Kevin Kunzmann

Lisabeth Mackall Bonafede was becoming undone, which previously seemed impossible.

A mother of 9, a longtime inpatient rehab manager at Regions Hospital in St. Paul and a stage IV breast cancer survivor, Mackall Bonefede rejects the notion that life is for anything other than living to the fullest capacity. She revels in multitasking. She’s a competitive dragon boat racer. She bought a farm before settling down and built her own chicken coops. Over the span of a 6-month chemotherapy regimen, she missed 7 days of work. “Who cares?” she said about her post-chemo recovery. “Pain is pain.”

But now she was failing—at simple tasks, no less. Work projects were falling through the cracks. Her memory was unreliable. And she was tired. At lunchtime, she would close her office door, turn off the light, roll out a yoga mat and nap through her break. She would go back to bed when she got home from her hour-long commute. She was missing her designated family time, her morning workout routine. Her ears kept ringing.

Mackall Bonafede believed it was a brain tumor. She made an appointment for a computerized tomography (CT) scan through the hospital’s oncology department. The good news: no tumor. The bad news: even the oncologists didn’t know what was wrong with her.

This was February 2021. In March, her mother called about an interview former National Institute of Allergic and Infectious Disease (NIAID) Director Anthony Fauci, MD, recently gave on the signs and symptoms of post-acute sequelae of COVID-19 (PASC), or popularly known as “long COVID-19.”

 Mackall Bonefede read the half-dozen known symptoms. She had all of them.

She and her daughter tested positive for COVID-19 in November 2020 and went through a mild acute illness for approximately a week before recovering and resuming life. More than 100 days later, she was breaking down. 

A referral to a specialist at the Mayo Clinic accelerated her worries. They confirmed she met the criteria for PASC and asked she take 6-8 weeks off work for rest; they were worried she could do irreparable damage to her heart while in a compromised state. She went to the Mayo campus’ chronic fatigue rehabilitation clinic, where she underwent more testing in 3 days than she ever had in her life: blood draws, overnight heart telemetry, numerous scans and stress tests.

She failed on a treadmill after 3 minutes of running. Her oxygen was dropping; her lung and heart capacities were low; her leave from work extended to until June, then until August. She never went back. Today she has been a patient with long COVID-19 for 28 months.

“This is not my life,” Mackall Bonefede told 

. “This is a fraction of my life. And no one knows what to do about it.”

Long COVID-19, today also known as post-COVID-19 condition (PCC), was still an emerging area of concern when Mackall Bonefede listened to Fauci’s statement in early 2021.

A longitudinal prospective cohort research letter published in 

 in February 2021 assessed longer-term sequelae in patients previously diagnosed with COVID-19.

 The investigators observed fatigue, loss of smell or taste, and brain fog as persistent symptoms in some patients after a mean 6 months. About 30% reported having worse health-related quality of life to that day.

“With 57.8 million (COVID-19) cases worldwide, even a small incidence of long-term debility could have enormous health and economic consequences,” investigators wrote at the time.

Today, the World Health Organization (WHO) defines PCC as a “continuation or development of new symptoms 3 months after initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation.” Common symptoms are fatigue, shortness of breath, and cognitive dysfunction—though they acknowledged more than 200 different symptoms being reported as of December 2022.

Anywhere from 10-20% of people infected with SARS-CoV-2 may develop symptoms of PCC. Though it is perpetually underreported, the WHO has confirmed more than 761 million global cases of COVID-19 as of last week.

 There is no accurate estimation for how many patients have or will develop long COVID-19.

Similarly to acute COVID-19 disease severity, investigators have begun to correlate demographic and clinical risk factors with increased likelihood of developing long COVID-19. Just last week, a meta-analysis from UK investigators showed female sex (odds ratio [OR], 1.56; 95% CI, 1.41 – 1.73), age ≥40 years (OR, 1.21; 95% CI, 1.11 – 1.33) BMI ≥30 (OR, 1.15; 95% CI, 1.08 – 1.23) and smoking status (OR, 1.10; 95% CI, 1.07 – 1.13) were all estimated risk factors for developing PCC.

Investigators additionally observed patients previously hospitalized or requiring intensive care unit admission for COVID-19 were at a more than 2-fold greater risk of developing long COVID-19. Baseline comorbidities including anxiety/depression, asthma, COPD, diabetes, immunosuppression and ischemic heart disease were also considered key risk factors, where as a 2-dose regimen of a COVID-19 vaccine was associated with a 43% reduced risk of PCC (OR, 0.57; 95% CI, 0.43 – 0.76).

Though a comprehensive understanding of long COVID-19 still eludes investigators, it’s come to be understood that it’s a rather unique phenomenon. Donald Alcendor, PhD, MS, associate professor of cancer biology at Meharry Medical College, and adjunct associate professor of pathology, microbiology and immunology at Vanderbilt University School of Medicine, explained that COVID-19 is among the “most rare viral infections” in how it may affect patients for years without the characteristics of a long-term infection.

