Expert Perspective

Neurology, once considered a “diagnose and adios” specialty, is gaining newfound, scientific respect. Our vastly improved understanding of neurologic pathophysiology has led to many Food and Drug Administration–approved medications that can specifically enhance treatment outcomes. Medications for migraine, multiple sclerosis, epilepsy, and other chronic neurological diseases have been extended and modernized; for millions of patients, these medicines fulfill their long-awaited needs.

What would Dr Osler have said if he witnessed today’s definition of the practice of medicine? As singular as our patients and their disorders are, the delivery of care is anything but. The processes in the delivery of this care have created many unforeseen twists and turns, thanks to the electronic health record (EHR), the resource-based relative value scale (RBRVS), evaluation and management (E&M) coding, and private health insurance (PHI).

From a neurologist’s perspective, I will elaborate upon these changes that have affected our day-to-day neurology practices. I have practiced general neurology and headache medicine both in private and academic practices, evaluating and treating thousands of inpatients and outpatients in urban and rural healthcare facilities since 1986.

The EHR

Despite herculean, lofty, and sustained efforts by the medical business world to promote EHR adoption worldwide, goals remain unmet. Intended to improve the quality of care and patient outcomes, reduce medical errors, and crystalize communications among providers and with patients, it is instead associated with physician burnout (B), lack of usability (U) and interoperability (I), has likability (L) issues, and provides no productive physician direction (D) – there is an enormous need to BUILD it better.

In my own practice, it is inevitable that I will use my EHR laptop with an unknowing patient. If so, I try to make her feel comfortable in its presence as I strive to stay intent on our discussion. Yet I invariably split my concentration between machine and patient. The machine often gets my full attention, with its confusing and unnecessary medical record notes, tech glitches and screen interruptions, let alone its complicated web of tabs, buttons, links, and obscure prompts. As for fulfilling CMS’ meaningful use criteria to reap financial benefits, I long ago abandoned that effort if earning benefits and reaching the desired patient outcome weren’t on the same path.

We are required to read numerous EHR windows, deal with misused, template-based medical records and the usually faulty copy-and-paste function, which results in flagrant errors. A common example is templating or copy-and-pasting normal examination findings such as “pupils equal, round, and reactive to light and accommodation (PERRLA),” without making modifications for a patient who has obvious abnormal pupillary findings.  It is the EHR that often induces these types of documentation errors.

The EHR, as it exists now, intrudes into our time with patients. But for the past 30 years, the RBRVs have defined how we are compensated for our services. This compensation scale was created to provide a standard system of paying physicians’ services based on resource costs associated with patient care. The resource components are physician work, practice expense, and professional liability insurance. These components make our compensation based on effort rather than effect.

Payments are calculated into relative value units (RVUs), which are often structured into physician employment contracts.¹ There are many RVU calculations and formulas that determine physician reimbursement and compensation; these are not entirely straightforward and too often lack transparency. Despite Dr Osler’s plea in Aequanimitas for physicians to maintain imperturbability and equanimity, that plea goes to the wayside when debating the value of the RBRVS. This system dilutes the complexities of the physician visit, especially for patients with comorbidities, polypharmacy, and cognitive and social concerns.²

Another frustrating, time-absorbing business requirement is E&M coding; the codes came about around the same time as RBRVs. Congress established E&M in the mid-1990s to facilitate medical billing by translating physician-patient encounters into 5-digit codes. In a neurology office, this authentication takes considerable effort, detracts from the patient’s visit, and adds to the documentation requirement to receive insured patient payments.

Years ago, I reviewed neurology insurance claims for a global health service company. I remember the considerable discussion over subjective documentation technicalities, attempting to justify the submitted E&M code. The onerous administrative burden E&M has created continues to evolve, with no end in sight.

Private insurance

When was the last time that you did not have to submit a prior authorization (PA) request to a payer in a week’s worth of days?

PA requests impede timely, efficient, and much-needed vital care while usurping a physician’s decision-making process. In 2020, the American Medical Association released the responses of 1000 physicians who were asked about making PA requests.³ Physicians said that the time delays affected their patients’ health and created adverse events, including hospitalizations. PAs are not only requested for new drugs; physicians report that the increase in the volume of PAs includes requests for existing drugs and services.

It takes staff days to make the requests; most medical practices interact with dozens of different health plans, all with different requirements related to PAs. Insurers often follow the lead of Medicare, and Medicare does not cover most self-injectable medications.⁴

I can report the same experiences. Ten years ago, private insurers rejected ~20% of my practice’s PA requests. Today, more than half of my patients need a PA from their insurer—often for 2 or 3 prescriptions each—and at least half of the requests are rejected. And, unlike 10 years ago, most of my requests are still denied after an appeal.

My patients are mostly migraine patients. When appropriate, I discuss with them the new acute and preventive anti–calcitonin gene-related peptides (anti-CGRPs), which, for the chronic migraine patient, can be a small slice of heaven. Reality strikes, however, when we discuss the likely PA process. This shift no longer focuses on getting likely migraine relief, but instead on the insurance company or companies approving the PA.

Sometimes the PA approval process is only accomplished by patients fighting the PA battle for themselves. One patient recently had to convince her PA oversight insurance representative that, if her PA was denied, her suicide would follow.

And what do patients do if the PA has been denied? Sometimes I must treat a patient with something else, which is often less appropriate for that patient. I have had many patients who have given up during the process.

Industry sees PAs in a different light. A survey⁵ of 44 payers conducted in 2019 found that PAs save money, improve evidence-based care, and so on. Physicians asking for the PAs were singled out as the reasons PAs were denied, as these physicians did not follow proper protocols.

Despite government and PHI policies that are supposed to enhance healthcare delivery and stabilize costs, US healthcare costs stand at $3.6 trillion.^6,7 These medical practice transitions have increased administrative burden, accounting for 34% of US total healthcare expenditures vs 17% in Canada.^8,9

In neurology, successful outcomes are predicated on recognizing the singularity of each patient. The current health system’s need for homogenization is making such recognition difficult. I invite you to read my commentary entitled The Practice of Medicine - Hazy or Invisible Lines, which discusses the unintended consequences of these well-intentioned medical practice adjustments. 

Comments from Alan Rapoport, MD

Editor in Chief, Neurology Reviews

Professor Landy’s article excellently details just some of the roadblocks all neurologists face in providing patient-centric care. Prescribing medication or devices alone does not provide such care, but that is what many doctors must do because of limited time with the patient. Dr Osler was correct; we have to treat the patient who has the disease, not the disease the patient has. Taking an adequate history, conducting a full neurologic examination, documenting both, reviewing outside records, discussing the diagnosis and plan with the patient, ordering appropriate testing, and dictating all of the above in 20 or 30 minutes is impossible to do well. Going forward, we can expect computers and some form of artificial intelligence will help us to be more efficient, but we must keep the patient in the center. No wonder patients are not as happy with the healthcare system and their doctors as they used to be.

Alan Rapoport, MD

Clinical Professor of Neurology

The David Geffen School of Medicine at UCLA, Los Angeles, California

Past President

The International Headache Society (IHS)

Neurology, once considered a “diagnose and adios” specialty, is gaining newfound, scientific respect. Our vastly improved understanding of neurologic pathophysiology has led to many Food and Drug Administration–approved medications that can specifically enhance treatment outcomes. Medications for migraine, multiple sclerosis, epilepsy, and other chronic neurological diseases have been extended and modernized; for millions of patients, these medicines fulfill their long-awaited needs.

What would Dr Osler have said if he witnessed today’s definition of the practice of medicine? As singular as our patients and their disorders are, the delivery of care is anything but. The processes in the delivery of this care have created many unforeseen twists and turns, thanks to the electronic health record (EHR), the resource-based relative value scale (RBRVS), evaluation and management (E&M) coding, and private health insurance (PHI).

From a neurologist’s perspective, I will elaborate upon these changes that have affected our day-to-day neurology practices. I have practiced general neurology and headache medicine both in private and academic practices, evaluating and treating thousands of inpatients and outpatients in urban and rural healthcare facilities since 1986.

The EHR

Despite herculean, lofty, and sustained efforts by the medical business world to promote EHR adoption worldwide, goals remain unmet. Intended to improve the quality of care and patient outcomes, reduce medical errors, and crystalize communications among providers and with patients, it is instead associated with physician burnout (B), lack of usability (U) and interoperability (I), has likability (L) issues, and provides no productive physician direction (D) – there is an enormous need to BUILD it better.

In my own practice, it is inevitable that I will use my EHR laptop with an unknowing patient. If so, I try to make her feel comfortable in its presence as I strive to stay intent on our discussion. Yet I invariably split my concentration between machine and patient. The machine often gets my full attention, with its confusing and unnecessary medical record notes, tech glitches and screen interruptions, let alone its complicated web of tabs, buttons, links, and obscure prompts. As for fulfilling CMS’ meaningful use criteria to reap financial benefits, I long ago abandoned that effort if earning benefits and reaching the desired patient outcome weren’t on the same path.

We are required to read numerous EHR windows, deal with misused, template-based medical records and the usually faulty copy-and-paste function, which results in flagrant errors. A common example is templating or copy-and-pasting normal examination findings such as “pupils equal, round, and reactive to light and accommodation (PERRLA),” without making modifications for a patient who has obvious abnormal pupillary findings.  It is the EHR that often induces these types of documentation errors.

The EHR, as it exists now, intrudes into our time with patients. But for the past 30 years, the RBRVs have defined how we are compensated for our services. This compensation scale was created to provide a standard system of paying physicians’ services based on resource costs associated with patient care. The resource components are physician work, practice expense, and professional liability insurance. These components make our compensation based on effort rather than effect.

Payments are calculated into relative value units (RVUs), which are often structured into physician employment contracts.¹ There are many RVU calculations and formulas that determine physician reimbursement and compensation; these are not entirely straightforward and too often lack transparency. Despite Dr Osler’s plea in Aequanimitas for physicians to maintain imperturbability and equanimity, that plea goes to the wayside when debating the value of the RBRVS. This system dilutes the complexities of the physician visit, especially for patients with comorbidities, polypharmacy, and cognitive and social concerns.²

Another frustrating, time-absorbing business requirement is E&M coding; the codes came about around the same time as RBRVs. Congress established E&M in the mid-1990s to facilitate medical billing by translating physician-patient encounters into 5-digit codes. In a neurology office, this authentication takes considerable effort, detracts from the patient’s visit, and adds to the documentation requirement to receive insured patient payments.

Years ago, I reviewed neurology insurance claims for a global health service company. I remember the considerable discussion over subjective documentation technicalities, attempting to justify the submitted E&M code. The onerous administrative burden E&M has created continues to evolve, with no end in sight.

Private insurance

When was the last time that you did not have to submit a prior authorization (PA) request to a payer in a week’s worth of days?

PA requests impede timely, efficient, and much-needed vital care while usurping a physician’s decision-making process. In 2020, the American Medical Association released the responses of 1000 physicians who were asked about making PA requests.³ Physicians said that the time delays affected their patients’ health and created adverse events, including hospitalizations. PAs are not only requested for new drugs; physicians report that the increase in the volume of PAs includes requests for existing drugs and services.

It takes staff days to make the requests; most medical practices interact with dozens of different health plans, all with different requirements related to PAs. Insurers often follow the lead of Medicare, and Medicare does not cover most self-injectable medications.⁴

I can report the same experiences. Ten years ago, private insurers rejected ~20% of my practice’s PA requests. Today, more than half of my patients need a PA from their insurer—often for 2 or 3 prescriptions each—and at least half of the requests are rejected. And, unlike 10 years ago, most of my requests are still denied after an appeal.

My patients are mostly migraine patients. When appropriate, I discuss with them the new acute and preventive anti–calcitonin gene-related peptides (anti-CGRPs), which, for the chronic migraine patient, can be a small slice of heaven. Reality strikes, however, when we discuss the likely PA process. This shift no longer focuses on getting likely migraine relief, but instead on the insurance company or companies approving the PA.

Sometimes the PA approval process is only accomplished by patients fighting the PA battle for themselves. One patient recently had to convince her PA oversight insurance representative that, if her PA was denied, her suicide would follow.

And what do patients do if the PA has been denied? Sometimes I must treat a patient with something else, which is often less appropriate for that patient. I have had many patients who have given up during the process.

Industry sees PAs in a different light. A survey⁵ of 44 payers conducted in 2019 found that PAs save money, improve evidence-based care, and so on. Physicians asking for the PAs were singled out as the reasons PAs were denied, as these physicians did not follow proper protocols.

Despite government and PHI policies that are supposed to enhance healthcare delivery and stabilize costs, US healthcare costs stand at $3.6 trillion.^6,7 These medical practice transitions have increased administrative burden, accounting for 34% of US total healthcare expenditures vs 17% in Canada.^8,9

In neurology, successful outcomes are predicated on recognizing the singularity of each patient. The current health system’s need for homogenization is making such recognition difficult. I invite you to read my commentary entitled The Practice of Medicine - Hazy or Invisible Lines, which discusses the unintended consequences of these well-intentioned medical practice adjustments. 

Comments from Alan Rapoport, MD

Editor in Chief, Neurology Reviews

Professor Landy’s article excellently details just some of the roadblocks all neurologists face in providing patient-centric care. Prescribing medication or devices alone does not provide such care, but that is what many doctors must do because of limited time with the patient. Dr Osler was correct; we have to treat the patient who has the disease, not the disease the patient has. Taking an adequate history, conducting a full neurologic examination, documenting both, reviewing outside records, discussing the diagnosis and plan with the patient, ordering appropriate testing, and dictating all of the above in 20 or 30 minutes is impossible to do well. Going forward, we can expect computers and some form of artificial intelligence will help us to be more efficient, but we must keep the patient in the center. No wonder patients are not as happy with the healthcare system and their doctors as they used to be.

Alan Rapoport, MD

Clinical Professor of Neurology

The David Geffen School of Medicine at UCLA, Los Angeles, California

Past President

The International Headache Society (IHS)

Neurology, once considered a “diagnose and adios” specialty, is gaining newfound, scientific respect. Our vastly improved understanding of neurologic pathophysiology has led to many Food and Drug Administration–approved medications that can specifically enhance treatment outcomes. Medications for migraine, multiple sclerosis, epilepsy, and other chronic neurological diseases have been extended and modernized; for millions of patients, these medicines fulfill their long-awaited needs.

What would Dr Osler have said if he witnessed today’s definition of the practice of medicine? As singular as our patients and their disorders are, the delivery of care is anything but. The processes in the delivery of this care have created many unforeseen twists and turns, thanks to the electronic health record (EHR), the resource-based relative value scale (RBRVS), evaluation and management (E&M) coding, and private health insurance (PHI).

From a neurologist’s perspective, I will elaborate upon these changes that have affected our day-to-day neurology practices. I have practiced general neurology and headache medicine both in private and academic practices, evaluating and treating thousands of inpatients and outpatients in urban and rural healthcare facilities since 1986.

The EHR

Despite herculean, lofty, and sustained efforts by the medical business world to promote EHR adoption worldwide, goals remain unmet. Intended to improve the quality of care and patient outcomes, reduce medical errors, and crystalize communications among providers and with patients, it is instead associated with physician burnout (B), lack of usability (U) and interoperability (I), has likability (L) issues, and provides no productive physician direction (D) – there is an enormous need to BUILD it better.

In my own practice, it is inevitable that I will use my EHR laptop with an unknowing patient. If so, I try to make her feel comfortable in its presence as I strive to stay intent on our discussion. Yet I invariably split my concentration between machine and patient. The machine often gets my full attention, with its confusing and unnecessary medical record notes, tech glitches and screen interruptions, let alone its complicated web of tabs, buttons, links, and obscure prompts. As for fulfilling CMS’ meaningful use criteria to reap financial benefits, I long ago abandoned that effort if earning benefits and reaching the desired patient outcome weren’t on the same path.

We are required to read numerous EHR windows, deal with misused, template-based medical records and the usually faulty copy-and-paste function, which results in flagrant errors. A common example is templating or copy-and-pasting normal examination findings such as “pupils equal, round, and reactive to light and accommodation (PERRLA),” without making modifications for a patient who has obvious abnormal pupillary findings.  It is the EHR that often induces these types of documentation errors.

