COVID-19 has already transformed many aspects of medical evaluation, disease diagnosis, and healthcare delivery. It has added complex new layers to the differential diagnosis of every acute and chronic medical condition, including pain syndromes. This article reviews important, potential diagnostic challenges for acute and chronic pain assessment brought about by the pandemic, using hypothetical patient scenarios.
A 58-year-old man with a history of hypertension and osteoarthritis presents with a 5-day history of “feeling out of sorts.” He reports exhaustion and pain in his neck, shoulders, and upper back, which he initially attributed to his arthritis. He increased his usual dose of ibuprofen without any improvement. Yesterday, he began experiencing chest pain. He describes the chest pain as heavy and says he feels better when he presses down on his chest wall. There has been no fever but this afternoon, a dry, hacking cough became very persistent. At this point, he has called his primary care physician and was told to go to the ER, but he is concerned about being exposed to COVID-19.
This patient likely has acute COVID-19 infection but he also may be having an acute cardiac event. While he does not report fever, up to 50% of COVID patients may not present with fever.
Chest pain can be common during acute COVID infection but may be a rather late manifestation, as recalled by a patient from Arizona to the New York Times, “On Day 10, I woke up at 2:30 a.m. holding a pillow on my chest. I felt like there was an anvil sitting on my chest. Not a pain, not any kind of jabbing — just very heavy. I’ve never felt so bizarre. My body felt like it was not my own. I had crazy back pain. Sometimes I felt like I couldn’t move my shoulders.”
Thirty to seventy percent of patients with acute COVID infection have myalgias and fatigue.2 These myalgias may be focal or widespread, mild or severe. This hypothetical patient has no shortness of breath or other pulmonary symptoms but, as noted by Dr. Richard Levitan, “…when Covid pneumonia first strikes, patients don’t feel short of breath, even as their oxygen levels fall. And by the time they do, they have alarmingly low oxygen levels and moderate-to-severe pneumonia (as seen on chest X-rays).”
Since the COVID-19 pandemic began, there has been a worldwide abrupt decrease in the number of ER visits and hospitalizations for acute cardiac events. At Adventist Health Lodi Memorial (LMH), a 150-bed community hospital in California, from March 19 to April 17, there was a 50% drop in ER visits at the same time as a 45% increase in out of hospital cardiac arrests. During the first 2 months of the pandemic in Italy, there was a 60% increase in out of hospital deaths compared to an identical pre-pandemic time frame. This data correlated with a 50% reduction in hospital admissions for acute heart attacks in Italy compared to the same time period one year earlier. In a nation-wide study from Austria, during the month of March 2020, there was a 40% reduction in the number of hospital admissions for acute heart attacks.
These statistics are especially disconcerting given that cardiovascular disease significantly increases the morbidity and mortality associated with COVID-19 infection. During the pandemic, clinicians should be seeing more patients with acute cardiac symptoms, not less.
Clinicians need to be alert to the possibility that chest pain, even mimicking a heart attack, may be a presenting manifestation of COVID-19 infection. At the same time, we must be aware that patients may avoid seeking medical care for fear of getting infected, leading to out-of-hospital cardiac arrests.
A 64-year-old woman with a history of hypertension, obesity, and type 2 diabetes describes “waking up with the worst headache of my life.” This patient is recovering from a week of flu-like symptoms, including low-grade fever, a cough, and some diarrhea. She went to a COVID-19 testing center 2 days ago for a nasal swab taken but has not gotten the results back.
She has a long-standing history of chronic, non-specific headaches but her current headache has been much more severe and present in varying degrees for the past 4 hours. Now, she has become confused and is experiencing left-sided weakness. This patient is likely having a stroke, possibly triggered by a COVID infection.
Neurological symptoms, including headaches, dizziness, confusion and mild cognitive impairment, have been present in 36% of COVID-19 cases to date. These symptoms often begin 5 to 7 days after the onset of fever, cough, and other characteristic signs of the acute infection. Neurologic involvement is more likely to occur in COVID patients with risk factors for severe disease, such as obesity, diabetes and hypertension, as in this patient.