“For a virus to do this, when there's no evidence of a latent infection in a person, that is something that is quite strange,” Alcendor told 

. He compared COVID-19 to another class of viruses: herpes infection, of which there are 8 different subtypes that can infect humans.

“What you have is a reactivation and a latency phase with those infections, meaning that the virus goes dormant and then there is some kind of stimuli that reactivates the viral genome and results in virus replication, and then you have clinical disease that follows,” Alcendor explained. “But again, it seems as though these (COVID-19) viruses, they don't go through a latency and reactivation period like the herpes virus family.”

Because long COVID-19 is not driven by viral replication, available and proven COVID-19 antiviral therapies like nirmatrelvir/ritonavir (Paxlovid) may not be helpful to patients beyond the acute infection stage in reducing the burden of chronic conditions. A persistent hypothesis in the long COVID-19 pathology is that residual virus is “constantly stimulating the immune system,” Alcendor explained.

“There's another issue with long COVID-19, in that the immune system is somehow disrupted or dysfunctional, and it can lead to the reactivation of other viruses that can cause symptoms associated with the disease as well,” he added.

There’s also a great deal of consideration as to how gut bacteria and cardiovascular system are influenced by COVID-19; Alcendor explained that gut dysbiosis could result in the symptomology of long COVID-19, while the acute microvascular dysfunction observed in infected patients can contribute to poorer long-term heart health. To no surprise, patients like Mackall Bonefede are frequenting gastroenterologists and cardiologists years after their initial infection.

The concept of curative strategies for long COVID-19 are not feasible so as long as these various means of disease pathology and exacerbation are being untangled, Alcendor explained. Rather, treatments deliberately targeting symptoms are currently needed.

Dina Liptsen was on her way to an acupuncture therapy session when she spoke with 

. The 28-year-old from Denver has been seeing the acupuncturist since November; her review after about 5 months is lukewarm at best.

“There are some days where I come out of it and I just feel a lot better, and I feel like my energy's back and I've mellowed out a little bit,” Liptsen said. “But I am not tracking any long-term improvements to my condition. I'm not really less tired. I'm not less brain foggy. I'm not really sure what acupuncture is doing.”

Liptsen tested positive for COVID-19 in August 2022. Like Mackall Bonefede, she dealt with mild symptoms for about 1 week, recovered, and resumed normal life. And like Mackall Bonefede, she considers herself an athlete—a very frequent runner. She began running again in December and found herself maxing out at about 2.5 miles. Over the span of 6 weeks, her stamina faltered; by the New Year, she couldn’t finish her warmup lap.

And again like Mackall Bonefide, her long COVID-19 diagnosis came by elimination of other concerns with a physician. Today she finds herself frequently exhausted, aching, and dealing with brain fog—her “big 3 symptoms.”

So yes, acupuncture is currently part of her regimen. A child to 2 former Soviet Union-based physicians, Liptsen acknowledges her embrace of combined Western medicine and Eastern healing practices—it was her own family that recommended an acupuncturist when her long COVID-19 symptoms began to manifest. She’s willing to try nearly anything to alleviate her symptoms; it’s just that so few fruitful options exist.

Liptsen and Mackall Bonafede are members of the 

, a UK-based registered charity that also hosts social media forums and programs for its users to engage with, commiserate with and help fellow patients with long COVID-19. It hosts nearly 60,000 members whom on the daily discuss their challenges, remedies—both over-the-counter and holistic—and progress.

Mackall Bonafede estimated that each member of the support group has tried at least 20 different forms of therapy for their long COVID-19; Liptsen likened it to “throwing darts at a wall.”

“People are using antihistamines or anti-inflammatories,” she said. “People are using stimulants to treat brain fog. I find that I’m on a lot more caffeine than I used to be to get through the day. If I can generalize about what I’m reading in my support group, we feel pretty helpless. There’s not a lot available to us right now.”

Liptsen has observed that many fellow patients have anxiety about pursuing follow-up care or referrals through their physicians; though long COVID-19 is a defined disease and an applicable cause of disability in the US, guidance through the treatment process is lacking for caregivers, and they may push back on patients’ requests. She circulated a small guide she drafted for other patients that helps them navigate the long COVID-19 discussion with their physicians—it very well should be a patient-led discussion as experts continue to work to understand it all.

“I think that we are going to start seeing a lot more research and more options for people with long COVID,” Liptsen said. “But…it's going to be a struggle to get there. We can't expect these things to pop up overnight, even with the entirety of the world fixated on it and working on it.”

For what it’s worth, many health systems did manage to create relevant long COVID-19 care teams—even in some cases, overnight.

The Northwestern Medicine Comprehensive COVID Center did not take its task lightly when launching in September 2020. The program launched in the heat of the pandemic as a consortium of 12 relevant specialties dedicated to the fallout of COVID-19; very few health crises warrant the collaboration of pulmonologists, neurologists, cardiologists and others, but the multisystemic impact of COVID-19 is a special exception.

