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COVID-19: What It Means for Diabetics, the Obese, and Those with Other Immune Diseases

Links are emerging between the coronavirus and patients with chronic pain, obesity, diabetes, and immune conditions such as IBD, MS, and psoriasis. Preliminary clinical treatment recommendations for both stable and infected patients are reviewed.

Any immune disorder increases the risk of SARS-CoV-2virus and COVID-19 illness. The most prevalent immune disease is diabetes. Type 2 diabetes and obesity have increased worldwide to epidemic proportions and, together, are deadly contributors to the COVID-19 pandemic. Obesity and type 2 diabetes also are important factors in the management of chronic pain disorders.

This article first reviews the multifaceted impact of diabetes and obesity on chronic pain. A comparison of the immune/inflammatory response in diabetes to that of the COVID-19 infection is included, as is current and emerging research regarding the risk of diabetes on COVID-19 infection. Preliminary data regarding COVID-19 infection in non-rheumatic immune diseases, including inflammatory bowel disease (IBD), psoriasis, and multiple sclerosis (MS), are presented. Finally, treatment recommendations are provided. See also, Managing Rheumatic/Immune Diseases During COVID-19, which focuses on rheumatoid arthritis and systemic lupus erythematosus. 

Obesity and type 2 diabetes have been associated with adipose tissue inflammation and alterations in immune activation. (Image: iStock)

 

Prevalence and Links among Chronic Pain, Obesity, and Diabetes

This review focuses on type 2 diabetes, which is closely related to the epidemic of obesity. The global prevalence of obesity has doubled in the past 20 years.1 Obesity, marked by BMI > 30, is the single most important risk factor for type 2 diabetes and there is a linear correlation of increased BMI with an increased risk of diabetes. Type 2 diabetes affects 500 million people worldwide and 10% of adults in the United States.1

Chronic pain affects one in three Americans and is the number-one symptom leading to physician visits.2 There is a strong correlation among obesity, type 2 diabetes, and chronic pain.2 The three broad categories of chronic pain - nociceptive (inflammatory), neuropathic, and nociplastic (central) - are each adversely affected by obesity and type 2 diabetes (see Table I.)

Obesity increases weight load and predisposes individuals to osteoarthritis of the knee and hip.3 The increased structural demands of obesity are also factors in chronic low back pain. For example, 12% of adults classified as obese have chronic low back pain compared to 3% of adults of normal weight.4 Obesity and type 2 diabetes activate inflammatory/immune mechanisms which can promote chronic pain. See also, Obesity and Pain Care: Multifaceted Considerations for Treatment, and Obesity and Rheumatoid Arthritis: What Clinicians Should Know.

Diabetic neuropathy is the most common complication of diabetes, affecting up to 50% of patients with type 2 diabetes. Carpal tunnel syndrome and other entrapment neuropathies are also more common in diabetic patients compared to the healthy population.

The prototypic nociplastic (central) chronic pain condition, fibromyalgia, is strongly associated with obesity as well. Between 25% and 60% of women with fibromyalgia are considered to be obese and type 2 diabetes is more common in those with fibromyalgia than in the general population.5 In a study of 123 obese fibromyalgia patients, those who lost at least 10% of their body weight showed greater improvement in pain and other symptoms.6

The Impact of the Immune System/Inflammatory System in Diabetic and Obese Patients on COVID-19 Infection

Obesity and type 2 diabetes have been associated with adipose tissue inflammation and alterations in immune activation.7 Specifically, tissue macrophages are involved in obesity-induced insulin resistance. T-cell subsets release cytokines which promote insulin resistance. Pro-inflammatory markers, including tumor necrosis factor (TNF) and C-reactive protein (CRP), can predict the subsequent development and severity of type 2 diabetes.8 Even short-term hyperglycemia has been shown to transiently blunt the immune response.9

Data to date* shows that inflammatory and immune mechanisms are involved in every aspect of COVID-19 infection.10 Once the viral-infected cells die, their necrosis triggers an inflammatory/immune response. In the initial phase of infection, there appears to be a fall-off in T-cell function and a reduction in natural killer cells. This can result in lymphocytopenia. Interferon (IFN) and complement activation limit viral spread but may quickly become overwhelmed. As a result, hyperinflammation can occur with massive release of cytokines, referred to as a cytokine storm. Levels of various interleukins (IL-2, IL-6 and IL-7), TNF, ferritin, troponin, and other inflammatory/immune markers end up being markedly elevated.

