Impact of the COVID-19 pandemic on chronic pain management

Introduction: The COVID-19 pandemic has generated considerable turmoil in the interventional pain management (IPM) community. Due to IPM being classified as ‘elective’, numerous pain practices across the United States were forced to close during the pandemic, leaving chronic pain patients untreated for indefinite periods, and IPM physicians with increased stress and burnout.

Results: In response to these detrimental effects, various re-opening tools and techniques have been created to facilitate a cautious resumption of in-person interventional pain practice. Due to their ability to minimize person-to-person contact, telehealth and pharmacotherapy played a more significant role in IPM during the pandemic, but their increased utilization has also led to the exacerbation of substance abuse and the opioid epidemic. The interplay between steroid use and its immunosuppressive effects, in relation to the COVID-19 infection and the COVID-19 vaccine, has also arisen as an issue of concern.

Conclusion: As practices begin to safely re-open throughout the United States, the effects felt by chronic pain patients during the pandemic must be emphasized and not ignored. This review emphasizes the struggles pain patients have had to face during the pandemic and the need to update and redefine regulations regarding interventional and chronic pain management

INTRODUCTION

Over the past eighteen months, the coronavirus disease 2019 (COVID-19) pandemic has caused dramatic societal, economic, and healthcare disruptions across the world. As of June 20th, 2021, in the United States alone, a total of 33,368,860 cases of COVID-19 have been reported, along with 599,354 COVID-19 deaths [1] (Table 1, Figure 1). The interventional pain management (IPM) community has been especially impacted by COVID-19 restrictions, which classify interventional techniques as ‘elective’, effectively excluding their use during the pandemic. This has led to chronic pain patients being left untreated for indefinite periods of time, worsening their outcomes and causing some to potentially pursue inappropriate alternatives to treatment. As for interventional pain physicians, increased stress and burnout, derived from the pandemic, has led a majority of practitioners to develop a negative outlook of the future.

Table 1. Centers for Disease Control (CDC) data on monthly COVID-19 cases and deaths, from March 2020 - May 2021

Figure 1. Centers for Disease Control (CDC) data on monthly COVID-19 cases and deaths, from March 2020 - May 2021

In order to safely resume in-person interventional pain practice, various screening, risk stratification, triaging, and resource utilization protocols were created, allowing practitioners to prioritize their most urgent cases while simultaneously limiting the spread of COVID-19. A significant shift towards telemedicine was also observed, as telehealth visits were utilized more frequently due to their ability to minimize contact between individuals. For that same reason, an emphasis was also placed on pharmacotherapy modalities to replace the treatment gap left by interventional techniques. However, a greater reliance on pharmacotherapy has subsequently led to the exacerbation of substance abuse and the opioid epidemic as well. Concerns over a potential link between steroid use and its immunosuppressive effects on COVID-19 infection and the COVID-19 vaccine have also surfaced due to uncertain outcomes and interactions.

COVID-19 IMPACT ON CHRONIC PAIN PATIENTS

Effect on patient outcomes

The implementation of COVID-19 restrictions, associated with social distancing, has resulted in the closure of adjuvant physical therapy centers, chiropractic clinics, and other healthcare services, severely limiting a patient’s access to various modalities for managing their chronic pain [2]. Moreover, maintaining pharmacological regimens with patients has proven challenging for pain physicians, as many have been forced to restrict their practices, both due to state-guided restrictions, as well as to the lack of support staff.

Individuals working virtually from home have also developed repetitive strain injuries, as a result of the poor ergonomics of suboptimal workstations [2]. With increased indoor family time and outdoor activity, associated with the pandemic, new injuries and acute exacerbations of chronic spinal conditions have also emerged from activities such as fixing one’s house or car, increasing one’s exercise routine, or playing with one’s children. Those who developed these new injuries or aggravated existing conditions mid-pandemic were left to manage their symptoms with minimal assistance, as they were unable to schedule appointments with their primary care physicians or physical therapists and prohibited from going to the emergency room or urgent care center.

While pharmacological therapy has become an important option, with pain practices being restricted, in terms of the breadth of services they can offer, the pandemic has seen an unfortunate rise in substance abuse, as well as opioid and non-opioid overdoses, accompanying this shift towards pharmacological therapy [3].

