See June 12, 2020 paper by Mikhail Blagosklonny: "From causes of aging to death from COVID-19"; Aging 2020.
An excellent analysis by the great Blagosklonny of why risk of death from biological age is so closely like to risk of death from Covid and why both reduced by rapamycin.
I have not been advised that any of my patients have died from Corona or been seriously sick and hospitalized on respirator. Many patients have gotten Corona; but their illness has been mild.
I believe Rapamycin is very good to help maintain a healthy immune system.
Hydroxychloroquine + Zithromycin might be effective treatment in the early stage of COVID-19 disease; but to date this has not been confirmed by controlled study. All published studies have focused on late stage disease in hospitalized patients with respiratory distress. Hydroxychloroquine is not helpful in late disease and the increased risk of cardiac complications makes Hydroxychloroquine contraindicated. My current advice on Hydroxychloroquine is not recommended until proven to work in early disease.
There are no published clinical studies showing sirolimus protects against COVID-19. Therefore I must provide the following warning:
There is NOT sufficient medical evidence to establish with scientific certainty the efficacy of sirolimus in the prevention and treatment of COVID-19 or furthermore whether sirolimus is contraindicated.
I have been inundated by the question of whether one should stop or not stop rapamycin in response to COVID-19. In response to those questions, I have prepared this summary of what I consider the best evidence that sirolimus provides protection against COVID-19. I think most of this protection is having a healthy immune system prior to exposure.
"Reduction and Functional Exhaustion of T cells in Pateints with Coronavirus Disease 2019.
Diao, 2020; Hubei province, China.
Methods: We reviewed the counts of total T cells, CD4, CD8 T cell subsets and serum cytokine from 522 inpatients COVID-19 admitted two hospitals Wuhan, December 2019 to January 2020 and 40 healthy controls.
Also measure T cell exhaustion markers PD-1, Tim-3.
Results: Total T cells, CD4, CD8 T cells were dramatically reduced in COVID-19 patients, especially elderly patients (>60 years) and in patients requiring ICU care.
Severe cases: Total T. CD4, CD8 down.
Serum cytokines: IL-6, IL-10, TNF-a are UP.
Higher levels exhaustion marker PD-1.
Increasing PD-1 and Tim-3 increase as patients progress from prodromal to overtly symptomatic, further indicative of T cell exhaustion."
"An effective immune response against viral infections depends on activation of cytotoxic T cells than can clear infection by killing virus-infected cells...Our results provide a preliminary demonstration of T cell exhaustion during COVID-19 infection."
1. Decreasing numbers total T cells, CD4 CD8
2. Negative correlation between T cell numbers and cytokines.
Increased in ICU patients: TNF-a, IL-6, IL-10.
The above cytokines decreased as patients improved.
"The phenomena suggests that the decrease on T cells is likely the result of high serum concentrations of TNF-a, IL-6 and IL-10 negatively regulation T cell survival and proliferation."
3. Enhancing T cell exhaustion in COVID-19 patients.
Low levels of PD-1, Tim-3 in prodromal stage; increase in symptomatic stage, highest in ICU period.
T cells play a vital role in viral clearance, with CD8 cytotoxic T cells capable of secreting an array of molecules to eradicate viruses. CD4 helper T cells can assist cytotoxic T cells and B cells.
Persistent stimulation by the virus may induce T cell exhaustion.
In ICU group 95% decrease in total T cells and CD4 and 100% decrease in CD8 T cells.
Cytokine storm is a phenomenon of excessive inflammatory reaction in which cytokines are rapidly produced in large amount in response to microbial infection. This phenomenon is considered to be an important contributor to acute respiratory distresss syndrome (ARDS). It has been implicated in respiratory virus infections such as SARS in 2002, avian H5N1 influenza. Cytokines TNF-a, IL-6, IL-10 increased in COVID-19.
TNF-a is a pro-inflammatory cytokine which can promote T cell apoptosis via interacting with its receptor, TNFR1, which is increased in aged T cells.
Our work suggests monocytes and macrophages as source of pro-inflammatory cytokines IL-6, IL-10, TNF-a.
T-cell exhaustion is a state of T cell dysfunction that arises in many chronic infections and cancer...Blocking IL-10 has been shown to prevent T cell exhaustion in animal models of chronic infection. COVID-19 patients have high levels of serum IL-10 while showing PD-1 and Tim-3 markers of T cell exhaustion.
"Taken together, we conclude that T cells are decreased and exhausted in patients with COVID-19. Cytokines such as IL-10, IL-6, TNF-a might directly mediate T cell reduction.
[AG note: These same cytokines are the usual suspects in various age-related diseases.]
"mTOR inhibition improves immune function in the elderly", Mannick, Dec 2014.
AG: This is the paper on which weekly rapamycin therapy is based. If rapamycin patients know just one thing, they should know they are not kidney transplant patients in whom daily rapamycin is being used to cause immune suppression; but rather they are anti-aging patients in whom weekly rapamycin is being used to improve immune function in the elderly.