The EHR, as it exists now, intrudes into our time with patients. But for the past 30 years, the RBRVs have defined how we are compensated for our services. This compensation scale was created to provide a standard system of paying physicians’ services based on resource costs associated with patient care. The resource components are physician work, practice expense, and professional liability insurance. These components make our compensation based on effort rather than effect.

Payments are calculated into relative value units (RVUs), which are often structured into physician employment contracts.¹ There are many RVU calculations and formulas that determine physician reimbursement and compensation; these are not entirely straightforward and too often lack transparency. Despite Dr Osler’s plea in Aequanimitas for physicians to maintain imperturbability and equanimity, that plea goes to the wayside when debating the value of the RBRVS. This system dilutes the complexities of the physician visit, especially for patients with comorbidities, polypharmacy, and cognitive and social concerns.²

Another frustrating, time-absorbing business requirement is E&M coding; the codes came about around the same time as RBRVs. Congress established E&M in the mid-1990s to facilitate medical billing by translating physician-patient encounters into 5-digit codes. In a neurology office, this authentication takes considerable effort, detracts from the patient’s visit, and adds to the documentation requirement to receive insured patient payments.

Years ago, I reviewed neurology insurance claims for a global health service company. I remember the considerable discussion over subjective documentation technicalities, attempting to justify the submitted E&M code. The onerous administrative burden E&M has created continues to evolve, with no end in sight.

Private insurance

When was the last time that you did not have to submit a prior authorization (PA) request to a payer in a week’s worth of days?

PA requests impede timely, efficient, and much-needed vital care while usurping a physician’s decision-making process. In 2020, the American Medical Association released the responses of 1000 physicians who were asked about making PA requests.³ Physicians said that the time delays affected their patients’ health and created adverse events, including hospitalizations. PAs are not only requested for new drugs; physicians report that the increase in the volume of PAs includes requests for existing drugs and services.

It takes staff days to make the requests; most medical practices interact with dozens of different health plans, all with different requirements related to PAs. Insurers often follow the lead of Medicare, and Medicare does not cover most self-injectable medications.⁴

I can report the same experiences. Ten years ago, private insurers rejected ~20% of my practice’s PA requests. Today, more than half of my patients need a PA from their insurer—often for 2 or 3 prescriptions each—and at least half of the requests are rejected. And, unlike 10 years ago, most of my requests are still denied after an appeal.

My patients are mostly migraine patients. When appropriate, I discuss with them the new acute and preventive anti–calcitonin gene-related peptides (anti-CGRPs), which, for the chronic migraine patient, can be a small slice of heaven. Reality strikes, however, when we discuss the likely PA process. This shift no longer focuses on getting likely migraine relief, but instead on the insurance company or companies approving the PA.

Sometimes the PA approval process is only accomplished by patients fighting the PA battle for themselves. One patient recently had to convince her PA oversight insurance representative that, if her PA was denied, her suicide would follow.

And what do patients do if the PA has been denied? Sometimes I must treat a patient with something else, which is often less appropriate for that patient. I have had many patients who have given up during the process.

Industry sees PAs in a different light. A survey⁵ of 44 payers conducted in 2019 found that PAs save money, improve evidence-based care, and so on. Physicians asking for the PAs were singled out as the reasons PAs were denied, as these physicians did not follow proper protocols.

Despite government and PHI policies that are supposed to enhance healthcare delivery and stabilize costs, US healthcare costs stand at $3.6 trillion.^6,7 These medical practice transitions have increased administrative burden, accounting for 34% of US total healthcare expenditures vs 17% in Canada.^8,9

In neurology, successful outcomes are predicated on recognizing the singularity of each patient. The current health system’s need for homogenization is making such recognition difficult. I invite you to read my commentary entitled The Practice of Medicine - Hazy or Invisible Lines, which discusses the unintended consequences of these well-intentioned medical practice adjustments. 

Comments from Alan Rapoport, MD

Editor in Chief, Neurology Reviews

Professor Landy’s article excellently details just some of the roadblocks all neurologists face in providing patient-centric care. Prescribing medication or devices alone does not provide such care, but that is what many doctors must do because of limited time with the patient. Dr Osler was correct; we have to treat the patient who has the disease, not the disease the patient has. Taking an adequate history, conducting a full neurologic examination, documenting both, reviewing outside records, discussing the diagnosis and plan with the patient, ordering appropriate testing, and dictating all of the above in 20 or 30 minutes is impossible to do well. Going forward, we can expect computers and some form of artificial intelligence will help us to be more efficient, but we must keep the patient in the center. No wonder patients are not as happy with the healthcare system and their doctors as they used to be.

Alan Rapoport, MD

Clinical Professor of Neurology

The David Geffen School of Medicine at UCLA, Los Angeles, California

Past President

The International Headache Society (IHS)

By Ruth Ann Marrie, MD, PhD, FRCPC, FCAHS

Waugh Family Chair in Multiple Sclerosis, Professor of Medicine & Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba and Director, Multiple Sclerosis Clinic, Winnipeg, Manitoba, Canada.

The diseases and disorders known to coexist with multiple sclerosis (MS), overall, are not passive bystanders. While they have not been proven to cause MS – or vice versa – some of these comorbidities advance MS disease at a quicker pace; some may lead to an earlier death; and others could be, and should be, considered relevant harbingers of a diagnosis to come.

These comorbidities are not isolated to 1 organ system, but rather have been found in the endocrine, cardiovascular, respiratory, central nervous, and immune systems. The more comorbidities someone has, the higher the frequency of relapses in those with relapsing MS, the most common type of MS.¹

Temporally speaking, the comorbidities can precede MS diagnosis or develop after diagnosis; they tend to increase in number with age and over time. As for their connection to MS, the very common denominator among many of these comorbidities is their inflammatory characteristic.

There are compelling reasons for specialists – endocrinologists, cardiologists, pulmonologists –and generalists, like primary care physicians, to appreciate the complexities of this disease, both in its prodromal state and beyond.

The literature shows how difficult diagnosis can be. A 2016 study of 4 MS centers found that 110 patients, 33% of the population, had been misdiagnosed for 10 years; their migraines had been misdiagnosed as MS.² Then again, migraine and MS frequently overlap; a 2012 study reported that 43% of patients with MS also have migraine.³ Considering that females present with relapsing-remitting MS more often than males and deal more with migraines, this observation should not be a big surprise.

Patients come with histories including medical, familial, and lifestyle histories. Exploring that history informs illness; how clinicians incorporate that history is important to disease management and patient outcomes.

What follows is an overview of comorbidities and MS.

MS and the immune system

MS, for which there is no known cure, permanently disables the body and mind by progressively damaging the myelin sheath that protects axons. It is usually diagnosed in adulthood.

The words chosen to describe MS, from a scientific vantage point, include heterogeneous, complex, and multifaceted. It is likely no one who has, treats, or researches this disease would argue those points. At least 3 journal articles dating back to 2013 all described a discovery about MS as another “brick in the wall.” The latest is a Science Immunology commentary on findings that gut-barrier-protecting Th17 cells could have an evil side, expressing a ligand called dual immunoglobulin domain containing cell adhesion molecule, allowing these cells to infiltrate the blood brain barrier during neuroinflammation.⁴

So far, 230 loci have been implicated in modulating the risk of MS development.⁵ That 230 is twice the number found in rheumatoid arthritis⁶ and more than triple the number of genes and loci linked to psoriasis.⁷ The genomic map of MS, showing involvement of peripheral immune cells and microglia in susceptibility, resembles a spider web more than genetic cartography.⁸

One review of the literature listed more than 50 comorbid conditions found in patients with MS. While many of these conditions do not occur more often in those with MS as opposed to those without the disease, a few comorbidities certainly do.⁹

The comorbidities

As defined, a comorbidity is a co-existing condition not directly related to the primary, or index, disease, which in this case is MS.¹⁰  One must wonder if, as the index disease, MS defies this definition, as depression, anxiety, hypertension, hyperlipidemia, and chronic lung disease are frequently found in patients with MS: when combined, depression and anxiety are found in nearly half of patients.^11,12 

But MS is not dependent on aberrant genes solely for its development. The environmental and lifestyle risk factors linked to an MS diagnosis include childhood obesity, Epstein Barr virus infection (the virus that causes infectious mononucleosis), smoking, and low levels of vitamin D.^13,14 A common denominator among virtually all these factors, not unlike the comorbidities themselves, is inflammation.

It is not uncommon for patients with MS to have psoriasis.^7,10 Nor is it uncommon for them to have other types of autoimmune diseases, such as inflammatory bowel disease. For patients with MS, the relative risk is increased for developing some other autoimmune diseases including inflammatory bowel disease, psoriasis, and bullous pemphigoid (another skin condition).

Studies of patients with rheumatoid arthritis (RA) have shown how RA is directly or indirectly responsible for the development of other diseases, primarily due to RA’s creation of inflammatory pathways.¹⁵ In patients with RA, comorbidities tend to become fewer as the disease progresses. As already discussed, in patients with MS, comorbidities generally increase over time.^15,16 As for whether a comorbidity could cause the development of MS, that question has yet to be answered.

Comorbidity specifics

There are a few comorbidities that appear in the literature more than others, with most of them falling into the vascular or the central nervous system. Diseases associated with the vascular system, including hypertension and diabetes, as they accumulate in number, will cause more physical impairment.¹⁷ A single vascular comorbidity at diagnosis was associated with a 51% increased risk of early gait disability, while 2 vascular comorbidities were associated with a 228% increased risk.¹⁸

Other comorbidities, like chronic obstructive pulmonary disease (COPD), can cause disease to progress at a quicker pace.¹⁰ COPD also can increase risk of an earlier death, as can epilepsy.^10,16 People with MS, mostly women diagnosed in the prime of their lives, live 6 to 8 fewer years than those without.¹⁹

Some coexistent diseases are also linked to a longer delay to MS diagnosis and lower rate of treatment. A large study in Canada showed ischemic heart disease and anxiety were linked with a patient’s lower rate of receiving disease-modifying therapies.⁹

In time

While not every patient with MS has co-existing disease at the time of diagnosis, it will be highly likely that these patients will have comorbidities as the years pass. In 1 study, researchers found that the prevalence of some comorbidities, like gastrointestinal disorders, thyroid disease, and anxiety, increased as patients aged.²⁰

When reviewing health claims data for patients with inflammatory bowel disease and RA, researchers found a similar risk of depression in both. Health claims data also show patients looking for treatment for anxiety 5 years before an MS diagnosis. Of patients who were not yet diagnosed, 19% had sought help for depression and 11% for anxiety.⁹

Researchers looked at 2526 patients diagnosed with MS and 9980 controls to compare the risk of developing comorbidities prior to MS diagnosis and after.¹⁶ At diagnosis, 22.7% of patients had at least one Charlson comorbidity compared with 16.8% of controls. (The Charlson comorbidity index is a weighted score comprised of several comorbidities. Scores span mild to severe, or 1 to above 5.) ²¹

Ten years prior to MS diagnosis, out of ~30 diseases, patients with MS were at risk to develop at least 20 of the 30, including various cancers, cardiovascular diseases, thyroid disorders, and neurologic and mental disorders. For the latter, the difference was 34.92% vs 17.87%. In the period after diagnosis, 17.23% of patients had a new comorbidity, as compared to 15.78% in the control population. The change was remarkable in the neurologic and mental disorders; prior to an MS diagnosis, there were no cases of dementia, but that changed post-diagnosis.

By Ruth Ann Marrie, MD, PhD, FRCPC, FCAHS

Waugh Family Chair in Multiple Sclerosis, Professor of Medicine & Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba and Director, Multiple Sclerosis Clinic, Winnipeg, Manitoba, Canada.

The diseases and disorders known to coexist with multiple sclerosis (MS), overall, are not passive bystanders. While they have not been proven to cause MS – or vice versa – some of these comorbidities advance MS disease at a quicker pace; some may lead to an earlier death; and others could be, and should be, considered relevant harbingers of a diagnosis to come.

These comorbidities are not isolated to 1 organ system, but rather have been found in the endocrine, cardiovascular, respiratory, central nervous, and immune systems. The more comorbidities someone has, the higher the frequency of relapses in those with relapsing MS, the most common type of MS.¹

Temporally speaking, the comorbidities can precede MS diagnosis or develop after diagnosis; they tend to increase in number with age and over time. As for their connection to MS, the very common denominator among many of these comorbidities is their inflammatory characteristic.

There are compelling reasons for specialists – endocrinologists, cardiologists, pulmonologists –and generalists, like primary care physicians, to appreciate the complexities of this disease, both in its prodromal state and beyond.

The literature shows how difficult diagnosis can be. A 2016 study of 4 MS centers found that 110 patients, 33% of the population, had been misdiagnosed for 10 years; their migraines had been misdiagnosed as MS.² Then again, migraine and MS frequently overlap; a 2012 study reported that 43% of patients with MS also have migraine.³ Considering that females present with relapsing-remitting MS more often than males and deal more with migraines, this observation should not be a big surprise.

Patients come with histories including medical, familial, and lifestyle histories. Exploring that history informs illness; how clinicians incorporate that history is important to disease management and patient outcomes.

What follows is an overview of comorbidities and MS.

MS and the immune system

MS, for which there is no known cure, permanently disables the body and mind by progressively damaging the myelin sheath that protects axons. It is usually diagnosed in adulthood.

The words chosen to describe MS, from a scientific vantage point, include heterogeneous, complex, and multifaceted. It is likely no one who has, treats, or researches this disease would argue those points. At least 3 journal articles dating back to 2013 all described a discovery about MS as another “brick in the wall.” The latest is a Science Immunology commentary on findings that gut-barrier-protecting Th17 cells could have an evil side, expressing a ligand called dual immunoglobulin domain containing cell adhesion molecule, allowing these cells to infiltrate the blood brain barrier during neuroinflammation.⁴

So far, 230 loci have been implicated in modulating the risk of MS development.⁵ That 230 is twice the number found in rheumatoid arthritis⁶ and more than triple the number of genes and loci linked to psoriasis.⁷ The genomic map of MS, showing involvement of peripheral immune cells and microglia in susceptibility, resembles a spider web more than genetic cartography.⁸

One review of the literature listed more than 50 comorbid conditions found in patients with MS. While many of these conditions do not occur more often in those with MS as opposed to those without the disease, a few comorbidities certainly do.⁹

The comorbidities

As defined, a comorbidity is a co-existing condition not directly related to the primary, or index, disease, which in this case is MS.¹⁰  One must wonder if, as the index disease, MS defies this definition, as depression, anxiety, hypertension, hyperlipidemia, and chronic lung disease are frequently found in patients with MS: when combined, depression and anxiety are found in nearly half of patients.^11,12 

But MS is not dependent on aberrant genes solely for its development. The environmental and lifestyle risk factors linked to an MS diagnosis include childhood obesity, Epstein Barr virus infection (the virus that causes infectious mononucleosis), smoking, and low levels of vitamin D.^13,14 A common denominator among virtually all these factors, not unlike the comorbidities themselves, is inflammation.

It is not uncommon for patients with MS to have psoriasis.^7,10 Nor is it uncommon for them to have other types of autoimmune diseases, such as inflammatory bowel disease. For patients with MS, the relative risk is increased for developing some other autoimmune diseases including inflammatory bowel disease, psoriasis, and bullous pemphigoid (another skin condition).

Studies of patients with rheumatoid arthritis (RA) have shown how RA is directly or indirectly responsible for the development of other diseases, primarily due to RA’s creation of inflammatory pathways.¹⁵ In patients with RA, comorbidities tend to become fewer as the disease progresses. As already discussed, in patients with MS, comorbidities generally increase over time.^15,16 As for whether a comorbidity could cause the development of MS, that question has yet to be answered.

