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      The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in Patients With Critical COVID-19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial*

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          OBJECTIVES:

          Respiratory failure is a lethal complication of COVID-19 that has remained resistant to drug therapy. Vasoactive intestinal peptide (VIP) is shown in nonclinical studies to upregulate surfactant production, inhibit cytokine synthesis, prevent cytopathy, and block replication of the severe acute respiratory syndrome coronavirus 2 virus in pulmonary cells. The study aims to determine whether Aviptadil (synthetic VIP) can improve survival and recovery in patients with COVID-19 respiratory failure compared with placebo and demonstrate biological effects in such patients.

          DESIGN:

          A multicenter, placebo-controlled trial.

          SETTING:

          Ten U.S. hospitals: six tertiary-care hospitals and four community hospitals.

          PATIENTS:

          A total of 196 patients with COVID-19 respiratory failure.

          INTERVENTIONS:

          Participants were randomized 2:1 to receive 3 days of IV Aviptadil or placebo.

          MEASUREMENTS AND MAIN RESULTS:

          The primary end point (alive and free from respiratory failure at day 60) did not reach statistical significance (odds ratio [OR], 1.6; 95% CI, 0.86–3.11) for patients treated with Aviptadil when controlling for baseline ventilation status as prespecified in the protocol. There was, however, a statistically significant two-fold odds of improved survival (OR, 2.0; 95% CI, 1.1–3.9) at 60 days ( p = 0.035). There was significant improvement in respiratory distress ratio and reduced interleukin 6 cytokine release ( p = 0.02) by day 3.

          Subgroup analysis identified a statistically significant likelihood of achieving primary end point among those treated with high-flow nasal oxygen at baseline ( p = 0.039). Subjects on mechanical ventilation also experienced a 10-fold increased odds of survival with drug versus placebo ( p = 0.031).

          CONCLUSIONS:

          The primary end point did not reach statistical significance, indicating that there was no difference between Aviptadil versus placebo. However, Aviptadil improves the likelihood of survival from respiratory failure at day 60 in critical COVID-19 across all sites of care. Given the absence of drug-related serious adverse events and acceptable safety profile, we believe the benefit versus risk for the use of Aviptadil is favorable for patient treatment.

