What We Know About mRNA Drugs and Covid. DRAFT. 2023-01-28. Jorma A. Jyrkkanen, BSc, PDP

What We Know About mRNA Drugs and Covid. DRAFT. 2023-01-28. Jorma A. Jyrkkanen, BSc, PDP WHO WAS ULTIMATELY BEHIND THE COVID 19 BIOWEAPON DEVELOPMENT? Truth Justice ™ @SpartaJustice BREAKING NEWS: The FDA was involved in the development of Covid-19 as an offensive biological warfare weapon at UNCBSL3. The Pentagon bought and paid for the toxic mRNA shots and helped create Covid-19. All are guilty of Nuremberg crimes, murder and conspiracy to commit murder. The CDC Director Rochelle Walensky is also accountable for these murders and Nuremberg crimes. The Harvard Medical School was also involved in the development of Covid-19 at the UNCBSL3 lab with Ralph Baric along with the FDA. The CDC has long been involved in offensive biological weapons dating back to the Reagan Administration. The Reagan Administration authorized the CDC to ship biological warfare agents to Saddam Hussein in Iraq hoping he would use them against Iran. U.S. International Lawyer Professor Francis Boyle states the end goal of DARPA, the Pentagon, the FDA, the CDC, the CIA, Bill Gates, Klaus Schwab, Ralph Baric, Peter Daszak, Anthony Fauci, the Rockefellers, Rothschilds and many others is population control and reduction while making billions of dollars. New reports show worldwide excess deaths of 12 million innocent people. Professor Boyle drafted the U.S. domestic implementing legislation for the Biological Weapons Convention, known as the Biological Weapons Anti-Terrorism Act of 1989, that was approved unanimously by both Houses of the U.S. Congress and signed into law by President George H.W. Bush. Professor Boyle has also advised numerous international bodies in the areas of human rights, war crimes and genocide, nuclear policy, and bio-warfare. From 1991-92, he served as Legal Advisor to the Palestinian Delegation to the Middle East Peace Negotiations. He goes on to say that the population control and reduction objective goes back to the National Security directive by the Henry Kissinger Report written in 1974 which stated that it was in the best interest of National Security for the United States and for Overseas Interests to have a population control and reduction policy. The National Security Study Memorandum NSSM200 Implications of Worldwide Population Growth For U.S. Security and Overseas Interests (THE KISSINGER REPORT) dated December 10, 1974 was Classified and Confidential until it was Declassified on 7/3/89. Read the entire report to understand what they are doing. All citizens of the world are strongly encouraged to go to their local Sheriff's Office, Police Office and District or State Attorney General's Office and file criminal charges of murder and conspiracy to commit murder, demanding that the people responsible be arrested and prosecuted. This must be done, be brave and act now humanity. The Chinese Communist Government also helped the Pentagon and the FDA create Covid-19. They new they were developing a dangerous offensive biological warfare weapon with gain of function properties that had HIV DNA genetically engineered into it and was combined with nanotechnology in order to aerosolize it enabling the bioweapon to travel up to 30 feet in the air. They deliberately created both biological warfare weapons Covid-19 and the lethal Covid vaccines long before the Pandemic and then they created a fraudulent Pandemic in order to release these deadly biological weapons of war on humanity to kill millions of innocent people worldwide. 39.1K views 0:03 / 17:16 11:37 AM · Apr 14, 2023 · 125.2K Views Where ws it made? DARPA DEFUSE Rejection indicates that the US Military was working on coronaviruses and had a vaccine for covid they said was questionable all before the pandemic. EcoHealth had a consortium who wanted todo Gain of Function but were put on hold by the military.

However, Russians 2023-01-28 have come out and said covid was developed in the Ukraine.

Zelensky today (Is it in response to covid origin accusation by Russia) Ordered all Data and Documents regarding METABIOTA Labs be destroyed. This points the finger at METABIOTA. Metabiota is Hunter Bidens Baby. Military operation in Ukraine 16 Jun 2022, 08:08 Hunter Biden lobbied in favor of Metabiota involved in bioprojects in Ukraine — top brass Igor Kirillov pointed out that Russia’s Defense Ministry had already noted Hunter Biden’s important role in creating a financial opportunity to work with pathogens on Ukrainian soil and attracting funds for Black & Veatch and Metabiota companies. MOSCOW, June 16. /TASS/. Hunter Biden’s correspondence indicates that in US government circles he lobbied in favor of Metabiota involved in biological projects in Ukraine, Chief of Russian Radiation, Chemical, and Biological

Pfizer CEO Outlines His Goals to Reduce the Population of the World by 60%

. https://twitter.com/i/status/1615319289178750977 1. Covid attacks mitochondria and troponin is an indictor. 2. mRNA vaccine code copied to nuclear DNA by reverse transcriptase. 3. Covid destroys the mitochondria, along with some antibiotics, some pesticides. 4. 'Vaccines' are not a real vaccine by definition. 5. VAccines are an experimental drug. 6. Have indicators of gain of function by experimental manipulation. 7. Epidemics with an increase in deaths in a number of countrys followed vaccination programs. Canadian Deaths Doubled with 85% of the Population Vaccinated. Health Canada reports Covid deaths week-by-week, starting from the beginning of the pandemic in 2020. In 2020, the total Covid deaths reported to the Public Health Agency Canada by provinces and territories was 9,225. In 2021, as vaccines became accessible to Canadians between January and July, Covid deaths didn’t decrease over the year. Instead, the figure slightly increased to 9,934. And, in 2022, with an approximately 85% vaccinated population in January and a less deadly Covid variant dominant, Covid deaths increased again. Over 2022, Health Canada data shows 15,844 deaths occurred due to Covid – almost double the number of deaths in 2020 when citizens were “unprotected.” BREAKING: Director of CDC Vaccine Task Force, Tom Shimabukuro just admitted C•19 Vaccines Are Causing Debilitating Illnesses pic.twitter.com/Shjj5E1icT — TexasLindsay™ (@TexasLindsay_) January 27, 2023 In other words, as the percentage of Canadians “vaccinated” against Covid increased, so too did the excess death total and the Covid deaths. 8. Long term consequences are unknown and in the short term unknowable, only time will tell. 9. Can cause incidents of sudden death.

10. Cannot prevent or may induce Long Covid. 11. Do not prevent infection. 12. Do not prevent covid infection spread. 13. Reduce short term mortality more than if not used. 14. Can cause Heart Problems. Kidney injury is associated with heart problems because it increases the work the heart has to do and this can shorten a life. 15. Can Cause Kidney damage. Pfizer-BNT appeared to have a stronger AKI correlation than MODERNA and JANSSEN, based on the highest reporting odds ratio (ROR = 2.15, 95% confidence interval = 1.97, 2.36) 16. May lead to Brain fog. 17. Increase risk of diabetes. People who get COVID-19 have a greater risk of developing diabetes up to a year later, even after a mild infection, compared with those who never had the disease, a massive study shows (Nature 604, 407 (2022). 18. Cancers worsening shortly after vaccines suggest mitochondrial immunity compromised. 19. May reduce short term post covid related mortality. 20. May damage mitochondria and lead to immune system compromise.