Comorbidity specifics

There are a few comorbidities that appear in the literature more than others, with most of them falling into the vascular or the central nervous system. Diseases associated with the vascular system, including hypertension and diabetes, as they accumulate in number, will cause more physical impairment.¹⁷ A single vascular comorbidity at diagnosis was associated with a 51% increased risk of early gait disability, while 2 vascular comorbidities were associated with a 228% increased risk.¹⁸

Other comorbidities, like chronic obstructive pulmonary disease (COPD), can cause disease to progress at a quicker pace.¹⁰ COPD also can increase risk of an earlier death, as can epilepsy.^10,16 People with MS, mostly women diagnosed in the prime of their lives, live 6 to 8 fewer years than those without.¹⁹

Some coexistent diseases are also linked to a longer delay to MS diagnosis and lower rate of treatment. A large study in Canada showed ischemic heart disease and anxiety were linked with a patient’s lower rate of receiving disease-modifying therapies.⁹

In time

While not every patient with MS has co-existing disease at the time of diagnosis, it will be highly likely that these patients will have comorbidities as the years pass. In 1 study, researchers found that the prevalence of some comorbidities, like gastrointestinal disorders, thyroid disease, and anxiety, increased as patients aged.²⁰

When reviewing health claims data for patients with inflammatory bowel disease and RA, researchers found a similar risk of depression in both. Health claims data also show patients looking for treatment for anxiety 5 years before an MS diagnosis. Of patients who were not yet diagnosed, 19% had sought help for depression and 11% for anxiety.⁹

Researchers looked at 2526 patients diagnosed with MS and 9980 controls to compare the risk of developing comorbidities prior to MS diagnosis and after.¹⁶ At diagnosis, 22.7% of patients had at least one Charlson comorbidity compared with 16.8% of controls. (The Charlson comorbidity index is a weighted score comprised of several comorbidities. Scores span mild to severe, or 1 to above 5.) ²¹

Ten years prior to MS diagnosis, out of ~30 diseases, patients with MS were at risk to develop at least 20 of the 30, including various cancers, cardiovascular diseases, thyroid disorders, and neurologic and mental disorders. For the latter, the difference was 34.92% vs 17.87%. In the period after diagnosis, 17.23% of patients had a new comorbidity, as compared to 15.78% in the control population. The change was remarkable in the neurologic and mental disorders; prior to an MS diagnosis, there were no cases of dementia, but that changed post-diagnosis.

By Ruth Ann Marrie, MD, PhD, FRCPC, FCAHS

Waugh Family Chair in Multiple Sclerosis, Professor of Medicine & Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba and Director, Multiple Sclerosis Clinic, Winnipeg, Manitoba, Canada.

The diseases and disorders known to coexist with multiple sclerosis (MS), overall, are not passive bystanders. While they have not been proven to cause MS – or vice versa – some of these comorbidities advance MS disease at a quicker pace; some may lead to an earlier death; and others could be, and should be, considered relevant harbingers of a diagnosis to come.

These comorbidities are not isolated to 1 organ system, but rather have been found in the endocrine, cardiovascular, respiratory, central nervous, and immune systems. The more comorbidities someone has, the higher the frequency of relapses in those with relapsing MS, the most common type of MS.¹

Temporally speaking, the comorbidities can precede MS diagnosis or develop after diagnosis; they tend to increase in number with age and over time. As for their connection to MS, the very common denominator among many of these comorbidities is their inflammatory characteristic.

There are compelling reasons for specialists – endocrinologists, cardiologists, pulmonologists –and generalists, like primary care physicians, to appreciate the complexities of this disease, both in its prodromal state and beyond.

The literature shows how difficult diagnosis can be. A 2016 study of 4 MS centers found that 110 patients, 33% of the population, had been misdiagnosed for 10 years; their migraines had been misdiagnosed as MS.² Then again, migraine and MS frequently overlap; a 2012 study reported that 43% of patients with MS also have migraine.³ Considering that females present with relapsing-remitting MS more often than males and deal more with migraines, this observation should not be a big surprise.

Patients come with histories including medical, familial, and lifestyle histories. Exploring that history informs illness; how clinicians incorporate that history is important to disease management and patient outcomes.

What follows is an overview of comorbidities and MS.

MS and the immune system

MS, for which there is no known cure, permanently disables the body and mind by progressively damaging the myelin sheath that protects axons. It is usually diagnosed in adulthood.

The words chosen to describe MS, from a scientific vantage point, include heterogeneous, complex, and multifaceted. It is likely no one who has, treats, or researches this disease would argue those points. At least 3 journal articles dating back to 2013 all described a discovery about MS as another “brick in the wall.” The latest is a Science Immunology commentary on findings that gut-barrier-protecting Th17 cells could have an evil side, expressing a ligand called dual immunoglobulin domain containing cell adhesion molecule, allowing these cells to infiltrate the blood brain barrier during neuroinflammation.⁴

So far, 230 loci have been implicated in modulating the risk of MS development.⁵ That 230 is twice the number found in rheumatoid arthritis⁶ and more than triple the number of genes and loci linked to psoriasis.⁷ The genomic map of MS, showing involvement of peripheral immune cells and microglia in susceptibility, resembles a spider web more than genetic cartography.⁸

One review of the literature listed more than 50 comorbid conditions found in patients with MS. While many of these conditions do not occur more often in those with MS as opposed to those without the disease, a few comorbidities certainly do.⁹

The comorbidities

As defined, a comorbidity is a co-existing condition not directly related to the primary, or index, disease, which in this case is MS.¹⁰  One must wonder if, as the index disease, MS defies this definition, as depression, anxiety, hypertension, hyperlipidemia, and chronic lung disease are frequently found in patients with MS: when combined, depression and anxiety are found in nearly half of patients.^11,12 

But MS is not dependent on aberrant genes solely for its development. The environmental and lifestyle risk factors linked to an MS diagnosis include childhood obesity, Epstein Barr virus infection (the virus that causes infectious mononucleosis), smoking, and low levels of vitamin D.^13,14 A common denominator among virtually all these factors, not unlike the comorbidities themselves, is inflammation.

It is not uncommon for patients with MS to have psoriasis.^7,10 Nor is it uncommon for them to have other types of autoimmune diseases, such as inflammatory bowel disease. For patients with MS, the relative risk is increased for developing some other autoimmune diseases including inflammatory bowel disease, psoriasis, and bullous pemphigoid (another skin condition).

Studies of patients with rheumatoid arthritis (RA) have shown how RA is directly or indirectly responsible for the development of other diseases, primarily due to RA’s creation of inflammatory pathways.¹⁵ In patients with RA, comorbidities tend to become fewer as the disease progresses. As already discussed, in patients with MS, comorbidities generally increase over time.^15,16 As for whether a comorbidity could cause the development of MS, that question has yet to be answered.

Comorbidity specifics

There are a few comorbidities that appear in the literature more than others, with most of them falling into the vascular or the central nervous system. Diseases associated with the vascular system, including hypertension and diabetes, as they accumulate in number, will cause more physical impairment.¹⁷ A single vascular comorbidity at diagnosis was associated with a 51% increased risk of early gait disability, while 2 vascular comorbidities were associated with a 228% increased risk.¹⁸

Other comorbidities, like chronic obstructive pulmonary disease (COPD), can cause disease to progress at a quicker pace.¹⁰ COPD also can increase risk of an earlier death, as can epilepsy.^10,16 People with MS, mostly women diagnosed in the prime of their lives, live 6 to 8 fewer years than those without.¹⁹

Some coexistent diseases are also linked to a longer delay to MS diagnosis and lower rate of treatment. A large study in Canada showed ischemic heart disease and anxiety were linked with a patient’s lower rate of receiving disease-modifying therapies.⁹

In time

While not every patient with MS has co-existing disease at the time of diagnosis, it will be highly likely that these patients will have comorbidities as the years pass. In 1 study, researchers found that the prevalence of some comorbidities, like gastrointestinal disorders, thyroid disease, and anxiety, increased as patients aged.²⁰

When reviewing health claims data for patients with inflammatory bowel disease and RA, researchers found a similar risk of depression in both. Health claims data also show patients looking for treatment for anxiety 5 years before an MS diagnosis. Of patients who were not yet diagnosed, 19% had sought help for depression and 11% for anxiety.⁹

Researchers looked at 2526 patients diagnosed with MS and 9980 controls to compare the risk of developing comorbidities prior to MS diagnosis and after.¹⁶ At diagnosis, 22.7% of patients had at least one Charlson comorbidity compared with 16.8% of controls. (The Charlson comorbidity index is a weighted score comprised of several comorbidities. Scores span mild to severe, or 1 to above 5.) ²¹

Ten years prior to MS diagnosis, out of ~30 diseases, patients with MS were at risk to develop at least 20 of the 30, including various cancers, cardiovascular diseases, thyroid disorders, and neurologic and mental disorders. For the latter, the difference was 34.92% vs 17.87%. In the period after diagnosis, 17.23% of patients had a new comorbidity, as compared to 15.78% in the control population. The change was remarkable in the neurologic and mental disorders; prior to an MS diagnosis, there were no cases of dementia, but that changed post-diagnosis.

While evaluating an adolescent who had endured a several-day history of vomiting and diarrhea, I mentioned the likelihood of a viral causation, including SARS-CoV-2 infection. His well-informed mother responded, “He has no respiratory symptoms. Does COVID cause GI disease?”

Indeed, not only is the gastrointestinal tract a potential portal of entry of the virus but it may well be the site of mediation of both local and remote injury and thus a harbinger of more severe clinical phenotypes.

As we learn more about the clinical spectrum of COVID, it is becoming increasingly clear that certain features of GI tract involvement may allow us to establish a timeline of the clinical course and perhaps predict the outcome.
 

The GI tract’s involvement isn’t surprising

The ways in which the GI tract serves as a target organ of SARS-CoV-2 have been postulated in the literature. In part, this is related to the presence of abundant receptors for SARS-CoV-2 cell binding and internalization. The virus uses angiotensin-converting enzyme 2 receptors to enter various cells. These receptors are highly expressed on not only lung cells but also enterocytes. Binding of SARS-CoV-2 to ACE2 receptors allows GI involvement, leading to microscopic mucosal inflammation, increased permeability, and altered intestinal absorption.

The clinical GI manifestations of this include anorexia, nausea, vomiting, diarrhea, and abdominal pain, which may be the earliest, or sole, symptoms of COVID-19, often noted before the onset of fever or respiratory symptoms. In fact, John Ong, MBBS, and colleagues, in a discussion about patients with primary GI SARS-CoV-2 infection and symptoms, use the term “GI-COVID.”
 

Clinical course of GI manifestations

After SARS-CoV-2 exposure, adults most commonly present with respiratory symptoms, with GI symptoms reported in 10%-15% of cases. However, the overall incidence of GI involvement during SARS-CoV-2 infection varies according to age, with children more likely than adults to manifest intestinal symptoms.

There are also differences in incidence reported when comparing hospitalized with nonhospitalized individuals. In early reports from the onset of the COVID-19 pandemic, 11%-43% of hospitalized adult patients manifested GI symptoms. Of note, the presence of GI symptoms was associated with more severe disease and thus predictive of outcomes in those admitted to hospitals.

In a multicenter study that assessed pediatric inpatients with COVID-19, GI manifestations were present in 57% of patients and were the first manifestation in 14%. Adjusted by confounding factors, those with GI symptoms had a higher risk for pediatric intensive care unit admission. Patients admitted to the PICU also had higher serum C-reactive protein and aspartate aminotransferase values.
 

Emerging data on MIS-C

In previously healthy children and adolescents, the severe, life-threatening complication of multisystem inflammatory syndrome in children (MIS-C) may present 2-6 weeks after acute infection with SARS-CoV-2. MIS-C appears to be an immune activation syndrome and is presumed to be the delayed immunologic sequelae of mild/asymptomatic SARS-CoV-2 infection. This response manifests as hyperinflammation in conjunction with a peak in antibody production a few weeks later.

One report of 186 children with MIS-C in the United States noted that the involved organ system included the GI tract in 92%, followed by cardiovascular in 80%, hematologic in 76%, mucocutaneous in 74%, and respiratory in 70%. Affected children were hospitalized for a median of 7 days, with 80% requiring intensive care, 20% receiving mechanical ventilation, and 48% receiving vasoactive support; 2% died. In a similar study of patients hospitalized in New York, 88% had GI symptoms (abdominal pain, vomiting, and/or diarrhea). A retrospective chart review of patients with MIS-C found that the majority had GI symptoms with any portion of the GI tract potentially involved, but ileal and colonic inflammation predominated.

Elizabeth Whittaker, MD, and colleagues described the clinical characteristics of children in eight hospitals in England who met criteria for MIS-C that were temporally associated with SARS-CoV-2. At presentation, all of the patients manifested fever and nonspecific GI symptoms, including vomiting (45%), abdominal pain (53%), and diarrhea (52%). During hospitalization, 50% developed shock with evidence of myocardial dysfunction.

Ermias D. Belay, MD, and colleagues described the clinical characteristics of a large cohort of patients with MIS-C that were reported to the U.S. Centers for Disease Control and Prevention. Of 1,733 patients identified, GI symptoms were reported in 53%-67%. Over half developed hypotension or shock and were admitted for intensive care. Younger children more frequently presented with abdominal pain in contrast with adolescents, who more frequently manifest respiratory symptoms.

In a multicenter retrospective study of Italian children with COVID-19 that was conducted from the onset of the pandemic to early 2021, GI symptoms were noted in 38%. These manifestations were mild and self-limiting, comparable to other viral intestinal infections. However, a subset of children (9.5%) had severe GI manifestations of MIS-C, defined as a medical and/or radiologic diagnosis of acute abdomen, appendicitis, intussusception, pancreatitis, abdominal fluid collection, or diffuse adenomesenteritis requiring surgical consultation. Overall, 42% of this group underwent surgery. The authors noted that the clinical presentation of abdominal pain, lymphopenia, and increased C-reactive protein and ferritin levels were associated with a 9- to 30-fold increased probability of these severe sequelae. In addition, the severity of the GI manifestations was correlated with age (5-10 years: overall response, 8.33; >10 years: OR, 6.37). Again, the presence of GI symptoms was a harbinger of hospitalization and PICU admission.

Given that GI symptoms are a common presentation of MIS-C, its diagnosis may be delayed as clinicians first consider other GI/viral infections, inflammatory bowel disease, or Kawasaki disease. Prompt identification of GI involvement and awareness of the potential outcomes may guide the management and improve the outcome.

These studies provide a clear picture of the differential presenting features of COVID-19 and MIS-C. Although there may be other environmental/genetic factors that govern the incidence, impact, and manifestations, COVID’s status as an ongoing pandemic gives these observations worldwide relevance. This is evident in a recent report documenting pronounced GI symptoms in African children with COVID-19.

It should be noted, however, that the published data cited here reflect the impact of the initial variants of SARS-CoV-2. The GI binding, effects, and aftermath of infection with the Delta and Omicron variants is not yet known.
 

Cause and effect, or simply coincidental?

Some insight into MIS-C pathogenesis was provided by Lael M. Yonker, MD, and colleagues in their analysis of biospecimens from 100 children: 19 with MIS-C, 26 with acute COVID-19, and 55 controls. They demonstrated that in children with MIS-C the prolonged presence of SARS-CoV-2 in the GI tract led to the release of zonulin, a biomarker of intestinal permeability, with subsequent trafficking of SARS-CoV-2 antigens into the bloodstream, leading to hyperinflammation. They were then able to decrease plasma SARS-CoV-2 spike antigen levels and inflammatory markers, with resulting clinical improvement after administration of larazotide, a zonulin antagonist.

These observations regarding the potential mechanism and triggers of MIS-C may offer biomarkers for early detection and/or strategies for prevention and treatment of MIS-C.
 

Bottom line

The GI tract is the target of an immune-mediated inflammatory response that is triggered by SARS-CoV-2, with MIS-C being the major manifestation of the resultant high degree of inflammation. These observations will allow an increased awareness of nonrespiratory symptoms of SARS-CoV-2 infection by clinicians working in emergency departments and primary care settings.

Clues that may enhance the ability of pediatric clinicians to recognize the potential for severe GI involvement include the occurrence of abdominal pain, leukopenia, and elevated inflammatory markers. Their presence should raise suspicion of MIS-C and lead to early evaluation.

Of note, COVID-19 mRNA vaccination is associated with a lower incidence of MIS-C in adolescents. This underscores the importance of COVID vaccination for all eligible children. Yet, we clearly have our work cut out for us. Of 107 children with MIS-C who were hospitalized in France, 31% were adolescents eligible for vaccination; however, none had been fully vaccinated. At the end of 2021, CDC data noted that less than 1% of vaccine-eligible children (12-17 years) were fully vaccinated.

