Early On Prevent Mucus Accumulations

Explorative Chapter

[written in April 2020, updates will be done soon, not all link may point currently]

Content

• Content
• Summary
  • Cascade of Influences
  • Causes for severe Outcome of Covid-19
  • Mucus Hypothesis
• Reverse Cascade - Backtracing ARDS to a High Viral Load Due to a Decreased Mucus Flow
  • Widespread Virus Distribution as an important Cause of ARDS
  • Possible Causes of Widespread Virus Distribution
• Ideas to Decrease Virus Distribution
  • Increase the Mucus Flow
  • Reduce the Spread of Viruses
  • Mechanical Ventilators and Particles Spread
• Appendix for Early On Ventilators
  • Factors Associated to severe Covid-19:
  • Factors Associated with ADRS in Influenza
  • Factors influencing the Mucus Flow
  • Humidity related Death Rates
  • Clearance in the Respiratory Tract
  • Clinical Observations

Summary

For the development of a virus-induced ARDS, a decreased mucus clearance seems to be a key factor; shown in the case of influenza induced ARDS by Yuen et al. The idea is to increase the clearance by increasing the mucus flow. The following observations suggest that the mucus flow is increased by humidified air:

• Hong and colleagues found that the mucus flow increases when using humidified air for ventilation.
• Hasani et al. found the same by humidifying the air in the entire room.

That humid air increases the mucus flow, can be used as described or in other settings e.g. a stand-alone heated humidifier.

Moreover, breath-support-devices can modify the distribution and spread of viruses in the lungs because of altered movement of the lungs and thus altered movement of air. The altered spread should be considered.

Cascade of Influences

Increase humidity of inhaled air –> Increases the mucus clearance –> Decrease the viral load in the lower respiratory tract –> Increase the well-being and the overall prognosis

Causes for severe Outcome of Covid-19

[in rework, 22.10.] A main complication of a severe Covid-19 and possible death cause is acute respiratory distress syndrome (ARDS) see e.g. findings from Song and colleagues.

Mucus Hypothesis

The reason for developing ADRS both for Covid-19 and influenza seems to be a delayed mucus clearance of viruses. This yields a high number of viruses distributed across the entire lungs.

Reverse Cascade - Backtracing ARDS to a High Viral Load Due to a Decreased Mucus Flow

In the following evidence is shown in reverse order for the cascade of influences. The cascade reversed:

• ARDS is caused by widespread virus distribution [how: work in progress]
• widespread virus distribution is caused by a decreased mucociliary clearance and increased distribution from locations of infected cells-
• decreased mucus clearance is caused by dry air, hypertension, diabetes

Widespread Virus Distribution as an important Cause of ARDS

• In most severe cases (especially, where ADRS is observed and mechanical ventilation is needed) the images show bilateral lung lesions/patches Bhatraju et al.,Zhong et al..
• Yuen et al found high late viral load for patients with an ARDS .

Possible Causes of Widespread Virus Distribution

For the widespread viral load distribution in the lower respiratory tract, possible causes are:

• increased replication
• increased distribution across the lungs
• decreased mucus clearance

Increased Replication?

likely NO, since: [in rework] There isn’t much evidence for an higher replication rate of Sars-CoV-2 in ARDS risk group compared to hospitalized cases which don’t develop ARDS. For people with only mild symptoms (especially children) early immune responses possibly limit the viral replication [in work]. There is limited data available comparing the viral load kinetics of people with mild symptoms [in rework: new studies suggest similar viral loads (May 2020)]. In the following the focus is on hospitalized cases.

• data suggest no strong correlation between a diminished immune system and severe Covid-19 (see e.g. zhong)
• patients with ADRS seem not to have especially low antibody levels as results obtained by To, Tsang et al. indicate.
• data by To, Tsang et al.,Yuen et al. suggest that an early high viral load is no clear indication for developing an ARDS.
• in young people the cell machinery tends to be more performant. So in theory viruses could spread more quickly. However their immune systeme is also more quick to react.

Increased Distribution?

likely NO, since:
ACE2 is expressed in alveolar type 2 cells. From these locations, particles are exhaled upon deep breathing [Larsson], which can yield spread both within the lungs and outside the lungs. Thus the virus distribution depends on breathing patterns and so active people would be more at risk. However this is not observed. So increased virus distribution alone, does not yield a bad prognosis.