21. Negative side effects knowledge suppression by top down media censorship prevented knowledge sharing Frequently Asked Questions on Mitochondrial Disease | CDC Centers for Disease Control and Prevention (.gov) · https://www.cdc.gov › mi... 22.: Do vaccines cause or worsen mitochondrial diseases? ... A: As of now, there are no scientific studies that say vaccines cause or worsen mitochondrial diseases except cancer worsening suggesting mitochondrial compromise. Suggestive of immune system damage and by proxy mitochondrial damage are the VAERS Safety indictors and Spikes in covid deaths in a number of countries with no serious pandemic prior.following vaccination program commencement. Effect of COVID-19 mRNA vaccine on in vitro glial cells of the brain studied by Raman spectroscopy and imaging Neha MathurBy Neha MathurMar 8 2022Reviewed by Danielle Ellis, B.Sc. In a recent study posted to the bioRxiv* preprint server, researchers studied how messenger ribonucleic acid (mRNA)-based BNT162b2 coronavirus disease 2019 (COVID-19) vaccine altered the biochemical composition of glial and glioma brain cells in vitro. Study: Decoding COVID-19 mRNA Vaccine Immunometabolism in Central Nervous System: human brain normal glial and glioma cells by Raman imaging. Image Credit: Kateryna Kon/Shutterstock Background Immunology eBook Immunology Industry Focus eBook Compilation of the top interviews, articles, and news in the last year. Raman spectroscopy imaging enables the examination of the biochemical composition of cell organelles non-invasively, valuable in monitoring molecular interactions in the tumor microenvironment and unraveling mechanisms governing immune response to pathogenic infections. COVID-19 mRNA vaccine mimics COVID-19 infection, but instead of the whole virus, synthesize only severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein for the immune response, without causing COVID-19 infection. The harmful effects of mRNA vaccine-produced high levels of S protein are not yet completely understood. Researchers have cautioned that they induce complex reprogramming of innate immune responses; moreover, the vaccine-produced S protein remains near the vaccination site and even circulates in the bloodstream to directly affect the host cells with long-term consequences. Therefore, it is crucial to monitor the biodistribution and location of S protein from mRNA vaccines. Studies have recovered COVID-19 mRNA from the cerebrospinal fluid of vaccinees, suggesting it can cross the blood-brain barrier (BBB). In addition, even without crossing the BBB, several cytokines induced by COVID-19 infection cross the BBB to affect central nervous system (CNS) function. In this way, COVID-19 mRNA reaches the brain, infects astrocytes, and triggers neuropathological changes that contribute to the structural and functional alterations in the brain of COVID-19 patients. The researchers have also raised concerns that the lipid nanoparticles (LNPs) can diffuse quickly to the CNS through the olfactory bulb or blood. However, these phenomenons, including the role of innate memory responses to LNPs, need to be further explored in future research. More Impacts 23. Covid Linked Diabetes, kidney disease, heart failure and stroke risk increase found by St Louis VA Healthcare Epidemiologists. 2022-05-06. Jorma Jyrkkanen 24. Disease in children may occur. Multisystem inflammatory syndrome in children (MIS-C) is a rare condition associated with SARS-CoV-2 (the virus that causes COVID-19), that usually occurs 2-6 weeks after a child is infected with SARS-CoV-2. The child’s SARS-CoV-2 infection may be very mild or have no symptoms at all and may go unrecognized. MIS-C causes different internal and external body parts to become inflamed, including the heart, lungs, kidneys, brain, skin, eyes, or gastrointestinal tract. MIS-C can be serious, even deadly, but most children who are diagnosed with this condition get better with medical care. Doctors believe that Kawasaki disease

is an unusual immune response to an infection, so it is not surprising that similar cases may show up during an outbreak of a new virus like SARS CoV-2 (the novel coronavirus)May 20, 2020. Upsurge in RSV influenza and covid called a TripleDemic in especially hard on infants infants suggests childrens immune systems are compromised by mother's vaccinations and or covid infections and adults resistance to influenza reduced by masking and spacing and isolation. Risks amplified Al-Aly and Yan Xie, an epidemiologist also at the VA St Louis Healthcare System, looked at the medical records of more than 180,000 people who had survived for longer than a month after catching COVID-19. They compared these with records from two groups, each of which comprised around four million people without SARS-CoV-2 infection who had used the VA health-care system, either before or during the pandemic. The pair previously used a similar method to show that COVID-19 increases the risk of kidney disease3, heart failure and stroke. The latest analysis found that people who had had COVID-19 were about 40% more likely to develop diabetes up to a year later than were veterans in the control groups. That meant that for every 1,000 people studied in each group, roughly 13 more individuals in the COVID-19 group were diagnosed with diabetes. Almost all cases detected were type 2 diabetes, in which the body becomes resistant to or doesn’t produce enough insulin. The chance of developing diabetes rose with increasing severity of COVID-19. People who were hospitalized or admitted to intensive care had roughly triple the risk compared with control individuals who did not have COVID-19. Even people who had mild infections and no previous risk factors for diabetes had increased odds of developing the chronic condition, says Al-Aly. Of the people with COVID-19 who avoided hospitalization, an extra 8 people out of every 1,000 studied had developed diabetes a year later compared with people who were not infected. People with a high body-mass index, a measure of obesity — and a considerable risk factor for type 2 diabetes — had more than double the risk of developing diabetes after a SARS-CoV-2 infection.

More Studies Suggesting Immune System Compromise by Vaccination programs THE FOLLOWING CHARTS WITH COVID MORTALITY ON THE VERTICAL AXIS AND TIME ON THE HORIZONTAL AXIS AND A DASHED VERTRICAL LINE FOR START OF MASS VACCINATION SUGGEST A VERY NEGATIVE IMPACT OF VACCINE EXHIBITING AN INCREASE IN VACCINE MORTALITY

THIS IS STRONG EVIDENCE FOR THE HYPOTHESIS THAT THE SPIKE PROTEIN OF THE VACCINE IS IN FACT WHACKING THE MITOCHONDRIA. THE OTHER INCONVENIENT TRUTH WAS DISCOVERED IN ISRAEL. UNVACCINATED PEOPLES IMMUNE SYSTEMS ARE BETTER THAN VACCINATED PEOPLES

THE VAERS STUDY EVENTS TO RAISE CONCERNS CDC Finally Releases VAERS Safety Monitoring Analyses For COVID Vaccines Tyler Durden's Photo by Tyler Durden Monday, Jan 09, 2023 - 04:25 AM Authored by Professor Josh Guetzkow via Jackanapes Junction (some emphasis ours), SUMMARY CDC’s VAERS safety signal analysis based on reports from Dec. 14, 2020 – July 29, 2022 for mRNA COVID-19 vaccines shows clear safety signals for death and a range of highly concerning thrombo-embolic, cardiac, neurological, hemorrhagic, hematological, immune-system and menstrual adverse events (AEs) among U.S. adults. There were 770 different types of adverse events that showed safety signals in ages 18+, of which over 500 (or 2/3) had a larger safety signal than myocarditis/pericarditis. The CDC analysis shows that the number of serious adverse events reported in less than two years for mRNA COVID-19 vaccines is 5.5 times larger than all serious reports for vaccines given to adults in the US since 2009 (~73,000 vs. ~13,000). Twice as many mRNA COVID-19 vaccine reports were classified as serious compared to all other vaccines given to adults (11% vs. 5.5%). This meets the CDC definition of a safety signal. There are 96 safety signals for 12-17 year-olds, which include: myocarditis, pericarditis, Bell’s Palsy, genital ulcerations, high blood pressure and heartrate, menstrual irregularities, cardiac valve incompetencies, pulmonary embolism, cardiac arrhythmias, thromboses, pericardial and pleural effusion, appendicitis and perforated appendix, immune thrombocytopenia, chest pain, increased troponin levels, being in intensive care, and having anticoagulant therapy. There are 66 safety signals for 5-11 year-olds, which include: myocarditis, pericarditis, ventricular dysfunction and cardiac valve incompetencies, pericardial and pleural effusion, chest pain, appendicitis & appendectomies, Kawasaki’s disease, menstrual irregularities, vitiligo, and vaccine breakthrough infection. The safety signals cannot be dismissed as due to “stimulated,” exaggerated, fraudulent or otherwise artificially inflated reporting, nor can they be dismissed due to the huge number of COVID vaccines administered. There are several reasons why, but the simplest one is this: the safety signal analysis does not depend on the number of reports, but whether or not some AEs are reported at a higher rate for these vaccines than for other non-COVID vaccines. Other reasons are discussed in the full post below. In August, 2022, the CDC told the Epoch Times that the results of their safety signal analysis “were generally consistent with EB [Empirical Bayesian] data mining [conducted by the FDA], revealing no additional unexpected safety signals.” So either the FDA’s data mining was consistent with the CDC’s method—meaning they "generally" found the same large number of highly alarming safety signals—or the signals they did find were expected. Or they were lying. We may never know because the FDA has refused to release their data mining results. INTRODUCTION Finally! Zachary Stieber at the Epoch Times managed to get the CDC to release the results of its VAERS safety signal monitoring for COVID-19 vaccines, and they paint a very alarming picture (see his reporting and the data files here, or if that is behind a paywall then here). The analyses cover VAERS reports for mRNA COVID vaccines from the period from the vaccine rollout on December 14, 2020 through to the end of July, 2022. The CDC admitted to only having started its safety signal analysis on March 25, 2022 (coincidentally 3 days after a lawyer at Children’s Health Defense wrote to them reminding them about our FOIA request for it). [UPDATE: T Coddington left a link in comments to a website where he made the data in the Excel files more accessible.] Like me, you might be wondering why the CDC waited over 15 months before doing its first safety signal analysis of VAERS, despite having said in a document posted to its website that it would begin in early 2021—especially since VAERS is touted as our early warning vaccine safety system. You might also wonder how they could insist all the while that the COVID-19 vaccines are being subjected to the most rigorous safety monitoring the world has ever known. I’ll come back to that later. First I’m going to give a little background information on the analysis they did (which you can skip if you’re up to speed) and then describe what they found. BACKGROUND ON SAFETY SIGNAL ANALYSIS