The presence of diabetes inhibits intracellular killing of any microbe.7 The increased susceptibility of COVID-19 infection in patients with diabetes may involve a more effective viral entry in cells, a decrease in viral clearance, and overall diminished T-cell function. Evidence from the 2003 severe acute respiratory syndrome (SARS), for example, found that SARS coronavirus readily entered islet cells, using angiotensin converting enzyme (ACE2) as its receptor, damaging islets and causing acute diabetes.11 Type 2 diabetes has been associated with increased expression of ACE in other tissues, including the lung, liver and heart, besides the pancreas. This connection may explain the higher rate of multi-organ failure and mortality in patients with type 2 diabetes and COVID-19 infection.12 Patients with diabetes also tend to have increased comorbidities, particularly cardiovascular disease, that have been associated with increased severity of COVID-19 infection.

Emerging Pandemic Data

Diabetes and cardiovascular disease appear to be the most common comorbidities in patients with COVID-19 infection. Data emerging from the SARS-CoV-2pandemic have shown an increased rate of COVID-19 infection and a higher risk for complications and death in patients with diabetes. Most of the statistics have not broken this down into type 1 or type 2 diabetes.

Data regarding COVID-19 in patients with diabetes is somewhat varied,with a prevalence of diabetes ranging from 10% to 20% in most series.12 In a series of more than 72,000 cases of COVID-19 from China, diabetes increased the mortality rate three-fold, from 2.3% to 7.3% of cases.13 Looking back, diabetes and blood glucose levels were important risk factors for morbidity and mortality in patients infected with Pandemic Influenza A 2009 (H1N1), the SARS coronavirus, and the Middle East Respiratory Syndrome-related coronavirus (MERSCoV).10  However, a very recent meta-analysis could not confirm that diabetes increased the risk of COVID-19 infection but did find that it worsened the outcome.14

Independent of diabetes, obesity is an important risk factor for morbidity and mortality in COVID-19 infection. In a study from Italy, 48% of patients with COVID-19 admitted to an intensive care unit were obese.15 The need for mechanical ventilation correlated with patients’ BMI. The worst prognosis was in patients with a BMI > 35kg/m2. Hypertension, a common comorbidity in type 2 diabetes, is also a risk factor for COVID-19 infection and disease severity. Patients with hypertension and those treated with ACE inhibitors may overly express ACE2, resulting in increased severity of coronavirus cell entry.

 

In the two largest, recently published series regarding patients with irritable bowel disease, there was no strong evidence that IBD was a risk factor for COVID-19 infection. (Image: iStock)

 

COVID-19 Infection in Other Immune Diseases: IBD, MS, Psoriasis

Inflammatory Bowel Disease (IBD)

SARS-CoV-2 has been shown to enter gastrointestinal (GI) cells and up to 50% of fecal samples in patients with COVID-19 infection were positive for persistent viral detection.16 This may explain why many patients with the virus have GI symptoms. As discussed in part 1 of this topic (https://www.practicalpainmanagement.com/pain/myofascial/managing-rheumatic-immune-diseases-during-covid-1), one might expect that these immune mechanisms would put patients with IBD, which includes ulcerative colitis and Crohn’s disease, at greater risk for developing the COVID-19 infection.

However, that does not seem to be the case. In the two largest, recently published series, there was no strong evidence that IBD was a risk factor for COVID-19 infection. In a GI referral center following 20,000 patients with IBD, there were no reported cases of COVID-19.17 In a study from Italy, no cases of COVID-19 infection had been detected in 522 patients with IBD who were followed closely for one month.18 Of this sample, 22% were taking immunosuppressive drugs. Those patients continued on those medication regimens.

