucus in the lungs (lung infection), then mechanical respiration ventilators and/or oxygen therapy may be utilized to prevent potential oxygen deficiency syndromes (hypoxemia and hypoxia); b) If host's APS/PIAPS do not respond to the infection or the APS/PIAPS growth rates are far slower than the pathogen growth rate (such as the host has certain immune deficiency syndromes), than either pathogen inhibitors/suppressors (if available) or APS/PIAPS boosters/enhancers (including certain white blood cell therapies, immunoglobin therapies, interferon therapies, as well as therapies utilizing plasma and antibodies obtained from the convalescent patients) may be administered to prevent potential viral damage resulted syndromes such as sepsis, but the APS (particularly PIAPS) booster applications (immunostimulations) must be at the right time (in stage I before te), right type (APS/PIAPS boosters/enhancers instead of inhibitors/suppressors), and at the right dosages (i.e., APS/PIAPS levels should be carefully monitored and controlled to be equal or close to their equilibrium or saturation levels xe). 2) In the stage II or the PIRP descending stage after te, when the PIAPS levels of the infected host is excessive or its growth is out of control (dysregulated), pathogen inhibitors/suppressors may not be needed at this time (unless the coupling of the hosted generated PIAPS to the pathogen is very poor, i.e., pathogen level are still largely positive even with excessive PIAPS levels). The most critical or essential therapeutic task in the post te period or stage II shall be to terminate or suppress the further growth of the PIAPS levels at or nearby their equilibrium levels xe. Certain host immune system generated anti-inflammatory species may try to grow in order to counter the PIAPS, but such response could be too slow and may eventually reduce the APS/PIAPS levels well below their equilibrium levels xe [20] . Though a number of therapeutic PIAPS control efforts have extensively been reported in recent years [4] [5] [6] [7] [8] [9] [10] [11] [12] , however, the timing, type, and dosages of PIAPS suppressors/antagonists must be carefully monitored and controlled, as therapeutic APS/PIAPS over-suppression could result in delayed pathogen elimination as well as vulnerability of host re-infection that may also result in sepsis [20] . Finally, since the host's mental/psychological status or modes (e.g., fear including claustrophobia, anxiety, distress, depression) could trigger catecholamine/adrenaline production which in turn could boost APS/PIAPS levels, macrophage-cytokine self-amplifying loop or MCSAL [11] , and inflammations [21] , and may result in mode-inflammation self-amplifying loop (MISAL), psychological counselling to the host thus also appear very important to improve host's PIRP. Precise, fast, convenient, and reliable protocols of measuring and monitoring pathogen and "Double-edged sword" PIAPS levels are essential not only to validate this model, but to eventually utilize this model for safe and effective therapeutic treatments of the infected hosts. Both pathogen and key PIAPS should be targeted as biomarkers. As an example, in the case of COVID-19, while there are lack of evidences of organ damages due to virus [22] , excess levels or presences of macrophage, neutrophil cells, and Interleukin-6 (IL-6) were observed in multiple damaged organs in the autopsies and biopsies of the COVID-19 infected hosts [18] . Though viral treatments using APS/PIAPS boosters (such as interferon INF-alpha, gamma immunoglobulin, convalescent plasma collected from recovered patients) were recommended for COVID-19 infection treatments [18] , based on this model, such treatments are needed only for those hosts with deficient or very weak anti-pathogen immune responses and should be administered within stage I but not in stage II when pathogen are absent. PIAPS suppression via a series of inflammation antagonists, or cytokine elimination via blood purification [18] appear useful for controlling CRS but they should be done after te in the stage II and the PIAPS level control are critical. Most importantly, the levels of COVID-19 virus and APS/PIAPS (particularly IL-6, macrophages, neutrophils) at appropriate time intervals need to be measured and monitored precisely and closely in order to determine the virus elimination onset time te and the corresponding APS/PIAPS equilibrium levels xe. For COVID-19 infection, it appears antibody lgG equilibrium level xe is about four times of its initial level x0 [18] . An approach on controlling dysregulated interferon INF-I production in COVID-19 infection [19] appears potentially useful for validating or utilizing this model, again the interferon INF-I level control should be done after te and the level should not be over suppressed well below xe. Finally, multiple host units may be utilized to obtain average values of all six parameters of this model (t0,, x0, te, xe, α, β) for a particular host group, and the average values may be useful for therapeutic treatments of an individual host that is same or similar to the members of the group. In summary, a bell shaped normal distribution function is proposed to model the Pathogen Infection Recovery Probability (PIRP) versus Proinflammatory Anti-pathogen Species (PIAPS) levels in a pathogen infected host. Based on this model, therapeutic strategies should be based on two stages: In the first or PIRP rising stage, treatments appears not necessary for most normal hosts as PIRPs are expected to grow and remain at the maximum due to APS/PIAPS growing to and remaining at the equilibrium levels xe for certain periods. Hosts with weak or deficient antipathogen immune responses may need either pathogen suppressors or APS/PIAPS boosters, however, timing, type, and dosages of both pathogen suppressors and APS/PIAPS boosters are critical. In the second or the PIRP descending stage II due to PIAPS excessive or abnormal growth or levels, it is essential to control the PIAPS around the equilibrium level xe. Again, timing, types, and dosages of therapeutic treatments are extremely critical depending on the PIRP stages and on pathogen/APS/PIAPS levels. Precise and timely monitoring and controls of both pathogen and PIAPS levels are essential in order to fully characterize and utilize this model. Increased PIRP or reduced mortality could be potential outcome if this model is further developed, well characterized, and implemented upon carefully designed and controlled clinical trials. For instance, for current COVID-19 infections, immunomodulation via timely and precise monitoring and level and controls of key biomarkers (including the virus, IL-6, macrophages and/or neutrophils) appear most essential to reduce the mortality. 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Pathological findings of COVID-19 associated with acute respiratory distress syndrome The author wishes to thank his child's allergy specialist Dr. Kelly Maples for helpful discussions on cytokines/chemokines related hyper-inflammations in pathogen infections and food allergies, and to thank biochemistry Professor/Dr. Joseph Hall for helpful discussions on pathogen/antipathogens. The author particularly wishes to acknowledge and thank his brother Mr. Honggang Sun on insightful discussions about "Happy Medium" doctrine of the Confucius philosophy that was established and taught in China for thousands of years. The authors declare no any conflict of interest for publishing this article.