Cancers Worsening Post Vaccination suggests by oncologists observation vaccine makes cancers worse. This may be a proxy clue that mitochondrial contributions to immunity and oxidative phosphorylation have been compromised leading to increased oncogenicity by way of metabolic transition fo cancer's favourite metabolism aerobic glycolysis ie Warburg effect. We need immediately to look for mitochondrial damage ie ccheck with XF Mito Tox Assay Kit Booster Jab boosts IgG4 Which Makes Cancer More Aggressive

REF: Bianchini R, Karagiannis SN, Jordakieva G, Jensen-Jarolim E. The Role of IgG4 in the Fine Tuning of Tolerance in IgE-Mediated Allergy and Cancer. Int J Mol Sci. 2020 Jul 16;21(14):5017. doi: 10.3390/ijms21145017. PMID: 32708690; PMCID: PMC7404042. Mechanism of Malfeasance. See Also REF: IgG4 induces tolerogenic M2-like macrophages and correlates with disease progression in colon cancer. Jordakieva G, Bianchini R, Reichhold D, Piehslinger J, Groschopf A, Jensen SA, Mearini E, Nocentini G, Crevenna R, Zlabinger GJ, Karagiannis SN, Klaus A, Jensen-Jarolim E. Oncoimmunology. 2021 Feb 8;10(1):1880687. doi: 10.1080/2162402X.2021.1880687. PMID: 33628623 CANCER WORSE

CANCER WORSE

THE WARBURG EFFECT KICKS IN WHEN MITOCHONDRIA ARE COMPROMISED AND THIS MAKES CANCER WORSE. THIS IS SUGGESTIVE THAT THE CAUSE OF THE WORSENING IS VACCINATION Prevention https://jorma-jyrkkanen.blogspot.com/2023/02/egg-yolk-anti-spike-s1-igys-antibodies.html

COVID-19-associated Guillain-Barré syndrome: The early pandemic experience. James B Caress 1 , Ryan J Castoro 1 , Zachary Simmons 2 , Stephen N Scelsa 3 , Richard A Lewis 4 , Aditi Ahlawat 5 , Pushpa Narayanaswami 5

COVID-19-associated Guillain-Barré syndrome: The early pandemic experience James B Caress 1 , Ryan J Castoro 1 , Zachary Simmons 2 , Stephen N Scelsa 3 , Richard A Lewis 4 , Aditi Ahlawat 5 , Pushpa Narayanaswami 5

Free PMC article Abstract Guillain-Barré syndrome (GBS) is an inflammatory polyradiculoneuropathy associated with numerous viral infections. Recently, there have been many case reports describing the association between coronavirus disease-2019 (COVID-19) and GBS, but much remains unknown about the strength of the association and the features of GBS in this setting. We reviewed 37 published cases of GBS associated with COVID-19 to summarize this information for clinicians and to determine whether a specific clinical or electrodiagnostic (EDx) pattern is emerging. The mean age (59 years), gender (65% male), and COVID-19 features appeared to reflect those of hospitalized COVID-19 patients early in the pandemic. The mean time from COVID-19 symptoms to GBS symptoms was 11 days. The clinical presentation and severity of these GBS cases was similar to those with non-COVID-19 GBS. The EDx pattern was considered demyelinating in approximately half of the cases. Cerebrospinal fluid, when assessed, demonstrated albuminocytologic dissociation in 76% of patients and was negative for severe acute respiratory distress syndrome-coronavirus-2 (SARS-CoV-2) in all cases. Serum antiganglioside antibodies were absent in 15 of 17 patients tested. Most patients were treated with a single course of intravenous immunoglobulin, and improvement was noted within 8 weeks in most cases. GBS-associated COVID-19 appears to be an uncommon condition with similar clinical and EDx patterns to GBS before the pandemic. Future studies should compare patients with COVID-19-associated GBS to those with contemporaneous non-COVID-19 GBS and determine whether the incidence of GBS is elevated in those with COVID-19. Keywords: Guillain-Barre syndrome; SARS-CoV- REFERENCES Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683-690. https://doi.org/10.1001/jamaneurol.2020.1127. 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Solomon IH, Normandin E, Bhattacharyya S, et al. Neuropathological features of Covid-19. N Engl J Med. 2020. https://doi.org/10.1056/NEJMc2019373. [published online ahead of print]. Kim JE, Heo JH, Kim HO, et al. Neurological complications during treatment of Middle East respiratory syndrome. J Clin Neurol Seoul Korea. 2017;13:227-233. Sharma K, Tengsupakul S, Sanchez O, Phaltas R, Maertens P. Guillain-Barré syndrome with unilateral peripheral facial and bulbar palsy in a child: a case report. SAGE Open Med Case Rep. 2019;7:1-5. Rees JH, Hughes RAC. Campylobacter jejuni infection and Guillain-Barré syndrome. N Engl J Med. 1995;333:6. Willison HJ, Jacobs BC, van Doorn PA. Guillain-Barré syndrome. Lancet. 2016;388:717-727. Fantini J, Chahinian H, Yahi N. Synergistic antiviral effect of hydroxychloroquine and azithromycin in combination against SARS-CoV-2: what molecular dynamics studies of virus-host interactions reveal. Int J Antimicrob Agents. 2020;106020:1-9. Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19. N Engl J Med. 2020;382:1653-1659. Dalakas MC. Guillain-Barré syndrome: the first documented COVID-19-triggered autoimmune neurologic disease: more to come with myositis in the offing. Neurol Neuroimmunol Neuroinflamm. 2020;7:e781. Hartung H-P, Toyka KV. T-cell and macrophage activation in experimental autoimmune neuritis and Guillain-Barré syndrome. Ann Neurol. 1990;27(suppl 1):S57-S63. Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, et al. Guillain-Barre syndrome following vaccination in the national influenza immunization program, United States, 1976-1977. Am J Epidemiol. 1979;110:105-123. Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barre syndrome and the 1992-1993 and 1993-1994 influenza vaccines. N Engl J Med. 1998;339:1797-1802. Grave C, Boucheron P, Rudant J, et al. Seasonal influenza vaccine and Guillain-Barre syndrome: a self-controlled case series study. Neurology. 2020;94:e2168-e2179. Vellozzi C, Iqbal S, Broder K. Guillain-Barre syndrome, influenza, and influenza vaccination: the epidemiologic evidence. Clin Infect Dis. 2014;58:1149-1155. Sivadon-Tardy V, Orlikowski D, Porcher R, et al. Guillain-Barre syndrome and influenza virus infection. Clin Infect Dis. 2009;48:48-56.