In patients with IBD, it has been postulated that ACE2 receptor viral affinity, important in initial upper respiratory infection, is different in the ileum and colon and up-regulation of ACE2 in the peripheral blood of IBD patients may limit COVID-19 infection.16 As detailed below, immunosuppressive drugs given to IBD patients may actually decrease the rate of infectivity and/or the severity of infection. Cytokines released in COVID-19 infection are similar to those found in the inflamed tissues of patients with irritable bowel disease.

A panel of IBD experts from China, the United Kingdom, and the US released guidelines for managing IBD patients, including recommendations regarding patient visits and medications.19 See Table II. The guidelines also include recommendations for treating a patient who has a fever. Importantly, it has also been recommended that any patient with IBD be screened for COVID-19 infection, even if asymptomatic.20

Multiple Sclerosis (MS)

There is no evidence to date that multiple sclerosis increases the risk of COVID-19 infection or any self-limited upper respiratory viral infection.21 However, there is an increased risk of pneumonia with MS and the risk of certain immune modulatory medications used in MS is not known.

Initial reviews by neurologists suggest that most MS patients should continue on immune therapy unless they have evidence of symptomatic COVID-19 infection.21 Certain medications used to manage MS are often associated with lymphopenias, such as alemtuzumab and cladribine, and patients taking these drugs may be at greater risk. Extended intervals between doses of immune therapies has therefore been recommended.21

Corticosteroids may be appropriate for acute disease exacerbations. Any patient hospitalized with COVID-19 should be taken off increased dose of corticosteroids within 4 weeks after recovery.21 The National Multiple Sclerosis Society has developed guidelines on the use of disease-modifying anti-rheumatic drugs (DMARDs) during the COVID-19 pandemic.22

Immunomodulators that do not suppress the immune system, such as interferons, glatiramer acetate, and natalizumab, are considered safest whereas other immunomodulators with immune actions, such as fingolimod and dimethyl fumarate, and immunosuppressants such as rituximab and alemtuzumab, have been shown more likely to increase the risk of the COVID infection.

Psoriasis and Related Skin Diseases

The most common immune-driven skin disease is psoriasis. Patients with psoriasis are often treated with immunosuppressive medications. There have been no studies linking psoriasis or other immune-related dermatologic conditions with increased risk of COVID-19 infection.

Lebwohl recently compared the rate of upper respiratory infections with most of the biologics/immune drugs used in psoriasis.23 According to his calculations, etanercept showed no increased infection compared to placebo whereas other TNF inhibitors had a 7% increased rate. Most of the interleukin blockers had a minimal rate of increased infections. The author cautioned that these data do not directly apply to COVID-19 and that there is evidence that immune therapy may prove helpful in the treatment of COVID-19 infection.

Immune-Related Medications and COVID-19

Hydroxychloroquine

Antimalarial medications, including hydroxychloroquine (HCQ) and chloroquine, have been featured prominently in media coverage of COVID-19.24 They also have been recommended by the Infectious Disease Society of America (IDSA) for those hospitalized with the infection, but only in the context of a clinical trial (updates on this below).

HCQ, branded Plaquenil, has been used to treat rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) for more than 50 years. The drug’suse has been especially prominent in India, where HCQ has been approved for the treatment of type 2 diabetes since 2014.25 It has anti-inflammatory and immune properties, as well as antimicrobial effects, although only well-documented for malaria. Laboratory studies have demonstrated that these drugs may block the coronavirus from entering cells and a few uncontrolled or very small studies from China suggested that it may have been helpful in patients with COVID-19 infection. However, the drug may prolong the QT interval and should be used with extreme caution in patients with a history of cardiac arrhythmias.22 A baseline electrocardiogram should be done in any subject with cardiovascular disease.