Consequences of delaying IPM

Chronic pain patients are often at high risk of COVID-19, as many are characteristically older patients and/or have a chronic underlying disease [4]. These risks are compounded for those who have limited access to healthcare. Ultimately, these factors make chronic pain patients more likely to avoid in-person clinical visits and postpone interventional pain procedures. For instance, patients with intrathecal drug infusion systems may suffer painful, distressing or life-threatening withdrawal symptoms if their pump cannot be refilled on time or their pump’s batteries die before replacement [5]. Consequently, patients may turn to other, more harmful treatments such as increased doses of non-steroidal anti-inflammatory drugs (NSAIDs), illicit drugs, or opioids [4].

Impact of elective surgery restrictions on interventional pain practices

Many ambulatory surgery centers (ASCs) and hospital administrators across the United States wrongly categorized most IPM services as ‘elective’ and closed their IPM services during the pandemic, as a result [2]. In these settings, interventional pain physicians or their representatives were often not consulted before these decisions were made. These actions were particularly deleterious for IPM practices, as only one-third of IPM physicians work in an office-based setting, thus leaving the larger proportion of IPM physicians, who rely on hospital suites or ASCs, without a facility to treat their patients [6]. Due to the unknown duration and severity of the COVID-19 pandemic and related societal shutdowns, pain patients braced themselves for dealing with untreated pain for an indeterminate length of time, which was coupled with worries about long-term effects of untreated pain [2].

COVID-19 IMPACT ON INTERVENTIONAL PAIN PRACTICE

Overview and impact on interventional pain physicians

Elective interventional pain management and office visits have been halted across the United States due to the COVID-19 pandemic [2]. With pain being the reason for 45% of visits to emergency departments, the postponement of IPM significantly impacted interventional pain practice [7]. In a survey conducted by the American Society of Interventional Pain Physicians (ASIPP) on the impact of COVID-19 on IPM physician burnout, 98% of respondents reported that their practices were affected by COVID-19, with 91% stating they were affected financially, 54% reporting new burnout secondary to COVID-19, 19.55% attempting to retire from medical practice, and 66% developing a negative outlook of the future [8].

Operational changes to interventional pain practices

1. Recommendations of the Centers for Disease Control (CDC)

The CDC recommends that individuals receiving treatment at an ambulatory care center or other outpatient institution be contacted prior to their visit and screened for COVID-19 risk over the phone [9]. If a patient with known or suspected COVID-19 needs to be treated in person, the patient should be requested to phone ahead of time so that personnel can be prepared (personal protective equipment - PPE, and infection control procedures) and the patient may be rapidly brought into the system and receive their care promptly. After surgical procedures, telephone follow-ups can be utilized to check on patients, confirm medication adherence, and answer any questions patients may have.

2. IPM resource utilization

A clinical team must evaluate a pain patient’s COVID-19 history via methods such as antigen or antibody testing and/or a chest X-ray when considering an interventional pain procedure [10]. Procedures must also be carried out in accordance with federal, state, and local regulations, and all individuals who are in close proximity to the patient must have access to adequate PPE. Equipment should also be kept to a minimum in the exam room, and what is left should be protected with disposable covers [11].

3. Definition of medical urgency of a case

The medical urgency of a patient can be stratified based on their clinical situation and by case [2]. Certain cases can be safely postponed for a limited period of time, while others can be postponed indefinitely without harming the patient. However, in many circumstances, risks compete, due to an interplay of factors. Assessing the risks between viral infection, untreated pain, and higher-than-usual drug doses is a common predicament many chronic pain patients face.

The type of pain a patient experiences is also a particularly important component for determining medical urgency. Acute pain may be a symptom of underlying disease and may be addressed as an emergency. Subacute or chronic pain conditions can be associated with potentially severe concomitant functional limitations. Inadequate management of subacute or chronic pain may result in increased comorbidities and patient harm. Studies have linked untreated chronic pain with a myriad of medical issues such as memory loss, dementia, depression, functional deficits, anxiety, insomnia, suicidality, and early mortality [12],[13],[14],[15],[16],[17],[18].