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          Cytokine Storm

          David C Fajgenbaum, Carl H. June (2020)
          The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has reminded us of the critical role of an effective host immune response and the devastating effect of immune dysregulation. This year marks 10 years since the first description of a cytokine storm that developed after chimeric antigen receptor (CAR) T-cell therapy 1 and 27 years since the term was first used in the literature to describe the engraftment syndrome of acute graft-versus-host disease after allogeneic hematopoietic stem-cell transplantation. 2 The term “cytokine release syndrome” was coined to describe a similar syndrome after infusion of muromonab-CD3 (OKT3). 3 Cytokine storm and cytokine release syndrome are life-threatening systemic inflammatory syndromes involving elevated levels of circulating cytokines and immune-cell hyperactivation that can be triggered by various therapies, pathogens, cancers, autoimmune conditions, and monogenic disorders. From a historical perspective, cytokine storm was previously referred to as an influenza-like syndrome that occurred after systemic infections such as sepsis and after immunotherapies such as Coley’s toxins. 4 Yersinia pestis infection (i.e., the plague) has led to major pandemics (e.g., the Black Death) and triggers alveolar macrophages to produce excessive amounts of cytokines, resulting in cytokine storm. 5 An exaggerated immune response was suspected to contribute to the lethality of the 1918–1919 influenza pandemic. In fact, a reconstructed H1N1 virus isolated from the 1918 pandemic, as compared with common reference strains of the virus that causes influenza A, triggered marked pulmonary inflammation in mice. 6 Recognition that the immune response to the pathogen, but not the pathogen itself, can contribute to multiorgan dysfunction and that similar cytokine storm syndromes could occur with no obvious infection led to the investigation of immunomodulators and cytokine-directed therapies. One of the earliest targeted therapies for abrogation of a cytokine storm was the anti–interleukin-6 receptor monoclonal antibody tocilizumab, which was developed for the treatment of idiopathic multicentric Castleman’s disease in the 1990s. A host of other disorders have been described as causes of cytokine storm and targeted with immune-directed therapies, such as sepsis, primary and secondary hemophagocytic lymphohistiocytosis (HLH), autoinflammatory disorders, and coronavirus disease 2019 (Covid-19). No single definition of cytokine storm or the cytokine release syndrome is widely accepted, and there is disagreement about how these disorders differ from an appropriate inflammatory response. The National Cancer Institute’s definition, based on the Common Terminology Criteria for Adverse Events (CTCAE), is too broad, since the criteria for an inflammatory syndrome can also apply to other physiological states, and the definition of the American Society for Transplantation and Cellular Therapy is based on criteria that focus too specifically on iatrogenic causes of cytokine storm alone. 7 Although cytokine storm is easy to identify in disorders with elevated cytokine levels in the absence of pathogens, the line between a normal and a dysregulated response to a severe infection is blurry, especially considering that certain cytokines may be both helpful in controlling an infection and harmful to the host. The interdependence of these inflammatory mediators further complicates the distinction between a normal and a dysregulated response. It is important for the clinician to recognize cytokine storm because it has prognostic and therapeutic implications. In this review, we propose a unifying definition of cytokine storm; discuss the pathophysiological features, clinical presentation, and management of the syndrome; and provide an overview of iatrogenic, pathogen-induced, neoplasia-induced, and monogenic causes. Our goal is to provide physicians with a conceptual framework, a unifying definition, and essential staging, assessment, and therapeutic tools to manage cytokine storm. Clinical Features and Laboratory Abnormalities Cytokine storm is an umbrella term encompassing several disorders of immune dysregulation characterized by constitutional symptoms, systemic inflammation, and multiorgan dysfunction that can lead to multiorgan failure if inadequately treated (Figure 1). The onset and duration of cytokine storm vary, depending on the cause and treatments administered. 7 Although the initial drivers may differ, late-stage clinical manifestations of cytokine storm converge and often overlap. Nearly all patients with cytokine storm are febrile, and the fever may be high grade in severe cases. 8 In addition, patients may have fatigue, anorexia, headache, rash, diarrhea, arthralgia, myalgia, and neuropsychiatric findings. These symptoms may be due directly to cytokine-induced tissue damage or acute-phase physiological changes or may result from immune-cell–mediated responses. Cases can progress rapidly to disseminated intravascular coagulation with either vascular occlusion or catastrophic hemorrhages, dyspnea, hypoxemia, hypotension, hemostatic imbalance, vasodilatory shock, and death. Many patients have respiratory symptoms, including cough and tachypnea, that can progress to acute respiratory distress syndrome (ARDS), with hypoxemia that may require mechanical ventilation. The combination of hyperinflammation, coagulopathy, and low platelet counts places patients with cytokine storm at high risk for spontaneous hemorrhage. In severe cases of cytokine storm, renal failure, acute liver injury or cholestasis, and a stress-related or takotsubo-like cardiomyopathy can also develop. 9 The combination of renal dysfunction, endothelial-cell death, and acute-phase hypoalbuminemia can lead to capillary leak syndrome and anasarca — changes that are similar to those observed in patients with cancer who are treated with high-dose interleukin-2. 10 Neurologic toxicity associated with T-cell immunotherapy is referred to as immune effector cell–associated neurotoxicity syndrome or cytokine release syndrome–associated encephalopathy. 7 The neurologic toxic effects are often delayed, developing several days after the onset of the cytokine storm. The laboratory findings in cytokine storm are variable and influenced by the underlying cause. Nonspecific markers of inflammation such as C-reactive protein (CRP) are universally elevated and correlate with severity. 11 Many patients have hypertriglyceridemia and various blood-count abnormalities, such as leukocytosis, leukopenia, anemia, thrombocytopenia, and elevated ferritin and d-dimer levels. Changes in circulating cell counts are most likely due to a complex interplay among cytokine-induced changes in production and mobilization of cells from the bone marrow, immune-mediated destruction, and chemokine-induced migration. Prominent elevations in serum inflammatory cytokine levels, such as interferon-γ (or CXCL9 and CXCL10, chemokines induced by interferon-γ), interleukin-6, interleukin-10, and soluble interleukin-2 receptor alpha, a marker of T-cell activation, are usually present. Highly elevated serum interleukin-6 levels are found in CAR T-cell therapy–induced cytokine storm and several other cytokine storm disorders. 8 The approach to evaluating a patient with cytokine storm should accomplish the following three main goals: identifying the underlying disorder (and ruling out disorders that may mimic cytokine storm), establishing severity, and determining the clinical trajectory. A complete workup for infection, as well as laboratory assessment of kidney and liver function, should be performed in all suspected cases of cytokine storm. Measurements of inflammatory acute-phase biomarkers, such as CRP and ferritin, and blood counts should be obtained, since they correlate with disease activity. Arterial blood-gas measurement should be performed if the respiratory evaluation warrants it. Cytokine profiles may be helpful in determining the trend from baseline values, although these findings are typically not available soon enough to include as part of the immediate workup or to guide treatment decisions. Establishing the disorder underlying the cytokine storm can be challenging. Cytokine storm is not a diagnosis of exclusion, and it can encompass many disorders. For example, patients may have both sepsis and cytokine storm. However, it is important to distinguish between cytokine storm due to an iatrogenic cause such as CAR T-cell therapy and cytokine storm due to systemic infection, since immunosuppressive treatments could be detrimental if used in patients with septicemia. Unfortunately, it is difficult to distinguish cytokine storm due to sepsis from cytokine storm due to CAR T-cell therapy on the basis of clinical features alone. Levels of serum cytokines — most prominently, interferon-γ — are often more elevated in patients with cytokine storm due to CAR T-cell therapy than in patients with sepsis-induced cytokine storm, who often have higher levels of circulating interleukin-1β, procalcitonin, and markers of endothelial damage. 12 Thus, combinations of assays to rule out infection and measure serum cytokines can help to identify the cause of the cytokine storm. However, CAR T-cell therapy and other noninfectious causes can also occur with infections, and infections can develop during the course of therapy, so continued monitoring for infections is warranted. Disorders that should be ruled out in considering cytokine storm include anaphylaxis and physiological responses to microbial infections. The grading systems used to predict and assess the severity of cytokine storm differ according to the cause. Serum biomarkers, including glycoprotein 130 (gp130), interferon-γ, and interleukin-1–receptor antagonist (IL1RA), can be used to predict the severity of cytokine storm induced by CAR T-cell therapy, 13 with a separate grading scale used to assess the current severity. 7 HScore and MS score are used for classifying HLH-associated cytokine storm, and HLH-2004 guides treatment. For the grading of cytokine storm due to other causes, the immune systems disorders section of CTCAE is used (https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf). Pathophysiological Features of Cytokine Storm Inflammation involves a set of biologic mechanisms that evolved in multicellular organisms to contain invasive pathogens and resolve injuries by activating innate and adaptive immune responses. The immune system is expected to recognize foreign invaders, respond proportionally to the pathogen burden, and then return to homeostasis. This response requires a balance between sufficient cytokine production to eliminate the pathogen and avoidance of a hyperinflammatory response in which an overabundance of cytokines causes clinically significant collateral damage. Cytokines play a key role in coordinating antimicrobial effector cells and providing regulatory signals that direct, amplify, and resolve the immune response. Cytokines have short half-lives, which normally prevents them from having effects outside lymphoid tissue and sites of inflammation. Although typically considered to be pathologic, sustained production of cytokines that leads to elevated circulating levels may be necessary to appropriately control some disseminated infections. At increased levels, cytokines can have systemic effects and cause collateral damage to vital organ systems. Immune hyperactivation in cytokine storm can occur as a result of inappropriate triggering or danger sensing, with a response initiated in the absence of a pathogen (e.g., in genetic disorders involving inappropriate inflammasome activation or idiopathic multicentric Castleman’s disease); an inappropriate or ineffective amplitude of response, involving excessive effector immune-cell activation (e.g., in cytokine storm due to CAR T-cell therapy), an overwhelming pathogen burden (e.g., in sepsis), or uncontrolled infections and prolonged immune activation (e.g., in HLH associated with Epstein–Barr virus [EBV]); or failure to resolve the immune response and return to homeostasis (e.g., in primary HLH) (Figure 2). In each of these states, there is a failure of negative feedback mechanisms that are meant to prevent hyperinflammation and the overproduction of inflammatory cytokines and soluble mediators. The excessive cytokine production leads to hyperinflammation and multiorgan failure. Regulatory cell types, decoy receptors for proinflammatory cytokines such as IL1RA, and antiinflammatory cytokines such as interleukin-10 are important for antagonizing inflammatory-cell populations and preventing immune hyperactivity. Given the lack of a unifying definition for cytokine storm 14 and disagreement about the distinction between cytokine storm and a physiologic inflammatory response, we propose the following three criteria for identifying cytokine storm: elevated circulating cytokine levels, acute systemic inflammatory symptoms, and either secondary organ dysfunction (often renal, hepatic, or pulmonary) due to inflammation beyond that which could be attributed to a normal response to a pathogen (if a pathogen is present), or any cytokine-driven organ dysfunction (if no pathogen is present). Improvement in outcomes with cytokine neutralization or antiinflammatory agents further supports the pathologic role of excessive cytokines and the classification of a condition as a cytokine storm. However, lack of a treatment response does not necessarily rule out cytokine storm, because underlying conditions are likely to play a part, a different cytokine may be the disease driver, or the timing of treatment may have been poor. In short, cytokine storm involves an immune response that causes collateral damage, which may be greater than the immediate benefit of the immune response. Thus, an exuberant inflammatory response to a large pathogen burden may be appropriate for controlling the infection if excessive secondary organ dysfunction does not occur, whereas similarly high levels of cytokines in cancer-associated HLH or idiopathic multicentric Castleman’s disease would be considered a pathologic state of cytokine storm because no pathogen requiring an immune response is involved and patients benefit from treatment with cytokine neutralization and other antiinflammatory agents. Circulating cytokine levels can be difficult to measure because cytokines have short half-lives, circulating levels may not accurately reflect local tissue levels, and measurements may not be easily obtained worldwide. We do not propose a specific threshold for elevations in cytokine levels above the normal range, and we do not recommend specific cytokine panels or list particular cytokines whose levels must be elevated, given the lack of available evidence. However, we believe that this is an important area for future research and could benefit from systematic assessment by a multidisciplinary consortium. Cell Types Involved in Cytokine Storm The cells of the innate immune system are the first line of defense against pathogens. Neutrophils, monocytes, and macrophages recognize pathogens, produce cytokines, and engulf pathogens and cells by phagocytosis. There are many other innate immune cells, such as dendritic cells, gamma–delta T cells, and natural killer (NK) cells. 