Although headaches are present in 10 to 15 % of patients with acute COVID-19 infection, the severity of this patient’s headache may be a red flag for possible stroke, or another life-threatening neurologic event. In fact, stroke may be the sole manifestation of an acute COVID-19 infection. In the largest single center series from China, acute cerebrovascular disease was the presenting manifestation in 5% of hospitalized COVID patients.
Strokes in younger people have been especially alarming, including a recent report describing five cases in New York of large-vessel strokes in patients aged 33, 37 39, 44, and This rate of strokes in patients under age 50 is more than 8-fold greater than expected based on prior years. Each patient was at home and each experienced the sudden onset of slurred speech, confusion, facial drooping, and dead feeling in one arm.
The increased incidence of strokes with COVID-19 infection has been associated with ischemic strokes as well as hemorrhagic strokes. Postulated mechanisms include cytokine storm with a resultant cascade of inflammatory cells as well as COVID-related hypercoagulability. Coagulopathy is a frequent complication of COVID-19 infection, increasing the risk of thromboembolic events. Laboratory evidence for hypercoagulability, including elevated D-dimer, fibrinogen and prothrombin times are suggestive of a hypercoagulable state and anticoagulation with low molecular weight heparin has been recommended as a treatment component for all patients hospitalized with COVID-19 infection.
The evaluation for potential strokes and heart attacks in the United States has fallen dramatically since the pandemic began. One study found that the number of imaging studies for possible stroke had decreased by 40% during the pandemic compared to a similar pre-pandemic time frame. This sharp decline in stroke imaging has been noted across the country and has not varied with patient age or gender. During the same month that LMH, the California community hospital, reported a 45% increase in the community’s out of hospital cardiac arrests, all of their stroke patients arrived at the hospital too late to receive tissue plasminogen activator (TPA).4 The authors commented that, “This information again suggested a new culture of waiting to seek emergency care and was supported by subsequent histories of patients who reported they chose to wait several days after the onset of stroke symptoms to present for care.”
Reshma Gupta, MD, at the University of California Health in Sacramentodescribed the collateral damage from delayed diagnosis and treatment during the pandemic: “Part of the problem is seeing everything through a coronavirus lens. There are catastrophic risks when doctors and patients wear COVID-19 blinders. Stroke, heart disease, cancer, and lung diseases — among the leading causes of death in the US — have not gone away just because COVID-19 has emerged. Patients and doctors are potentially missing or ignoring worrisome symptoms unrelated to COVID-19 and not addressing them. Interrupting care for patients with chronic conditions can lead to disastrous outcomes.”
As with chest pain, clinicians must recognize that new worrisome symptoms, including sudden onset of severe headaches or other neurologic symptoms, may be presenting manifestations of acute COVID-19 infection. Persons with such worrisome symptoms may too avoid seeking medical care out of fear of becoming infected.
A 65-year-old male nursing-home resident presents with a 1-day history of numbness and tingling in both legs, as well as ataxia, and exhaustion. Over the past 24 hours, he has developed bilateral leg and facial muscle weakness. He has no history suggesting recent infection, but two residents and one caretaker of the nursing home were just diagnosed with COVID-19 infection. This patient may have Guillain Barre Syndrome (GBS), possibly triggered by COVID-19.
A number of similar cases of COVID-19 related GBS have been reported from China, Iran, and Italy. One case described a 61-year-old man who had recovered from a confirmed COVID-19 infection and, after 10 days, developed a right facial nerve palsy. His physicians considered this facial diplegia to be an atypical variant of GBS as a late manifestation of his COVID-19 infection.
There have also been scattered case reports of persistent axonal neuropathy and vasculitis following COVID-19.
COVID-19 has been associated with unusual neurologic symptoms, such as GBS. Neurologic symptoms warrant timely referral to a neurologist and diagnostic testing, including electromyogram (EMG), a nerve conduction velocity test, and confirmatory tests for acute infection or antibodies obtained.
