key: cord-0809431-lcmjylnv
authors: Liu, Gui-E.; Tian, Yuan; Zhao, Wen-Jun; Song, Shuang-Ming; Li, Lei
title: From H1N1 to 2019-nCoV, what do we learn?
date: 2020-06-25
journal: Chin J Traumatol
DOI: 10.1016/j.cjtee.2020.06.005
sha: 4f98da45a705a18586da949c4689881d4b8ebe35
doc_id: 809431
cord_uid: lcmjylnv

The COVID-19 pandemic is still raging across the world. Everyday thousands of infected people lost their lives. What's worse, there is no specific medicine and we do not know when the end of the pandemic will come. The nearest global pandemic is the 1918 influenza, which caused about 50 million deaths and partly terminate the World WarⅠ. We believe that no matter the virus H1N1 for the 1918 influenza or 2019-nCoV for COVID-19, they are essentially the same and the final cause of death is sepsis. The definition and diagnostic/management criteria of sepsis have been modified several times but the mortality rate has not been improved until date. Over decades, researchers focus either on the immunosuppression or on the excessive inflammatory response following trauma or body exposure to harmful stimuli. But the immune response is very complex with various regulating factors involved in, such as neurotransmitter, endocrine hormone, etc. Sepsis is not a kind of disease instead of a misbalance of the body following infection, trauma or other harmful stimulation. Therefore we should re-think sepsis comprehensively with the concept of systemic biology, i.e. inflammationomics.

February, the risk was promoted to be "very high" but the word "pandemic" was still refused. On 11 March, about 4 month from the primary reported infections, COVID-19 was finally defined as "pandemic". Till the date of 15 June, 2020, there were 216 countries involved with 7823289 confirmed cases and 431541 deaths reported all over the world. 4 The frequent international exchange quickens the transmission of infectious diseases and complexes their control and prevention.

What has taught us after a century of vicissitudes? Unfortunately, the answer is no breakthrough. When facing the centurial outbreak, extincting pathogens, isolating the source of infection, cutting the transmission route and enhancing the Herd immunity are still the most effective measures to fight against the pandemic. Moreover, to date, no existing medicine has been found to be effective or specific to 2019-nCoV. As for the development of vaccines that can be of immunoprotective effects, there is still a long way to go. The only choice we have at present is repeated screening and isolation of infection sources to cut off the transmission route, which means endless cancel and shutdown of any social gathering.

A virus is a non-cellular nucleic acid, essentially single-stranded RNA or double-stranded DNA. Viruses must parasitize host cells, which thereby may cause destruction to host cells and result in infectious diseases.

When pathogenic microorganisms invade the body, colonize & proliferate in the body, and cause local or systemic toxic reactions, it is called infection. If the infection aggravates and further induces organ dysfunction, it is called sepsis.

No matter H1N1 or 2019-nCoV is essentially pathogenic microorganism; and thus the first targeted organ is the lung.

The main cause of death for either the 1918 influenza pandemic a hundred years ago (lethal pneumonia) or COVID-19 (respiratory failure) is believed by the managing editor Lei Li to be the same in essence---sepsis, although the pathological mechanism may be somewhat different.

Sepsis was first mentioned by scriptures in ancient Greece. The word "sepsis" came from the Greek word "sepo", which means "make rotten", and was first used in medical context in Homer's poems. The Austria scientist Ignaz Semmelweiss first introduced "sepsis" in modern medicine as the result of an infection. Then, the study by Joseph Lister, Louis Pasteur and Robert Koch further enriched our understanding of microbiology and infectious disease. Whether H1N1 or 2019-nCoV, they can trigger abnormal immune responses or overwhelming inflammatory response, which leads to endothelial damage, deregulation of coagulation, and eventually changes in microvascular permeability, tissue edema, and shock in the end.