15 Innate immune cells use pattern-recognition receptors, which are not specific for any particular antigen, to recognize and respond to a wide variety of microbial invaders by producing cytokines that activate cells of the adaptive immune system. Innate cells that are most often implicated in the pathogenesis of cytokine storm include neutrophils, macrophages, and NK cells. Neutrophils can produce neutrophil extracellular traps, a network of fibers that contribute to thrombi formation and amplify cytokine production during cytokine storm. Macrophages, which are tissue-resident cells that are often derived from circulating monocytes, do not divide; they have diverse functions, from the removal of senescent cells by engulfment, to tissue repair and immunoregulation, to antigen presentation. In many forms of cytokine storm, macrophages become activated and secrete excessive amounts of cytokines, ultimately causing severe tissue damage that can lead to organ failure. Hemophagocytic macrophages are often observed in bone marrow biopsy specimens from patients with cytokine storm. Interferon-γ can induce hemophagocytosis by macrophages, and this may contribute to the cytopenias commonly observed in patients with cytokine storm. 16 The cytolytic function of NK cells is diminished in some forms of cytokine storm, which can lead to prolonged antigenic stimulation and difficulty resolving inflammation. 17 Excess interleukin-6 may mediate the impairment in NK-cell function by lowering perforin and granzyme production. The adaptive immune system is composed of B cells and T cells. T cells differentiate into a number of subsets with distinct effector-cell functions potentially involved in cytokine storm (Figure 3). Type 1 helper T (Th1) cells and cytotoxic T lymphocytes (CTLs) are primarily responsible for the host defense against viral infections. Th1 cells regulate the recruitment of macrophages, whereas type 2 helper T (Th2) cells recruit eosinophils and basophils, type 9 helper T (Th9) cells recruit mast cells, and type 17 helper T (Th17) cells recruit neutrophils. 18 An exaggerated Th1-type inflammatory response often occurs during cytokine storm. Th1 cells produce large quantities of interferon-γ, induce delayed hypersensitivity reactions, activate macrophages, and are essential for defense against intracellular pathogens. 19 Iatrogenic causes of cytokine storm involving excessive T-cell activation, such as CAR T-cell and anti-CD28 antibody therapy, point to the ability of activated T cells to initiate cytokine storm. Impaired granule-mediated killing of infected cells or tumor cells by CTLs is a key aspect of some forms of cytokine storm. 20 Data from mouse models of HLH and patients with cytokine storm indicate that the inability of CTLs to kill efficiently leads to prolonged activation of T cells, triggering a cascade of inflammatory tissue damage. 21-23 Th17 cells have a major role in host defense, particularly antifungal protection, and abnormal Th17-cell function can lead to autoimmunity. 24 An experimental model of macrophage activation syndrome (a form of secondary HLH) provides evidence that Th17 cells can be drivers of a cytokine storm that is independent of interferon-γ. 25 B cells are not often associated with the pathogenesis of cytokine storm. However, the effectiveness of B-cell depletion in treating some cytokine storm disorders, such as human herpesvirus 8 (HHV-8)–associated multicentric Castleman’s disease, suggests that these cells are capable of initiating or propagating cytokine storm, particularly when virally infected. Cytokines As noted above, the recognition of cytokine storm as an entity is relatively recent. The advent of molecular cloning technologies led to the discovery of the panoply of cytokines and chemokines involved in cytokine storm (Table 1); the realization that diverse entities can cause cytokine storm (Table 2) also contributed to its recognition. The administration of recombinant cytokines (e.g., interleukin-1, interleukin-6, interleukin-12, interleukin-18, tumor necrosis factor [TNF], and interferon-γ) in animal models and for cancer treatment in humans induces severe toxic effects or lethality consistent with the central role of cytokines as mediators of hyperinflammation in cytokine storm. 27-29 Conversely, reduction in symptoms and improvement in organ function with neutralization of specific cytokines with monoclonal antibodies also reveal that excessive levels of certain cytokines play a critical role in a number of cytokine storm disorders. A complex, interconnected network of cell types, signaling pathways, and cytokines is involved in cytokine storm disorders. Interferon-γ, interleukin-1, interleukin-6, TNF, and interleukin-18 are key cytokines that often have elevated levels in cytokine storm and are thought to have central immunopathologic roles. The pattern of cytokine elevations varies on the basis of such factors as the microbiome, genetic features, and underlying disorders. 30 The specific immune cells that secrete the various cytokines are not fully understood and most likely vary among cytokine storm disorders. Interferon-γ is primarily secreted by activated T cells and NK cells and is a potent activator of macrophages. Clinically, interferon-γ causes fever, chills, headache, dizziness, and fatigue. 31 Emapalumab, a monoclonal antibody that binds interferon-γ, was recently approved for the treatment of cytokine storm in patients with primary HLH. 32 This agent may also be useful in other cytokine storm disorders, such as macrophage activation syndrome or CAR T-cell–associated cytokine storm, although in the latter case, it may diminish antitumor effects. Fever, a clinical hallmark of cytokine storm, can be elicited by interleukin-1, interleukin-6, or TNF through distinct mechanisms. Interleukin-1 is encoded by two genes (IL1A and IL1B), both of which bind to the same interleukin-1 receptor, activating a cascade of intracellular signaling pathways, including nuclear factor κB (NF-κB). The interleukin-1–receptor antagonist anakinra is effective as a single agent and in combination with other agents for the treatment of some forms of cytokine storm. 33,34 Levels of interleukin-6, an important mediator of the acute inflammatory response and pathophysiological features of cytokine storm, are highly elevated across various underlying immunopathologic disorders 35,36 and in mouse models of cytokine storm. 37 Both tocilizumab, a monoclonal antibody directed at the interleukin-6 receptor (interleukin-6R), and siltuximab, which neutralizes interleukin-6 directly, have been shown to be effective in a number of cytokine storm disorders, including HLH, idiopathic multicentric Castleman’s disease, and CAR T-cell–induced cytokine storm. 38 Interleukin-6 is one of the more complex cytokines, since it is produced by and acts on immune and nonimmune cells across multiple organ systems. It can signal through two main pathways, referred to as classic cis signaling and trans signaling. 38 The membrane-bound interleukin-6R does not possess intracellular signaling domains but signals instead through interaction with membrane-bound gp130. In cis signaling, soluble interleukin-6 binds to membrane-bound interleukin-6R, forming an interleukin-6–interleukin-6R complex that binds to gp130, which then initiates signaling through its intracellular domain. Downstream signal transduction is mediated by JAKs (Janus kinases) and STAT3 (signal transducer and activator of transcription 3), as well as by Akt–mTOR (mammalian target of rapamycin) and MAPK–ERK (mitogen-activated protein kinase–extracellular signal-regulated kinase) pathways. Membrane-bound gp130 is ubiquitously expressed, whereas expression of membrane-bound interleukin-6R is restricted largely to immune cells. Activation of cis signaling results in pleiotropic effects on the immune system, which can contribute to cytokine storm. 38 In the presence of high circulating levels of interleukin-6, which can be present in cytokine storm, trans signaling occurs through the binding of interleukin-6 to the soluble form of interleukin-6R, forming a complex with a gp130 dimer on potentially all cell surfaces. The resultant interleukin-6–soluble interleukin-6R–gp130–JAK-STAT3 signaling is then activated in cells that do not express the membrane-bound interleukin-6R, such as endothelial cells. This results in systemic hyperinflammation involving secretion of monocyte chemoattractant protein 1 (MCP-1), interleukin-8, and additional interleukin-6, as well as increased vascular endothelial growth factor (VEGF) and reduced E-cadherin expression on endothelial cells, which contribute to vascular hyperpermeability, leakiness, hypotension, and pulmonary dysfunction. 38 TNF is a potent, multifunctional, proinflammatory cytokine that belongs to the TNF–TNF receptor superfamily. In addition to inducing fever, augmenting systemic inflammation, and activating antimicrobial responses such as interleukin-6, TNF can induce cellular apoptosis and regulate immunity. TNF and other cytokines in the TNF–TNF receptor superfamily are potent inducers of NF-κB, leading to the expression of multiple proinflammatory genes. In mouse models of toxic shock, TNF is the cytokine driver of superantigen-driven cytokine storm. 39 The effectiveness of anti-TNF therapies in certain autoinflammatory-driven cytokine storm conditions points to their potential role in the treatment of cytokine storm, but the limitations and dangers of anti-TNF therapies in patients with sepsis indicate that more work is needed. Interleukin-18 is a member of the large interleukin-1 family 40 that has recently been associated with cytokine storm disorders. Interleukin-18 and interleukin-1β are activated from precursors by inflammasomes. The inflammasome is a multimolecular cytosolic sensor that detects pathogenic microorganisms and sterile stressors and activates caspase-1 during the process of pyroptosis, which, in turn, causes the inactive precursor forms of interleukin-1β and interleukin-18 to become the active forms. 41,42 Macrophages and dendritic cells are the primary sources of bioactive interleukin-18, which has many proinflammatory effects. Most important, it synergizes with interleukin-12 or interleukin-15 to stimulate secretion of interferon-γ from T cells and NK cells, and thus promotes Th1-type inflammatory responses. The interleukin-18 receptor is constitutively expressed on NK cells and induced on activation in most T cells. Interleukin-1β and interleukin-18 are also potent inducers of interleukin-6 secretion from macrophages. 43 Patients with cytokine storm due to macrophage activation syndrome have high levels of interleukin-18 in serum, 44 and interleukin-18 is a biomarker of severity that correlates with hyperferritinemia, elevated aminotransferase levels, and disease flare. 45 The proinflammatory effects of interleukin-18 are normally kept in check by the interleukin-18–binding protein (IL18BP), which prevents the binding of interleukin-18 to its receptor. 46 The ratio of free interleukin-18 to bound interleukin-18–IL18BP complexes in serum is an important indicator of the severity of the macrophage activation syndrome. 44,47 Tadekinig alfa is a recombinant IL18BP currently under investigation as a treatment for hyperinflammation. Chemokines are a class of cytokines that contribute to a variety of immune-cell functions, including leukocyte recruitment and trafficking. Dysregulated trafficking during inflammation may have a role in hyperinflammation. Numerous regulatory cytokines such as interleukin-10 and natural cytokine antagonists such as IL1RA serve as buffers to limit systemic off-target effects. Interleukin-10 inhibits the production of TNF, interleukin-1, interleukin-6, and interleukin-12 and down-regulates antigen presentation. Furthermore, in mice lacking interleukin-10, infection leads to cytokine storm. 48 Though interleukin-10 and IL1RA are often elevated in cytokine storm, this finding most likely reflects a secondary, albeit insufficient, counterregulatory response to the proinflammatory cytokines. Anakinra is a therapeutic agent that mimics the endogenous immunoregulatory effects of IL1RA. Plasma proteins such as complement proteins and other inflammatory mediators can contribute to the pathogenesis of cytokine storm. These soluble proteins recognize pathogens, amplify cellular responses, and provide feedback on cytokine signaling. In fact, cytokines can enhance the production of complement proteins, which in turn can enhance or inhibit cytokine production. Thus, complement can be highly effective in eliminating microbes but can also cause collateral damage if excessive. Hypocomplementemia, resulting from increased consumption by immune complexes, can be observed in cytokine storm. 