Posture Change may Result in Dysfunction of Heart Rate Response in Some Long Haul Covidians. 2022-06-21. Jorma Jyrkkanen

REF:WebMD.

Covid Side Effects Continued. COVID-19 and POTS: What You Should Know In this Article What Is POTS? How Is POTS Linked to COVID-19? Who Gets Post-COVID POTS? What Can You Do? How Do Doctors Diagnose Post-COVID POTS? How Do Doctors Treat Post-COVID POTS? There is some evidence that the coronavirus that causes COVID-19 may also trigger a condition called postural orthostatic tachycardia syndrome (POTS) in people with long-haul COVID-19 (people who have recovered from the initial illness but still have lingering symptoms). What Is POTS? POTS is a debilitating condition that causes your heart to speed up by at least 30 beats per minute after you move from sitting or lying down to standing. This happens when your body’s autonomic nervous system, which should work automatically, fails to control your blood pressure and heart rate to make up for your change in posture. It doesn’t always happen immediately. It can sometimes take as long as 10 minutes after you stand. You may get dizzy and even faint. POTS isn’t well-known. Many people with the condition report that it took them quite a while to get a diagnosis. How Is POTS Linked to COVID-19? POTS can be triggered by a number of things like infection or surgery. But viruses or bacteria seem to trigger it most often, and some scientists think the coronavirus might be among them. That’s because some people who recovered from COVID-19 seem to have POTS-like symptoms like: A faster heart rate with slight increase in activity Trouble thinking (brain fog) Lightheadedness Headaches Nausea and vomiting Extreme tiredness that won’t go away (severe chronic fatigue) Who Gets Post-COVID POTS? It appears that anyone who has had COVID-19 can get POTS, whether the virus initially caused serious symptoms or mild ones. But there are some things that seem to raise your risk for post-COVID POTS, though scientists aren’t yet sure about them. These include a pre-COVID history of: Concussion Dizziness Lightheadedness or passing out Racing or skipping heart (palpitations) A faulty immune system that mistakenly attacks your body’s tissues (autoimmune response) also seems to play a part in POTS. People with POTS tend to have higher rates of autoimmune markers like those from thyroid disease, rheumatoid arthritis, and celiac disease. They also have signs of inflammation, including in the heart. COVID-19 may also be a cause of this autoimmune response, though more study is needed.

Antibiotics Use in Hospitalised COVID-19 Patients in a Tertiary Care Centre: A Descriptive Cross-sectional Study and Heart Mitochondria. JORMA JYRKKANEN 2023-03-23

Antibiotics Use in Hospitalised COVID-19 Patients in a Tertiary Care Centre: A Descriptive Cross-sectional Study and Heart Mitochondria. JORMA JYRKKANEN 2023-03-23