The Pfizer-BioNTech vaccine is now authorized for receipt by children aged 5-11 years, the age group that is at highest risk for MIS-C. However, despite the approval of vaccines for these younger children, there is limited access in some parts of the United States at a time of rising incidence.

We look forward to broad availability of pediatric vaccination strategies. In addition, with the intense focus on safe and effective therapeutics for SARS-CoV-2 infection, we hope to soon have strategies to prevent and/or treat the life-threatening manifestations and long-term consequences of MIS-C. For example, the recently reported central role of the gut microbiota in immunity against SARS-CoV-2 infection offer the possibility that “microbiota modulation” may both reduce GI injury and enhance vaccine efficacy.

Dr. Balistreri has disclosed no relevant financial relationships.

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; director emeritus, Pediatric Liver Care Center; medical director emeritus, liver transplantation; and professor, University of Cincinnati College of Medicine, department of pediatrics, Cincinnati Children’s Hospital Medical Center. He has served as director of the division of gastroenterology, hepatology, and nutrition at Cincinnati Children’s for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for this news organization. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. In his spare time, he coaches youth lacrosse.

A version of this article first appeared on Medscape.com.

While evaluating an adolescent who had endured a several-day history of vomiting and diarrhea, I mentioned the likelihood of a viral causation, including SARS-CoV-2 infection. His well-informed mother responded, “He has no respiratory symptoms. Does COVID cause GI disease?”

Indeed, not only is the gastrointestinal tract a potential portal of entry of the virus but it may well be the site of mediation of both local and remote injury and thus a harbinger of more severe clinical phenotypes.

As we learn more about the clinical spectrum of COVID, it is becoming increasingly clear that certain features of GI tract involvement may allow us to establish a timeline of the clinical course and perhaps predict the outcome.
 

The GI tract’s involvement isn’t surprising

The ways in which the GI tract serves as a target organ of SARS-CoV-2 have been postulated in the literature. In part, this is related to the presence of abundant receptors for SARS-CoV-2 cell binding and internalization. The virus uses angiotensin-converting enzyme 2 receptors to enter various cells. These receptors are highly expressed on not only lung cells but also enterocytes. Binding of SARS-CoV-2 to ACE2 receptors allows GI involvement, leading to microscopic mucosal inflammation, increased permeability, and altered intestinal absorption.

The clinical GI manifestations of this include anorexia, nausea, vomiting, diarrhea, and abdominal pain, which may be the earliest, or sole, symptoms of COVID-19, often noted before the onset of fever or respiratory symptoms. In fact, John Ong, MBBS, and colleagues, in a discussion about patients with primary GI SARS-CoV-2 infection and symptoms, use the term “GI-COVID.”
 

Clinical course of GI manifestations

After SARS-CoV-2 exposure, adults most commonly present with respiratory symptoms, with GI symptoms reported in 10%-15% of cases. However, the overall incidence of GI involvement during SARS-CoV-2 infection varies according to age, with children more likely than adults to manifest intestinal symptoms.

There are also differences in incidence reported when comparing hospitalized with nonhospitalized individuals. In early reports from the onset of the COVID-19 pandemic, 11%-43% of hospitalized adult patients manifested GI symptoms. Of note, the presence of GI symptoms was associated with more severe disease and thus predictive of outcomes in those admitted to hospitals.

In a multicenter study that assessed pediatric inpatients with COVID-19, GI manifestations were present in 57% of patients and were the first manifestation in 14%. Adjusted by confounding factors, those with GI symptoms had a higher risk for pediatric intensive care unit admission. Patients admitted to the PICU also had higher serum C-reactive protein and aspartate aminotransferase values.
 

Emerging data on MIS-C

In previously healthy children and adolescents, the severe, life-threatening complication of multisystem inflammatory syndrome in children (MIS-C) may present 2-6 weeks after acute infection with SARS-CoV-2. MIS-C appears to be an immune activation syndrome and is presumed to be the delayed immunologic sequelae of mild/asymptomatic SARS-CoV-2 infection. This response manifests as hyperinflammation in conjunction with a peak in antibody production a few weeks later.

One report of 186 children with MIS-C in the United States noted that the involved organ system included the GI tract in 92%, followed by cardiovascular in 80%, hematologic in 76%, mucocutaneous in 74%, and respiratory in 70%. Affected children were hospitalized for a median of 7 days, with 80% requiring intensive care, 20% receiving mechanical ventilation, and 48% receiving vasoactive support; 2% died. In a similar study of patients hospitalized in New York, 88% had GI symptoms (abdominal pain, vomiting, and/or diarrhea). A retrospective chart review of patients with MIS-C found that the majority had GI symptoms with any portion of the GI tract potentially involved, but ileal and colonic inflammation predominated.

Elizabeth Whittaker, MD, and colleagues described the clinical characteristics of children in eight hospitals in England who met criteria for MIS-C that were temporally associated with SARS-CoV-2. At presentation, all of the patients manifested fever and nonspecific GI symptoms, including vomiting (45%), abdominal pain (53%), and diarrhea (52%). During hospitalization, 50% developed shock with evidence of myocardial dysfunction.

Ermias D. Belay, MD, and colleagues described the clinical characteristics of a large cohort of patients with MIS-C that were reported to the U.S. Centers for Disease Control and Prevention. Of 1,733 patients identified, GI symptoms were reported in 53%-67%. Over half developed hypotension or shock and were admitted for intensive care. Younger children more frequently presented with abdominal pain in contrast with adolescents, who more frequently manifest respiratory symptoms.

In a multicenter retrospective study of Italian children with COVID-19 that was conducted from the onset of the pandemic to early 2021, GI symptoms were noted in 38%. These manifestations were mild and self-limiting, comparable to other viral intestinal infections. However, a subset of children (9.5%) had severe GI manifestations of MIS-C, defined as a medical and/or radiologic diagnosis of acute abdomen, appendicitis, intussusception, pancreatitis, abdominal fluid collection, or diffuse adenomesenteritis requiring surgical consultation. Overall, 42% of this group underwent surgery. The authors noted that the clinical presentation of abdominal pain, lymphopenia, and increased C-reactive protein and ferritin levels were associated with a 9- to 30-fold increased probability of these severe sequelae. In addition, the severity of the GI manifestations was correlated with age (5-10 years: overall response, 8.33; >10 years: OR, 6.37). Again, the presence of GI symptoms was a harbinger of hospitalization and PICU admission.

Given that GI symptoms are a common presentation of MIS-C, its diagnosis may be delayed as clinicians first consider other GI/viral infections, inflammatory bowel disease, or Kawasaki disease. Prompt identification of GI involvement and awareness of the potential outcomes may guide the management and improve the outcome.

These studies provide a clear picture of the differential presenting features of COVID-19 and MIS-C. Although there may be other environmental/genetic factors that govern the incidence, impact, and manifestations, COVID’s status as an ongoing pandemic gives these observations worldwide relevance. This is evident in a recent report documenting pronounced GI symptoms in African children with COVID-19.

It should be noted, however, that the published data cited here reflect the impact of the initial variants of SARS-CoV-2. The GI binding, effects, and aftermath of infection with the Delta and Omicron variants is not yet known.
 

Cause and effect, or simply coincidental?

Some insight into MIS-C pathogenesis was provided by Lael M. Yonker, MD, and colleagues in their analysis of biospecimens from 100 children: 19 with MIS-C, 26 with acute COVID-19, and 55 controls. They demonstrated that in children with MIS-C the prolonged presence of SARS-CoV-2 in the GI tract led to the release of zonulin, a biomarker of intestinal permeability, with subsequent trafficking of SARS-CoV-2 antigens into the bloodstream, leading to hyperinflammation. They were then able to decrease plasma SARS-CoV-2 spike antigen levels and inflammatory markers, with resulting clinical improvement after administration of larazotide, a zonulin antagonist.

These observations regarding the potential mechanism and triggers of MIS-C may offer biomarkers for early detection and/or strategies for prevention and treatment of MIS-C.
 

Bottom line

The GI tract is the target of an immune-mediated inflammatory response that is triggered by SARS-CoV-2, with MIS-C being the major manifestation of the resultant high degree of inflammation. These observations will allow an increased awareness of nonrespiratory symptoms of SARS-CoV-2 infection by clinicians working in emergency departments and primary care settings.

Clues that may enhance the ability of pediatric clinicians to recognize the potential for severe GI involvement include the occurrence of abdominal pain, leukopenia, and elevated inflammatory markers. Their presence should raise suspicion of MIS-C and lead to early evaluation.

Of note, COVID-19 mRNA vaccination is associated with a lower incidence of MIS-C in adolescents. This underscores the importance of COVID vaccination for all eligible children. Yet, we clearly have our work cut out for us. Of 107 children with MIS-C who were hospitalized in France, 31% were adolescents eligible for vaccination; however, none had been fully vaccinated. At the end of 2021, CDC data noted that less than 1% of vaccine-eligible children (12-17 years) were fully vaccinated.

The Pfizer-BioNTech vaccine is now authorized for receipt by children aged 5-11 years, the age group that is at highest risk for MIS-C. However, despite the approval of vaccines for these younger children, there is limited access in some parts of the United States at a time of rising incidence.

We look forward to broad availability of pediatric vaccination strategies. In addition, with the intense focus on safe and effective therapeutics for SARS-CoV-2 infection, we hope to soon have strategies to prevent and/or treat the life-threatening manifestations and long-term consequences of MIS-C. For example, the recently reported central role of the gut microbiota in immunity against SARS-CoV-2 infection offer the possibility that “microbiota modulation” may both reduce GI injury and enhance vaccine efficacy.

Dr. Balistreri has disclosed no relevant financial relationships.

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; director emeritus, Pediatric Liver Care Center; medical director emeritus, liver transplantation; and professor, University of Cincinnati College of Medicine, department of pediatrics, Cincinnati Children’s Hospital Medical Center. He has served as director of the division of gastroenterology, hepatology, and nutrition at Cincinnati Children’s for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for this news organization. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. In his spare time, he coaches youth lacrosse.

A version of this article first appeared on Medscape.com.

While evaluating an adolescent who had endured a several-day history of vomiting and diarrhea, I mentioned the likelihood of a viral causation, including SARS-CoV-2 infection. His well-informed mother responded, “He has no respiratory symptoms. Does COVID cause GI disease?”

Indeed, not only is the gastrointestinal tract a potential portal of entry of the virus but it may well be the site of mediation of both local and remote injury and thus a harbinger of more severe clinical phenotypes.

As we learn more about the clinical spectrum of COVID, it is becoming increasingly clear that certain features of GI tract involvement may allow us to establish a timeline of the clinical course and perhaps predict the outcome.
 

The GI tract’s involvement isn’t surprising

The ways in which the GI tract serves as a target organ of SARS-CoV-2 have been postulated in the literature. In part, this is related to the presence of abundant receptors for SARS-CoV-2 cell binding and internalization. The virus uses angiotensin-converting enzyme 2 receptors to enter various cells. These receptors are highly expressed on not only lung cells but also enterocytes. Binding of SARS-CoV-2 to ACE2 receptors allows GI involvement, leading to microscopic mucosal inflammation, increased permeability, and altered intestinal absorption.

The clinical GI manifestations of this include anorexia, nausea, vomiting, diarrhea, and abdominal pain, which may be the earliest, or sole, symptoms of COVID-19, often noted before the onset of fever or respiratory symptoms. In fact, John Ong, MBBS, and colleagues, in a discussion about patients with primary GI SARS-CoV-2 infection and symptoms, use the term “GI-COVID.”
 

Clinical course of GI manifestations

After SARS-CoV-2 exposure, adults most commonly present with respiratory symptoms, with GI symptoms reported in 10%-15% of cases. However, the overall incidence of GI involvement during SARS-CoV-2 infection varies according to age, with children more likely than adults to manifest intestinal symptoms.

There are also differences in incidence reported when comparing hospitalized with nonhospitalized individuals. In early reports from the onset of the COVID-19 pandemic, 11%-43% of hospitalized adult patients manifested GI symptoms. Of note, the presence of GI symptoms was associated with more severe disease and thus predictive of outcomes in those admitted to hospitals.

In a multicenter study that assessed pediatric inpatients with COVID-19, GI manifestations were present in 57% of patients and were the first manifestation in 14%. Adjusted by confounding factors, those with GI symptoms had a higher risk for pediatric intensive care unit admission. Patients admitted to the PICU also had higher serum C-reactive protein and aspartate aminotransferase values.
 

Emerging data on MIS-C

In previously healthy children and adolescents, the severe, life-threatening complication of multisystem inflammatory syndrome in children (MIS-C) may present 2-6 weeks after acute infection with SARS-CoV-2. MIS-C appears to be an immune activation syndrome and is presumed to be the delayed immunologic sequelae of mild/asymptomatic SARS-CoV-2 infection. This response manifests as hyperinflammation in conjunction with a peak in antibody production a few weeks later.

One report of 186 children with MIS-C in the United States noted that the involved organ system included the GI tract in 92%, followed by cardiovascular in 80%, hematologic in 76%, mucocutaneous in 74%, and respiratory in 70%. Affected children were hospitalized for a median of 7 days, with 80% requiring intensive care, 20% receiving mechanical ventilation, and 48% receiving vasoactive support; 2% died. In a similar study of patients hospitalized in New York, 88% had GI symptoms (abdominal pain, vomiting, and/or diarrhea). A retrospective chart review of patients with MIS-C found that the majority had GI symptoms with any portion of the GI tract potentially involved, but ileal and colonic inflammation predominated.

Elizabeth Whittaker, MD, and colleagues described the clinical characteristics of children in eight hospitals in England who met criteria for MIS-C that were temporally associated with SARS-CoV-2. At presentation, all of the patients manifested fever and nonspecific GI symptoms, including vomiting (45%), abdominal pain (53%), and diarrhea (52%). During hospitalization, 50% developed shock with evidence of myocardial dysfunction.

Ermias D. Belay, MD, and colleagues described the clinical characteristics of a large cohort of patients with MIS-C that were reported to the U.S. Centers for Disease Control and Prevention. Of 1,733 patients identified, GI symptoms were reported in 53%-67%. Over half developed hypotension or shock and were admitted for intensive care. Younger children more frequently presented with abdominal pain in contrast with adolescents, who more frequently manifest respiratory symptoms.

In a multicenter retrospective study of Italian children with COVID-19 that was conducted from the onset of the pandemic to early 2021, GI symptoms were noted in 38%. These manifestations were mild and self-limiting, comparable to other viral intestinal infections. However, a subset of children (9.5%) had severe GI manifestations of MIS-C, defined as a medical and/or radiologic diagnosis of acute abdomen, appendicitis, intussusception, pancreatitis, abdominal fluid collection, or diffuse adenomesenteritis requiring surgical consultation. Overall, 42% of this group underwent surgery. The authors noted that the clinical presentation of abdominal pain, lymphopenia, and increased C-reactive protein and ferritin levels were associated with a 9- to 30-fold increased probability of these severe sequelae. In addition, the severity of the GI manifestations was correlated with age (5-10 years: overall response, 8.33; >10 years: OR, 6.37). Again, the presence of GI symptoms was a harbinger of hospitalization and PICU admission.

Given that GI symptoms are a common presentation of MIS-C, its diagnosis may be delayed as clinicians first consider other GI/viral infections, inflammatory bowel disease, or Kawasaki disease. Prompt identification of GI involvement and awareness of the potential outcomes may guide the management and improve the outcome.

These studies provide a clear picture of the differential presenting features of COVID-19 and MIS-C. Although there may be other environmental/genetic factors that govern the incidence, impact, and manifestations, COVID’s status as an ongoing pandemic gives these observations worldwide relevance. This is evident in a recent report documenting pronounced GI symptoms in African children with COVID-19.

It should be noted, however, that the published data cited here reflect the impact of the initial variants of SARS-CoV-2. The GI binding, effects, and aftermath of infection with the Delta and Omicron variants is not yet known.
 

Cause and effect, or simply coincidental?