49 Complement inhibitors are under evaluation for the treatment of cytokine storm disorders. Iatrogenic Cytokine Storm Infusion of CAR T cells engineered to recognize and eliminate CD19+ lymphoma cells can induce cytokine storm, with supraphysiologic levels of interferon-γ and interleukin-6. 50 The highly activated CAR T cells are clearly the initiators of the cytokine storm. Although some studies suggest that the driver cytokines are released by CAR T cells, resulting in a positive feedback loop of T-cell activation and inflammatory cytokine release, 51 recent studies in mice suggest that the cytokines and factors mediating the severity of cytokine storm are produced not by the CAR T cells but by macrophages and can be reversed by interleukin-6 and interleukin-1 blockade. 52-54 Tumor lysis most likely also contributes to the cytokine storm through the induction of pyroptosis in target cells. 55 Since interleukin-6 blockade is highly effective at reversing symptoms and organ dysfunction in most patients, it is the likely cytokine driver of cytokine storm induced by CAR T-cell therapy. Glucocorticoids and interleukin-1 inhibition can also be effective in the treatment of this type of cytokine storm. Cytokine storm can be observed with other T-cell–engaging immunotherapies as well, such as blinatumomab, a bispecific antibody that binds to CD19+ and CD3+ T cells. 56 Like CAR T cells, activated T cells initiate the cytokine storm, and macrophage activation propagates blinatumomab-induced cytokine storm, which also responds to anti–interleukin-6 antibody therapy. 36 The unfortunate consequences of another T-cell–activating treatment with the anti-CD28 superagonist TGN1412 show that rapid activation of large numbers of T cells can result in severe cytokine storm within minutes after infusion. 57 However, cytokine storm does not develop in all patients treated with CAR T cells or blinatumomab, so additional factors, such as CAR structure and design, 51 disease burden, 58 and host genomic background, 59 are likely to play a part. In a recent study of NK-cell CAR therapy, there were no reported cases of cytokine storm or even elevated interleukin-6 levels, 60 possibly because of lower interleukin-6 production by NK cells than by T cells and different cross-talk with myeloid cells. Additional iatrogenic causes of cytokine storm include rituximab, 35 gene therapies, immune checkpoint inhibitors, cardiac-bypass surgery, 61 and allogeneic stem-cell transplantation, as well as bioterrorism agents such as staphylococcal enterotoxin B and Francisella tularensis. Pathogen-Induced Cytokine Storm Cytokine storm can also result from naturally occurring microbial infections. Though data on relative frequencies are limited, infections are most likely the most common trigger of cytokine storm. Distinguishing between appropriate cytokine production for controlling a widespread infection and excessive cytokine production is challenging. Disseminated bacterial infections causing sepsis induce the production of many cytokines that can lead to fever, cell death, coagulopathies, and multiorgan dysfunction. The collateral damage caused by the immune response as it attempts to clear the pathogen can be more deadly than the pathogen itself. Certain bacteria, including streptococcus species and Staphylococcus aureus, can produce superantigens that cross-link the major histocompatibility complex and T-cell receptors, leading to polyclonal activation of T cells, cytokine production, and toxic shock syndrome. Superantigens are the most powerful T-cell mitogens, and bacterial superantigen concentrations of less than 0.1 pg per milliliter are sufficient to stimulate T cells in an uncontrolled manner, resulting in fever, shock, and death. In sepsis-associated cytokine storm, it is unclear which immune cell types and cytokines may be responsible for propagating the pathologic hyperinflammation. Antibiotics are the mainstay of treatment. The administration of monoclonal antibodies directed at specific cytokines and the use of apheresis or medical devices to remove cytokines from circulation have had generally disappointing results in clinical trials. 62 Although the timing of treatment in these studies may have contributed to the lack of benefit, additional host or pathogen factors may be important, beyond the specifically elevated cytokine levels. For example, reanalysis of a negative trial of interleukin-1β blockade in patients with sepsis identified a subgroup of patients with elevated ferritin levels who seemed to benefit from the treatment. 63 Disseminated viral infections can also induce profound cytokine storm. Patients with hyperinflammatory responses to microbes often have defects in pathogen detection, effector and regulatory mechanisms, or resolution of inflammation. For example, patients lacking functional perforin, which is critical for resolving infections and inflammation, have prolonged CD8+ T-cell production of interferon-γ and TNF, and HLH-associated cytokine storm develops in such patients when they are infected with EBV or cytomegalovirus. 64 Experimental models suggest that cytokine storm occurs in these patients from defective perforin-mediated cytolysis that leads to prolonged engagement between lymphocytes and antigen-presenting cells and defective clearance of antigen-bearing dendritic cells, resulting in continuous activation and proliferation of T cells and macrophages, hemophagocytosis, and an autocrine loop of proinflammatory cytokines. 21,65-67 Furthermore, retrospective analyses of data from persons who died from coagulopathies and hemophagocytosis during the H1N1 influenza pandemic of 2009 revealed germline mutations previously associated with HLH-associated cytokine storm. 30 Thus, the pathogen initiates and T-cell activation propagates cytokine storm in patients with a genetic susceptibility. Cyclosporine and anti–interleukin-6 receptor monoclonal antibody therapy can be effective in some virus-driven forms of HLH-associated cytokine storm, indicating the critical role of T-cell activation and interleukin-6. Another pathogen-induced form of cytokine storm is HHV-8–associated multicentric Castleman’s disease. In this disorder, uncontrolled infection with HHV-8 (also known as Kaposi’s sarcoma herpesvirus) leads to a cytokine storm driven primarily by excessive production of human interleukin-6 and viral interleukin-6 by HHV-8–infected plasmablasts. 68 Patients with HHV-8–associated multicentric Castleman’s disease are immunocompromised as a result of human immunodeficiency virus infection or a genetic susceptibility, making it difficult to control the HHV-8 infection, which is a common, typically asymptomatic infection in the general population. 69 A recent study showed that the effect of tocilizumab in patients with HHV-8–associated multicentric Castleman’s disease was minimal and short-lived, most likely because of viral interleukin-6 signaling that was independent of the neutralized interleukin-6 receptor. 70 As with EBV-associated HLH, 71 rituximab is highly effective in patients with HHV-8–associated multicentric Castleman’s disease, since B-cell depletion removes the primary reservoir for HHV-8. 72 Many additional microbes can trigger cytokine storm, including other herpesviruses, such as herpes simplex virus, and other influenza viruses, such as H5N1. Targeted treatment is more challenging in patients with viral infections than in patients with bacterial infections, since fewer antiviral agents are available. Intravenous immune globulin and convalescent plasma are sometimes used to help control the pathogen and provide beneficial immunomodulation. For some viral infections, treating patients with proinflammatory cytokines in the early stages of infection can help to control the virus before detrimental effects of the immune response occur. 73 Monogenic or Autoimmune Cytokine Storm In rare cases, a pathogen triggers cytokine storm in patients with monogenic disorders, and in other cases, cytokine storm has autoimmune, neoplastic, or idiopathic causes. In patients with primary HLH, various autosomal recessive monogenic abnormalities in granule-mediated cytotoxicity lead to cytokine storm. Common pathologic mutations include those occurring in PRF1, UNC13D, STXBP1, RAB27A, STX11, SH2D1A, XIAP, and NLRC4. 23 In patients with secondary HLH, viral, autoimmune, or neoplastic disorders trigger cytokine storm, and such patients often have heterozygous polymorphisms in the same genes that are altered in primary HLH. 65,74 Elevated levels of interferon-γ, TNF, interleukin-1, interleukin-4, interleukin-6, interleukin-8, interleukin-10, CXCL9, CXCL10, and interleukin-18 are frequently associated with HLH. Anti–interferon-γ antibody therapy with emapalumab has recently been approved for the treatment of primary HLH, as a bridge to allogeneic stem-cell transplantation, which is typically curative. The beneficial effects of glucocorticoids, cyclosporine, anti–interleukin-1 antibody, JAK1 and JAK2 inhibitors, anti–interleukin-6 antibody, and cytotoxic chemotherapies in some patients with primary or secondary HLH suggest that pathways targeted by these agents are key to pathogenesis. Cyclophosphamide and etoposide, which are broadly cytotoxic but particularly effective at eliminating activated CD8+ T cells, are often effective in patients with primary HLH, secondary HLH (including macrophage activation syndrome), and corresponding models. 75 Etoposide also targets macrophages, including those involved in regulating inflammation, which could be harmful. Generalized T-cell and B-cell ablation with alemtuzumab and T-cell ablation with antithymocyte globulin have been reported; ablation most likely works by depleting the pathogenic CD8+ T cells, among other cell types. 76 Nonablative inhibition of T cells with cyclosporine can also be helpful. 77 Autoinflammatory diseases are characterized by seemingly unprovoked inflammation and cytokine storm without signs of infection or autoimmunity. Affected patients have germline mutations in genes regulating the innate immune system and activation of the inflammasome. Several genetic disorders are associated with altered regulation of the innate immune system, including familial Mediterranean fever (MEFV), TNF receptor–associated periodic syndrome (TNFRSF1A), hyperimmunoglobulinemia D with periodic fever syndrome (MVK), familial cold autoinflammatory syndrome (NLRP3), the Muckle–Wells syndrome (NLRP3), neonatal-onset multisystem inflammatory disease (NLRP3), deficiency of ADA2 (CECR1), NLRC4 inflammasomopathies, X-linked lymphoproliferative type 2 disorder (XIAP), the Takenouchi–Kosaki syndrome (CDC42), and the Wiskott–Aldrich syndrome (CDC42). Although all patients with these disorders have periodic fevers, only a portion have cytokine storm. Given the primary genetic defects and the effective treatments that are available, innate cells are most likely the primary cell drivers involved, and TNF, interleukin-1, interleukin-18, or a combination of these cytokines probably drives pathogenesis. Patients with genetic immunodeficiency syndromes such as chronic granulomatous disease and STAT1 gain-of-function disease can, paradoxically, present with cytokine storm from overwhelming infections. 78 Idiopathic multicentric Castleman’s disease is another cytokine storm disorder that is similar to HHV-8–associated multicentric Castleman’s disease, but the cause is unknown. Patients with the thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) subtype tend to have the most severe cytokine storm. 79 Although the cause is unknown, interleukin-6 is the driver of pathogenesis in a large portion of patients. As a result, tocilizumab, which targets the interleukin-6 receptor, and siltuximab, which targets interleukin-6 directly, were developed and approved by regulatory agencies in Japan (tocilizumab) and in the United States and dozens of other countries (siltuximab) for the treatment of idiopathic multicentric Castleman’s disease. Both siltuximab and tocilizumab have been shown to resolve disease flares and sustain remission in approximately one third to one half of patients. 80 However, some patients with low circulating interleukin-6 levels have a response to interleukin-6 blockade, and some patients with high systemic interleukin-6 levels do not have a response. A seven-protein panel that can predict which patients with idiopathic multicentric Castleman’s disease are most likely to benefit from siltuximab was recently identified and validated (https://ashpublications.org/blood/article/132/Supplement%201/3716/265269/Serum-Proteomics-Reveals-Distinct-Subtypes?searchresult=1). Patients with idiopathic multicentric Castleman’s disease who have progressive organ dysfunction and who do not have a response to anti–interleukin-6 therapy are often treated with combination cytotoxic chemotherapy to nonspecifically eliminate hyperinflammatory cells. 81 Other elevated serum cytokines and cellular signaling pathways that could be considered for therapeutic targeting include CXCL13, CXCL10 (interferon-inducible protein 10 [IP-10]), VEGF-A, 82 type I interferon, 83 mTOR complex 1 (mTORC1), 84 and JAK-STAT3. These findings have led to treatment with the mTORC1 inhibitor sirolimus in patients with idiopathic multicentric Castleman’s disease who do not have a response to anti–interleukin-6 therapy. 85 Sirolimus therapy is being evaluated in an ongoing clinical trial involving patients with active disease who do not yet have fulminant cytokine storm (ClinicalTrials.gov number, NCT03933904). Covid-19–Associated Cytokine Storm Covid-19, which is caused by SARS-CoV-2, is characterized by heterogeneous symptoms ranging from mild fatigue to life-threatening pneumonia, cytokine storm, and multiorgan failure. Cytokine storm was also reported in patients with SARS and was associated with poor outcomes. 