Thapa B, Pathak SB, Jha N, Sijapati MJ, Shankar PR. Antibiotics Use in Hospitalised COVID-19 Patients in a Tertiary Care Centre: A Descriptive Cross-sectional Study. JNMA J Nepal Med Assoc. 2022 Jul 1;60(251):625-630. doi: 10.31729/jnma.7394. PMID: 36705203; PMCID: PMC9297358. ABSTRACT Introduction: Antimicrobial resistance is a global health problem. The widespread and improper antibiotics use is the leading cause of antimicrobial resistance. Bacterial co-infection in COVID-19 patients is the basis for the use of antibiotics in the management of COVID-19. COVID-19 pandemic has seriously impacted antibiotic stewardship and increased the global usage of antibiotics, worsening the antimicrobial resistance problem. The use of antibiotics among COVID-19 patients is high but there are limited studies in the context of Nepal. This study aimed to find out the prevalence of antibiotic use among hospitalised COVID-19 patients in a tertiary care centre. Introduction: Antimicrobial resistance is a global health problem. The widespread and improper antibiotics use is the leading cause of antimicrobial resistance. Bacterial co-infection in COVID-19 patients is the basis for the use of antibiotics in the management of COVID-19. COVID-19 pandemic has seriously impacted antibiotic stewardship and increased the global usage of antibiotics, worsening the antimicrobial resistance problem. The use of antibiotics among COVID-19 patients is high but there are limited studies in the context of Nepal. This study aimed to find out the prevalence of antibiotic use among hospitalised COVID-19 patients in a tertiary care centre. Methods: A descriptive cross-sectional study was conducted on hospitalised COVID-19 patients from April 2021 to June 2021 in a tertiary care centre. Ethical approval was taken from the Institutional Review Committee (Reference number: 2078/79/05). The hospital data were collected in the proforma by reviewing the patient's medical records during the study period of 2 months. Convenience sampling was used. Point estimate and 95% Confidence Interval were calculated. Results: Among 106 hospitalised COVID-19 patients, the prevalence of antibiotics use was 104 (98.11%) (95.52-100, 95% Confidence Interval). About 74 (71.15%) of patients received multiple antibiotics. The most common classes of antibiotics used were cephalosporins, seen in 85 (81.73%) and macrolides, seen in 57 (54.81%) patients. Conclusions: The prevalence of antibiotics use among hospitalised COVID-19 patients was found to be higher when compared to other studies conducted in similar settings. Keywords: antibiotics, bacterial infection, co-infection, COVID-19 Go to: INTRODUCTION Antimicrobial resistance (AMR) is a major threat to global public health due to the increasing incidence of resistant human pathogens.1,2 The widespread and improper use of antibiotics is the leading cause of AMR.1 Coronavirus Disease 2019 (COVID-19) is a viral disease thus untreatable by antibiotics, but the viral respiratory infections may clinically progress to bacterial pneumonia requiring antibiotic administration.2 This co-pathogenesis is the basis for use of antibiotics in COVID-19. But appropriate use of antibiotics is utmost to prevent AMR. COVID-19 pandemic has seriously impacted antibiotic stewardship and single-handedly increased the global usage of antibiotics, causing a cascading effect on the AMR problem. The use of antibiotics among COVID-19 patients is high but there are limited studies in the context of Nepal.3-5 This study aimed to find out the prevalence of antibiotics use among COVID-19 patients of a tertiary care centre. Go to: METHODS A descriptive cross-sectional study was conducted at KIST Medical College and Teaching Hospital after taking ethical approval from the Institutional Review Committee (Reference number: 2078/79/05). The study was conducted during the study period from 6 August 2021 to 6 October 2021 during which hospitalised COVID-19 patients admitted from April 2021 to June 2021 were studied. All the COVID-19 cases confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) test who were admitted in the dedicated COVID-19 ward, high dependency unit (HDU) and intensive care units (ICU) were enrolled. Patients who had incomplete documentation were excluded from the study. Convenience sampling was used. The sample size was calculated using the following formula: n=Z2×p×qe2=1.962×0.50×0.500.102=97 Where, n = minimum required sample size Z = 1.96 at 95% Confidence Interval (CI) p = prevalence taken as 50% for maximum sample size calculation q = 1-p e = margin of error, 10% Minimum sample size calculated was 97. However, we enrolled 106 cases. The collected data from hospital records was entered in the proforma by reviewing the patient's medical records during the study period of two months. Demographic profile of patients like age and sex, clinical profile like co-morbidity and disease severity, management profile like level of care required for patients' treatment, number and type of antibiotics used, route of antibiotic administration, duration of antibiotics used, and estimated cost of antibiotics used for the treatment were assessed. The patients who were treated with at least one antibiotic were included. All the cases were classified as a mild disease, moderate disease, or severe disease.6 In our study, 17 different antibiotics were used belonging to seven different antibiotic classes. They are namely cephalosporin (ceftriaxone, cefixime, cefoperazone, and cefepime), macrolides (azithromycin, clindamycin, and erythromycin), penicillin group (piperacillin, amoxicillin), quinolones (moxifloxacin, levofloxacin, ciprofloxacin), imidazoles (metronidazole), carbapenem (meropenem) and beta-lactamase inhibitors (clavulanic acid, tazobactam, sulbactam). The data were entered and analysed using IBM SPSS Statistics 21.0. Point estimate and 95% CI were calculated. Go to: RESULTS Among 106 hospitalised COVID-19 patients, the prevalence of use of antibiotics was 104 (98.11%) (95.52-100, 95% CI). The mean number of antibiotics used per patient was 1.86 ±0.64. A total of 74 (71.15%) patients were under two or more antibiotic therapy. Around 60 (57.69%) patients were treated with intravenous as well as per oral route of administration of antibiotics. The mean number of days of admission was 6.44±4.81 days. The mean duration of antibiotics use was 6.33 ±2.72 days. About 30 (28.85%) received a 5 day course of antibiotics while 25 (24.04%) patients received a 7 days course of antibiotics. Only 23 (22.12%) received antibiotic therapy for more than 7 days. The mean estimated expenditure on antibiotics was NPR 4,645±8, 498 (USD 38.71±70.82) (Table 1). Table 1 Use of antibiotics in management of COVID-19 patients (n = 104). Characteristics n (%) Number of antibiotics used 1 30 (28.85) 2 59 (56.73) 3 15 (14.42) Route of antibiotics Intravenous route only 37 (35.58) Per oral route only 7 (6.73) Intravenous and per oral route 60 (57.69) Total number of days of antibiotics use ≤7 days 81 (77.88) >7 days 23 (22.12) Estimated expenditure on antibiotics therapy NPR (US dollar) ≤1,200 (USD 10) 43 (41.35) 1201 to 6,000 (USD 11 to 50) 42 (40.38) 6,001 to 12, 000 (USD 51 to 100) 8 (7.69) 12,001 to 24,000 (USD 101 to 200) 7 (6.73) >24,000 (USD 200) 4 (3.85) Open in a separate window The mean age of the patients was 55.84±18 years. A total of 54 (51.92%) patients were males. Around 59 (56.73%) had at least one comorbid condition with the most common conditions being hypertension seen in 39 (37.50%) and diabetes mellitus seen in 23 (22.16%) (Table 2). Table 2 Demographic characteristics of hospitalised COVID-19 patients who received antibiotic therapy (n= 104). Age group n (%) ≤20 years 5 (4.81) 21 to 40 years 18 (17.31) 41 to 60 years 37 (35.58) 61 to 80 years 37 (35.58) >80 years 7 (6.73) Sex Males 54 (51.92) Females 50 (48.08) Comorbidities Diabetes mellitus 23 (22.16) Hypertension 39 (37.50) Chronic Obstructive Pulmonary 10 (9.62) Disease (COPD) Hypothyroidism 12 (11.54) Psychiatric illness 2 (1.92) Heart failure 2 (1.92) Autoimmune disease 2 (1.92) Chronic kidney disease 1 (0.96) Open in a separate window Severe COVID-19 represented 37 (35.58%) of total patients, 16 (15.38%) of them were managed in ICU with ventilator support. Moderate COVID-19 cases also accounted for 37 (35.58%) of total patients. These patients were mostly managed in a dedicated COVID-19 ward with 2 (1.92%) cases managed in ICU and 2 (1.92%) in HDU. All 30 (28.84%) mild cases were managed in the ward (Table 3). Table 3 COVID-19 severity and level of care received by the patients who received antibiotic therapy (n = 104). Level of care Mild n (%) Moderate n (%) Severe n (%) Total n (%) ICU with ventilator support - - 16 (15.38) 16 (15.38) ICU without ventilator support - 2 (1.92) 4 (3.85) 6 (5.77) HDU - 2 (1.92) 15 (14.42) 17 (16.35) Ward 30 (28.84) 33 (31.73) 2 (1.92) 65 (62.50) Open in a separate window The most common class of antibiotics used was cephalosporins in 85 (81.73%) patients followed by macrolides in 57 (54.81 %). Cefixime used in all cases was a substitute for ceftriaxone in oral form in 18 (17.31%) patients who were previously prescribed ceftriaxone. Beta-lactamase inhibitors were used in 35 (33.65%) in conjunction with penicillin (amoxicillin) or cephalosporin group of drugs (cefoperazone, cefepime). The most common combination used was cephalosporin with macrolides at 38 (36.54%) (Table 4). Table 4 Types of antibiotics used in management of COVID-19 patients (n = 104). Antibiotics n (%) Cephalosporins prescribed parenterally 85 (81.73) Ceftriaxone 76 (73.08) Cefepime sulbactam 3 (2.88) Cefoperazone sulbactam 6 (5.77) Cephalosporins prescribed enterally 18 (17.31) Cefixime 18 (17.31) Macrolides 57 (54.81) Azithromycin 55 (52.88) Erythromycin 1 (0.96) Clindamycin 1 (0.96) Penicillins 26 (25.00) Piperacillin tazobactam 14 (13.46) Amoxicillin