Some insight into MIS-C pathogenesis was provided by Lael M. Yonker, MD, and colleagues in their analysis of biospecimens from 100 children: 19 with MIS-C, 26 with acute COVID-19, and 55 controls. They demonstrated that in children with MIS-C the prolonged presence of SARS-CoV-2 in the GI tract led to the release of zonulin, a biomarker of intestinal permeability, with subsequent trafficking of SARS-CoV-2 antigens into the bloodstream, leading to hyperinflammation. They were then able to decrease plasma SARS-CoV-2 spike antigen levels and inflammatory markers, with resulting clinical improvement after administration of larazotide, a zonulin antagonist.

These observations regarding the potential mechanism and triggers of MIS-C may offer biomarkers for early detection and/or strategies for prevention and treatment of MIS-C.
 

Bottom line

The GI tract is the target of an immune-mediated inflammatory response that is triggered by SARS-CoV-2, with MIS-C being the major manifestation of the resultant high degree of inflammation. These observations will allow an increased awareness of nonrespiratory symptoms of SARS-CoV-2 infection by clinicians working in emergency departments and primary care settings.

Clues that may enhance the ability of pediatric clinicians to recognize the potential for severe GI involvement include the occurrence of abdominal pain, leukopenia, and elevated inflammatory markers. Their presence should raise suspicion of MIS-C and lead to early evaluation.

Of note, COVID-19 mRNA vaccination is associated with a lower incidence of MIS-C in adolescents. This underscores the importance of COVID vaccination for all eligible children. Yet, we clearly have our work cut out for us. Of 107 children with MIS-C who were hospitalized in France, 31% were adolescents eligible for vaccination; however, none had been fully vaccinated. At the end of 2021, CDC data noted that less than 1% of vaccine-eligible children (12-17 years) were fully vaccinated.

The Pfizer-BioNTech vaccine is now authorized for receipt by children aged 5-11 years, the age group that is at highest risk for MIS-C. However, despite the approval of vaccines for these younger children, there is limited access in some parts of the United States at a time of rising incidence.

We look forward to broad availability of pediatric vaccination strategies. In addition, with the intense focus on safe and effective therapeutics for SARS-CoV-2 infection, we hope to soon have strategies to prevent and/or treat the life-threatening manifestations and long-term consequences of MIS-C. For example, the recently reported central role of the gut microbiota in immunity against SARS-CoV-2 infection offer the possibility that “microbiota modulation” may both reduce GI injury and enhance vaccine efficacy.

Dr. Balistreri has disclosed no relevant financial relationships.

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; director emeritus, Pediatric Liver Care Center; medical director emeritus, liver transplantation; and professor, University of Cincinnati College of Medicine, department of pediatrics, Cincinnati Children’s Hospital Medical Center. He has served as director of the division of gastroenterology, hepatology, and nutrition at Cincinnati Children’s for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for this news organization. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. In his spare time, he coaches youth lacrosse.

A version of this article first appeared on Medscape.com.

Edoardo Caronna, MD and Patricia Pozo-Rosich, MD, PhD,  Neurology Department, Hospital Universitari Vall d’Hebron, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; and Headache and Neurological Pain Research Group, Vall d’Hebron Research Institute, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. Dr. Pozo-Rosich also serves on the boards of the International Headache Society and Council of the European Headache Federation and is an editor for various peer-reviewed journals, including Cephalalgia and Headache.

Headache is a symptom of the coronavirus disease 2019 (Covid-19), caused by the novel, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the pandemic began, researchers have tried to describe, understand, and help clinicians manage headache in the setting of Covid-19.

The reason is simple: Headache is common, often debilitating, and difficult to treat.¹

Moreover, headache could manifest both in the acute phase of the infection and, once the infection has resolved, in the post-acute phase.¹ Therefore, it is critical for clinicians to know more about headache, as headache can be a common reason that patients seek help, both in the specialized and non-specialized medical care setting.

Definitions and manifestations

While the first step in such a communication would be to define headache attributed to Covid-19, no specific definition exists, as this is a new disease. Therefore, headache attributed to Covid-19 should be defined under the diagnostic criteria, as contained in the International Classification of Headache Disorders-3, as headache attributed to a systemic viral infection.² As this is a secondary headache appearing with an infection, the treating physician needs to rule out possible underlying meningitis and/or encephalitis in the diagnosis. Moreover, other secondary headaches (eg, cerebral venous thrombosis) may appear, so clinicians need to carefully evaluate patients with headache during Covid-19 to detect signs or symptoms that point to other etiologies.

It is also advisable to know the clinical manifestations of headache attributed to Covid-19. Studies published so far have observed two main phenotypes of headache in the acute phase of the infection: one resembles migraine, the other, a tension-type headache.^1,3 Although patients with history of migraine who contract Covid-19 report headache that is more similar to primary headache disorder,⁴ two relevant aspects should be considered. Namely, migraine-like features can be observed in patients without personal migraine history; and Covid-19 patients with such history may perceive that headache they experience in the infection’s acute phase differs from their usual experience, especially regarding increased severity or duration.^5,6 Of note, headache can be a prodromal symptom of the SARS-CoV-2 infection.¹

Evolution of a headache

 Because headache appearing after the acute phase of the infection can persist, often manifesting migraine-like features, it is inordinately helpful for clinicians to know its evolution.¹ This persistent headache, sometimes referred to as post-covid headache, is not aptly named because the post-covid headache is not just one type of headache, but instead can manifest as different headache types.

 A recently published case series in Headache discussed three Covid patients who all experienced persistent headache during the infection’s post-acute phase.⁷ These patients experienced a migraine-like phenotype as have others with mild Covid-19, but their personal history of migraine, as well as their experience with Covid-19 related headache, were substantially different. Some patients had personal migraine history while others did not; some patients experienced no headache in the acute phase but did so in the post-acute phase; and the concomitant symptoms of the post-acute phase, such as insomnia, memory loss, dizziness, fatigue, and brain fog, were differentially expressed by patients.⁷ 

 This case series introduces the concept that patients with no prior history of migraine or any other primary headache disorder can develop a de novo headache because of their SARS-CoV-2 infection. Moreover, it could manifest as a new daily persistent headache. And patients with personal history of migraine may experience sudden chronification in their headache’s characteristics, rather than develop a new type of headache.⁷

 In another study, soon to be published in Cephalalgia, researchers observed that the median duration of headache in the acute phase is 2 weeks. This multicenter Spanish study, in which data on headache duration were available for 874 patients, found that 16% of these particular patients had persistent headache after 9 months. According to this study, headache that does not resolve within the first 3 months is less likely to do so later on.

Treatment

For clinicians, the significance of these findings is straightforward: Patients with headache experienced in the infection’s acute phase that does not seem to resolve post-infection requires continued medical attention. Patients should be monitored, carefully managed, and treated to avoid the onset of a persisting headache. This applies to patients with or without personal migraine history.

But which treatments should be prescribed? As there are no specific therapies for headache attributed to Covid-19, either in the acute or post-acute phase of the infection, clinicians must turn to existing therapies.

As with patients with migraine, patients with persistent headache post-Covid infection need a headache prevention strategy.

The strategy should be based on the following principles:

• treat headache
• treat comorbidities including mood disorders,  insomnia, and so on
• avoid complications such as medication overuse, which may be very common in these patients.

Acute medications

Despite the lack of specific literature on this matter, migraine-like phenotypes may respond to triptans and probably, where available, lasmiditan and gepants. These medications probably represent a therapeutic option for Covid patients with headache, but before prescribing them clinicians should carefully evaluate their use.

Before deciding on the prescription, clinicians should consider not only the medications’ most common contraindications, but also those that are related to Covid-19: the phase of the infection (acute/post-acute); the infection’s severity; and the presence of other Covid-related health problems. The concerns over the use of nonsteroidal anti-inflammatory medications (NSAIDs) and corticosteroids, raised when the pandemic first struck, have greatly dissipated.^8,9 Some patients with prolonged headache may benefit from a brief cycle of corticosteroids, similar to the treatment given to those patients with status migrainosus. Nerve blocks could also be considered.

Preventive medications

Drugs can be prescribed according to the headache phenotype too, but there are no published studies that specifically evaluate headache prevention treatments in patients with persistent headache post-infection. The case series mentioned earlier in this article recorded that patients whose headaches were treated with amitriptyline and onabotulinumtoxinA had reported variable treatment responses to this regimen, according to the patients’ characteristics.⁷

However, one important question regarding the safety of Covid patients with migraine – specifically patients on preventive treatments during the infection’s acute phase – has been somewhat resolved.

Medications such as renin-angiotensin system (RAS) blockers, suspected of possible involvement in the SARs-CoV-2 pathogenicity, seem to be safe.^8,10 And, in another multicenter Spanish study, researchers found that the use of anti-CGRP monoclonal antibodies did not seem to be associated with worse Covid-19 outcomes despite the possible implication of CGRP in modulating inflammatory responses during a viral infection.¹¹

The study of anti-CGRP monoclonal antibodies could be important in the future for another reason: To see whether these medications could be effective as a preventive treatment in patients with persistent headache after Covid-19, regardless of whether these patients have personal migraine history.

An interesting and important message to close this article. Although headache experienced in the infection’s acute phase could be extremely disabling for patients, the evidence points to the presence of headache as a marker of a better Covid-19 prognosis, in terms of a shorter infection period and a lower risk of mortality among hospitalized patients.^1,3,12  

This brief communication contains current information to help clinicians treat and inform their patients with Covid-sourced headache. Yet, we must keep in mind that the majority of the data reported here and published in the literature refer to studies conducted during the first wave of the pandemic. The emergence of new SARS-CoV-2 variants and vaccines have enormously changed the disease’s clinical presentation and course, so future studies are warranted to re-assess the validity of these findings under new conditions.

Edoardo Caronna, MD and Patricia Pozo-Rosich, MD, PhD,  Neurology Department, Hospital Universitari Vall d’Hebron, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; and Headache and Neurological Pain Research Group, Vall d’Hebron Research Institute, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. Dr. Pozo-Rosich also serves on the boards of the International Headache Society and Council of the European Headache Federation and is an editor for various peer-reviewed journals, including Cephalalgia and Headache.

Headache is a symptom of the coronavirus disease 2019 (Covid-19), caused by the novel, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the pandemic began, researchers have tried to describe, understand, and help clinicians manage headache in the setting of Covid-19.

The reason is simple: Headache is common, often debilitating, and difficult to treat.¹

Moreover, headache could manifest both in the acute phase of the infection and, once the infection has resolved, in the post-acute phase.¹ Therefore, it is critical for clinicians to know more about headache, as headache can be a common reason that patients seek help, both in the specialized and non-specialized medical care setting.

Definitions and manifestations

While the first step in such a communication would be to define headache attributed to Covid-19, no specific definition exists, as this is a new disease. Therefore, headache attributed to Covid-19 should be defined under the diagnostic criteria, as contained in the International Classification of Headache Disorders-3, as headache attributed to a systemic viral infection.² As this is a secondary headache appearing with an infection, the treating physician needs to rule out possible underlying meningitis and/or encephalitis in the diagnosis. Moreover, other secondary headaches (eg, cerebral venous thrombosis) may appear, so clinicians need to carefully evaluate patients with headache during Covid-19 to detect signs or symptoms that point to other etiologies.

It is also advisable to know the clinical manifestations of headache attributed to Covid-19. Studies published so far have observed two main phenotypes of headache in the acute phase of the infection: one resembles migraine, the other, a tension-type headache.^1,3 Although patients with history of migraine who contract Covid-19 report headache that is more similar to primary headache disorder,⁴ two relevant aspects should be considered. Namely, migraine-like features can be observed in patients without personal migraine history; and Covid-19 patients with such history may perceive that headache they experience in the infection’s acute phase differs from their usual experience, especially regarding increased severity or duration.^5,6 Of note, headache can be a prodromal symptom of the SARS-CoV-2 infection.¹

Evolution of a headache

 Because headache appearing after the acute phase of the infection can persist, often manifesting migraine-like features, it is inordinately helpful for clinicians to know its evolution.¹ This persistent headache, sometimes referred to as post-covid headache, is not aptly named because the post-covid headache is not just one type of headache, but instead can manifest as different headache types.

 A recently published case series in Headache discussed three Covid patients who all experienced persistent headache during the infection’s post-acute phase.⁷ These patients experienced a migraine-like phenotype as have others with mild Covid-19, but their personal history of migraine, as well as their experience with Covid-19 related headache, were substantially different. Some patients had personal migraine history while others did not; some patients experienced no headache in the acute phase but did so in the post-acute phase; and the concomitant symptoms of the post-acute phase, such as insomnia, memory loss, dizziness, fatigue, and brain fog, were differentially expressed by patients.⁷ 

 This case series introduces the concept that patients with no prior history of migraine or any other primary headache disorder can develop a de novo headache because of their SARS-CoV-2 infection. Moreover, it could manifest as a new daily persistent headache. And patients with personal history of migraine may experience sudden chronification in their headache’s characteristics, rather than develop a new type of headache.⁷

 In another study, soon to be published in Cephalalgia, researchers observed that the median duration of headache in the acute phase is 2 weeks. This multicenter Spanish study, in which data on headache duration were available for 874 patients, found that 16% of these particular patients had persistent headache after 9 months. According to this study, headache that does not resolve within the first 3 months is less likely to do so later on.

Treatment

For clinicians, the significance of these findings is straightforward: Patients with headache experienced in the infection’s acute phase that does not seem to resolve post-infection requires continued medical attention. Patients should be monitored, carefully managed, and treated to avoid the onset of a persisting headache. This applies to patients with or without personal migraine history.

But which treatments should be prescribed? As there are no specific therapies for headache attributed to Covid-19, either in the acute or post-acute phase of the infection, clinicians must turn to existing therapies.

As with patients with migraine, patients with persistent headache post-Covid infection need a headache prevention strategy.

The strategy should be based on the following principles:

• treat headache
• treat comorbidities including mood disorders,  insomnia, and so on
• avoid complications such as medication overuse, which may be very common in these patients.

Acute medications

Despite the lack of specific literature on this matter, migraine-like phenotypes may respond to triptans and probably, where available, lasmiditan and gepants. These medications probably represent a therapeutic option for Covid patients with headache, but before prescribing them clinicians should carefully evaluate their use.

Before deciding on the prescription, clinicians should consider not only the medications’ most common contraindications, but also those that are related to Covid-19: the phase of the infection (acute/post-acute); the infection’s severity; and the presence of other Covid-related health problems. The concerns over the use of nonsteroidal anti-inflammatory medications (NSAIDs) and corticosteroids, raised when the pandemic first struck, have greatly dissipated.^8,9 Some patients with prolonged headache may benefit from a brief cycle of corticosteroids, similar to the treatment given to those patients with status migrainosus. Nerve blocks could also be considered.

Preventive medications

Drugs can be prescribed according to the headache phenotype too, but there are no published studies that specifically evaluate headache prevention treatments in patients with persistent headache post-infection. The case series mentioned earlier in this article recorded that patients whose headaches were treated with amitriptyline and onabotulinumtoxinA had reported variable treatment responses to this regimen, according to the patients’ characteristics.⁷

However, one important question regarding the safety of Covid patients with migraine – specifically patients on preventive treatments during the infection’s acute phase – has been somewhat resolved.

Medications such as renin-angiotensin system (RAS) blockers, suspected of possible involvement in the SARs-CoV-2 pathogenicity, seem to be safe.^8,10 And, in another multicenter Spanish study, researchers found that the use of anti-CGRP monoclonal antibodies did not seem to be associated with worse Covid-19 outcomes despite the possible implication of CGRP in modulating inflammatory responses during a viral infection.¹¹

The study of anti-CGRP monoclonal antibodies could be important in the future for another reason: To see whether these medications could be effective as a preventive treatment in patients with persistent headache after Covid-19, regardless of whether these patients have personal migraine history.

An interesting and important message to close this article. Although headache experienced in the infection’s acute phase could be extremely disabling for patients, the evidence points to the presence of headache as a marker of a better Covid-19 prognosis, in terms of a shorter infection period and a lower risk of mortality among hospitalized patients.^1,3,12  

This brief communication contains current information to help clinicians treat and inform their patients with Covid-sourced headache. Yet, we must keep in mind that the majority of the data reported here and published in the literature refer to studies conducted during the first wave of the pandemic. The emergence of new SARS-CoV-2 variants and vaccines have enormously changed the disease’s clinical presentation and course, so future studies are warranted to re-assess the validity of these findings under new conditions.