86 Although the mechanisms of lung injury and multiorgan failure in Covid-19 are still under investigation, 14 reports of hemophagocytosis and elevated cytokine levels — as well as beneficial effects of immunosuppressant agents — in affected patients, particularly those who are the most severely ill, suggest that cytokine storm may contribute to the pathogenesis of Covid-19. 87,88 Serum cytokine levels that are elevated in patients with Covid-19–associated cytokine storm include interleukin-1β, interleukin-6, IP-10, TNF, interferon-γ, macrophage inflammatory protein (MIP) 1α and 1β, and VEGF. 89,90 Higher interleukin-6 levels are strongly associated with shorter survival. 91 The relative frequencies of circulating activated CD4+ and CD8+ T cells and plasmablasts are increased in Covid-19. 92 In addition to the elevated systemic cytokine levels and activated immune cells, several clinical and laboratory abnormalities, such as elevated CRP and d-dimer levels, hypoalbuminemia, renal dysfunction, and effusions, are also observed in Covid-19, as they are in cytokine storm disorders. Laboratory test results reflecting hyperinflammation and tissue damage were found to predict worsening outcomes in Covid-19. 93 Although immunologic dysregulation has been observed in severe cases of Covid-19, 26 it is not known whether immune hyperactivity or a failure to resolve the inflammatory response because of ongoing viral replication or immune dysregulation underlies severe cases. The correlation between the nasopharyngeal viral load and cytokine levels (e.g., interferon-α, interferon-γ, and TNF), as well as a declining viral load in moderate but not severe cases, suggests that the immune response is positively associated with the viral burden. 26 Alternatively, the discoveries of inborn errors of type I interferon immunity and autoantibodies against type I interferons in the most severe cases of Covid-19 suggest that an inadequate antiviral response may be contributory in some patients with Covid-19. 94,95 Host immune responses and immune-related symptoms are extremely variable between asymptomatic patients (who have effective control of SARS-CoV-2) and patients with severe Covid-19 (who are unable to control the virus), which suggests that host immune dysregulation contributes to pathogenesis in some cases. Another hypothesized mechanism involves autoimmunity due to molecular mimicry between SARS-CoV-2 and a self-antigen. These mechanisms may be involved in subgroups of patients, such as children with postinfection multisystem inflammatory syndrome, a condition that seems to be ameliorated by immunomodulatory therapies such as intravenous immune globulin, glucocorticoids, and anti–interleukin-1 and anti–interleukin-6 therapies. Patients with multisystem inflammatory syndrome very clearly meet the definition of cytokine storm, since SARS-CoV-2 is no longer present; however, it is unclear whether the cytokine storm is a driver of Covid-19 or a secondary process. Furthermore, it is now clear that patients with SARS-CoV-2 infection can be asymptomatic or can have acute Covid-19 with heterogeneous severity, a chronic course of Covid-19, or multisystem inflammatory syndrome. A critical question concerns the factors that contribute to the severe cytokine storm–like phenotype observed in a small fraction of patients. Coexisting conditions such as hypertension, diabetes, and obesity are associated with more severe cases of Covid-19, possibly because of the preexisting chronic inflammatory state or a lower threshold for the development of organ dysfunction from the immune response. Several important differences in therapeutic considerations should be noted between Covid-19–associated cytokine storm and many other cytokine storm disorders. First, cytokine storm triggered by infection with SARS-CoV-2 may require different therapies from those used for cytokine storm due to other causes. Cytokines may be both a key component of the cytokine storm and an essential factor in the antimicrobial response. Thus, blocking cytokine signaling may actually impair clearance of SARS-CoV-2, increase the risk of secondary infections, and lead to worse outcomes, as seen with influenza virus. 96 Since interleukin-6 and other cytokines are potentially critical for both a healthy response to SARS-CoV-2 and a detrimental cytokine storm, it is particularly important that the right subgroups of patients with Covid-19 are selected for treatments at the right time. Despite positive anecdotal reports, two large, randomized, controlled trials of anti–interleukin-6 receptor antibody therapies did not show a survival benefit in hospitalized patients with Covid-19. 97,98 Second, the primary site of infection and disease most likely contributes to differences in immune responses and mechanisms underlying the cytokine storm, which have implications for treatment. For example, selective elimination of the primary viral reservoir is beneficial in patients with HHV-8–associated multicentric Castleman’s disease but is not possible in patients with Covid-19. Third, lymphopenia is not often observed in cytokine storm disorders, but it is a hallmark of severe Covid-19. It is currently unclear whether the lymphopenia observed in Covid-19 is due to tissue infiltration or destruction of lymphocytes. Fourth, clotting issues can occur across cytokine storm disorders, but thromboembolic events appear to be more frequent in Covid-19–associated cytokine storm. 99 Finally, although cytokine panels have not been measured simultaneously on the same platform across Covid-19–associated cytokine storm and other cytokine storm disorders, preliminary results suggest that circulating levels of several cytokines, such as interleukin-6, as well as other inflammatory markers, such as ferritin, are less severely elevated in Covid-19 than in some of the other cytokine storm disorders. 26 Levels of inflammatory mediators in pulmonary tissue during infection with SARS-CoV-2 remain unknown. Despite the many unknowns, a recent randomized, controlled trial showing that dexamethasone reduces mortality among the most severe cases of Covid-19, characterized by elevated CRP levels and supplemental oxygen requirements, and potentially worsens outcomes in milder cases suggests that excessive, late-stage inflammation contributes to mortality. 88 A meta-analysis of seven randomized trials showed that 28-day all-cause mortality in critically ill patients with Covid-19 was lower among those who were treated with glucocorticoids than among those who received usual care or placebo. 100 An observational study suggesting that patients with Covid-19 have a good response to glucocorticoids when the CRP level is high but a poor response when the level is low is consistent with these findings. 101 Further support comes from positive anecdotal reports of targeted antagonists against interleukin-1, granulocyte–macrophage colony-stimulating factor, and JAK1 and JAK2 in patients with Covid-19. 102-105 Likewise, the observation that proinflammatory agents such as inhaled interferon-β have a positive effect if given early in the disease course is consistent with a model in which immunostimulation that enhances antiviral activity is helpful early (and probably harmful late), whereas immunosuppression is helpful late and harmful early. As with dexamethasone, the timing of treatment and selection of subgroups of patients included in studies will most likely have an effect on outcomes. Despite unknowns regarding the role of immune dysregulation and cytokine storm in Covid-19, hundreds of immunomodulatory drugs are currently under investigation. 102 Many of these treatments have been used for other cytokine storm disorders. Canakinumab, an anti–interleukin-1β monoclonal antibody, and anakinra are both being studied for Covid-19–induced ARDS. Acalabrutinib, a selective inhibitor of Bruton tyrosine kinase that regulates B-cell and macrophage signaling and activation, may have promise for dampening the hyperinflammatory response in Covid-19. 106 JAK1 and JAK2 inhibitors, which are approved for the treatment of a number of autoimmune and neoplastic conditions, have the potential to inhibit signaling downstream of type I interferon, interleukin-6 (and other gp130 family receptors), interferon-γ, and interleukin-2, among other cytokines. 107 Much like anti–interleukin-6 antibody therapy, inhibition of Bruton tyrosine kinase and JAK could prove to be damaging or unhelpful if given too soon, when the immune response to SARS-CoV-2 is critical in controlling viral replication and clearance. Therapeutics The general treatment strategy for cytokine storm involves supportive care to maintain critical organ function, control of the underlying disease and elimination of triggers for abnormal immune system activation, and targeted immunomodulation or nonspecific immunosuppression to limit the collateral damage of the activated immune system. As noted throughout this review, a number of drugs are effective across multiple disorders under the cytokine storm umbrella and still more may be effective in multiple conditions that have not yet been studied. Given the growing number of new therapeutics targeting various aspects of the immune system and our ability to probe the biologic mechanisms of disease, further research should focus on the identification of drugs that can be used across cytokine storm disorders and precision diagnostics for selecting the right drugs for the right patients, regardless of the underlying condition. 108,109 A study involving patients with systemic juvenile idiopathic arthritis revealed subgroups of patients with cytokine profiles in which interleukin-6 and interleukin-18 predominated, pointing toward available therapeutic approaches. 110 Likewise, biomarkers were recently shown to effectively predict which patients with adult-onset Still’s disease would have a response to anakinra or tocilizumab. 111 The progress made in precision oncology suggests that similar efforts across cytokine storm disorders are warranted to identify specific therapeutic targets and signatures of response to certain drugs that cross disease boundaries. JAK signaling is an interesting target in cytokine storm, because multiple cytokine–receptor pairs can be targeted simultaneously, an approach that may be effective for multiple diseases driven by different cytokines. In addition, plasma exchange and plasma filtration columns for the adsorption of cytokines are both under evaluation for cytokine storm disorders. It is important to consider several factors in managing cytokine storm. Neutralization of a particular cytokine whose level is elevated in the circulation with an existing agent (anti–interleukin-6, anti-TNF, anti–interferon-γ, or anti–interleukin-1β antibody) will not always be effective, and blocking a cytokine with a low or normal circulating level can be effective if it is a key component of the hyperinflammatory circuit or if its level is potentially elevated in tissue. In addition, the various therapies mentioned in this review have distinctive side-effect and risk profiles. All targeted agents have target-specific risks, and combination therapy has more potential risks than single-agent therapy. Furthermore, pathologic hyperinflammation itself is an immunodeficiency that can put patients at risk for infections, and immunosuppressive agents most likely increase the risk further. In this age of cytokine profiling and individualized medicine, patients must be monitored and given appropriate prophylaxis when treated empirically, and randomized, controlled trials should always be performed to assess efficacy and safety. Advancing the research and treatment of cytokine storm will require pooling of samples for “omics” studies and collaboration among experts across conditions. The introduction of an International Classification of Diseases, 10th Revision, code for cytokine release syndrome in 2021 should facilitate electronic health record–based research into its natural history, pathogenesis, and treatments. Once sufficient scientific progress has been achieved toward biomarker-guided, individualized treatment of cytokine storm, reliable, quick, and accessible assays will be needed to measure soluble mediators of inflammation in plasma and tissues. Summary Mild, secondary organ dysfunction during an inflammatory response is evolutionarily acceptable if it allows the host to overcome the infection and survive. If the inflammatory response causes excessive organ dysfunction that puts host survival and reproductive fitness at risk (in the absence of ventilatory support and dialysis), then it is pathologic. Extensive regulatory mechanisms exist that modulate the immune response and prevent cytokine storm. Nevertheless, the disorder can still occur due to iatrogenic causes, pathogens, cancers, autoimmunity, and autoinflammatory mechanisms. Distinguishing between protective inflammatory responses and pathologic cytokine storm has important implications for treatment and is quite challenging. No unifying definition of cytokine storm exists, and there is much disagreement about what the definition should be and whether specific conditions such as Covid-19 should be included in the spectrum of cytokine storm disorders. We propose a unifying definition for cytokine storm that is based on the following criteria: elevated circulating cytokine levels, acute systemic inflammatory symptoms, and secondary organ dysfunction beyond that which could be attributed to a normal response to a pathogen, if a pathogen is present. Targeted therapeutic approaches to cytokine storm associated with idiopathic multicentric Castleman’s disease, HLH, or CAR T-cell therapy have turned deadly conditions into often reversible states. Given advances in “multi-omic” profiling and therapeutic modulation of the immune system, as well as concerted efforts to work across the cytokine storm umbrella, we expect to see continued improvements in outcomes.
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            Pathogenesis of COVID-19 from a cell biologic perspective