clavulanic acid 12 (11.54) Quinolones 11 (10.58) Moxifloxacin 9 (8.65) Levofloxacin 2 (1.92) Ciprofloxacin 1 (0.96) Imidazoles 10 (9.62) Metronidazole 10 (9.62) Carbapenems 4 (3.85) Meropenem 4 (3.85) THIS IS A COCKTAIL THAT IS VERY DANGEROUS TO HEART MITOCHONDRIA-JORMA JYRKKANEN COMMENT DISCUSSION The prevalence of use of antibiotics was 98.1%. About 71.15% patients were treated with two or more antibiotics. The mean number of antibiotics used per patient was 1.86. The mean duration of antibiotics use was 6.33 days. Seventeen different antibiotics were used belonging to 7 different antibiotic classes. The most common class of antibiotics used was cephalosporin at 85 (81.73%) and macrolides at 57 (54.81%). Even before the COVID-19 pandemic, AMR was projected to become responsible for approximately 10 million deaths worldwide in the coming three decades.7 COVID-19 has undoubtedly affected antibiotic stewardship and has increased antibiotic consumption patterns globally, adding to the already existing global AMR problem. Because of this, the mortality due to AMR is expected to be higher in post COVID era.2 This pandemic has disrupted health delivery systems worldwide. This has increased the overuse of antibiotics, eventually leading to resistant organisms requiring aggressive treatment.8 Thus AMR is a problem of greater concern than COVID-19 which has unfortunately been overshadowed amidst the pandemic.7,9 Increased use of antibiotics is more challenging, especially in the low and middle-income countries (LMIC) due to the inefficiency and inadequacy of health care services.2 The Infectious Diseases Society of America (IDSA) states that only 8% of the COVID-19 patients acquired bacterial/fungal superinfections requiring antibiotics.10 However, a study showed 72% of COVID-19 patients received empirical broad-spectrum antibiotics, even when bacterial coinfection was absent.11 Current World Health Organization guidelines indicate that antibiotics should not be prescribed in mild or moderate COVID-19 cases unless there are pre-existing symptoms of bacterial co-infection. Furthermore, when treating severe cases with an empirical antimicrobial agent, the overall condition of the patient, local bacterial epidemiology, and clinical judgement should be integrated, to ensure judicial antimicrobial usage.12 In COVID-19 patients, antibiotics are used for potential anti-inflammatory, immune-modulating, and potential antiviral properties. But the antiviral mechanism of these agents is doubtful. This widespread antibiotic use is likely to worsen preexisting AMR crisis.13 The influenza pandemic was largely a problem of viral infection complicated by bacterial co-pathogenesis.14 This has been our basis for use of a wide range antibiotics empirically though COVID-19 is primarily a viral pathology and is not conventionally treated with antibiotics. In a study, 71.00% of the hospitalised COVID-19 patients received antibiotics despite a confirmed bacterial co-infection rate of only 1%.3 Antibiotic was used in 95.00% COVID-19 patients when secondary bacterial infection was only found in 15.00%.4 A systematic review showed the mean rate of antibiotic use was 74.00 %.5 In our study, the prevalence of use of antibiotics was 98.10% which is very high when compared to above studies. In most cases antibiotics use often empirical. Empiric antibiotics were often used for the concern of community-acquired pneumonia (89.00%).15 This showed that antibiotic therapy has been used often empirically in the majority of patients even when very few were proven to have bacterial coinfection. In our study, 17 different antibiotics belonging to seven antibiotic classes were used. Similar to our study a wide range of antibiotics use was documented in other studies.1,5,10,13,15-18 Many other classes of antibiotics other than above were used in other studies for the management of COVID-19 patients. They are aminoglycosides,1 glycopeptide antibiotic like vancomycin and teicoplanin,10 oxazolidinones like linezolid, tetracycline and cyclic lipopeptides like daptomycin.17 Most of these are newer classes of antibiotics and increased use of these should raise a red flag among concerned clinicians, pharmacists, microbiologists, public health experts, hospitals, local authorities as well as regulatory bodies. Carbapenem, fluoroquinolones, and aminoglycoside were highly prevalent in ICU patients.1 Similar to this carbapenem was exclusively used for ICU patients in our study. Other commonly used antibiotics among ICU patients were fluoroquinolones, cephalosporin, piperacillin with tazobactam, and macrolides. In general, ICU addmission compromises of a very sick patient with superadded bacterial infection and in regard to COVID-19, it comprises of severe COVID-19 infection often requiring ventilatory support. In such conditions, it is common practice to use multiple higher and broad-spectrum antibiotics. The common antibiotics in use were ceftriaxone (54.00%), vancomycin (48.00%), azithromycin (47.00%), and cefepime (45.00%).10 In our study ceftriaxone (73.08%) and azithromycin (52.88%) were widely used but cefepime was used in 2.88% of patients and vancomycin was not used at all. Higher antibiotics like cefepime and vancomycin should only be used when there is a valid indication, otherwise, it may result in resistant infection which will be very hard to treat. Ceftriaxone and azithromycin are often the most common antibiotics used in the management of COVID-19 patients.10,13,15,16 Most of the local guidelines as well as some international guidelines advocate for use of these antibiotics based on the epidemiology of local pathogens and resistance patterns. The advantage of the use of these antibiotics is that it covers most of the opportunistic pathogens that could cause secondary infection in COVID-19. But on the other hand, wide and inappropriate use of these antibiotics can lead to with emergence resistance of these common, cheap, and very efficient antibiotics. Macrolide, specifically azithromycin, was the most common antibiotic used in the clinical management of COVID-19.13 Macrolides, particularly azithromycin, were used in the treatment of more than half of the patients in our study. These drugs are often used to cover atypical organism that have the potential to cause a secondary infection.10,11 Fluoroquinolones were most used, (56.80%), followed by ceftriaxone (39.50%), then azithromycin (29.10%), and carbapenems were only used in two patients.18 Unlike to above study, in our study fluoroquinolones were used less (10.58%) and ceftriaxone and azithromycin was basically used in most patients. But similarity was observed between ours and the above study regarding the use of carbapenems, which was used in 3.85% of patients. Wide use of carbapenem, used in up to 40.10% of patients was also reported.5 carbapenem is often used as a reserved antibiotic for severe infection thus minimal use of these in COVID-19 signifies the presence of good antibiotics stewardship and antibiotic management system among concerned institutions while wide use can signify the opposite. The most common antibiotic used was third-generation cephalosporin (ceftriaxone) (53.80%), moxifloxacin (29.50%), and doxycycline (25.40%).5 Similar to the above study the most common class of antibiotics used in our study was cephalosporin (81.74%), around 90.00% of which was third-generation cephalosporin namely ceftriaxone (76/85). But unlike the above, Moxifloxacin was used in only 8.65% and doxycycline or other tetracycline group of drugs was not used at all in our study. A study showed all patients were receiving at least one antibiotic with 31.08% receiving a single antibiotic and 68.91% receiving multiple antibiotics.5 Similar to this study, 98.10% of patients in our study received at least one antibiotic, 28.35% received single antibiotic agents and 71.15% received multiple antibiotics. But the mean number of antibiotics used in the study above was 2.02 which is more when compared to 1.85 in our study. In 34.6%, three antibiotics were given simultaneously while 9.6% received only one antibiotic.16 Unlike the above, in our study three antibiotics were used in only 14.42% and a single antibiotic was used in 28.85%. The use of multiple antibiotics is worrisome as this might represent unchecked use of antibiotics which will contribute to the worldwide problem of AMR. In our study, patients with comorbidity were found to have received multiple antibiotics (72.90%). Around 74.00% of patients with diabetes were on multiple antibiotics. Similar findings were documented in another study.5 This might be due to COVID-19 patients with comorbidities like diabetes, airway diseases, hypertension being at greater risk of developing secondary bacterial infection.19 After predicting the risk of secondary infection, multiple antibiotics were used empirically in those patients. Overall, patients presenting with severe disease received more antibiotics.5 This is also true for our study. COVID-19 patients with co-morbidities and severe COVID-19 are the two most vulnerable groups of patients, thus multiple antibiotics have been found to be used liberally in these patients. These situations can be dealt with systematically by establishing standard antibiotic prescribing guidelines considering local pathogens and sensitivity patterns to antibiotics. This could be further reinforced by appropriate clinical knowledge, laboratory facilities, and surveillance systems. In our study the mean duration of antibiotics treatment was 6.33 days which is nearly half when compared to 12.71 days with a range from 3 days to 23 days.16 Similar result was found in another study.18 Both of these, decreased and extended duration of antibiotic treatment might represent inappropriate and improper use of antibiotics regimen. Because both, underuse and overuse of antibiotics can result in the emergence of resistance. Our study is a single centred study and has a small sample size. Therefore, our findings may not be generalizable to other settings. Go to: CONCLUSIONS The prevalence of use of antibiotics among hospitalised COVID-19 patients was found to be higher when compared to other studies conducted in similar settings. Potential bacterial co-infection has been the basis for the use of antibiotics in the management of COVID-19 patients. The rate and number of antibiotics used for mild to moderate disease were also high. The common class of antibiotics used are cephalosporin and macrolides namely ceftriaxone and azithromycin. Higher class antibiotics were mostly used in the management of severe disease in ICU and with ventilator support. However, judicial use of antibiotics among COVID-19 patients with variable severity especially among those admitted in ICU and on ventilatory support could be promoted in order to reduce AMR during this COVID-19 pandemic. Robust antibiotic stewardship programs and surveillance systems should be implemented. Go to: ACKNOWLEDGMENTS The authors would like to acknowledge KIST Medical College and Teaching Hospital for their support. Go to: Conflict of Interest None. Go to: REFERENCES 1. Zeshan B, Karobari MI, Afzal N, Siddiq A, Basha S, Basheer SN, et al. The Usage of Antibiotics by COVID-19 Patients with Comorbidities: The Risk of Increased Antimicrobial Resistance. Antibiotics (Basel). 