Decreased Mucus Clearance?

likely YES, since:

• observed for influenza by Yuen et al
• Factors known to decrease the mucus clearance are major risk factors for developing ARDS, both for influenza and Covid-19. For more detail on factors see appendix:
  • intern factors
    • age
    • obesity
    • diabetes
    • hypertension
    • smoking history
    • air pollution history (likely a risk factor for ARDS since most deaths are in larger cities. A decreased clearance has been shown for a variety of pollutants.)
  • extern factors
    • dry air
      • humidified air increases mucus transport Hong, Hasani
      • generally fare fewer deaths and a lower death-rate in humid air countries, see death rates. Rough estimate 0.2 % in humide air countries. Dry air countries are more difficult to estimate since treatment likely is much more relevant, see methods.
      • For greyhounds under anesthesia, breathing air at 37 °C, a decrease in the tracheal mucus flow was observed if the relative humidity was decreased below 50% [Forbes].
• Virus RNA early on in the alimentary seems not to be an indication for ARDS even though this indicates a high overall viral load:
  • there’s indication that patients with early detection of viruses in stool, do not have worse outcome case-series-france
  • diarrhea is not risk for ADRS in influenza Yuen.
  • increased nausea or vomiting seem to be no indication for a severe disease outcome Zhong(despite these indicating higher a viral load in the stomach, so viruses are just better cleared to the alimentary). However vomiting a slight indication for ADRS in influenza Yuen.

Ideas to Decrease Virus Distribution

New Methods ideally are

• thought through by a variety specialists from different fields
• simulated if possible
• tightly supervised, observed and recorded test
• published, including raw data

Note: These are unchecked proposals and should be carefully supervised. Ideally methods are first simulated, e.g. by methods described in the section Particle Dynamics in Respiratory Tract. Anything that alters the natural airflow and thus possibly the distribution of viruses could cause irritations and infections in new locations. Methods likely doing this (e.g. High Flow Therapy) will not be further discussed here.

Increase the Mucus Flow

Increase the mucus flow and clearance by increasing the humidity Hong, Hasani This prevents the accumulation of viral loaded and dry mucus early on. This in turn should both increase the well-being as well as the overall prognosis.

Caution: If there are already a lot of (dry) mucus accumulations, liquefying them could yield a likely temporary but possibly dangerous increased distribution of virus parts and therefore an additional inflammation/irritation. While immune suppresive are generally discouraged, because they could yield a diminished immune reaction and possibly yield prolonged virus spread, in this situation they can be appropriate.

• heated humidifiers in combination with a ventilator as described by Hong et al. in 2014 i.e. in the way in which many pneumonia patients around the world receive successful treatment. Benefit: This increases both the humidity and also decreases the spread of particles from the alveoli as observed by Lindstedt and colleagues. Risk: general risks of invasive ventilation, temporary irritation due to liquefying of mucus.

• a heated humidifier stand-alone i.e. as above but with no ventilator. Benefit: Increase humidity and thus mucus flow and easy to use with an oxygen mask. Risk: temporary irritation due to liquefying of mucus.

• Increasing the humidity in the entire room, increases the mucus flow too, as shown by Hasani and colleagues. Benefit: Simple use and a slight increase in mucus flow. Risk: Some irritation due to liquefying can be possible. “Well tested” in tropical clima zones around the world.

• Steam inhalation in the traditional way with a pot of hot water and a towel can help too. Careful handling:

  • The steam inhaled should not be very hot, so some distance to the hot water is required.
  • Start carefully and see how the body reacts
  • Start early on. Good for mild Covid. If in severe condition the steam may further irritate the mucous membranes and doctors should give treatment schemes.
  • Careful handling of the hot pot: A solid stand/table is recommended.

  Benefit: Simple use and a temporary increase in mucus flow. Risk: If handled carefully the risks should be little. Irritation due to liquefying the mucus or because to hot steam is inhaled is possible.