4. IPM acuity scale

Whether or not a procedure is urgently or emergently indicated cannot be determined purely on the basis of whether or not the operation is ‘elective’ [19]. An interventional pain specialist should be responsible for assessing if a procedure is medically necessary, taking into account a variety of factors such as the patient’s pain severity, physical incapacitation, underlying conditions, comorbidities, disease progression, mental health status, response to alternative treatments, visits to other healthcare professionals, extent of analgesic management (including opioid use), and likely outcomes, if a procedure is performed or delayed. The IPM environment is a dynamic one, as there are distinct differences between the types of pain patients and their accompanying functional impairments, regions from which these pain patients come from, and regional regulations. Hence, blanket decisions regarding procedures should be avoided.

5. Reopening interventional pain practices

Throughout the months of June and July 2020, 195 Spine Intervention Society members were surveyed regarding the demographics of their practices, perception of COVID-19 prevalence, financial impact of COVID-19 on their practices, and implementation of new re-opening tools and procedures [20]. Risk stratification tools and scheduling pattern changes were used by most respondents (71%). Initial assessments and follow-ups were conducted via telehealth by almost 70% and 87%, respectively. Upon a patient’s in-person entrance into a clinic or facility, over 80% performed symptom/temperature checks, and 63% screened patients over the phone. For office visits, patients were not tested for COVID-19 by more than half of the respondents (58%), but 38% did test patients, if they were symptomatic. Of the total number of respondents, 43% did not test patients for COVID-19 prior to epidural injections, intra-articular injections, and radiofrequency neurotomy procedures, but 36% did test patients, if they were symptomatic. Mask wearing was deemed a requirement for entering the clinic or facility by a majority of respondents (70%). Surgical masks (85%), gloves (35%), face shields/goggles (24%), N95 respirators (15%), and gowns (6%) were used for non-procedure encounters. A minority (26%) provided written information concerning unique COVID-19 risks and complications, while 66% discussed them verbally. Steroid dosage (67%) and peri-procedural anticoagulation management (97%) remained unchanged by most. A large majority (81%) estimated a moderate to severe financial impact on their practice due to COVID-19.

GUIDELINE METHODOLOGY

Numerous organizations have released their respective guidelines for the care of non-COVID-19 patients during the pandemic. The ASIPP has developed the COVID-ASIPP Risk Mitigation and Stratification (COVIDARMS) Return to Practice Task Force, to provide interventional pain practices with a framework for cautious and strategic reopening [10].

The COVID-ARMS Return to Practice Task Force created a point-based system of risk stratification with regards to patients presenting for interventional pain procedures, for decreasing COVID-19 morbidity. Risk factors and comorbidities of interest for the risk stratification system were chosen based on their increased prevalence among overall COVID-19 hospitalizations. These included age, nursing home or long-term care residence, pulmonary disease, cardiovascular conditions, obesity, diabetes, renal dysfunction, hepatic dysfunction, and immunocompromised state. Each risk factor or comorbidity is assigned a point value depending on the severity of its manifestation in the respective individual. With increasing severity observed, a higher point value is assigned. Once points are assigned to all risk factors and comorbidities present in the individual, they are summed to produce a total value, which, in turn, can be used to classify the patient’s overall risk as ‘low’, ‘moderate’, or ‘high’, with respect to pursuing an interventional pain procedure.

In addition to risk stratification, the ASIPP has also provided guidance for triaging pain interventions as ‘emergent’, ‘urgent’, or ‘elective’ based on descriptive indications, the location of treatment, situation specific examples, intervention examples, and timing factors [2]. The COVID-ARMS Return to Practice Task Force has also produced a flow chart for mitigating the risks of COVID-19 morbidity during interventional pain encounters, to be used in conjunction with risk stratification and triaging tools [10].

Legislatively, guideline changes and the relaxation of various regulations allowed providers more flexibility to treat patients, while still maintaining COVID-19 precautions. The introduction of telehealth, in particular, has helped expand coverage to those who would not have qualified under non-pandemic circumstances. Legal changes, such as the Coronavirus Preparedness and Response Supplemental Appropriations Act and 1135 Waiver, have allowed Medicare and Medicaid services to expand the offerings of telehealth appointments to “office, hospital, and other visits furnished via telehealth across the country including in patients’ places of residence” [21]. Additionally, the United States Drug Enforcement Administration (DEA) also relaxed regulations, allowing DEA-registered physicians to “prescribe opioids via telehealth visits provided they are issued for a legitimate medical purpose by a practitioner acting in the usual course of his/her professional practice; the telemedicine communication is conducted using an audio-visual, real-time, two-way interactive communication system; and the practitioner is acting in accordance with applicable federal and state law” [21].