2021 Dec 29;11(1):35. doi: 10.3390/antibiotics11010035. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 2. Rizvi SG, Ahammad SZ. COVID-19 and antimicrobial resistance: A cross-study. Sci Total Environ. 2022 Feb 10;807(Pt 2):150873. doi: 10.1016/j.scitotenv.2021.150873. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 3. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 15;395(10223):507–13. doi: 10.1016/S0140-6736(20)30211-7. 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Jyrkkanen, Jorma. (2020). Antibiotic induced changes to mitochondria result in potential contributions to carcinogenesis, heart pathologies, other medical conditions and ecosystem risks. Journal of Cardiology and Cardiovascular Medicine. 5. 163-171. 10.29328/journal.jccm.1001104. In addition to providing energy to support the synthesis of the macromolecules essential for immune cell proliferation, mitochondria also act as signaling organelles, driving activation of immune cells via metabolic intermediates, mitochondrial DNA (mtDNA), and reactive oxygen species (ROS).Mar 22, 2022 Introduction Immune dysregulation, characterized by an imbalance between a systemic inflammatory response syndrome and a compensatory anti-inflammatory response syndrome, is often observed in critically ill patients [1, 2]. This imbalance between the pro- and anti-inflammatory responses frequently leads to immunoparalysis in critically ill patients, rendering them more susceptible to further infections, and is associated with increased mortality [3]. Currently, no effective treatments are available to restore immune homeostasis and reduce mortality in these patients, largely due to the heterogeneity in patients’ immune status and more importantly the lack of understanding of the underlying cause of such immune dysfunction [2, 4]. Immune response is not a standalone process but is interconnected with other cellular activities, a very important one of which is cellular metabolism. Metabolic pathways and immune response are tightly intertwined both in health and in disease [5]. The link between immune cell function and mitochondrial function is now well recognized and a field known as “immunometabolism” is dedicated to understanding the relationship between immune and metabolic pathways [6,7,8]. Mitochondria play a crucial role in regulating not only the growth, but also the function, of immune cells. In addition to providing energy to support the synthesis of the macromolecules essential for immune cell proliferation, mitochondria also act as signaling organelles, driving activation of immune cells via metabolic intermediates, mitochondrial DNA (mtDNA), and reactive oxygen species (ROS). In addition, mitochondrial dynamics (fusion and fission), biogenesis (synthesis of new mitochondria), and mitophagy (degradation of damaged mitochondria) also play important roles in regulating immune cell functions. Knowledge in immunometabolism in critical illness, in particularly sepsis, opens up a new paradigm in patient care. Potential therapies targeting metabolic pathways, instead of solely immune-related pathways, might be the way to repair cellular function and restore immune homeostasis [4]. The other aspect of immunometabolism—looking at how immune responses influence metabolic pathways—is equally important, but beyond the scope of this review. Interaction between metabolism and immune response at the organ level has been reviewed elsewhere [6]. Mitochondrial Machinery That Mediates and Regulates Immune Responses in Critical Illness Apart from being the powerhouse of the cell, the mitochondrion has emerged as a signaling hub that shapes and modulates how the immune system responds to infection or trauma. Mitochondrial dysfunction is evident in leukocytes from critically ill patients, and is believed to be the underlying cause of immunoparalysis and may account for the development of organ dysfunction [7,8,9]. Early recovery of mitochondrial function correlates with improved recovery in critically ill patients [10]. Metabolic Reprogramming The immune-regulating mitochondrial machinery is a complex network involving many pathways and mechanisms that diverge and converge at various levels. Metabolic reprogramming is one mechanism that has been well studied in both innate and adaptive immune cells. Immune cells at different activation states (quiescent vs. activated), or with different functions (pro-inflammatory vs. anti-inflammatory), and different cell types (granulocytes, macrophages, dendritic cells, T- and B-lymphocytes), make use of different metabolic pathways (e.g., glycolysis, oxidative phosphorylation, fatty acid metabolism) to produce ATP [11]. The choice of different metabolic pathways, supports the energy demand of cells at different activation state. For example, upon infection or stimulation, immune cells become activated and produce cytokines and hence tend to favor glycolysis over oxidative phosphorylation for fast turnaround of ATP. Although the same amount of starting material, such as glucose, is used, oxidative phosphorylation generates 18 times more ATP than glycolysis, although is a lot slower. On the other hand, the choice of metabolic pathway determines the fate of the immune cells, i.e., naïve or memory, effector or regulatory, etc. However, the environment that the cells are in in the first place, triggers the changes in the metabolic pathways. The overall trend is that neutrophils, inflammatory macrophages (M1 macrophages), activated effector T cells, and dendritic cells rely more on aerobic glycolysis, whereas alternatively polarized macrophages (M2 macrophages), regulatory T cells (Tregs), and memory T cells prefer oxidative phosphorylation and fatty acid oxidation for energy production [8, 11, 12]. Metabolic reprogramming serves an important role in catering for the immune cells’ energy demand at different phases of their activation and proliferation. However, imbalance across the metabolic pathways could have serious pathological impact. One example may be the hyperlactatemia often seen in critically ill patients. Increased aerobic glycolysis in the activated immune cells during the initial hyper- inflammatory response is believed to contribute to the increase in blood lactate levels in sepsis [13, 14]. Mitochondrial ROS and mtDNA Metabolic reprogramming sets the scene for the immune response, which is then subjected to many more modifications and regulations by factors that are directly or indirectly related to mitochondrial metabolism. Two important mitochondria-related immune regulators that have been well studied are mitochondrial ROS and mtDNA. Mitochondrial ROS are produced in healthy mitochondria, as a by-product of oxidative phosphorylation. At low dose, mitochondrial ROS serve important signaling functions, especially in the innate immune response. They are known to mediate NLRP3 inflammasome activation, leading to production of the pro-inflammatory cytokines, interleukin (IL)-1β and IL-18 [8, 15]. Mitochondrial ROS also induce a type-I interferon (IFN) response via mitochondrial antiviral-signaling (MAVS) and the IFN regulatory factor 3 (IRF3) pathway [16]. However, the level of mitochondrial ROS needs to be tightly regulated by the antioxidant system. Excessive mitochondrial ROS can cause oxidative damage to proteins/enzymes involved in oxidative phosphorylation and create mutations in mtDNA, contributing to the immune dysregulations as seen in critical illness [17]. Like mitochon-drial ROS, mtDNA also plays an important role in innate immunity [12]. In healthy cells, mtDNA is located in the matrix of mitochondria, encoding 13 proteins, all of which are components of oxidative phosphorylation. mtDNA is released to the cytosol upon mitochondrial dysfunction which involves changes to the integrity or permeability of the mitochondrial membrane. mtDNA, released into the cytosol, can activate the NLRP3 inflammasome with release of IL-1β and IL-18. Due to its bacterial origin, cytosolic mtDNA also serves as a damage-associated molecular pattern (DAMP), which can be recognized by intracellular pattern recognition receptors (PRRs), such as Toll-like receptor 9 (TLR9), and initiate the nuclear factor-kappa B (NF-κB)-dependent pro-inflammatory signaling pathway. In addition, cytosolic mtDNA can also be sensed by cyclic GMP-AMP synthase (cGAS) and activate the cGAS/stimulator of IFN genes (cGAS/STING) pathway and its downstream IFN response [18]. mtDNA