Edoardo Caronna, MD and Patricia Pozo-Rosich, MD, PhD,  Neurology Department, Hospital Universitari Vall d’Hebron, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; and Headache and Neurological Pain Research Group, Vall d’Hebron Research Institute, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. Dr. Pozo-Rosich also serves on the boards of the International Headache Society and Council of the European Headache Federation and is an editor for various peer-reviewed journals, including Cephalalgia and Headache.

Headache is a symptom of the coronavirus disease 2019 (Covid-19), caused by the novel, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the pandemic began, researchers have tried to describe, understand, and help clinicians manage headache in the setting of Covid-19.

The reason is simple: Headache is common, often debilitating, and difficult to treat.¹

Moreover, headache could manifest both in the acute phase of the infection and, once the infection has resolved, in the post-acute phase.¹ Therefore, it is critical for clinicians to know more about headache, as headache can be a common reason that patients seek help, both in the specialized and non-specialized medical care setting.

Definitions and manifestations

While the first step in such a communication would be to define headache attributed to Covid-19, no specific definition exists, as this is a new disease. Therefore, headache attributed to Covid-19 should be defined under the diagnostic criteria, as contained in the International Classification of Headache Disorders-3, as headache attributed to a systemic viral infection.² As this is a secondary headache appearing with an infection, the treating physician needs to rule out possible underlying meningitis and/or encephalitis in the diagnosis. Moreover, other secondary headaches (eg, cerebral venous thrombosis) may appear, so clinicians need to carefully evaluate patients with headache during Covid-19 to detect signs or symptoms that point to other etiologies.

It is also advisable to know the clinical manifestations of headache attributed to Covid-19. Studies published so far have observed two main phenotypes of headache in the acute phase of the infection: one resembles migraine, the other, a tension-type headache.^1,3 Although patients with history of migraine who contract Covid-19 report headache that is more similar to primary headache disorder,⁴ two relevant aspects should be considered. Namely, migraine-like features can be observed in patients without personal migraine history; and Covid-19 patients with such history may perceive that headache they experience in the infection’s acute phase differs from their usual experience, especially regarding increased severity or duration.^5,6 Of note, headache can be a prodromal symptom of the SARS-CoV-2 infection.¹

Evolution of a headache

 Because headache appearing after the acute phase of the infection can persist, often manifesting migraine-like features, it is inordinately helpful for clinicians to know its evolution.¹ This persistent headache, sometimes referred to as post-covid headache, is not aptly named because the post-covid headache is not just one type of headache, but instead can manifest as different headache types.

 A recently published case series in Headache discussed three Covid patients who all experienced persistent headache during the infection’s post-acute phase.⁷ These patients experienced a migraine-like phenotype as have others with mild Covid-19, but their personal history of migraine, as well as their experience with Covid-19 related headache, were substantially different. Some patients had personal migraine history while others did not; some patients experienced no headache in the acute phase but did so in the post-acute phase; and the concomitant symptoms of the post-acute phase, such as insomnia, memory loss, dizziness, fatigue, and brain fog, were differentially expressed by patients.⁷ 

 This case series introduces the concept that patients with no prior history of migraine or any other primary headache disorder can develop a de novo headache because of their SARS-CoV-2 infection. Moreover, it could manifest as a new daily persistent headache. And patients with personal history of migraine may experience sudden chronification in their headache’s characteristics, rather than develop a new type of headache.⁷

 In another study, soon to be published in Cephalalgia, researchers observed that the median duration of headache in the acute phase is 2 weeks. This multicenter Spanish study, in which data on headache duration were available for 874 patients, found that 16% of these particular patients had persistent headache after 9 months. According to this study, headache that does not resolve within the first 3 months is less likely to do so later on.

Treatment

For clinicians, the significance of these findings is straightforward: Patients with headache experienced in the infection’s acute phase that does not seem to resolve post-infection requires continued medical attention. Patients should be monitored, carefully managed, and treated to avoid the onset of a persisting headache. This applies to patients with or without personal migraine history.

But which treatments should be prescribed? As there are no specific therapies for headache attributed to Covid-19, either in the acute or post-acute phase of the infection, clinicians must turn to existing therapies.

As with patients with migraine, patients with persistent headache post-Covid infection need a headache prevention strategy.

The strategy should be based on the following principles:

• treat headache
• treat comorbidities including mood disorders,  insomnia, and so on
• avoid complications such as medication overuse, which may be very common in these patients.

Acute medications

Despite the lack of specific literature on this matter, migraine-like phenotypes may respond to triptans and probably, where available, lasmiditan and gepants. These medications probably represent a therapeutic option for Covid patients with headache, but before prescribing them clinicians should carefully evaluate their use.

Before deciding on the prescription, clinicians should consider not only the medications’ most common contraindications, but also those that are related to Covid-19: the phase of the infection (acute/post-acute); the infection’s severity; and the presence of other Covid-related health problems. The concerns over the use of nonsteroidal anti-inflammatory medications (NSAIDs) and corticosteroids, raised when the pandemic first struck, have greatly dissipated.^8,9 Some patients with prolonged headache may benefit from a brief cycle of corticosteroids, similar to the treatment given to those patients with status migrainosus. Nerve blocks could also be considered.

Preventive medications

Drugs can be prescribed according to the headache phenotype too, but there are no published studies that specifically evaluate headache prevention treatments in patients with persistent headache post-infection. The case series mentioned earlier in this article recorded that patients whose headaches were treated with amitriptyline and onabotulinumtoxinA had reported variable treatment responses to this regimen, according to the patients’ characteristics.⁷

However, one important question regarding the safety of Covid patients with migraine – specifically patients on preventive treatments during the infection’s acute phase – has been somewhat resolved.

Medications such as renin-angiotensin system (RAS) blockers, suspected of possible involvement in the SARs-CoV-2 pathogenicity, seem to be safe.^8,10 And, in another multicenter Spanish study, researchers found that the use of anti-CGRP monoclonal antibodies did not seem to be associated with worse Covid-19 outcomes despite the possible implication of CGRP in modulating inflammatory responses during a viral infection.¹¹

The study of anti-CGRP monoclonal antibodies could be important in the future for another reason: To see whether these medications could be effective as a preventive treatment in patients with persistent headache after Covid-19, regardless of whether these patients have personal migraine history.

An interesting and important message to close this article. Although headache experienced in the infection’s acute phase could be extremely disabling for patients, the evidence points to the presence of headache as a marker of a better Covid-19 prognosis, in terms of a shorter infection period and a lower risk of mortality among hospitalized patients.^1,3,12  

This brief communication contains current information to help clinicians treat and inform their patients with Covid-sourced headache. Yet, we must keep in mind that the majority of the data reported here and published in the literature refer to studies conducted during the first wave of the pandemic. The emergence of new SARS-CoV-2 variants and vaccines have enormously changed the disease’s clinical presentation and course, so future studies are warranted to re-assess the validity of these findings under new conditions.

Health care’s modern-day version of the Greek chorus is growing louder and more persistent. My colleagues and I have long been among them.

In news conferences, journal articles, and podcasts, this chorus is pleading with the public to pay attention to its message: SARs-CoV-2 is not done with us. Omicron can kill; it can infect the vaccinated.

We have found, like everyone else, that Omicron runs on its rules; with Delta, two vaccine shots were able to lower the positivity rate. With Omicron, two shots have not been enough.

The WHO used the word “surprise” in its November announcement that Omicron was a variant of “concern.”

So did Trevor Bedford, a computational biologist and infectious disease scientist at the Fred Hutchinson Cancer Center in Seattle, who said that Omicron “took me and everyone by surprise.”¹ Speaking on KevinMD’s podcast, he told his host that with the degree of immunity in the global population, he was expecting subsequent evolving strains to have minor, subtle genetic mutations, akin to how flu varies from year to year. What was a surprise was the giant leap in evolution that occurred with Omicron, which contains 36 mutations in the spike protein and approximately 50 mutations in total. Because of these mutations, the original two-shot mRNA COVID vaccines becomes only 40% effective against symptomatic disease after several months (thankfully a booster shot increases this to ~80%).² But the decreased vaccine protection without a booster, along with relaxation of mitigation measures, brought us to where we are now.

In Chicago, we knew the Omicron variant would move quickly, considering how it moved through South Africa and the United Kingdom. What we didn’t anticipate was that in one week’s time, our hospital would need to add another 100 dedicated COVID ICU beds. Nor did we anticipate the extent that Omicron would affect staffing levels in the same amount of time.

At our hospital, we have eliminated elective surgeries that require a hospital stay, which includes surgeries for cancer. One of my colleagues, Ryan Merkow, MD, a surgical oncologist, remarked recently he had to cancel half of his scheduled surgeries because of a lack of hospital space.³

Dispelling Myths

What is concerning about this current wave is how many unvaccinated are hospitalized. Because Omicron is so infectious and because of lower vaccination rates in younger adults and children, we have a younger group of adults and children admitted with COVID, who had been uninfected by previous surges.

A major myth that makes health care workers so frustrated is the tale that Omicron is milder. Unvaccinated people infected with this variant are seriously ill and are dying. Despite its “mild” label, once a patient is hospitalized, Omicron can be just as severe as its predecessors.⁴ For many, getting vaccinated is the difference between staying at home with some symptoms and being in the ICU.

As of January 10, according to the CDC, although 88% of people over the age of 65 are vaccinated, only 37.5% have gotten boosters which are key to restoring protection against Omicron. And among children, only 54% between 12- and 17-years-old are fully vaccinated, and a mere 17% of children aged 5 to 11 have gotten both of their shots.

Remember the conversations regarding natural immunity? Omicron has muffled that conversation. Those who have been infected with SARS-Co-V2 before can still get infected and very ill with Omicron. So now is the time to get vaccinated.

Transmissibility

We knew SARS-CoV-2 could spread 1 of 2 ways: large virus-carrying droplets that enter through the nose, mouth, and eyes, as well as miniscule airborne droplets of virus that float in the air and travel further than 6 feet. However, prior to Omicron, transmission of these smaller droplets via the air was not as frequent. But with Omicron, while it still travels by larger respiratory droplets, it appears to have more airborne spread.

In late December, The Lancet Regional Health published results of research conducted one month earlier at a designated quarantine hotel in Hong Kong.⁵ The index case was housed in the room across a hallway from the second case, who developed their case 8 days into quarantine. Testing showed the Omicron variant in both cases. Environmental testing of the walls and ceiling suggested airborne spread of the virus in places unreachable by large respiratory droplets.

Now with Omicron, people need to wear high-filtering masks that fit tight against the face, such as a N95, KN-95, or KF-94 if possible. And when removing the mask to eat and drink, one should be in well-ventilated areas, away from others.

People should avoid getting Omicron, regardless of vaccination status. This variant is so infectious that, compared to the Delta variant, people are twice as likely to infect others that live with them. And infecting others leads to a chain of transmission that can close schools, take over hospital beds, and disable or kill the most vulnerable in our communities.

Public and private behavior, and public policy

In July, months before that WHO announced Omicron’s existence, Rella and colleagues reported in Scientific Reports on the outcome of a new model designed to show how a vaccine-resistant strain could rapidly transmit through a highly vaccinated population if transmission mitigation interventions are dropped too soon.⁶

The authors wrote that the success of a vaccine-resistant strain making inroads into a population depends on the obvious – it finds populations with a low rate of vaccination. What is not so obvious, the authors wrote, is that a vaccine-resistant virus does its worst when transmission is not well controlled in a highly vaccinated population. What can prevent a surge like this are social behaviors and public policy that decrease the chain of transmission of SARS-CoV-2, such as vaccination, masking, and testing.

It is people’s behavior, and ineffective public policy, that are so frustrating to us. The WHO’s secretary general warned against relying solely on vaccines in December. “Vaccines alone will not get any country out of this crisis.”

Omicron takes a new mindset. What we were doing before is not protecting now. Unchecked spread is overwhelming our health care systems and putting the vulnerable in our population at risk. The ramification of this unchecked spread reaches everywhere – into the economy, our educational system, and our nation’s mental health.

When the pandemic started, the policies to control its spread rested on local government and public agencies; we all would have been better served had there been a unified, national response to an infectious threat that does not obey municipal or state boundaries.

 The universal sentiment among health care workers is frustration with local and state governments that are either dictating policy that can harm the public we are trying to protect.

As of September, at least 23 state legislatures have passed laws changing a governor’s executive power reach. Many have taken it away. Others are fighting in the courts over mask mandates.

As for when the pandemic will subside, that appears to be up to the public and public policy makers. They will determine how long this will last and how many will die or be disabled before its end.

Health care’s modern-day version of the Greek chorus is growing louder and more persistent. My colleagues and I have long been among them.

In news conferences, journal articles, and podcasts, this chorus is pleading with the public to pay attention to its message: SARs-CoV-2 is not done with us. Omicron can kill; it can infect the vaccinated.

We have found, like everyone else, that Omicron runs on its rules; with Delta, two vaccine shots were able to lower the positivity rate. With Omicron, two shots have not been enough.

The WHO used the word “surprise” in its November announcement that Omicron was a variant of “concern.”

So did Trevor Bedford, a computational biologist and infectious disease scientist at the Fred Hutchinson Cancer Center in Seattle, who said that Omicron “took me and everyone by surprise.”¹ Speaking on KevinMD’s podcast, he told his host that with the degree of immunity in the global population, he was expecting subsequent evolving strains to have minor, subtle genetic mutations, akin to how flu varies from year to year. What was a surprise was the giant leap in evolution that occurred with Omicron, which contains 36 mutations in the spike protein and approximately 50 mutations in total. Because of these mutations, the original two-shot mRNA COVID vaccines becomes only 40% effective against symptomatic disease after several months (thankfully a booster shot increases this to ~80%).² But the decreased vaccine protection without a booster, along with relaxation of mitigation measures, brought us to where we are now.

In Chicago, we knew the Omicron variant would move quickly, considering how it moved through South Africa and the United Kingdom. What we didn’t anticipate was that in one week’s time, our hospital would need to add another 100 dedicated COVID ICU beds. Nor did we anticipate the extent that Omicron would affect staffing levels in the same amount of time.

At our hospital, we have eliminated elective surgeries that require a hospital stay, which includes surgeries for cancer. One of my colleagues, Ryan Merkow, MD, a surgical oncologist, remarked recently he had to cancel half of his scheduled surgeries because of a lack of hospital space.³

Dispelling Myths

What is concerning about this current wave is how many unvaccinated are hospitalized. Because Omicron is so infectious and because of lower vaccination rates in younger adults and children, we have a younger group of adults and children admitted with COVID, who had been uninfected by previous surges.

A major myth that makes health care workers so frustrated is the tale that Omicron is milder. Unvaccinated people infected with this variant are seriously ill and are dying. Despite its “mild” label, once a patient is hospitalized, Omicron can be just as severe as its predecessors.⁴ For many, getting vaccinated is the difference between staying at home with some symptoms and being in the ICU.

As of January 10, according to the CDC, although 88% of people over the age of 65 are vaccinated, only 37.5% have gotten boosters which are key to restoring protection against Omicron. And among children, only 54% between 12- and 17-years-old are fully vaccinated, and a mere 17% of children aged 5 to 11 have gotten both of their shots.

Remember the conversations regarding natural immunity? Omicron has muffled that conversation. Those who have been infected with SARS-Co-V2 before can still get infected and very ill with Omicron. So now is the time to get vaccinated.

Transmissibility

We knew SARS-CoV-2 could spread 1 of 2 ways: large virus-carrying droplets that enter through the nose, mouth, and eyes, as well as miniscule airborne droplets of virus that float in the air and travel further than 6 feet. However, prior to Omicron, transmission of these smaller droplets via the air was not as frequent. But with Omicron, while it still travels by larger respiratory droplets, it appears to have more airborne spread.

In late December, The Lancet Regional Health published results of research conducted one month earlier at a designated quarantine hotel in Hong Kong.⁵ The index case was housed in the room across a hallway from the second case, who developed their case 8 days into quarantine. Testing showed the Omicron variant in both cases. Environmental testing of the walls and ceiling suggested airborne spread of the virus in places unreachable by large respiratory droplets.

Now with Omicron, people need to wear high-filtering masks that fit tight against the face, such as a N95, KN-95, or KF-94 if possible. And when removing the mask to eat and drink, one should be in well-ventilated areas, away from others.