Efforts have also been made to combine classification systems from various organizations, such as the American Society of Regional Anesthesia and Pain Medicine (ASRA), European Society of Regional Anesthesia and Pain Therapy (ESRA), and American Society of Pain and Neuroscience (ASPN), to produce a new framework of guidelines aimed at providing a consensus and a streamlined reopening approach for interventional pain practices [22]. In the aforementioned combined classification system, the components of risk stratification, triaging, and PPE requirements continue to be emphasized.

TELEMEDICINE

An adaptation to the COVID-19 pandemic was the implementation of telehealth visits, in order to meet the needs of patient care, while limiting potential patient exposure to COVID-19. While, in theory, telehealth should be able to meet patient needs and demands related to care and pain management, subtleties in the patient-physician interaction related to communication and nonverbal cues, which are absent in telehealth visits, may affect treatment and the overall patient experience. In a survey conducted by Berwick et al., the researchers retrospectively evaluated the service of a remote telehealth follow-up clinic, on themes including communication, self-help advice, and understanding [23]. Of the 30 chronic pain patients involved in the survey, 25 were on long-term follow-up. Pain etiology included musculoskeletal, neuropathic, chronic primary pain, and chronic postsurgical pain. Anatomically related pain included: back, shoulder, leg, arm, and generalized pain. From this survey, the researchers found that 19/30 patients reported the consultation had met their needs and 21/30 had been able to say all that they were required to. Despite these findings, however, 25/30 patients would still prefer to have a face-toface appointment, while 17/30 patients would prefer video conferencing over telehealth appointments [23]. These results demonstrate that patients prefer traditional clinic visits over telehealth appointments, if given the opportunity, despite the reported satisfaction with telehealth appointments. Explanations for this finding include a significant reduction in the patient experience ratings regarding communication and missed symptom validation from the physician, due to the lack of a physical examination. Overall, these findings suggest that patients do not prefer telehealth to conventional consultations. This conclusion, combined with the fact that telehealth is no more efficacious than face-to-face consultations, should be taken into consideration when determining future standards of care and training related to pain management [24].

PHARMACOTHERAPY

Chronic pain had been severely affecting individuals and society alike, long before the COVID-19 pandemic emerged. However, it has been severely exacerbated in patients since the onset of the pandemic, due to the decimation of most conventional medical services, with the exception of virtual care and telehealth. In addition to worsening and untreated pain symptoms, many chronic pain patients have also been impacted in numerous other ways, with increases in cardiovascular disease, mental health problems, cognitive dysfunction, and early death [25]. Many different modalities have been utilized to manage and treat chronic pain throughout the years, including surgical and interventional techniques, physical therapy, and pharmacotherapy [25]. Due to the decline in interventional techniques and elective surgical procedures during the pandemic, treatment has been focused on commonly used pharmacological agents, including opioids, NSAIDs, local anesthetics, and steroids [26],[27]. Use of these pharmacological agents, however, generates concern due to their immunosuppressive effects and consequently susceptibility to COVID-19, as chronic pain itself may already be a risk factor, due to immunosuppression.

Opioids have been well-documented to suppress the immune system [28]. NSAIDs generated concern when non-peer-reviewed case reports emerged of several young patients infected with COVID-19 deteriorating after taking ibuprofen. However, neither the United States Food and Drug Administration (FDA) nor the European Medicines Agency (EMA) are aware of any evidence linking the use of ibuprofen or other NSAIDs to worsening COVID-19, though the agencies do caution that “the pharmacological activity of NSAIDs in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections” [29]. Acetaminophen is an alternative to NSAIDs, but has been shown in clinical trials to have weaker antipyretic and analgesic effects [30]. Nociceptive selective block of local anesthetics is valuable in chronic pain injections, especially in maintaining a patient’s well-being and avoiding respiratory depression [27]. Finally, because of the pandemic, the multiple side effects of steroids, such as immunosuppression, have raised concerns, and recommendations have been made to utilize local anesthetic alone or limited doses of steroids [31],[32]. In fact, systematic and focused review of local anesthetics and steroids utilized in interventional pain management for epidural injections, peripheral nerve blocks, and intraarticular injections, have shown that no significant difference was identified, based on whether or not steroids are added to local anesthetic, for epidural as well as facet joint injections [31],[33],[34]. Thus, steroids may be omitted in certain procedures, if fear of immunosuppression is a concern. Additionally, although steroids have been linked to infections caused by immunosuppression in the past, in a position paper from the Spine Intervention Society, the Patient Safety Committee concluded “there is no clear evidence of a causative effect between spinal injections and periprocedural infections and complications in immunosuppressed patients” [35]. Most are linked to contaminated solutions or poor infection control practice.