            Robert J Mason (2020)
            COVID-19 is a major health concern and can be devastating, especially for the elderly. COVID-19 is the disease caused by SARS-CoV2 the virus. Although much is known about the mortality of the clinical disease, much less is known about its pathobiology. Although details of the cellular responses to this virus are not known, a probable course of events can be postulated based on past studies with SARS-CoV. A cellular biology perspective is useful for framing research questions and explaining the clinical course by focusing on the areas of the respiratory tract that are involved. Based on the cells that are likely infected, COVID-19 can be divided into three phases that correspond to different clinical stages of the disease [1].
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              Improving the reporting of pragmatic trials: an extension of the CONSORT statement

              Merrick Zwarenstein, Shaun Treweek, Joel Gagnier … (2008)
              Randomised controlled trials are used to assess the benefits and harms of interventions in health care. If conducted properly, they minimise the risk of bias (threats to internal validity), particularly selection bias.1 2 There is, however, considerable evidence that trials are not always well reported,3 4 and this can be associated with bias, such as selective reporting of outcomes.5 The usefulness of a trial report also depends on the clarity with which it details the relevance of its interventions, participants, outcomes, and design to the clinical, health service, or policy question it examines. Furthermore, a trial may be valid and useful in the healthcare setting in which it was conducted but have limited applicability (also known as generalisability or external validity) beyond this because of differences between the trial setting and other settings to which its results are to be extrapolated. Schwartz and Lellouch6 coined the terms “pragmatic” to describe trials designed to help choose between options for care, and “explanatory” to describe trials designed to test causal research hypotheses—for example, that an intervention causes a particular biological change. Table 1 shows some key differences between explanatory and pragmatic trials. Table 2 compares a trial that was highly explanatory in attitude7 with one that was highly pragmatic.8 There is a continuum rather than a dichotomy between explanatory and pragmatic trials. In fact, Schwartz and Lellouch characterised pragmatism as an attitude to trial design rather than a characteristic of the trial itself. The pragmatic attitude favours design choices that maximise applicability of the trial’s results to usual care settings, rely on unarguably important outcomes such as mortality and severe morbidity, and are tested in a wide range of participants.9 10 11 As Schwartz and Lellouch wrote: “Most trials done hitherto have adopted the explanatory approach without question; the pragmatic approach would often have been more justifiable.”6 Table 1 Key differences between trials with explanatory and pragmatic attitudes, adapted from a table presented at the 2008 Society for Clinical Trials meeting by Marion Campbell, University of Aberdeen Question Efficacy—can the intervention work? Effectiveness—does the intervention work when used in normal practice? Setting Well resourced, “ideal” setting Normal practice Participants Highly selected. Poorly adherent participants and those with conditions which might dilute the effect are often excluded Little or no selection beyond the clinical indication of interest Intervention Strictly enforced and adherence is monitored closely Applied flexibly as it would be in normal practice Outcomes Often short term surrogates or process measures Directly relevant to participants, funders, communities, and healthcare practitioners Relevance to practice Indirect—little effort made to match design of trial to decision making needs of those in usual setting in which intervention will be implemented Direct—trial is designed to meet needs of those making decisions about treatment options in setting in which intervention will be implemented Table 2 Comparison of trial that was highly explanatory in attitude with trial that was highly pragmatic Highly explanatory attitude (NASCET7) Highly pragmatic attitude (Thomas et al8) Question Among patients with symptomatic 70-99% stenosis of carotid artery can carotid endarterectomy plus best medical therapy reduce outcomes of major stroke or death over next two years compared with best medical therapy alone? Does a short course of acupuncture delivered by a qualified acupuncturist reduce pain in patients with persistent non-specific low-back pain? Setting Volunteer academic and specialist hospitals with multidisciplinary neurological-neurosurgical teams and high procedure volumes with low mortality in US and Canada General practice and private acupuncture clinics in UK Participants Symptomatic patients stratified for carotid stenosis severity, with primary interest in severe carotid stenosis (high risk) group, who were thought to be most likely to respond to endarterectomy. Exclusions included mental incompetence and another illness likely to cause death within 5 years. Patients also were temporarily ineligible if they had any of seven transient medical conditions (eg, uncontrolled hypertension or diabetes) Anyone aged 18-65 with non-specific low back pain of 4-52 weeks’ duration who were judged to be suitable by their general practitioner. There were some exclusion criteria, eg those with spinal disease Intervention Endarterectomy had to be carried out (rather than stenting or some other operation), but the surgeon was given leeway in how it was performed. Surgeons had to be approved by an expert panel, and were restricted to those who had performed at least 50 carotid endarterectomies in the past 24 months with a postoperative complication rate (stroke or death within 30 days) of less than 6%. Centre compliance with the study protocol was monitored, with the chief investigator visiting in the case of deficiencies Acupuncturists determined the content and number of treatments according to patients’ needs Outcomes The primary outcome was time to ipsilateral stroke, the outcome most likely to be affected by carotid endarterectomy. Secondary outcomes: all strokes, major strokes, and mortality Primary outcome was bodily pain as measured by SF-36. Secondary outcomes included use of pain killers and patient satisfaction Relevance to practice Indirect—patients and clinicians are highly selected and it isn’t clear how widely applicable the results are Direct—general practitioners and patients can immediately use the trial results in their decision making Calls have been made for more pragmatic trials in general,6 12 13 and in relation to specific clinical problems.14 15 16 Articles have been published discussing the characteristics and value of pragmatic trials17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 or proposing improvements in the design and conduct of these trials.36 37 38 Patients, advocacy groups, clinicians, systematic reviewers, funders, and policymakers want to use the results of randomised controlled trials. As such, a clear description of the design and execution of the trial, the intervention and comparator, and the setting in which health care is provided may simplify their decision on the likely benefits, harms, and costs to be expected when implementing the intervention in their own situation. There is, however, no accepted standard to guide reporting on the aspects of design and conduct of trials that affect their usefulness for decision making, particularly considerations that would affect the applicability of the results. We propose here guidance for reporting pragmatic trials, as a specific extension of the CONSORT statement. Our aim is to identify information which, if included in reports of pragmatic trials, will help users determine whether the results are applicable to their own situation and whether the intervention might be feasible and acceptable. Reporting this information is crucial for any trial that is intended to inform decisions about practice. CONSORT initiative The original CONSORT statement (www.consort-statement.org), last revised in 2001, was developed by clinical trialists, methodologists, and medical journal editors to help improve the reporting of parallel (two) group randomised trials.39 The objective of the statement is to enable readers to critically appraise and interpret trials by providing authors with guidance about how to improve the clarity, accuracy, and transparency of their trial reports. It consists of a 22-item checklist and a diagram, detailing the flow of participants through the trial. It is a living document that is updated as needed, incorporating new evidence.40 The guidelines have been endorsed by more than 300 journals,41 and by several editorial groups, including the International Committee of Medical Journal Editors.42 The CONSORT statement has been translated into several languages.43 Since its original publication in 1996 the quality of reports of controlled trials has improved.44 The CONSORT recommendations are intentionally generic, and necessarily do not consider in detail all types of trials. Extensions of the CONSORT statement have been developed for non-inferiority and equivalence,45 cluster randomised designs,46 reporting of abstracts,47 data on harms,48 trials of herbal interventions,49 and of non-pharmacological interventions,50 51 but not yet for the reporting of pragmatic trials, although some issues pertaining to pragmatic trials were discussed in the CONSORT explanation and elaboration paper.4 Methods In January 2005 and in March 2008, we held two-day meetings in Toronto, Canada, to discuss ways to increase the contribution of randomised controlled trials to healthcare decision making, focusing on pragmatic trials. Participants included people with experience in clinical care, commissioning research, healthcare financing, developing clinical practice guidelines, and trial methodology and reporting. Twenty four people participated in 2005 and 42 in 2008, including members of the CONSORT and Pragmatic Trials in Healthcare (Practihc) groups.52 After the 2005 meeting a draft revised checklist for the extension was circulated to a writing group, including some of those invited to the meeting but unable to attend. After several revisions the writing group produced a draft summary paper. At the 2008 meeting the draft was discussed and modified. It was circulated to the CONSORT group for feedback, modified, and submitted for publication. Recommendations for reporting pragmatic trials Meeting participants agreed that no items needed to be added to the CONSORT checklist and that the flow diagram did not need modification. However, participants felt that eight items (2-4, 6, 7, 11, 13, and 21) needed additional text specific to the reporting of pragmatic trials (see table 3). Although participants discussed additional text for item 1 of the checklist (title/abstract), principally adding the word pragmatic to the title or abstract, we decided against making this recommendation because it may reinforce the misconception that there is a dichotomy between pragmatic and explanatory trials rather than a continuum. We elected not to extend item 5 (objectives), although we would encourage trialists to report the purpose of the trial in relation to the decisions that it is intended to inform and in which settings; we have included this recommendation in connection with the extension of item 2 (background). Table 3 Checklist of items for reporting pragmatic trials Section Item Standard CONSORT description Extension for pragmatic trials Title and abstract 1 How participants were allocated to interventions (eg, “random allocation,” “randomised,” or “randomly assigned”) Introduction Background 2 Scientific background and explanation of rationale Describe the health or health service problem that the intervention is intended to address and other interventions that may commonly be aimed at this problem Methods Participants 3 Eligibility criteria for participants; settings and locations where the data were collected Eligibility criteria should be explicitly framed to show the degree to which they include typical participants and/or, where applicable, typical providers (eg, nurses), institutions (eg, hospitals), communities (or localities eg, towns) and settings of care (eg, different healthcare financing systems) Interventions 4 Precise details of the interventions intended for each group and how and when they were actually administered Describe extra resources added to (or resources removed from) usual settings in order to implement intervention. Indicate if efforts were made to standardise the intervention or if the intervention and its delivery were allowed to vary between participants, practitioners, or study sites Describe the comparator in similar detail to the intervention Objectives 5 Specific objectives and hypotheses Outcomes 6 Clearly defined primary and secondary outcome measures and, when applicable, any methods used to enhance the quality of measurements (eg, multiple observations, training of assessors) Explain why the chosen outcomes and, when relevant, the length of follow-up are considered important to those who will use the results of the trial Sample