People should avoid getting Omicron, regardless of vaccination status. This variant is so infectious that, compared to the Delta variant, people are twice as likely to infect others that live with them. And infecting others leads to a chain of transmission that can close schools, take over hospital beds, and disable or kill the most vulnerable in our communities.

Public and private behavior, and public policy

In July, months before that WHO announced Omicron’s existence, Rella and colleagues reported in Scientific Reports on the outcome of a new model designed to show how a vaccine-resistant strain could rapidly transmit through a highly vaccinated population if transmission mitigation interventions are dropped too soon.⁶

The authors wrote that the success of a vaccine-resistant strain making inroads into a population depends on the obvious – it finds populations with a low rate of vaccination. What is not so obvious, the authors wrote, is that a vaccine-resistant virus does its worst when transmission is not well controlled in a highly vaccinated population. What can prevent a surge like this are social behaviors and public policy that decrease the chain of transmission of SARS-CoV-2, such as vaccination, masking, and testing.

It is people’s behavior, and ineffective public policy, that are so frustrating to us. The WHO’s secretary general warned against relying solely on vaccines in December. “Vaccines alone will not get any country out of this crisis.”

Omicron takes a new mindset. What we were doing before is not protecting now. Unchecked spread is overwhelming our health care systems and putting the vulnerable in our population at risk. The ramification of this unchecked spread reaches everywhere – into the economy, our educational system, and our nation’s mental health.

When the pandemic started, the policies to control its spread rested on local government and public agencies; we all would have been better served had there been a unified, national response to an infectious threat that does not obey municipal or state boundaries.

 The universal sentiment among health care workers is frustration with local and state governments that are either dictating policy that can harm the public we are trying to protect.

As of September, at least 23 state legislatures have passed laws changing a governor’s executive power reach. Many have taken it away. Others are fighting in the courts over mask mandates.

As for when the pandemic will subside, that appears to be up to the public and public policy makers. They will determine how long this will last and how many will die or be disabled before its end.

Health care’s modern-day version of the Greek chorus is growing louder and more persistent. My colleagues and I have long been among them.

In news conferences, journal articles, and podcasts, this chorus is pleading with the public to pay attention to its message: SARs-CoV-2 is not done with us. Omicron can kill; it can infect the vaccinated.

We have found, like everyone else, that Omicron runs on its rules; with Delta, two vaccine shots were able to lower the positivity rate. With Omicron, two shots have not been enough.

The WHO used the word “surprise” in its November announcement that Omicron was a variant of “concern.”

So did Trevor Bedford, a computational biologist and infectious disease scientist at the Fred Hutchinson Cancer Center in Seattle, who said that Omicron “took me and everyone by surprise.”¹ Speaking on KevinMD’s podcast, he told his host that with the degree of immunity in the global population, he was expecting subsequent evolving strains to have minor, subtle genetic mutations, akin to how flu varies from year to year. What was a surprise was the giant leap in evolution that occurred with Omicron, which contains 36 mutations in the spike protein and approximately 50 mutations in total. Because of these mutations, the original two-shot mRNA COVID vaccines becomes only 40% effective against symptomatic disease after several months (thankfully a booster shot increases this to ~80%).² But the decreased vaccine protection without a booster, along with relaxation of mitigation measures, brought us to where we are now.

In Chicago, we knew the Omicron variant would move quickly, considering how it moved through South Africa and the United Kingdom. What we didn’t anticipate was that in one week’s time, our hospital would need to add another 100 dedicated COVID ICU beds. Nor did we anticipate the extent that Omicron would affect staffing levels in the same amount of time.

At our hospital, we have eliminated elective surgeries that require a hospital stay, which includes surgeries for cancer. One of my colleagues, Ryan Merkow, MD, a surgical oncologist, remarked recently he had to cancel half of his scheduled surgeries because of a lack of hospital space.³

Dispelling Myths

What is concerning about this current wave is how many unvaccinated are hospitalized. Because Omicron is so infectious and because of lower vaccination rates in younger adults and children, we have a younger group of adults and children admitted with COVID, who had been uninfected by previous surges.

A major myth that makes health care workers so frustrated is the tale that Omicron is milder. Unvaccinated people infected with this variant are seriously ill and are dying. Despite its “mild” label, once a patient is hospitalized, Omicron can be just as severe as its predecessors.⁴ For many, getting vaccinated is the difference between staying at home with some symptoms and being in the ICU.

As of January 10, according to the CDC, although 88% of people over the age of 65 are vaccinated, only 37.5% have gotten boosters which are key to restoring protection against Omicron. And among children, only 54% between 12- and 17-years-old are fully vaccinated, and a mere 17% of children aged 5 to 11 have gotten both of their shots.

Remember the conversations regarding natural immunity? Omicron has muffled that conversation. Those who have been infected with SARS-Co-V2 before can still get infected and very ill with Omicron. So now is the time to get vaccinated.

Transmissibility

We knew SARS-CoV-2 could spread 1 of 2 ways: large virus-carrying droplets that enter through the nose, mouth, and eyes, as well as miniscule airborne droplets of virus that float in the air and travel further than 6 feet. However, prior to Omicron, transmission of these smaller droplets via the air was not as frequent. But with Omicron, while it still travels by larger respiratory droplets, it appears to have more airborne spread.

In late December, The Lancet Regional Health published results of research conducted one month earlier at a designated quarantine hotel in Hong Kong.⁵ The index case was housed in the room across a hallway from the second case, who developed their case 8 days into quarantine. Testing showed the Omicron variant in both cases. Environmental testing of the walls and ceiling suggested airborne spread of the virus in places unreachable by large respiratory droplets.

Now with Omicron, people need to wear high-filtering masks that fit tight against the face, such as a N95, KN-95, or KF-94 if possible. And when removing the mask to eat and drink, one should be in well-ventilated areas, away from others.

People should avoid getting Omicron, regardless of vaccination status. This variant is so infectious that, compared to the Delta variant, people are twice as likely to infect others that live with them. And infecting others leads to a chain of transmission that can close schools, take over hospital beds, and disable or kill the most vulnerable in our communities.

Public and private behavior, and public policy

In July, months before that WHO announced Omicron’s existence, Rella and colleagues reported in Scientific Reports on the outcome of a new model designed to show how a vaccine-resistant strain could rapidly transmit through a highly vaccinated population if transmission mitigation interventions are dropped too soon.⁶

The authors wrote that the success of a vaccine-resistant strain making inroads into a population depends on the obvious – it finds populations with a low rate of vaccination. What is not so obvious, the authors wrote, is that a vaccine-resistant virus does its worst when transmission is not well controlled in a highly vaccinated population. What can prevent a surge like this are social behaviors and public policy that decrease the chain of transmission of SARS-CoV-2, such as vaccination, masking, and testing.

It is people’s behavior, and ineffective public policy, that are so frustrating to us. The WHO’s secretary general warned against relying solely on vaccines in December. “Vaccines alone will not get any country out of this crisis.”

Omicron takes a new mindset. What we were doing before is not protecting now. Unchecked spread is overwhelming our health care systems and putting the vulnerable in our population at risk. The ramification of this unchecked spread reaches everywhere – into the economy, our educational system, and our nation’s mental health.

When the pandemic started, the policies to control its spread rested on local government and public agencies; we all would have been better served had there been a unified, national response to an infectious threat that does not obey municipal or state boundaries.

 The universal sentiment among health care workers is frustration with local and state governments that are either dictating policy that can harm the public we are trying to protect.

As of September, at least 23 state legislatures have passed laws changing a governor’s executive power reach. Many have taken it away. Others are fighting in the courts over mask mandates.

As for when the pandemic will subside, that appears to be up to the public and public policy makers. They will determine how long this will last and how many will die or be disabled before its end.

Consider the following clinical scenarios.

Ellen, a 42-year-old married woman, presents to Dr. H’s office with a recent increase in her migraines. She looks sad and worried.

Dr. H. walks into the room, introduces himself, and immediately opens the electronic record to review her medical history forms. Her migraine episodes have increased from once biweekly to 1 to 2 times weekly; with additional less intense headaches on many other days. She uses both a triptan and an over-the-counter medication to control the pain–she gets a limited number of sumatriptan each month and is beginning to escalate her OTC usage. Dr. H. asks her about the intensity and duration of her headaches, reviews her medication use, and questions her about associated symptoms such as nausea or light and sound sensitivity? Ellen responds with yes and no answers. Dr. H. reviews different medication options, prescribes an older preventative medication and renews her sumatriptan.

In the second scenario, Ellen is in Dr. J’s office. When Dr. J enters the doorway to her office, she introduces herself and is welcoming and seated in a less formal manner. Dr. J is making eye contact with Ellen and not looking at her computer.

Instead of asking her questions that require a yes or no reply, she asks Ellen to walk her through her migraine experiences. She learns that the patient has been under much stress with work, and hears about troubling family issues, and that she is worried about her increased number of headaches and decreased functionality. Dr. J says, let’s talk about options. She tells her the first thing is to optimize acute care in order treat the acute attacks effectively. Simply “taking” a medication is insufficient to know whether a patient is taking that medication optimally. She asks Ellen to take her through her process in treating a migraine.

Ellen, Dr. J surmises, has a penchant for treating any sensation associated with a possible approaching headache with OTCs, which needs to be curtailed. Her use of OTCs could be at medication overuse levels thereby contributing to her headaches. Dr. J explains and shows Ellen a simple headache diary. Dr. J then discusses the future: the two of them will develop a plan to control the migraine frequency for the long term. The plan will include ways to control the stressors in Ellen’s life. Dr. J provides Ellen with names of psychologists with expertise in cognitive behavior therapies and relaxation-based treatments; they can help Ellen manage stressors that could be impacting her headaches. Dr. J communicates that migraine management requires a comprehensive approach that can involve behavioral as well as pharmacological therapies to maximize both headache relief and reduce disability. 

Migraine is a brain disease that can often be fueled by behavioral issues. Psychological stress, sleep problems, mood and anxiety issues can transform migraine from episodic to chronic. The operative word here is can. Patients with migraine who learn to better manage stress, employ simple relaxation strategies, and identify and treat comorbid psychiatric issues may show significant improvement. Migraine treatment can require more than one health care professional asheadache specialists, psychologists, perhaps psychiatrists, and sleep specialists may all be involved

Getting migraine under control often cannot be accomplished in just one visit; it can take time, as medications might need to be added or adjusted, sleep, diet, and physical activity modified along with stressors identified and managed. Helping patients optimize their acute treatment regimen is critical so they get quick relief while limiting overuse. Overuse of either prescription or OTC medications can lead to medication overuse headache (MOH). MOH can increase headache frequency and reduce the effectiveness of some preventive medications as well as other therapies. 

All these steps require good communication strategies by the physician and an understanding of the benefit of comprehensive treatment strategies that include behavioral therapies.

Helping motivation to change

Readiness to change will vary with different patients. Some people will be open to treating stress-related issues in an initial session while others will require many sessions in which the physician gently explores these concerns. It is helpful for the physician to ask open-ended questions, helping patients to “tell their stories.” The clinician needs to actively listen and accurately reflect patient’s thoughts and feelings (“it sounds like you…”) Avoiding overinterpretation and occasionally summarizing ensures clear communication. Both patients and physicians have identified high quality communication in the patient-physician relationship to be a key factor in adherence with acute headache medications.

Anxiety is common in migraine sufferers and predicts long-term migraine persistence. Some individuals with high levels of anxiety may overuse immediate relief medications because of worry about getting a migraine. Many migraineurs have a significant amount of fear about any sensation that may herald a migraine. Consequently, some medicate fear, preemptively. Patients also can fear side effects to new medications, thereby reducing their willingness to change existing therapy for a potentially more effective treatment.

Biological rhythms, sleep and coping skills

Managing migraine also includes managing consistent biological rhythms. The literature has shown that chronobiological issues can be a driver of headache frequency and may also contribute to mood and anxiety disorders. Studies have shown that a simple cognitive-behavioral treatment for insomnia has transformed many migraineurs from chronic migraine to episodic migraine. 

Studies have demonstrated that a combination of optimal medication and cognitive behavioral therapy can be very effective. Behavioral therapies increase self-efficacy, a belief that patients have the requisite skills to manage a complicated disorder like migraine. A few sessions of stress management training combined with preventive medications and maximizing acute care options may have significant added value—reducing migraine frequency and related disability and ensuring better disease-coping mechanisms.

Final notes

Migraine is a biobehavioral disorder and it is important for the clinician to evaluate a diverse set of factors and come up with a comprehensive plan. This is particularly important for the patient with high frequency migraine who exhibits stress-related factors and possible psychiatric comorbidities. There are numerous cognitive behavioral therapies incorporating relaxation strategies and stress management techniques that can be very effective in caring for these complicated patients.   

Consider the following clinical scenarios.

Ellen, a 42-year-old married woman, presents to Dr. H’s office with a recent increase in her migraines. She looks sad and worried.

Dr. H. walks into the room, introduces himself, and immediately opens the electronic record to review her medical history forms. Her migraine episodes have increased from once biweekly to 1 to 2 times weekly; with additional less intense headaches on many other days. She uses both a triptan and an over-the-counter medication to control the pain–she gets a limited number of sumatriptan each month and is beginning to escalate her OTC usage. Dr. H. asks her about the intensity and duration of her headaches, reviews her medication use, and questions her about associated symptoms such as nausea or light and sound sensitivity? Ellen responds with yes and no answers. Dr. H. reviews different medication options, prescribes an older preventative medication and renews her sumatriptan.

In the second scenario, Ellen is in Dr. J’s office. When Dr. J enters the doorway to her office, she introduces herself and is welcoming and seated in a less formal manner. Dr. J is making eye contact with Ellen and not looking at her computer.

Instead of asking her questions that require a yes or no reply, she asks Ellen to walk her through her migraine experiences. She learns that the patient has been under much stress with work, and hears about troubling family issues, and that she is worried about her increased number of headaches and decreased functionality. Dr. J says, let’s talk about options. She tells her the first thing is to optimize acute care in order treat the acute attacks effectively. Simply “taking” a medication is insufficient to know whether a patient is taking that medication optimally. She asks Ellen to take her through her process in treating a migraine.

Ellen, Dr. J surmises, has a penchant for treating any sensation associated with a possible approaching headache with OTCs, which needs to be curtailed. Her use of OTCs could be at medication overuse levels thereby contributing to her headaches. Dr. J explains and shows Ellen a simple headache diary. Dr. J then discusses the future: the two of them will develop a plan to control the migraine frequency for the long term. The plan will include ways to control the stressors in Ellen’s life. Dr. J provides Ellen with names of psychologists with expertise in cognitive behavior therapies and relaxation-based treatments; they can help Ellen manage stressors that could be impacting her headaches. Dr. J communicates that migraine management requires a comprehensive approach that can involve behavioral as well as pharmacological therapies to maximize both headache relief and reduce disability. 

Migraine is a brain disease that can often be fueled by behavioral issues. Psychological stress, sleep problems, mood and anxiety issues can transform migraine from episodic to chronic. The operative word here is can. Patients with migraine who learn to better manage stress, employ simple relaxation strategies, and identify and treat comorbid psychiatric issues may show significant improvement. Migraine treatment can require more than one health care professional asheadache specialists, psychologists, perhaps psychiatrists, and sleep specialists may all be involved

Getting migraine under control often cannot be accomplished in just one visit; it can take time, as medications might need to be added or adjusted, sleep, diet, and physical activity modified along with stressors identified and managed. Helping patients optimize their acute treatment regimen is critical so they get quick relief while limiting overuse. Overuse of either prescription or OTC medications can lead to medication overuse headache (MOH). MOH can increase headache frequency and reduce the effectiveness of some preventive medications as well as other therapies. 

All these steps require good communication strategies by the physician and an understanding of the benefit of comprehensive treatment strategies that include behavioral therapies.

Helping motivation to change

Readiness to change will vary with different patients. Some people will be open to treating stress-related issues in an initial session while others will require many sessions in which the physician gently explores these concerns. It is helpful for the physician to ask open-ended questions, helping patients to “tell their stories.” The clinician needs to actively listen and accurately reflect patient’s thoughts and feelings (“it sounds like you…”) Avoiding overinterpretation and occasionally summarizing ensures clear communication. Both patients and physicians have identified high quality communication in the patient-physician relationship to be a key factor in adherence with acute headache medications.