can also be released into the circulation and cause systemic inflammation. Circulating mtDNA has been associated with mortality in critically ill patients [19]. Succinate and Itaconate In addition to mitochondrial ROS and mtDNA, metabolites such as succinate and itaconate have also emerged as part of immune-regulating mitochondrial machinery [4, 20]. Both succinate and itaconate are intermediates from the tricarboxylic acid (TCA) cycle with opposite effects on the immune response. The TCA cycle generates nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2), providing electrons to fuel oxidative phosphorylation. Succinate accumulation occurs under conditions such as hypoxia or inflammation. It can be released from mitochondria into the cytosol and functions as a signal transducer promoting pro-inflammatory gene expression via hypoxia-inducible factor 1α (HIF-1α) activation. Accumulation and oxidation of succinate by succinate dehydrogenase (SDH) in the mitochondria also leads to increased production of mitochondrial ROS via a process called reverse electron transport. This further enhances the pro- inflammatory effect of succinate. Like ROS, the level of succinate needs to be carefully regulated due to its inflammation aggravating effect. Plasma succinate has been proposed as a predictor of mortality for critically ill patients who are severely injured [21]. Itaconate, which is derived from cis-aconitate of the TCA cycle, is a succinate-regulating factor. It is shown to counteract the pro-inflammatory effect of succinate by inhibiting SDH. Itaconate can also be released into the cytosol and activate transcription factor NF-E2 p45-related factor 2 (Nrf2), a master regulator of antioxidant and anti-inflammatory responses [22]. Recently, itaconate has also been shown to inhibit the inflammatory response in macrophages through activating transcription factor 3 (ATF3). Mitochondrial Dynamics The above mentioned immune-regulating mitochondrial factors are centered around the biochemical aspect of mitochondrial biology. Another important aspect of immune-regulating mitochondrial machinery is mitochondrial dynamics, which is to maintain and provide infrastructural support for the immune response. The size and shape of mitochondria undergo constant change through fusion and fission, which is important for maintaining the health and function of mitochondria. First, fusion incorporates newly synthesized mitochondria (from mitochondrial biogenesis) into the current mitochondrial network. Second, fusion also allows for mixing of proteins and/or mtDNA between the existing mitochondria, which on one hand enhances the metabolic capacity of the mitochondria, and on the other enables the damaged proteins and/or mutated mtDNA to be segregated from the healthy ones. Finally, segregation is achieved via fission and the damaged mitochondria can be destroyed through a process known as mitophagy. The proportion of mitochondria with damaged proteins or mutated mtDNA is kept below a critical threshold level through this process to maintain mitochondrial function [23, 24]. In addition to quality control, mitochondrial fusion and fission also participate in immune regulation. In activated T cells, there is an increase in fission, which creates round and fragmented mitochondria with loose cristae, favoring aerobic glycolysis. And in 146 memory T cells, increased fusion generates elongated mitochondria which favors oxidative phosphorylation and fatty acid oxidation [8, 25]. Immunometabolism: The Perfect World Scenario vs. the Critical Illness Scenario So far, we have presented a list of mitochondrial components that are thought to play important roles in regulating the immune response. Our list is far from complete, but does highlight a few mechanisms that could relate to the development of immune dysregulation in critical illness. Figure 1 illustrates what we think would happen to the immune response when metabolism was in perfect control (the perfect world scenario) and when it became inconsistent and changeable (the critical illness scenario). In the perfect world scenario, the presence of an insult (e.g., infection or a trauma-related stress signal), would trigger metabolic reprogramming, switching from oxidative phosphorylation to glycolysis. This would enable activation of immune cells and production of pro-inflammatory cytokines and other mediators. At the same time, mitochondrial fission would increase to keep up with the metabolic reprogramming. The slightly elevated mitochondrial ROS and succinate in response to initial insult or cytokines would promote the pro-inflammatory response. Once the insult was eliminated, mitochondrial fusion would increase to create fused elongated mitochondria that favor oxidative phosphorylation and fatty acid oxidation. This would allow activation of regulatory immune cells and production of anti-inflammatory cytokines and other mediators. And itaconate would counteract the effect of succinate, activate the Nrf2-mediated antioxidant pathway to dampen down mitochondrial ROS, and activate ATF3 to inhibit the inflammatory response in macrophages. Immune homeostasis would be achieved as a result. Fig. 1 figure 1 Immunometabolism in the ‘perfect world scenario’ vs. the ‘critical illness scenario’. OXPHOS oxidative phosphorylation, FAO fatty acid oxidation Full size image In the critical illness scenario, initial metabolic reprogramming from oxidative phosphorylation to glycolysis would go on for longer than necessary, generating excessive lactate (hyperlactatemia) and pro-inflammatory cytokines and mediators. A disrupted mitochondrial fusion/fission cycle could be to blame, one which could not support the timely switch to oxidative phosphorylation and fatty acid oxidation. The anti-inflammatory response would eventually kick in but by then damage would already have occurred to mitochondria and mtDNA because of excessive production of ROS in response to stress or cytokines. Excessive ROS and released mtDNA would aggravate the pro-inflammatory response, which in turn would trigger a more aggressive anti-inflammatory response to try and salvage the situation. The competition between pro- and anti-inflammatory responses would exhaust the nutrients and lead to shutdown of the whole metabolic system. Cells would either die or go into hibernation to preserve energy [26]. This scenario is an over-simplified version of what might happen in the actual disease setting, without considering the crosstalk between cells and organs and many other factors that are not included here. It is designed to shed light on the interaction between the immune response and metabolism. Potential of Mitochondria-Targeting Therapy in Critical Care Our understanding thus far leads us to think that targeting mitochondria could perhaps correct the underlying cause of immune dysfunction in critical illness and lead to better recovery of the patients. The central role of mitochondrial dynamics in supporting and initiating metabolic reprogramming would make it the perfect therapeutic target. To get the fusion/fission cycle going, the mitochondrial network needs to be replenished by newly synthesized mitochondria via biogenesis. Therapies that could potentially boost mitochondrial biogenesis are mitochondrial transplantation, metformin, nitric oxide (NO), and carbon monoxide. Mitochondrial transplantation has been used successfully in pediatric patients with myocardial ischemia–reperfusion injury [27]. Metformin can activate peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1α (PGC-1α), and Nrf2, the master regulator of mitochondrial biogenesis and antioxidant systems [28]. Premorbid use of metfor-min is associated with lower mortality in sepsis [29]. NO and carbon monoxide can also enhance mitochondrial biogenesis [30,31,32]. Dietary nitrite has been trialed in patients with coronary artery disease (ClinicalTrials.gov Identifier: NCT00069654). Other therapies, such as mitochondria-targeted antioxidant (MitoQ) [33], could also be beneficial in protecting mtDNA and oxidative phosphorylation from oxidative damage. MitoQ has been trialed in people with Parkinson’s disease (ClinicalTrials. gov Identifier: NCT00329056). Challenges of Applying Mitochondria-Targeting Therapy in Critical Care There are challenges to overcome before mitochondria-targeting therapy would be possible. First, how do we assess mitochondrial dysfunction in the clinic and identify patients who would benefit from such therapy? A few possible ways could be considered. Non-invasive assessment of mitochondrial oxygen metabolism using a novel device called the COMET monitor was tested on 40 patients during the acute phase of sepsis. This device is based on the protoporphyrin IX-triplet state lifetime technique (PpIX-TSLT) and has been shown to be feasible [33]. This technology is still in its early phase of clinical application but does offer some hope. Another possible biomarker that could potentially be used for assessing mitochondrial dysfunction is plasma mtDNA, but its sensitivity and specificity need further investigation [19, 34, 35]. Furthermore, we could consider using immune response markers as a surrogate markers, one such example could be IFNα inducible protein 27 (IFI27) [36]. If we could overcome the first challenge, the second would be how to deliver mitochondria-targeting therapies to the right organ at the right time. Conclusion In this chapter, we have demonstrated the important role of mitochondria in regulating the immune response and proposed a scenario that explains immune–metabolism crosstalk in the context of critical illness. We have highlighted the role of mitochon-drial dynamics in overseeing and supporting metabolic reprogramming during immune cell activation. Mitochondrial ROS can be friend or foe when it comes to immune regulation. 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