A 15-year-old boy presents with a red rash on his hands and shares that he started feeling tired 2 weeks ago. His parents have noticed redness in his eyes, similar to when he had conjunctivitis a few years earlier. Over the past few days, he lost his appetite and began experiencing pain throughout his arms and legs with fever.
This young man may have the recently described Multisystem Inflammatory Syndrome in Children (MIS-C). His intense pain was similar to that described by a 14-year-old patient to the New York Times, “a throbbing, stinging rush. You could feel it going through your veins and it was almost like someone injected you with straight-up fire.”
As of May 22, 2020, 161 children in New York and hundreds of children across the United States and Europe had been reported to have MIS-C. Manifestations have included high fevers, rashes, eye and mouth inflammation, skin lesions, lymphadenopathy, gastrointestinal and renal manifestations, and life-threatening cardiac disease. These symptoms resemble Kawasaki disease, a vasculitic, multisystem disease more common in children of Asian ethnicity, often following a viral illness. The cardiac symptoms in Kawasaki disease are more often related to coronary artery aneurysms, whereas a diffuse myocarditis has been more often present in the new COVID-19 related syndrome.
Investigators at an Italian pediatric hospital compared the 19 cases of Kawasaki disease admitted to their hospital between 2015 to 2020 to the 10 children admitted with the MIS-C in a 1-month period from mid-March to mid-April 2020.19 The comparison revealed a 30-fold increase in Kawasaki-like cases; in addition, the pediatric patients were much sicker, including 50% with shock-like symptoms.
Two of these patients in the Italian hospital were PCR positive and the other eight were PCR negative for acute infection but had serologic evidence of antibodies against COVID-19. Like Kawasaki disease, the MIS-C is thought to be related to an abnormal hyperimmune reaction to recent infection rather than to direct tissue invasion by the virus. Kawasaki disease has previously been linked to infections with other coronaviruses. Treatment for this new multisystemic inflammatory syndrome has been similar to that of Kawasaki disease, including the use of high doses of corticosteroids and intravenous immunoglobulin.
Unusual painful skin lesions have also been considered to be part of the infection or a post-infectious immune process. Such lesions often have developed weeks after the acute COVID-19 infection and have included purpura, chilblains-like lesions and more generalized rashes, often seen in patients with systemic vasculitis. Painful skin lesions in the feet have been dubbed as COVID-toe.
Akin to what dermatologists describe as chilblains, Lindy Fox, MD, a dermatologist in San Francisco, shared, “All of a sudden, we are inundated with toes, I’ve got clinics filled with people coming in with new toe lesions. And it’s not people who had chilblains before — they’ve never had anything like this.” These skin lesions do occur in adults as well, including a recent report from Spain of a 91-year-old and a 44-year-old, both male.
A 62-year-old female, previously very healthy, was discharged from the hospital 6 weeks ago after recovering from acute COVID-19 infection. She was hospitalized for two weeks with lung involvement and breathing difficulties although she did not require intubation or mechanical ventilation. Her treatment included nasal oxygen and anti-viral drug therapy. Once her breathing improved and her chest CT scan demonstrated resolution of the lung infiltrates, she was discharged. Since being home, she has had persistent generalized pain but no joint swelling or inflammation. She continues to be exhausted and reports difficulty sleeping or concentrating.
This patient is likely experiencing a prolonged, post-COVID-19 convalescence. Her symptoms are similar to those reported to the New York Times by patients from Italy, “But even some of the infected who have avoided pneumonia describe a maddeningly persistent and unpredictable illness, with unexpected symptoms. Bones feel broken. The senses dull. Lack of energy. Stomachs are constantly upset. There are good days and then bad days without apparent rhyme nor reason. The afflicted find the simplest tasks taxing.”
Alessandro Venturi, MD, director of the San Matteo Hospital in the Lombardy town of Pavia, Italy, noted, “It’s not the sickness that lasts for 60 days, it is the convalescence. It’s a very long convalescence. We have seen many cases in which people take a long, long time to recover.”
Clinicians should expect recovering COVID patients to have a prolonged convalescence, with potential new – or worsened – bouts of chronic pain (more on this below), exhaustion, and cognitive disturbances.