Reduce the Spread of Viruses

reduce spread -> reduce opening and closing of alveoli i.e. deep breathing [Larsson][to be confirmed and checked how relevant this is for pathogenesis][particle based simulation may be possible]

• patients should breath as calm as possible
• slightly increased pressure may reduce opening and closing of alveoli [to be confirmed]
• ventilators possibly reduce the spread of particles (Vents and Particle Spread)

Mechanical Ventilators and Particles Spread

“Mechanically ventilated patients exhibit decreased particle flow in exhaled breath as compared to normal breathing patients” by Lindstedt and colleagues.
To be investigated:

• it could mean that they shed less viruses and less viruses are distributed throughout the lungs. Likely: since only part of the air is exhaled and most stays in the lungs and there are many brochni and alveolis the air can go back
• it could mean that more viruses stay in the lungs since there is less clearance. Unlikely: since the major clearance occurs through mucus.

Appendix for Early On Ventilators

Just indications are listened and no statistical testing has been done. Some times correlations have been determined in the papers given as sources. Ideally the statistics takes into account correlations between the various factors too; e.g. there is likely a correlation between age and chronic heart disease]. [todo: math, check dependence between observables][todo: add average for entire populations as comparison]

Factors Associated to severe Covid-19:

• Zhong et al. noted characteristics of hospital admitted Covid-19 patients which are grouped into mild, severe and fatal cases. The numbers in parenthesis are
  • observation rates in % of (fatal cases, severe cases(including fatal), mild hospitalized)

  strong relation:

  • Chronic obstructive pulmonary disease (10.4 vs 3.5 vs 0.6)
  • Diabetes (27 v 16 vs 5.7)
  • Hypertension (36 vs 23.7 vs 13.4)
  • Coronary heart disease (9 vs 6 vs 2)
  • (Cerebrovascular disease)

  weak relation:

  • cancer (1.5 vs 1.7 vs 0.8)
  • chronic renal disease (3 vs 2 vs 0.5)

  very weak/no relation:

  • immunodeficiency (0 vs 0 vs 0.2)

• Bhatraju et al. noted characteristics of Covid-19 patients from the Seattle-area with ARDS.

  strong relation:

  • Diabetes 58%
  • high body mass index (33.2±7.2)
  • Age (64±18 (23–97))

  weak relation:

  • former/current smoker 22%
  • asthma 14%

• In Italy Onder et al. analysed a subsample of 355 patients with COVID-19 who died in Italy:

  strong relation:

  • mean age was 79.5 years (SD, 8.1)
  • 117 patients (30%) had ischaemic heart disease
  • 126 (35.5%) had diabetes
  • 72 (20.3%) had active cancer
  • 87 (24.5%) had atrial fibrillation

  some relation:

  • 24 (6.8%) had dementia
  • 34 (9.6%) had a history of stroke
• The Covid-19 fatality rates are higher in cities and especially in cities which are not known for very clean air. Many Covid-19 related deaths are recorded in: Madrid, Milano, Tehran, New York and Wuhan [citation to be added]. According to findings from Wolff dirty air can reduce the mucus clearance in various ways.

Factors Associated with ADRS in Influenza

The following characteristics are observed by Yuen et al.:

• For patient developing a ARDS coughing was more common than for patients, who didn’t develop an ARDS. Since coughing is an emergency measure of the body to clear respiratory tract this an indication of bad clearance.
• The Nasopharyngeal Viral load was even a little higher in the group, who didn’t develop an ARDS.
• The tracheal viral load was much higher in the ARDS groups (less clearance!)
• Diabetis, Age, Chronic hear disease positively correlate with ARDS development.

Factors influencing the Mucus Flow

• Nakagawa et al. found that “Ageing, Diabetes, and Hypertension Are Associated With Decreased Nasal Mucociliary Clearance”. The mechanisms of mucus production in the nose are likely similar to those in the trachea and therefore similar associations are expected [to be confirmed].

• In the review from Houtmeyers et al. “Regulation of mucociliary clearance in health and disease” has references to findings which indicate a decreased mucus flow and ciliary activity with age.

• Dry Air especially below 50% relative humidity decreases the mucus flow in the trachea. Observed by Forbes for greyhounds under barbiturate anaesthesia breathing air at 37 °C.

• Leopold et al. observed smoking-associated shorter airway epithelial cilia which, according to their argumentation, yields a decreased mucus flow (described in the section “Implications of Reduction of Cilia Length on Mucociliary Clearance”).

• In his review on “Effects of Airborne Pollutants on Mucociliary Clearance” Ronald K. Wolff summarizes “A variety of pollutants have been shown to impair mucociliary clearance following acute or subchronic exposures.”