Plaquenil and other antimalarials are being routinely given to patients hospitalized with COVID-19 infection in the US.  Daniel H. Sterman, MD, the critical care director at New York University’s Langone Health, noted that data about HCQ’s effectiveness are “weak and unsubstantiated” and…we do not know whether our patients are benefiting from hydroxychloroquine treatment at the present time.”26

In fact, a number of medical experts, including NAID Director Anthony Fauci, MD, have raised caution about widespread use of these drugs. Dr. Fauci told The New York Times: “I think we’ve got to be careful that we don’t make that majestic leap to assume that this is a knockout drug… We still need to do the kinds of studies that definitively prove whether any intervention, not just this one, any intervention is truly safe and effective.”26

For those with rheumatic disease already on HCQ and antimalarials, the American College of Rheumatology has recommended that their HCQ and similar medication regimens be continued as long as the patients are stable and have no signs of infection or SARS-CoV-2 exposure. (See their full recommendations). See also, Hydroxychloroquine Use and Risk in the Management of Systemic Lupus Erythematosus.

Corticosteroids

Corticosteroids have been used in COVID-19 infected patients with pneumonia, especially in those with acute respiratory distress syndrome (ARDS). Most observational studies have not found evidence for their efficacy and guidelines from the World Health Organization (WHO) did not support the use of corticosteroids for pneumonia or ARDS associated with COVID-19 infection.27

TNF Inhibitors, Interleukins, and JAK Inhibitors

Like the antimalarial drugs, immunosuppressive and immune-modulating drugs have been tried in many hospitals throughout the world in patients with life-threatening COVID-19 infection. Their impact on immune receptors and cytokines may have a beneficial effect in certain phases of COVID-19 infection, such as the so-called cytokine storm. There is no evidence that TNF inhibitors are helpful or harmful in patients with COV-19 infection.28 Interleukins, including IL-1 and IL-6, seem to contribute to the cytokine storm of COVID-19 pulmonary disease. The IL-6 blocker, tocilizumab, is considered to be a good candidate for severe COVID-19 infection.28

Enzymes associated with intracellular signaling, janus kinase (JAK) inhibitors, including tofacitinib and baricitinab, are also being evaluated.

Ongoing Trials and Other Potentially Helpful Drugs

Overall, antimalarial drugs, corticosteroids, and other anti-inflammatory medications and immune-modulating drugs for the treatment of COVID-19 infection are being studied in clinical trials throughout the world.29

Update on HCQ and COVID: As of April 10, 2020, there were 440 studies dedicated to COVID-19 listed on ClinicalTrials.gov. The most commonly studied medication in these trials is hydroxychloroquine, with 15 clinical trials in COVID-19 infection.30 However, in June 2020, NEJM published data from a RCT which demonstrated that "after high-risk or moderate-risk exposure to COVID-19, hydroxychloroquine did not prevent illness compatible with COVID-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure." Further, the RCT showed more side effects with HCQ use than with placebo (40.1% vs. 16.8%); no serious adverse events occurred. Then, on July 1, 2020 FDA issued a statement cautioning against the use of hydroxychloroquine or chloroquine for COVID-19 outside of a hospital setting or a clinical trial due to risk of heart rhythm problems.

Other medications being tested for COVID in a number of countries include: tocilizumab, with 8 clinical trials, tofacitinib and sarilumab, as well as corticosteroids, each with 4 clinical trials listed. These medications are being evaluated primarily in hospitalized patients with severe infection but there are some studies looking at these drugs in early disease and a few using such medications as a prophylactic approach in high-risk subjects.

Since ACE inhibitors, angiotensin receptor antagonists and NSAIDs each may alter ACE2 receptor activity, there has been concern that such medications may enhance viral attachment and should not be used during the current pandemic.31 However, most reviews currently recommend that these drugs not be discontinued in subjects who have no signs of COVID-19 infection.32 There is anecdotal evidence that vitamin D supplementation could be helpful in COVID-19 infection.33

 

With regard to type 2 diabetes and COVID-19, comorbid diseases, including hypertension and cardiovascular disease, need to be carefully monitored. (Image: iStock)

 

Preliminary Recommendations for Patients with Chronic Pain and Immune Diseases

Type 2 Diabetes

Every attempt should be made to achieve optimal control of the metabolic aspects of type 2 diabetes during the current COVID-19 pandemic.34 Good blood glucose control, updated immunizations, and diet/weight loss are important now more than ever. Comorbid diseases, including hypertension and cardiovascular disease, need to be carefully monitored. Such monitoring should include more frequent patient visits.