As the pandemic continues to afflict nations worldwide, it is concurrently worsening a public health crisis in the United States that had slowly been on the decline in the past few years: the opioid epidemic [25]. With the onset of the pandemic, many chronic pain patients’ conditions have worsened due to delay of treatment from the decline in conventional health services. Correspondingly, chronic pain management has been significantly affected, causing severe restrictions in non-opioid therapy. According to health tracker data, there was a near 88% decline in elective surgeries and 15.1% in pain-related prescriptions [25]. As a result, many chronic pain patients are seeking out alternate and potentially harmful remedies to alleviate their symptoms, such as elevated doses of NSAIDs, illicit drugs, or opioids [4]. Drug deaths, which decreased for the first time in 25 years, in 2018, rose to record numbers in 2019 and are continuing to climb, worsened by the pandemic. Although the opioid epidemic was “already resurfacing with a 5% increase in overall deaths from 2018, the preliminary data show that prescription opioid deaths continued to decline, while at the same time deaths due to fentanyl, methamphetamine, and cocaine climbed, with some reductions in heroin deaths” [25]. It is crucial to develop appropriate regulations that will provide proper opioid therapy while containing the opioid epidemic, without limiting access to therapeutic opioids for chronic pain patients.

CHRONIC PAIN MANAGEMENT AND THE COVID-19 VACCINE

As the development and approval of vaccines for the COVID-19 pandemic progress worldwide, questions regarding the potential effects of pain treatments utilizing steroids on vaccine efficacy have started to arise. Corticosteroid injections often have systemic effects, two of which are systemic immune depression and hypothalamic-pituitary-adrenal (HPA) axis depression [36]. According to studies, the humoral immune response may be disrupted in immunocompromised people, resulting in a reduced immune response to vaccination. For example, in a large retrospective study, influenza-vaccinated patients who had undergone joint corticosteroid injections were 52% more likely to develop influenza than non-injection control patients, with women younger than 65 years being at the highest risk [37]. As a result, guidelines developed at the Institute for Pain Medicine, Tel Aviv state that patients are warned of the immunosuppression risks and are advised not to receive steroid injections during the 5-week period beginning one week prior to the first dose of the vaccine and ending one week after the second dose. However, if the patient insists on receiving an injection, dexamethasone is used due to a shorter duration of systemic effects [38].

The primary concern regarding COVID-19 vaccines in the setting of steroid use is efficacy, given the immunosuppressive hallmarks of corticosteroids. Regarding the clinical trials of specific vaccines, patients with systemic immunosuppression were excluded from participating in all except the Johnson & Johnson vaccine trial [39]. In the Moderna trial, for example, systemic treatment of corticosteroids was limited to ≥20 mg/day. Thus, lots of uncertainty surrounds the efficacy of vaccines administered concurrently with systemic corticosteroid use. With respect to efficacy, previous studies have demonstrated evidence of delayed response to hepatitis B vaccination in children receiving high-dose steroid therapy for nephrotic syndrome, as well as delayed response to the influenza vaccine in cancer patients receiving systemic steroids [40],[41]. The effect on efficacy in these studies, however, was not statistically significant and cannot be used to confirm that chronic high dose steroids may impair vaccine-based immunity. Furthermore, while epidural steroids may be absorbed systemically, they are unlikely to have the immunosuppressive effects seen with chronic high-dose systemic steroid usage, based on current dosage regimens and the pharmacodynamics of these injections [39]. Additionally, short-term systemic bolus steroids have not been demonstrated to impact vaccine responsiveness. With respect to safety, corticosteroid use is a concern in the setting of live immunization and at systemic dosages equivalent to 2 mg/kg or a dose of 20 mg/day of prednisone equivalents for two or more weeks. However, all of the adenovirus vector vaccines approved by the FDA so far are considered appropriate for use in immunocompromised hosts, because there is no risk for reversion to a virulent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain, as may be the case with a traditional live vaccine [39].