Humidity related Death Rates

written in and data from April 2020

• Around the world fewer deaths per capita in humid air countries indicating a lower death-rate. There is a lower death-rate in Singapore/Kuwait/Qatar/Isreal than in Island/Norway, countries which all have a good health care system and do widespread testing (data specifications).
  • Remark: Norway and Israel probably get half of the cases tested positive, so the death rate should be divided by 2.
  • Remark: Mucus clearance may not be the only reason for lower death rates in humid air, but also that Dry Form Infection and aerosol infection is less likely and therefore Covid-19 starts more in the upper respiratory tract than in the bronchi or alveolis disease pattern.

• In a analysis “Effects of temperature variation and humidity on the death of COVID-19 in Wuhan, China” Luo et al. find a correlation in a time series analysis between a decreased humidity and and increased death rates (which likely corresponds to lowering the ARDS risk). The argumentation given here provides a possible explanation for their findings. The analysis depends however, on how accurate and consistent the analysed data are. In nearly all heavy hit regions around the world, the priority was and is and should be to save lives and not to count accurately. Remark: To recent news, the deaths published in Wuhan were those in hospitals and not the total number of deaths. In this case the data is consistent and the treatment schemes tend to be more uniform for people in hospitals, so to analyse to impact of humidity this data is suited for analysis data specifications.

Clearance in the Respiratory Tract

• yuen

  Kelvin K. W. To, Ivan F. N. Hung, Iris W. S. Li, Kar-Lung Lee, Chi-Kwan Koo, Wing-Wa Yan, Raymond Liu,Ka-Ying Ho, Kwok-Hong Chu, Chi-Leung Watt, Wei-Kwang Luk, Kang-Yiu Lai, Fu-Loi Chow, Thomas Mok, Tom Buckley, Jasper F. W. Chan, Samson S. Y. Wong, Bojian Zheng, Honglin Chen, Candy C. Y. Lau, Herman Tse, Vincent C. C. Cheng, Kwok-Hung Chan, Kwok-Yung Yuen, and the Pandemic H1N1 Study Group Delayed Clearance of Viral Load and Marked Cytokine Activation in Severe Cases of Pandemic H1N1 2009 Influenza Virus Infection Clinical Infectious Diseases 2010;50:850–859 2010 by the Infectious Diseases Society of America https://doi.org/10.1086/650581

• hong

  Hyungseok Seo, Sung-Hoon Kim, Jae-Hyung Choi, Jeong-Yeon Hong and Jai-Hyun Hwang Effect of heated humidified ventilation on bronchial mucus transport velocity in general anaesthesia: A randomized trial Journal of International Medical Research 2014, Vol. 42(6) 1222–1231 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav https://doi.org/10.1177/0300060514548291

• forbes

  A. R. FORBES, M.B., CH.B., F.F.A.R.C.S., HUMIDIFICATION AND MUCUS FLOW IN THE INTUBATED TRACHEA, BJA: British Journal of Anaesthesia, Volume 45, Issue 8, August 1973, Pages 874–878, https://doi.org/10.1093/bja/45.8.874

• hasani

  Hasani, A., Chapman, T., McCool, D., Smith, R., Dilworth, J., & Agnew, J. (2008). Domiciliary humidification improves lung mucociliary clearance in patients with bronchiectasis. Chronic Respiratory Disease, 81–86. https://doi.org/10.1177/1479972307087190

• nakagawa

  Janaína Proença de Oliveira-Maul, Heráclito Barbosa de Carvalho, Danielle Miyuki Goto, Raphaela Mendonça Maia, Claudia Fló, Viviane Barnabé, Denise Reis Franco, Simon Benabou, Monica Rodrigues Perracini, Wilson Jacob-Filho, Paulo Hilário Nascimento Saldiva, Geraldo Lorenzi-Filho, Bruce K. Rubin, Naomi Kondo Nakagawa, Aging, Diabetes, and Hypertension Are Associated With Decreased Nasal Mucociliary Clearance Chest,Volume 143, Issue 4,2013,Pages 1091-1097,ISSN 0012-3692, https://doi.org/10.1378/chest.12-1183. (http://www.sciencedirect.com/science/article/pii/S0012369213602226)

• houtmeyers

  E Houtmeyers, R Gosselink, G Gayan-Ramirez, M Decramer Regulation of mucociliary clearance in health and disease European Respiratory Journal May 1999, 13 (5) 1177-1188;