Rapalog was used to ameliorate immunosenescence (the decline in immune function during aging) in elderly volunteers. Rapalog enhanced response to influenza vaccine by about 20%.
Rapalog also reduced the percentage of CD4 and CD8 T lymphocytes expressing the programmed death-1 (PD-1) receptor, which inhibits T cell signaling and is more highly expressed with age.
Immunosenescence is the decline in immune function that occurs in the elderly, leading to an increased susceptibility to infection...Adults 65 years of age and older account for 90% of influenza related deaths in the United States compared to younger adults.
"The decline in immune function with age is due to an accumulation of immune defects, including a decrease in the ability of hematopoietic stem cells (HSCs) to generate naive lymphocytes and an increase in numbers of "exhausated programmed death (PD-1) positive T lymphocytes that have diminished responses to antigenic stimulation in elderly mice.
Decrease in percent PD-1 positive T cells
6 weeks 12 weeks
CD4 30% 33%
CD8 37% 41%
Patient were given rapalog for 6 weeks. Then tests for PD-1 cells compared to baseline. 2 weeks later given flu shot. 4 weeks later (12 weeks) tests for CD-1 cells. Note: There is a marked reduction from baseline in PD-1 cells.
Rapalog treatment decreased the percentage of PD-1 positive CD4 and CD8 T cells compared to placebo. PD-1 positive CD4 and CD8 T cells accumulate with age and have diminished response to antigen stimulation because PD-1 inhibits T cell receptor-induced T cell proliferation, cytokine production, and cytolytic function. PD-1 expression is induced by T cell signaling and remains high in the setting of persistent antigen stimulation, including chronic viral infection.
"A rapalog associated decrease in the percentage of PD-1 positive CD4 and CD8 T cells may contribute to enhanced immune function and improve the quality of T cell responses to antigenic stimulation in the elderly."
AG note: The decrease in PD-1 T lymphocytes was directly on point to the finding in the above study from Wuhan China.
Wang, Chun-Hua, American Thoracic Conference, 2012.
This is 2012 study from Taipei, Taiwan involving the treatment of patients with ARDS (Acute Respiratory Distress Syndrome) due to H1N1, also known as Avian flu (Bird flu).
39 patients with confirmed H1N1 pneumonia and on mechanical ventilator support (respirator) were randomized to receive either 10 days of Oseltamir (Tamiflu) alone or Oseltamir with rapamycin 2 mg day.
Rapamycin +Tamiflu Tamiflu alone
Mortality 20% 42%
Days on Respirator 14 days 33 days
Improved PaO2/FiO2 106 to 164 at 3 days None (106-107)
Conclusion: "Early adjuvant rapamycin therapy was significantly associated with a greater improvement in lung injury and multiple organ dysfunction, and shortened the duration of ventilator support in survivors."
Same group did a similar study with Steroids with or without rapamycin 2 mg a day.
"Adjuvant Treatment with a Mammalian Target of Rapamycin Inhibitor, Sirolimus, and Steroids Improves Outcome in Patients with Severe HiN1 Pneumonia and Acute Respiratory Failure. Wang, Chun-Hua. Taiwan. 2014, Critical Care Medicine. (only abstract available).
"Severe H1N1 pneumonia with acute respiratory failure (ARDS) results in infiltration of lungs due to presence of hyperactive immune cells. Rapamycin and corticosteroids inhibit this immune response by blocking the activation of T and B cells.
Patients: Between 2009 and 2011, of 4,012 H1N1-infected patients, 38 patients with severe H1N1 pneumonia and acute respiratory failure enrolled.
38 patients with confirmed HIN1 pneumonia on respirator were randomized to receive treatment of corticosteroids with sirolimus (2 mg/day) or without sirolimus.
Results: Sirolimus group: 7 days respirator; vs non-sirolimus 15 days respirator.
After treatment PaO2/FIO2 values:
Day 3: Sirolimus group significantly better: 167.5 vs 106.8.
Day 7: Sirolimus group: 241.6 vs 147.0.
Sirolimus plus steroid group had rapid clearance of virus.
"In patients with severe H1N1 pneumonia, early adjuvant treatment with corticosteroid and an mTOR inhibitor was associated with improvement in outcomes, such as hypoxia, multiple organ dysfunction, virus clearance, and shortened ventilator days."
AG note: Tamiflu seems of minimal value while rapamycin reduced mortality from 42% to 20%.
Rapamycin was also much better than corticosteroids alone without rapamycin.
Tamiflu, A BRAND NAME DRUG, is now promoted as the standard of care for bird flu. Rapamycin, a generic drug, was totally ignored.
Although H1N1 and COVID-19 are different virus; this is not about killing the virus. Rapamycin works by modulating the human response side of the equation. The human side of COVID-19 and Avian flu as regards ARDS should be essentially the SAME.
This 2002 Taiwan study suggests that rapamycin should be the number one drug in the universe being studied for treatment of respiratory failure and ARDS due to COVID-19. The problem is rapamycin doesn't have a billion dollar price tag. Rapamycin as a generic drug has ZERO commercial value.
Svatek, 2018, Journal of immunology.