Anxiety is common in migraine sufferers and predicts long-term migraine persistence. Some individuals with high levels of anxiety may overuse immediate relief medications because of worry about getting a migraine. Many migraineurs have a significant amount of fear about any sensation that may herald a migraine. Consequently, some medicate fear, preemptively. Patients also can fear side effects to new medications, thereby reducing their willingness to change existing therapy for a potentially more effective treatment.

Biological rhythms, sleep and coping skills

Managing migraine also includes managing consistent biological rhythms. The literature has shown that chronobiological issues can be a driver of headache frequency and may also contribute to mood and anxiety disorders. Studies have shown that a simple cognitive-behavioral treatment for insomnia has transformed many migraineurs from chronic migraine to episodic migraine. 

Studies have demonstrated that a combination of optimal medication and cognitive behavioral therapy can be very effective. Behavioral therapies increase self-efficacy, a belief that patients have the requisite skills to manage a complicated disorder like migraine. A few sessions of stress management training combined with preventive medications and maximizing acute care options may have significant added value—reducing migraine frequency and related disability and ensuring better disease-coping mechanisms.

Final notes

Migraine is a biobehavioral disorder and it is important for the clinician to evaluate a diverse set of factors and come up with a comprehensive plan. This is particularly important for the patient with high frequency migraine who exhibits stress-related factors and possible psychiatric comorbidities. There are numerous cognitive behavioral therapies incorporating relaxation strategies and stress management techniques that can be very effective in caring for these complicated patients.   

Consider the following clinical scenarios.

Ellen, a 42-year-old married woman, presents to Dr. H’s office with a recent increase in her migraines. She looks sad and worried.

Dr. H. walks into the room, introduces himself, and immediately opens the electronic record to review her medical history forms. Her migraine episodes have increased from once biweekly to 1 to 2 times weekly; with additional less intense headaches on many other days. She uses both a triptan and an over-the-counter medication to control the pain–she gets a limited number of sumatriptan each month and is beginning to escalate her OTC usage. Dr. H. asks her about the intensity and duration of her headaches, reviews her medication use, and questions her about associated symptoms such as nausea or light and sound sensitivity? Ellen responds with yes and no answers. Dr. H. reviews different medication options, prescribes an older preventative medication and renews her sumatriptan.

In the second scenario, Ellen is in Dr. J’s office. When Dr. J enters the doorway to her office, she introduces herself and is welcoming and seated in a less formal manner. Dr. J is making eye contact with Ellen and not looking at her computer.

Instead of asking her questions that require a yes or no reply, she asks Ellen to walk her through her migraine experiences. She learns that the patient has been under much stress with work, and hears about troubling family issues, and that she is worried about her increased number of headaches and decreased functionality. Dr. J says, let’s talk about options. She tells her the first thing is to optimize acute care in order treat the acute attacks effectively. Simply “taking” a medication is insufficient to know whether a patient is taking that medication optimally. She asks Ellen to take her through her process in treating a migraine.

Ellen, Dr. J surmises, has a penchant for treating any sensation associated with a possible approaching headache with OTCs, which needs to be curtailed. Her use of OTCs could be at medication overuse levels thereby contributing to her headaches. Dr. J explains and shows Ellen a simple headache diary. Dr. J then discusses the future: the two of them will develop a plan to control the migraine frequency for the long term. The plan will include ways to control the stressors in Ellen’s life. Dr. J provides Ellen with names of psychologists with expertise in cognitive behavior therapies and relaxation-based treatments; they can help Ellen manage stressors that could be impacting her headaches. Dr. J communicates that migraine management requires a comprehensive approach that can involve behavioral as well as pharmacological therapies to maximize both headache relief and reduce disability. 

Migraine is a brain disease that can often be fueled by behavioral issues. Psychological stress, sleep problems, mood and anxiety issues can transform migraine from episodic to chronic. The operative word here is can. Patients with migraine who learn to better manage stress, employ simple relaxation strategies, and identify and treat comorbid psychiatric issues may show significant improvement. Migraine treatment can require more than one health care professional asheadache specialists, psychologists, perhaps psychiatrists, and sleep specialists may all be involved

Getting migraine under control often cannot be accomplished in just one visit; it can take time, as medications might need to be added or adjusted, sleep, diet, and physical activity modified along with stressors identified and managed. Helping patients optimize their acute treatment regimen is critical so they get quick relief while limiting overuse. Overuse of either prescription or OTC medications can lead to medication overuse headache (MOH). MOH can increase headache frequency and reduce the effectiveness of some preventive medications as well as other therapies. 

All these steps require good communication strategies by the physician and an understanding of the benefit of comprehensive treatment strategies that include behavioral therapies.

Helping motivation to change

Readiness to change will vary with different patients. Some people will be open to treating stress-related issues in an initial session while others will require many sessions in which the physician gently explores these concerns. It is helpful for the physician to ask open-ended questions, helping patients to “tell their stories.” The clinician needs to actively listen and accurately reflect patient’s thoughts and feelings (“it sounds like you…”) Avoiding overinterpretation and occasionally summarizing ensures clear communication. Both patients and physicians have identified high quality communication in the patient-physician relationship to be a key factor in adherence with acute headache medications.

Anxiety is common in migraine sufferers and predicts long-term migraine persistence. Some individuals with high levels of anxiety may overuse immediate relief medications because of worry about getting a migraine. Many migraineurs have a significant amount of fear about any sensation that may herald a migraine. Consequently, some medicate fear, preemptively. Patients also can fear side effects to new medications, thereby reducing their willingness to change existing therapy for a potentially more effective treatment.

Biological rhythms, sleep and coping skills

Managing migraine also includes managing consistent biological rhythms. The literature has shown that chronobiological issues can be a driver of headache frequency and may also contribute to mood and anxiety disorders. Studies have shown that a simple cognitive-behavioral treatment for insomnia has transformed many migraineurs from chronic migraine to episodic migraine. 

Studies have demonstrated that a combination of optimal medication and cognitive behavioral therapy can be very effective. Behavioral therapies increase self-efficacy, a belief that patients have the requisite skills to manage a complicated disorder like migraine. A few sessions of stress management training combined with preventive medications and maximizing acute care options may have significant added value—reducing migraine frequency and related disability and ensuring better disease-coping mechanisms.

Final notes

Migraine is a biobehavioral disorder and it is important for the clinician to evaluate a diverse set of factors and come up with a comprehensive plan. This is particularly important for the patient with high frequency migraine who exhibits stress-related factors and possible psychiatric comorbidities. There are numerous cognitive behavioral therapies incorporating relaxation strategies and stress management techniques that can be very effective in caring for these complicated patients.   

What the Future May Hold for Covid-19 Survivors

More than 3 million Americans¹ have been hospitalized with Covid-19, and 770,000 of them have died. ² As of this writing,  49,000 Americans are hospitalized, with 12,000 remaining in intensive care units.³ With growing numbers of patients being discharged from extensive stays in the ICU for severe Covid, it remains to be seen what the long-term impact will be on these patients, their families and on society writ large.

And these are just the patients with severe Covid: those who were never hospitalized are also showing deleterious effects from the effects of their illness.

Covid in the ICU

 What we know is that prior to Covid, 10% of all patients were admitted to ICU with acute respiratory distress syndrome⁴ (ARDS), despite receiving such life-saving measures as mechanical ventilation, medication, and supportive nutrition. Those who do survive face a long journey.⁴ Besides the specific respiratory recovery needed in those with ARDS, patients who have spent time in the ICU can develop multiple non-respiratory complications, including muscle wasting, generalized weakness, and delirium. The physical, cognitive, and psychological impairments that follow an ICU stay are termed postintensive care syndrome (PICS). PICS is an underrecognized phenomenon that describes the immense complications of an ICU stay for any reason. Recognition of this entity, and education of patients, is particularly important now as we face an ongoing pandemic which is creating a burgeoning number of ICU graduates.

PICS

Cognitive dysfunction is one hallmark of PICS. Delirium is a common complication of any hospitalization, with critically ill patients particularly susceptible given the severity of their illness and their exposure to medications such as sedatives. However, persistent global cognitive impairment is unique to PICS. Up to 40% ⁴ of ICU survivors have been found to have cognitive test results similar to those with moderate traumatic brain injury 3 months after discharge;  approximately 34% were still affected at 1 year. Similar findings were seen in a different study of ARDS patients.⁵ Hopkins et al. found that in these patients the rate of neurocognitive deficit persisted in 47% of patients at their 2-year follow-up. Patients describe being unable to re-enter their prior lives, troubled by difficulties with complex thinking and activities of daily living.

The second aspect of PICS is its psychological component. In the Hopkins study,⁵  23% ultimately reported persistent symptoms of depression and/or anxiety two years afterwards. Some patients have described intrusive distorted memories from their time in ICU; one patient detailed a recurring memory of an hallucination in which the nurses were transformed into demons hovering over his bed. Others have described feelings akin to depression, anxiety, and posttraumatic stress syndrome (PTSD).

The final component of PICS is physical impairment. Those who are critically ill commonly suffer intensive care unit-acquired weakness,⁶ which is a term to describe generalized limb and diaphragmatic weakness with no other medical cause. Risk factors for this entity include sepsis, multi-organ failure, mechanical ventilation, hyperglycemia, extensive immobilization, and exposure to steroids and neuromuscular blocking agents. ICU-acquired weakness can resolve within weeks to months but in some studies can persist for years. It has been observed that survivors of ARDS experience persistent physical limitations, even 5 years later.

Covid in the ICU

Estimates of the incidence of PICS due to Covid are evolving. A report on 1700 Covid hospitalized patients in Wuhan, China demonstrated a large prevalence of residual symptoms at 6 months. The most common symptoms were fatigue and weakness (63%), insomnia (26%), and anxiety or depression (23%).⁷ Furthermore, one-fourth to one-third of those with severe illness fell below the lower limit of normal for a 6-minute walk test. An Italian study demonstrated decreased global quality of life indices for Covid ICU survivors⁸ 3 months from discharge, particularly with mobility, eating, and resuming usual activities. In a Michigan observational⁹ study, which included all hospitalized patients with Covid including those never in ICU, one-third of respondents said they continued to cough or have shortness of breath. Only one-fourth had returned to work, with many of them having to modify activities or reduce hours due to their health. Nearly half reported being negatively emotionally impacted by their health issues. Last, a single French hospital¹⁰ discovered that Covid patients 4 months after hospital discharge experienced numerous, persistent symptoms. 38% of patients confirmed some form of cognitive impairment, with 17% reporting memory difficulties, 10% mental slowness, and 10% concentration problems. Of patients who were intubated, one-third still reported subjective dyspnea. Nearly a third still struggled with weakness.

As more centers track the progress of their ICU graduates over time, we can better understand the profound impact of critical illness on our Covid patients and better educate our patients and families on what to expect. One might be able to gain some clues from what is known regarding the prior coronavirus epidemics, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). In these diseases, a meta-analysis showed significant rates of      lung function abnormalities,¹¹ physical deconditioning, and mental health disorders during the 6 months after discharge. It might be that the impact of SARS-CoV2 is even more profound on survivors; additional studies need to be done.

Additional issues

What is particularly unique to Covid is the prevalence of long-term symptoms in those who were never hospitalized for Covid. Recent estimates of non-hospitalized patients who had Covid are showing at least 25% of them have had long-lasting effects, including stomach pain and respiratory issues.¹² We are continuing to learn more about what is described as “long-haul syndrome.” It has been described in both hospitalized and non-hospitalized patients, and therefore it can be hard to distinguish which symptoms are attributable to long-term effects of Covid infection versus the critical illness/PICS itself. These long-haul symptoms range from persistent lack of smell and taste, cognitive dysfunction, fatigue, decreased exercise endurance, and an increase in mental health disorders. The prognosis and spectrum of disease, as well as treatment, have yet to be determined, and the NIH is initiating a multicenter research study, RECOVER, to better characterize this syndrome.¹³  Patients who are interested in enrolling can fill out an interest form at recoverCovid.org.

Financially 1/3¹⁴ of patients were impacted by their hospitalization for Covid, with nearly 10% using most or all their savings, despite many being covered by cost-sharing waivers for Covid care. A study reviewing Medicare data noted that the mean cost of a hospitalization for Covid is $21,752,¹⁵ increasing to nearly $50,000 if mechanical ventilation is needed. This does not account for the cost of rehabilitative care, as 40%¹⁶ of patients are discharged either to home with additional services or to other facilities (skilled nursing facility, hospice). As insurance companies increasingly lift the cost-sharing waivers and patients assume more responsibility for paying more of this cost, the financial burden on individual patients will increase. Furthermore, given a prolonged course of mental and physical disabilities after severe Covid, patients may lose their ability to return to work, their medical insurance, or their ability to provide childcare, further compounding their family’s financial woes.

Conclusion

The long-term effects of hospitalization from Covid argues further for continued work on increasing the vaccination rate of our population. Even with Delta variant, vaccines decrease the risk of hospitalization and death by more than a factor of 10.¹⁷ The profound medical and financial effects of severe Covid, and the repercussions on their family, should compel us as health care practitioners to inform those who are vaccine hesitant and to inform patients that they are eligible for vaccine boosters. The combination of colder weather and loosening of social distancing has already led to another surge of Covid infections and makes expedient vaccination the priority.

What the Future May Hold for Covid-19 Survivors

More than 3 million Americans¹ have been hospitalized with Covid-19, and 770,000 of them have died. ² As of this writing,  49,000 Americans are hospitalized, with 12,000 remaining in intensive care units.³ With growing numbers of patients being discharged from extensive stays in the ICU for severe Covid, it remains to be seen what the long-term impact will be on these patients, their families and on society writ large.

And these are just the patients with severe Covid: those who were never hospitalized are also showing deleterious effects from the effects of their illness.

Covid in the ICU

 What we know is that prior to Covid, 10% of all patients were admitted to ICU with acute respiratory distress syndrome⁴ (ARDS), despite receiving such life-saving measures as mechanical ventilation, medication, and supportive nutrition. Those who do survive face a long journey.⁴ Besides the specific respiratory recovery needed in those with ARDS, patients who have spent time in the ICU can develop multiple non-respiratory complications, including muscle wasting, generalized weakness, and delirium. The physical, cognitive, and psychological impairments that follow an ICU stay are termed postintensive care syndrome (PICS). PICS is an underrecognized phenomenon that describes the immense complications of an ICU stay for any reason. Recognition of this entity, and education of patients, is particularly important now as we face an ongoing pandemic which is creating a burgeoning number of ICU graduates.

PICS

Cognitive dysfunction is one hallmark of PICS. Delirium is a common complication of any hospitalization, with critically ill patients particularly susceptible given the severity of their illness and their exposure to medications such as sedatives. However, persistent global cognitive impairment is unique to PICS. Up to 40% ⁴ of ICU survivors have been found to have cognitive test results similar to those with moderate traumatic brain injury 3 months after discharge;  approximately 34% were still affected at 1 year. Similar findings were seen in a different study of ARDS patients.⁵ Hopkins et al. found that in these patients the rate of neurocognitive deficit persisted in 47% of patients at their 2-year follow-up. Patients describe being unable to re-enter their prior lives, troubled by difficulties with complex thinking and activities of daily living.

The second aspect of PICS is its psychological component. In the Hopkins study,⁵  23% ultimately reported persistent symptoms of depression and/or anxiety two years afterwards. Some patients have described intrusive distorted memories from their time in ICU; one patient detailed a recurring memory of an hallucination in which the nurses were transformed into demons hovering over his bed. Others have described feelings akin to depression, anxiety, and posttraumatic stress syndrome (PTSD).

The final component of PICS is physical impairment. Those who are critically ill commonly suffer intensive care unit-acquired weakness,⁶ which is a term to describe generalized limb and diaphragmatic weakness with no other medical cause. Risk factors for this entity include sepsis, multi-organ failure, mechanical ventilation, hyperglycemia, extensive immobilization, and exposure to steroids and neuromuscular blocking agents. ICU-acquired weakness can resolve within weeks to months but in some studies can persist for years. It has been observed that survivors of ARDS experience persistent physical limitations, even 5 years later.

Covid in the ICU