Telehealth and other virtual/on-line medical visits are the best way to achieve such visits during the current pandemic. See, How HCPs Can Use Telemedicine in the Time of Coronavirus. There should be a lower threshold for hospitalizing patients with diabetes and suspected COVID-19 infection.

Other Immune Diseases

There is currently no strong evidence that the majority of patients with immune diseases, including rheumatic diseases, inflammatory bowel disease, multiple sclerosis, and psoriasis, are at increased risk for COVID-19 infection or for greater morbidity and mortality if infected. Nevertheless, clinicians should maintain a high index of suspicion for any patient with a significant immune disorder. It is imperative that the underlying immune disease be under good control. If patients are stable, they should be maintained on their current medications during the COVID-19 pandemic. If a new medication is being considered, a specialist may consider that certain immune-modulating medications may be potentially safer than others although there are no adequate studies.

If a patient has an active infection, particularly if hospitalized, immunosuppressive medications and corticosteroids should be transiently suspended, unless there are medical contraindications. However, as discussed, immunosuppressive and immune modulators are being used in life-threatening situations and may be found efficacious in the treatment of COVID-19. The community needs controlled clinical trials to ascertain whether that is true.

As noted, the IDSA published recommended guidelines for medications currently being treated in the COVID-19 pandemic.35 Their conclusions included that antimalarials and tocilizumab be used in hospitalized patients only in the context of a clinical trial. They suggested against the use of corticosteroids for treatment in hospitalized patients and only using them in patients with ARDS within a clinical trial.

Additional Considerations Regarding Chronic Pain, Stress, and the Immune System

Pain management providers know well that chronic stress, sleep, and mood disturbances are major factors in the development and severity of chronic pain. The impact of chronic stress on cortisol secretion and on the hypothalamic-pituitary-adrenal (HPA) axis plays a major role in chronic pain. The odds of an individual developing chronic widespread pain later in life has correlated with baseline HPA reactivity.36

Depression is closely linked to chronic pain, as detailed in the many reviews dedicated to the pain-depression dyad.37  Persistent sleep disturbances are one of the most important predictors of chronic pain.38 The current COVID-19 pandemic has put everyone in a state of hypervigilance. Increases in insomnia, anxiety, depression, cognitive disturbances, and suicidal ideation were seen in the initial wave of COVID-19 infection in China.39

Successful telemedicine and collaborative management of patients with chronic pain are well-documented.40 The novel coronavirus pandemic has forced more healthcare providers to utilize this technology which is becoming the primary point of contact for patients.41 Clinicians also must take advantage of web-based evaluation and treatment programs. These may include psychological as well as physical therapy, including relaxation techniques, guided imagery, and group classes. See Table III.

 

Conclusion

Individuals with type 2 diabetes are at increased risk for COVID-19 infection and have a worse prognosis if infected. This risk may be more related to comorbidities, especially obesity and hypertension, than to immune mechanisms. Thus far, there has been no evidence that common systemic, immune diseases such as IBD, MS, or psoriasis increase the risk of COVID-19 infection or its morbidity and mortality. Nevertheless, it is likely that patients with type 2 diabetes and other immune diseases will experience exacerbations of chronic pain triggered by increased stress, mood, and sleep disturbances. These factors increase the challenges faced by pain specialists and all healthcare providers.

 

*This article was written in early April 2020. Data and recommendations around COVID-19 continue to be released.

Last updated on: July 9, 2020
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How Clinicians Can Manage Rheumatic and Immune Diseases During COVID-19
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