size 7 How sample size was determined; explanation of any interim analyses and stopping rules when applicable If calculated using the smallest difference considered important by the target decision maker audience (the minimally important difference) then report where this difference was obtained Randomisation—sequence generation 8 Method used to generate the random allocation sequence, including details of any restriction (eg, blocking, stratification) Randomisation—allocation concealment 9 Method used to implement the random allocation sequence (eg, numbered containers or central telephone), clarifying whether the sequence was concealed until interventions were assigned Randomisation—implementation 10 Who generated the allocation sequence, who enrolled participants, and who assigned participants to their groups Blinding (masking) 11 Whether participants, those administering the interventions, and those assessing the outcomes were blinded to group assignment If blinding was not done, or was not possible, explain why Statistical methods 12 Statistical methods used to compare groups for primary outcomes; methods for additional analyses, such as subgroup analyses and adjusted analyses Results Participant flow 13 Flow of participants through each stage (a diagram is strongly recommended)—specifically, for each group, report the numbers of participants randomly assigned, receiving intended treatment, completing the study protocol, and analysed for the primary outcome; describe deviations from planned study protocol, together with reasons The number of participants or units approached to take part in the trial, the number which were eligible, and reasons for non-participation should be reported Recruitment 14 Dates defining the periods of recruitment and follow-up Baseline data 15 Baseline demographic and clinical characteristics of each group Numbers analysed 16 Number of participants (denominator) in each group included in each analysis and whether analysis was by “intention-to-treat”; state the results in absolute numbers when feasible (eg, 10/20, not 50%) Outcomes and estimation 17 For each primary and secondary outcome, a summary of results for each group and the estimated effect size and its precision (eg, 95% CI) Ancillary analyses 18 Address multiplicity by reporting any other analyses performed, including subgroup analyses and adjusted analyses, indicating which are prespecified and which are exploratory Adverse events 19 All important adverse events or side effects in each intervention group Discussion Interpretation 20 Interpretation of the results, taking into account study hypotheses, sources of potential bias or imprecision, and the dangers associated with multiplicity of analyses and outcomes Generalisability 21 Generalisability (external validity) of the trial findings Describe key aspects of the setting which determined the trial results. Discuss possible differences in other settings where clinical traditions, health service organisation, staffing, or resources may vary from those of the trial Overall evidence 22 General interpretation of the results in the context of current evidence For each of the eight items we present the standard CONSORT text and additional guidance, an example of good reporting for the item, and an explanation of the issues. The selection of examples is illustrative for a specific item and should not be interpreted as a marker of quality for other aspects of those trial reports. The suggestions in this paper should be seen as additional to the general guidance in the main CONSORT explanatory paper and where relevant, other CONSORT guidance. Item 2: introduction; background Scientific background and explanation of rationale Extension for pragmatic trials: Describe the health or health service problem that the intervention is intended to address, and other interventions that may commonly be aimed at this problem. Example (a): Describe the health or health service problem which the intervention is intended to address—“Although interventions such as telephone or postal reminders from pharmacists improve compliance their effect on clinical outcome is not known. We investigated whether periodic telephone counselling by a pharmacist . . . reduced mortality in patients” receiving polypharmacy.53 Explanation—Users of pragmatic trial reports seek to solve a health or health service problem in a particular setting. The problem at which the intervention is targeted should thus be described. This enables readers to understand whether the problem confronting them is similar to the one described in the trial report, and thus whether the study is relevant to them. Ideally, the report should state that the trial is pragmatic in attitude (and why) and explain the purpose of the trial in relationship to the decisions that it is intended to inform and in which settings. Example (b): Describe other interventions that may commonly be aimed at this problem—“Sublingual buprenorphine is increasingly being prescribed by General Practitioners for opiate detoxification, despite limited clinical and research evidence. Comparing methadone, dihydrocodeine and buprenorphine it is important to note several factors which may impact upon prescribing and use of these agents”.54 Explanation—The background of the trial report should mention the intervention under investigation and the usual alternative(s) in relevant settings. To help place the trial in the context of other settings authors should explain key features that make the intervention feasible in their trial setting and elsewhere (such as, the widespread availability of the trial drug, the availability of trained staff to deliver the intervention, electronic databases that can identify eligible patients). Item 3: methods; participants Eligibility criteria for participants and the settings and the locations where the data were collected Extension for pragmatic trials: Eligibility criteria should be explicitly framed to show the degree to which they include typical participants and, where applicable, typical providers (eg, nurses), institutions (eg, hospitals), communities (or localities eg, towns) and settings of care (eg, different healthcare financing systems). Examples—“The study population included all National Health System physicians in the Northern Region of Portugal except for those not involved in any clinical activity (eg, administrators, laboratory analysis); those working in substance abuse and rehabilitation centers or specialty hospitals (because they cover multiple geographical areas); and those working at the regional pharmacosurveillance center or any department having a specific voluntary ADR reporting program.”55 “Our study took place in the three public hospitals (totalling 850 beds) in southern Adelaide, Australia, with a regional population of about 350 000. In Australia, entry to long term care (nursing home) can occur only after an independent clinical assessment by the aged care assessment team (ACAT), who determine level of dependency.”56 Explanation—Treatments may perform better when evaluated among selected, highly adherent patients with severe but not intractable disease and few comorbidities. Reports of these restricted trials may be of limited applicability. Excessively stringent inclusion and exclusion criteria reduce the applicability of the results and may result in safety concerns,57 so the method of recruitment should be completely described. This stringency seems to be reducing over time but remains a problem.58 In some trials the unit of randomisation and intervention might be healthcare practitioners, communities, or healthcare institutions such as clinics (that is, cluster randomised pragmatic trials). In these trials volunteer institutions may be atypically well resourced or experienced, successful innovators. Since the feasibility and success of an intervention may depend on attributes of the healthcare system and setting, reporting this information enables readers to assess the relevance and applicability of the results in their own, possibly different, settings. Item 4: methods; interventions Precise details of the interventions intended for each group and how and when they were actually administered. Extension for pragmatic trials: Describe extra resources added to (or resources removed from) usual settings in order to implement the intervention. Indicate if efforts were made to standardise the intervention or if the intervention and its delivery were allowed to vary between participants, practitioners or study sites. Describe the comparator in similar detail to the intervention. Example: (a) Describe extra resources added to (or resources removed from) usual settings in order to implement the intervention—“The hospitals and a private long term care provider developed and ran the off-site transitional care facility, which was 5-25 km from the study hospitals. The private provider supplied accommodation, catering, cleaning, nursing (5.0 full time equivalents in 24 hours), and career staff (10.0 full time equivalents in 24 hours) while the hospitals provided the allied health staff (4.4 full time equivalents), medical staff, and a transitional care nurse coordinator (1.0 full time equivalent). The whole team assessed all patients on admission to the transitional care unit and had weekly case conferences. Specialist medical staff visited the site for the case conferences and reviewed all admissions. On-call medical care was available 24 hours a day.”56 Explanation—If the extra resources to deliver the intervention are not described, readers cannot judge the feasibility of the intervention in their own setting. When relevant, authors should report details (experience, training etc) of those who delivered the intervention51 and its frequency and intensity. If multicomponent interventions are being evaluated, details of the different components should be described. Example: (b) Indicate if efforts were made to standardise the intervention or if the intervention and its delivery were allowed to vary between participants, practitioners or study sites—“Two trained leaders introduced a structured sequence of topics using a collaborative approach. All leaders had run at least one previous group. Throughout the 12 week programme leaders received three hours of supervision each week from a certified trainer.59 Explanation—In explanatory trials the intervention is standardised, and thus the results may not apply under usual conditions of care where no such standardisation is enforced. Pragmatic trials are conducted in typical care settings, and so care may vary between similar participants, by chance, by practitioner preference, and according to institutional policies.60 For pragmatic trials, efforts that may reduce this natural variation in the intervention and its delivery should be described. However, if reducing variation in a care process or shifting practice patterns is itself the main purpose of the intervention, this should be explicit in the title, abstract, and introduction. Regardless of the extent to which the intervention was standardised, pragmatic trials should describe the intervention in sufficient detail that it would be possible for someone to replicate it, or include a reference or link to a detailed description of the intervention. Unfortunately, this information is often lacking in reports of trials.61 Examples: (c) Describe the comparator in similar detail to the intervention—“Standard advice was given as for the naproxen group. Participants were provided with co­codamol for additional pain relief and an information leaflet about “tennis elbow” based on the Arthritis Research Campaign publication but omitting specific treatment recommendations.”62 “Women assigned to the control group received usual care from the healthcare team and completed all outcome measures on the same time frame as the intervention group. After randomisation, this group received a two page leaflet entitled “Exercise after cancer diagnosis,” which provided safe guidelines. After the six month follow-up, these women were helped to construct their own personalised exercise plan and invited to join a local general practice exercise referral scheme.”63 Explanation—In a randomised controlled trial the effects of the intervention are always related to a comparator. To increase applicability, and feasibility, pragmatic trials often compare new interventions to usual care. The chosen comparator should be described in sufficient detail for readers to assess whether the incremental benefits or harms reported are likely to apply in their own setting, where usual care may be more, or less, effective. Item 6: methods; outcomes Clearly defined primary and secondary outcome measures, and, when applicable, any methods used to enhance the quality of measurements (eg, multiple observations, training of assessors) Extension for pragmatic trials: Explain why the chosen outcomes and, when relevant, the length of follow-up are considered important to those who will use the results of the trial. Example—“The patient-based outcomes used in the evaluation were selected on the basis of empirical evidence from consumers about the most important outcomes from SDM [shared decision making] and risk communication.”64 The total number of days off work in the year after inclusion was calculated for each patient. Days off were defined as days 100% compensated by the NIA [National Insurance