Increased stress, anxiety, lack of exercise, and worry about access to healthcare professionals all may precipitate migraine. Thus, patients with chronic migraine are likely to have increased attacks related to the COVID-19 pandemic.
There has been concern that renin-angiotensin blockers and angiotensin-converting enzyme (ACE) inhibitors, often used as off-label prophylactic treatment of migraine, may increase the risk for COVID-19 infection. Such medications upregulate ACE2, a potential mechanism invoked in facilitating viral cell entry. However, studies have demonstrated no evidence that these drugs predispose patients to COVID-19 infection or increase its severity. Stopping these drugs suddenly might precipitate a sudden increase in blood pressure, which could aggravate migraine and increase risk of poor outcome if a patient does have the virus.
Of note, there has been no evidence that NSAIDS, including ibuprofen, need to be discontinued if COVID-19 infection is suspected. Traditional drug treatment for acute migraine, including NSAIDS, triptans and anti-emetics, also need not be altered during the pandemic. Newer medications, such as calcitonin gene-related peptide (CGRP) receptor antagonists, gepants, and neuromodulation devices are safe to be self-administered. Also noteworthy, intranasal vazegepant, currently in phase 3 development for acute migraine, is being tested as a potential therapy for acute pulmonary inflammation during COVID-19 infection.
Clinicians can use telemedicine to manage migraine attacks throughout the pandemic, with careful attention to potential “red flags” that could require immediate ER evaluation.
Patients who have been hospitalized with COVID-19, as well those of us indirectly affected, may develop a post-traumatic stress disorder (PTSD). Drs. Dhruv Khullar and Daniela Lamas , both critical care physicians in New York and Boston, described their concern with post-COVID recovery.
Lamas wrote: “At least we know how to track and treat the physical consequences of our patients’ prolonged ICU stays. These outcomes are visible. More insidious are the potential psychiatric and cognitive dysfunction that some former ICU patients describe — anxiety and depression; hyperarousal and flashbacks to delirium-induced hallucinations that are characteristic of post-traumatic stress; poor planning skills and forgetfulness that might make it hard to remember medications or appointments. These are far trickier to screen for and to treat.”
Khullar shared: “The joy we all feel when patients at our hospital survive acute COVID-19 is followed, quickly, by the acknowledgment that it could be a long time before they fully recover, if they ever do. Many will suffer through months of rehabilitation in unfamiliar facilities, cared for by masked strangers, unable to receive friends or loved ones. Families who just weeks ago had been happy, healthy, and intact now face the prospect of prolonged separation. Many spouses and children will become caregivers, which comes with its own emotional and physical challenges. Roughly two-thirds of family caregivers show depressive symptoms after a loved one’s stay in the ICU. Many continue to struggle years later.”
The prevalence of such PTSD symptoms in the general population since the pandemic began is not yet known. Early population estimates from China and Italy found a two to three-fold increase in depression and anxiety since SARS-CoV-2 began to spread. There have been no accounts yet of an uptick in cases of migraine, fibromyalgia, tension headaches, or irritable bowel syndrome (IBS), but such common chronic pain conditions have often been linked to physical and emotional trauma.
It is very likely that we will also see a surge in chronic pain conditions in the general population. Most chronic pain conditions are aggravated by stress and intimately tied to increasing mood and sleep disturbances.
Chest pain, severe headaches, or any new neurologic symptoms may represent manifestations of acute COVID-19 infection. Such symptoms may also develop later in the viral infection, even when the patient seems to be on the road to recovery. Unique, post-infectious, multisystemic complaints, although still rare, have drawn increased attention. These symptoms include conditions similar to Kawaski disease, Guillain-Barre Syndrome, and vasculitis, and are likely secondary to an immune response following the infection.
Patients often have a prolonged post-COVID-19 convalescence, with persistent chronic pain, exhaustion and cognitive disturbances. It is likely that chronic pain conditions in the general population, including migraine and fibromyalgia, will be more problematic in the coming months following the increased stress we all feel as a result of the pandemic.