The concept of modern sepsis, especially the understanding of its pathological mechanisms, has experienced some twists and turns. As early as 1992, sepsis was defined as systemic inflammatory response syndrome. Sepsis can be diagnosed with signs of infection and any two of the following symptoms: (1) tachycardia or tachypnea (>20 breaths/min),

(2) fever (temperature>38℃) or hypothermia (temperature<36℃), (3) leukopenia (<4000/μL), leukocytosis (>10000/μL), or immature neutrophil >10%, and (4) heart rate>90 beats/min This is the first diagnostic standard for sepsis, namely sepsis definition version 1, or sepsis-1. Because the diagnostic standard is too broad, sepsis-1 was criticized and unpopular in clinical practice. The core improvement for sepsis-3 lay in that sepsis was defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For clinical operationalization, organ dysfunction can be represented by a >10% in-hospital mortality with an increase in the sequential (sepsis-related) organ failure assessment (SOFA) score ≥2 points.

Septic shock was defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure ≥65 mm Hg and serum lactate level >2 mmol/L (>180 mg/L) in the absence of hypovolemia. This combination is associated with a hospital mortality rate >40%. In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA: respiratory rate ≥22/min, altered mentation, or systolic blood pressure ≤100 mm Hg. 5 Actually we believe that sepsis is essentially a kind of excessive inflammatory response against pathogenic microbes, during which some other harmful stimuli such as necrotic tissue and/or cells debris aggravate the inflammatory insults.

Although the concept of sepsis and the international guidelines for its management have been constantly updating, the mortality rate caused by sepsis has not been significantly reduced. For severe trauma patients, the major cause of death is In recent years, autopsy of trauma sepsis death revealed numerous necrotic and apoptotic immune cells in the patient's spleen and lymph nodes, which gradually guide the understanding of trauma sepsis back to rationality, i.e. the body reaction after severe trauma include not only excessive inflammation but also obviously suppressed immune defense function.

Excessive inflammatory response and suppressed immune function, this is a dilemma during the treatment of trauma patients at the middle and late stages. To enhance the immune function may further aggravate inflammatory damage, whereas to control the inflammatory response may accelerate the already existing immunosuppression state. Many factors can trigger sepsis, such as various pathogenic microorganisms. Some broken tissue cells and metabolites can also aggravate septic reaction, and even induce inflammatory damage like sepsis to a certain extent.

During the onset and progress of sepsis, the participating cells are not limited to immune inflammatory cells; others like endothelial cells, liver cells, kidney cells, etc. are also involved. Regarding the signaling pathways to regulate inflammatory response receptors, it has been found that both intracellular receptors (membrane receptors, cytoplasmic receptors, nucleus receptors) and extracellular receptors (soluble receptors) are jointly involved. In additional, endocrine factors and neurotransmitters also participate in the regulation of host response. Over the years, we have focused too much on the signaling pathways of some receptors, but the most basic pathophysiological responses were ignored. Now is the time to be more rational and balance a certain focus on the systems biology.

Once a trauma occurs, immune inflammation reaction appears. Until wound healing, inflammation, immunity, coagulation, and more important systemic biological response after trauma should be monitored. Since we have proteomics, genomics, and metabolomics, and so on, why cannot we create an inflammationomics. 6 The so-called inflammationomics is an emerging discipline that studies the onset and progress of inflammation and its outcome with the concept of systems biology, specifically inflammationomics comprehensively analyze the heat map of activated whole genome expression (genomic heat maps), the spectrum expression pattern of total protein, and the predictive value on the prognosis of inflammation via the technologies of genomics, proteomics, and metabonomics. Based on big data, inflammationomics is supposed to provide a dynamic all-sided analysis and research on the pathophysiological process of body inflammatory response, which may set the theoretical foundation for revealing the mechanism of inflammation outcome and exploring strategies for inflammation prevention and control.

Test your knowledge of the 1918 Influenza Pandemic, commonly known as Spanish Flu

History and Evolution of Influenza Control Through Vaccination: From the First Monovalent Vaccine to Universal Vaccines

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

Inflammationomics---A new concept to explore the new sepsis