Administration]. Thus, days on ASL [Active Sick Leave] were considered as days absent. After a full year of sick leave, administrative proceedings are initiated to transfer the beneficiary to other measures of rehabilitation or disability pension within the NIA system. One year of absence was therefore a proxy measure for long-term disability.”65 Explanation—The primary outcome(s)66 in pragmatic trials are chosen to be relevant to the participants and key decision makers at whom the trial is aimed. The length of follow-up should be appropriate to the decision the trial is designed to inform. If the target decision makers are patients and their clinicians, the primary outcome is likely to be a health outcome, while trials aimed at policymakers and institutional leaders may focus on a process or system efficiency or equity outcome. Explicitly indicating that the chosen outcome is important to decision makers, and specifying the decision makers to whom it was important will assist other readers to decide whether the results are relevant to them. Item 7: methods; sample size How sample size was determined; when applicable, explanation of any interim analyses and stopping rules Extension for pragmatic trials: If calculated using the smallest difference considered important by the target decision maker audience (the minimally important difference) then report where this difference was obtained. Example—“There were no previous data using the main outcome measure on which to base the sample size calculation, and therefore the sample size was calculated on the number of days with URTI [upper respiratory tract infection]. It was decided, in line with other rigorous pragmatic studies that the smallest difference worth detecting was a 20% reduction in number of days with URTI.”67 Explanation—The minimally important difference (MID) is the size of a change in the primary outcome which would be important to the key decision making audience. The MID may differ between settings, consequently readers need to know what MID was considered important in the trial setting, and by whom, to contrast with their own expectations. Item 11: methods; blinding (masking) Whether participants, those administering the interventions, and those assessing the outcomes were blinded to group assignment Extension for pragmatic trials: If blinding was not done, or was not possible, explain why. Example—“Randomisation was done by telephone to an interactive voice response system. We entered and managed all data in an anonymised format; we held data on patient contacts and other administrative data in a separate database. The study was a pragmatic, randomised, prospective, open trial. In exercise studies, blinding the participants to allocation is not possible. We took steps to blind the evaluation of outcomes by having questionnaire responses in sealed envelopes and ensuring that outcome measures were taken by researchers who were not involved in exercise classes.”63 Explanation—In explanatory trials blinding68 prevents belief in the effectiveness of the intervention (by participant, clinician and/or assessor) from confounding the causal link between the intervention and the primary outcome. In pragmatic trials, as in the real world delivery of care, blinding of participants and clinicians may be impossible. Belief (or disbelief) in the intervention, extra enthusiasm and effort (or less), and optimism (or pessimism) in the self-assessment of outcomes may thus add to (or detract from) the effects of an intervention. Pragmatic trials may incorporate these factors into the estimate of effectiveness, rendering the findings more applicable to usual care settings. Authors should speculate on the effect of any suspected modifying factors, such as belief in the intervention, in the discussion (item 20). Moreover, in pragmatic trials, it is still desirable and often possible to blind the assessor or obtain an objective source of data for evaluation of outcomes. Item 13: results; participant flow Flow of participants through each stage (a diagram is strongly recommended). Specifically, for each group report the numbers of participants randomly assigned, receiving intended treatment, completing the study protocol, and analyzed for the primary outcome. Describe protocol deviations from study as planned, together with reasons Extension for pragmatic trials: The number of participants or units approached to take part in the trial, the number which were eligible and reasons for non-participation should be reported. Example—“These practices ascertained 3392 registered patients with Parkinson’s disease; 3124 were eligible for study of whom 1859 (59.5%) agreed to participate (fig 3). Twenty-three patients died during recruitment, leaving 1836 patients when the intervention began. Seventeen of the 1836 patients were not traced at the NHS central registry and are therefore not included in mortality analyses”.69 Explanation—The more similar the participants, practitioners, or other units of intervention or randomisation are to those in usual care, the more likely that the results of the trial will be applicable to usual care. Consequently the text and/or the trial flow diagram should mention, if known, the number of participants or units approached to take part in the trial, the number whom were eligible, and reasons for non-participation. Although this information is requested in the CONSORT statement, the need for it is greater when reporting a pragmatic trial. Item 21: generalisability (applicability, external validity) Generalisability of the trial findings Extension for pragmatic trials: Describe key aspects of the setting which determined the trial results. Discuss possible differences in other settings where clinical traditions, health service organisation, staffing, or resources may vary from those of the trial. Examples—“The intervention was tailored to the specific study population and may not be as effective in a different group. The positive results may reflect in part unique aspects of the Portuguese health care system or the regional physician culture. Willingness to report adverse drug reactions may be less in countries in which there is greater concern about malpractice liability.”55 “The incentive for implementing the clinical pathway will be different for a single-payer third-party system, as exists in Canada, in which costs of the pathway and offsetting hospital costs are realized by the same payer, than for a multiple payer system as exists in the United States, in which hospital cost offsets will be realized by the hospital and not the nursing home payer.”70 Explanation—The usefulness of the trial report is critically dependent on how applicable the trial and its results are and how feasible the intervention would be. The authors are well placed to suggest how feasible the intervention might be, which aspects of their setting were essential to achieve the trial result, and how that result might differ in other settings. The applicability of the study result could be encapsulated here by reference to the setting (is it a usual care setting), the participants and providers (how selected were they), intensity of intervention and follow up (how much like usual care was this), adherence to the intervention and whether efforts were made to standardise its delivery, the use of intention to treat analysis, and the amount of loss to follow up. Feasibility can be encapsulated by reference to economic, political, and logistic barriers to implementation and by the range of settings and societies in which these barriers would be low. Discussion As demand rises for more pragmatic trials to inform real world choices,13 so too does the need to ensure that the results are clearly reported. Readers need to be able to evaluate the validity of the results, the extent to which they are applicable to their settings, and the feasibility of the tested interventions. The existing CONSORT statement applies fully and directly to pragmatic trials. Here we have proposed extensions for eight items in the statement to make more explicit the important attributes of pragmatic trials and thus to ease the task of users in assessing feasibility, relevance, and likely effects of the intervention in their own setting. We reached consensus that the trial results are likely to be more widely applicable if the participants, communities, practitioners, or institutions were not narrowly selected; if the intervention was implemented without intense efforts to standardise it; if the comparator group received care or other interventions already widely used; and if the outcomes studied were of importance to the relevant decision makers. The intervention needs to be precisely described if readers are to be able to assess its feasibility. The multiplicity and independence of the elements constituting the design of pragmatic trials guarantee that pragmatism is not an all or none attribute; rather, it might be best conceived as a continuum along several dimensions. For example, a randomised trial could have broad inclusion criteria for participants but rely primarily on a short term, physiological outcome rather than one that is more meaningful to the participants. Alternatively, a trial might include a wide range of participants, meaningfully assess the effect, but evaluate an intervention that is enforced or tightly monitored and thus not widely feasible. Other permutations probably exist. It is not the case that more pragmatic is always better; a trial’s design should be such that the results will meet the needs of the intended users. A trial intended to inform a research decision about the biological effect of a new drug is likely to be more explanatory in design. At a later date, a trial of that same drug aimed at helping patients, practitioners, or policymakers to decide whether it should be prescribed is likely to be more pragmatic in design. To help display this multidimensionality, we have developed of a tool, primarily intended to be used in designing a trial, for characterising where it will stand along the pragmatic-explanatory continuum in relation to each design decision.71 We hope that these reporting guidelines will help editors, reviewers, trialists, and policy makers in reporting, reviewing, and using pragmatic trials. Journals that have endorsed the CONSORT statement could also support CONSORT for pragmatic trials, by including reference to this extension paper in the journal’s instructions to authors. We also invite editorial groups to consider endorsing the CONSORT extension for pragmatic trials and encourage authors to adhere to it. Up to date versions of all CONSORT guidelines can be found on the CONSORT website (www.consort-statement.org).
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                Journal
                Journal ID (nlm-ta): Crit Care Med
                Journal ID (iso-abbrev): Crit Care Med
                Journal ID (publisher-id): CCM
                Title: Critical Care Medicine
                Publisher: Lippincott Williams & Wilkins (Hagerstown, MD )
                ISSN (Print): 0090-3493
                ISSN (Electronic): 1530-0293
                Publication date (Print): November 2022
                Publication date (Electronic): 13 October 2022
                Volume: 50
                Issue: 11
                Pages: 1545-1554
                Affiliations
                [1 ] Houston Methodist Pulmonary Transplant Center, Houston Methodist Hospital, Houston, TX.
                [2 ] Department of Academic Pulmonology, Houston Methodist Hospital, Houston, TX.
                [3 ] Boston Biostatistics Research Foundation Inc, Framingham, MA.
                [4 ] Massachusetts General Hospital, Harvard Medical School, Boston, MA.
                [5 ] University of California, Irvine, CA.
                [6 ] The University of Louisville, Louisville, KY.
                [7 ] St. Jude Medical Center, Fullerton, CA.
                [8 ] Baptist Hospital, Miami, FL.
                [9 ] Oregon Clinic, Portland, OR.
                [10 ] Johns Hopkins University School of Medicine, Baltimore, MD.
                [11 ] NRx Pharmaceuticals, Inc., Wilmington, DE.
                [12 ] The University of Miami, Miller School of Medicine, Miami, FL.
                Author notes
                For information regarding this article, E-mail: jgyoussef@ 123456houstonmethodist.org
                Article
                Accession ID: 00001
                DOI: 10.1097/CCM.0000000000005660
                PMC ID: 9555831
                PubMed ID: 36044317
                SO-VID: b725ab9b-54fe-4884-904f-6fe1e829cbaa
                Copyright © Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.
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                This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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                Keywords: acute lung injury,acute respiratory distress syndrome,alveolar type ii,coronavirus,covid-19,severe acute respiratory syndrome coronavirus 2,surfactant,vasoactive intestinal peptide
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                Keywords: acute lung injury, acute respiratory distress syndrome, alveolar type ii, coronavirus, covid-19, severe acute respiratory syndrome coronavirus 2, surfactant, vasoactive intestinal peptide

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