In addition to concerns regarding the efficacy of COVID-19 vaccines in relation to corticosteroids, NSAIDs and cyclooxygenase (COX) inhibitors have also been under consideration. When used in pharmacological quantities, acetaminophen, aspirin, and naproxen have shown similar results in inhibiting antibody formation, with studies revealing a direct proportional association between greater NSAID dosages and decreased immunoglobulin synthesis [39]. In addition to their anti-inflammatory effect, NSAIDs exert immunomodulatory effects by interfering with human monocyte and T-lymphocyte activation, proliferation, and cytokine synthesis. However, previous research has found that low-dose aspirin had no effect on the efficacy of the H1N1 influenza vaccine in elderly people and that acetaminophen-associated antibody blunting still resulted in protective antibody levels [42],[43]. Thus, data on the effect of NSAIDs and COX inhibitors on immunity and vaccine efficiency is often inconclusive or insufficient to determine if they are an appropriate substitute for corticosteroid injections.

Overall, there is currently no direct evidence to suggest that a corticosteroid injection, before or after the administration of an adenovirus vector-based COVID-19 vaccine, decreases the efficacy of the vaccine. However, based on the known timeline of HPA axis suppression following epidural and intraarticular corticosteroid injections, and the timeline of the reported peak efficacy of the Johnson & Johnson and AstraZeneca vaccines, physicians should consider timing an elective corticosteroid injection in such a way that it is administered no less than two weeks prior to and no less than two weeks following a COVID-19 adenovirus vector-based vaccine dose, whenever possible [44]. Given these facts, it is still recommended that physicians determine each individual patient’s level of acuity and weigh out specific risks/benefits before considering the treatment plan.

CONCLUSION

It is clear that the COVID-19 pandemic has caused significant disruptions in all aspects of life within the past year. At the start of the pandemic, with the exception of emergency care, most conventional health services were put on hold as a transition to online and telehealth appointments was observed. This transition was particularly deleterious for chronic pain patients, as it severely limited the different treatment options and modalities available. As a result, guidelines concerning the definition of elective procedures were forced to be reexamined with respect to IPM. Many IPM physicians argued that patients must be considered holistically with respect to factors such as daily function, pharmacological drug use, comorbidities, other risk factors, mental health, social risk factors, and prognosis, when determining whether certain surgeries or procedures were classified as elective. Urgent and emergency acuity classification for IPM patients may be carried out when the clinician assesses that a delay would result in unacceptable disease progression, intractable pain, disability, or suffering. Additionally, with the transition to online and telehealth services, treatment shifted towards other pharmacotherapy methods, including opioids and other non-illicit drugs, further exacerbating the opioid epidemic. Steroids, another common pharmacotherapy used in pain management, were also heavily scrutinized due to the concern of their immunosuppressive effects on susceptibility to contract COVID-19, as well as effects on vaccine efficacy. Steroid distancing is recommended in response to inconclusive evidence regarding the effect of steroids on COVID-19 infection or vaccination. Physicians should consider timing an elective corticosteroid injection in such a way that it is administered no less than two weeks prior to and no less than two weeks following a COVID-19 adenovirus vector-based vaccine dose. The findings discussed and observed in this review should be taken into consideration when evaluating the guidelines of IPM practices in the future.

LIST OF ABBREVIATIONS

COVID-19 - Coronavirus Disease 2019
NSAIDs - non-steroidal anti-inflammatory drugs
ASCs - ambulatory surgery centers
IPM - interventional pain management
ASIPP - American Society of Interventional Pain Physicians
CDC - Centers for Disease Control
PPE - personal protective equipment
COVID-ARMS - COVID-ASIPP Risk Mitigation and Stratification
DEA - United States Drug Enforcement Agency
ASRA - American Society of Regional Anesthesia and Pain Medicine
ESRA - European Society of Regional Anesthesia and Pain Therapy
ASPN - American Society of Pain and Neuroscience
FDA - United States Food and Drug Administration
HPA - hypothalamic-pituitary-adrenal
SARS-CoV-2 - severe acute respiratory syndrome coronavirus 2
COX - cyclooxygenase