• leopold-mahony-lian

  Leopold, P. L., O’Mahony, M. J., Lian, X. J., Tilley, A. E., Harvey, B. G., & Crystal, R. G. (2009). Smoking is associated with shortened airway cilia. PloS one, 4(12), e8157. https://doi.org/10.1371/journal.pone.0008157

• luo

  Yueling Ma, Yadong Zhao, Jiangtao Liu, Xiaotao He, Bo Wang, Shihua Fu, Jun Yan, Jingping Niu, Ji Zhou, Bin Luo, Effects of temperature variation and humidity on the death of COVID-19 in Wuhan, China Science of The Total Environment, 2020,138226,ISSN 0048-9697, https://doi.org/10.1016/j.scitotenv.2020.138226. (http://www.sciencedirect.com/science/article/pii/S0048969720317393)

• wolff

  Wolff, R. (1986). Effects of Airborne Pollutants on Mucociliary Clearance. Environmental Health Perspectives, 66, 223-237. doi:10.2307/3430237

Clinical Observations

Covid-19

• shi

  Heshui Shi, Xiaoyu Han, Nanchuan Jiang*, Yukun Cao, Osamah Alwalid, Jin Gu, Yanqing Fan†, Chuansheng Zheng† Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study Lancet Infect Dis 2020 Published Online February 24, 2020 https://doi.org/10.1016/S1473-3099(20)30086-4

• wong

  SARS-CoV-2 Infection in Children This letter was published on March 18, 2020, at NEJM.org. https://doi.org/10.1056/NEJMc2005073

• zhang

  Chen, Nanshan et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study The Lancet, Volume 395, Issue 10223, 507 - 513 https://doi.org/10.1016/S0140-6736(20)30211-7

• zhong

  W. Guan, Z. Ni, Yu Hu, W. Liang, C. Ou, J. He, L. Liu, H. Shan, C. Lei, D.S.C. Hui, B. Du, L. Li, G. Zeng, K.-Y. Yuen, R. Chen, C. Tang, T. Wang, P. Chen, J. Xiang, S. Li, Jin-lin Wang, Z. Liang, Y. Peng, L. Wei, Y. Liu, Ya-hua Hu, P. Peng, Jian-ming Wang, J. Liu, Z. Chen, G. Li, Z. Zheng, S. Qiu, J. Luo, C. Ye, S. Zhu, and N. Zhong Clinical Characteristics of Coronavirus Disease 2019 in China February 28, 2020,last updated on March 6, 2020, at NEJM.org. https://doi.org/10.1056/NEJMoa2002032

• bhatraju

  Pavan K. Bhatraju, M.D., Bijan J. Ghassemieh, M.D., Michelle Nichols, M.D., Richard Kim, M.D., Keith R. Jerome, M.D., Arun K. Nalla, Ph.D., Alexander L. Greninger, M.D., Sudhakar Pipavath, M.D., Mark M. Wurfel, M.D., Ph.D., Laura Evans, M.D., Patricia M. Kritek, M.D., T. Eoin West, M.D., M.P.H., Andrew Luks, M.D., Anthony Gerbino, M.D., Chris R. Dale, M.D.,Jason D. Goldman, M.D., Shane O’Mahony, M.D., and Carmen Mikacenic, M.D.
  Covid-19 in Critically Ill Patients in the Seattle Region — Case Series This article was published on March 30, 2020, at NEJM.org. https://doi.org/10.1056/NEJMoa2004500

• song

  Ruan, Q., Yang, K., Wang, W. et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med (2020). https://doi.org/10.1007/s00134-020-05991-x

• onder

  Onder G, Rezza G, Brusaferro S. Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy. JAMA. Published online March 23, 2020. https://doi.org/10.1001/jama.2020.4683

SARS

• zaki

  Wun-Ju Shieh MD, MPH, PhDa, Cheng-Hsiang Hsiao MDb, Christopher D. Paddock MDa,Jeannette Guarner MDa, Cynthia S. Goldsmith MSa, Kathleen Tatti PhDa, Michelle Packard MPHa, Laurie Mueller BA, BSa, Mu-Zong Wub, Pierre Rollin MDc, Ih-Jen Su MD, PhDd, Sherif R. Zaki MD, PhDa Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan Human Pathology (2005) 36, 303 – 309 https://doi.org/10.1016/j.humpath.2004.11.006