Marc A. Sala, MD, co-director of the center, told 

 that much of the consortium’s earliest work involved anticipation of COVID-19’s long-term effects.

“You would have people coming out of the ICU after a really debilitating illness—some spending time on life support—and trying to get back on their feet at all if they had survived,” Sala said. “There were large groups coming through with a lot of rehabilitative needs.”

But more and more, patients were presenting with persistent symptoms—despite having never been hospitalized for their infection. They lacked the acute-stage pneumonia or critical pulmonary distress that plagued most rehabilitation patients, but had new troubles with breathing and cognition all the same. They were, in some ways, the more difficult patients to treat.

Now, in the “post-vaccine era” of early 2023, this latter patient population is the one most frequenting Sala’s center. Vaccines have helped curbed acute hospitalizations and ICU admissions, but PCC rages practically all the same. “We don't often see people come in having been on life support for four months,” Sala said. “Now instead, we have a group of individuals who were…very active physically in a lot of cases, but got COVID-19 and now are at a baseline that’s very far from (their standard).”

Like many PCC clinics, Sala and colleagues currently seek to better patients’ symptoms, quality of life and capabilities—in lieu of resolving the long COVID-19 altogether. The individual patient’s treatment goal may be clearly defined by clinical standards, or it may be subjective; the latter patients are generally seeking the ability to resume normal living and their profession, Sala said.

“A lot of these individuals report that they really have to adapt and time their exertion, energy and focus around their symptoms,” Sala said. “You’ll have people who will have to take a midday nap to get back to being with their families or in work meetings.”

Clinical goals at PCC clinics generally vary by the patient’s impacted systems. As a pulmonologist, Sala emphasized the need to gauge structural changes to patients’ lung tissue and monitor risk of developing pulmonary fibrosis—not that there’s much capability in preventing this development in patients with long COVID-19.

Regarding pharmacotherapy, Sala was not surprised to hear Mackall Bonafede’s 20-therapies-per-patient estimate.

“I think that’s par for the course, unfortunately,” he said. “I would say that the evidence base for any of those (treatments) is probably dismal.” Randomized trial data assessing even the most common over-the-counter drugs for long COVID-19 symptoms are minimal; the FDA is not close to approving any established agent for the treatment of PCC; and many popular regimens adopted by patients, including invasive blood filtering and blood thinners, involve “very unfounded biology,” Sala said.

From the perspective of treating eligible patients with pulmonary symptoms of long COVID-19, Sala did point to the advantage of “repurposed ideas” of care, like glucocorticoids or steroids for patients at risk of fibrotic lung complications. But nothing yet exists solely for the case of a patient with PCC-related respiratory disease.

Whatever the future of treating long COVID-19 entails, it will require a highly individualized approach.

“What we found is that while most people need to see more than 1 specialist to deal with their symptoms, not everyone needs to see all the specialists,” Sala said. “When we look back at our data, we found that most people saw 2 more specialists, and they were rarely the same one.”

The 3 most commonly referred, though, were pulmonologists, neurologists, and cardiologists.

Laurie Goldberg struggles to accept the idea of hope.

The 55-year-old St. Louis native was once a companion to the elderly—helping them drive to doctor’s appointments, providing them help with errands, providing them company and comfort. She is now often bed-bound herself, in frequent need of help with simplistic chores.

she experiences some extent of fatigue, nausea, lightheadedness and shortness of breath daily. A die-hard St. Louis Cardinals fan, she now finds the game broadcast to be a sensory overload. She describes her physical exertions as “like walking through mud and with cement in my veins.” Like Sala described other patients, she strategizes and times daily tasks like bathing and cooking to ensure she has enough energy to complete them.

Like Liptsen, Goldberg tested positive for COVID-19 in August 2022. Due to comorbities including overweight, she was put on a 5-day Paxlovid regimen to reduce her risk of severe disease. She recovered from the acute disease, but couldn’t evade long COVID-19.

There is a certain cruelty to seemingly untreatable fatigue. The tiredness that Goldberg and others experience is overwhelming not only to their bodies, but their minds. Goldberg describes the recommendations of her fellow patients on the Long Covid Support threads defeatedly—“We are just constantly grasping at straws,” she said—and notes how hard it is to do something as simple as take a walk outside to clear her head.

Depression and anxiety are leading symptoms of PCC, and not just because of its cognitive and neurological effects. Some patients have been working without clear guidance for up to 3 years now; they don’t see an end in sight. In fact, many see a more bleak future, if anything. Goldberg noted the Biden administration’s intent to disband the COVID-19 Response Team at the conclusion of the pandemic’s public health emergency this May.

“I don’t think this a priority at all,” Goldberg said. “It’s not like (earlier) when everyone was dying from COVID-19 and they were rushing through emergency vaccines. I think a lot of people don’t believe it. I feel like my life has changed overnight, and I just don’t have a lot of hope.”

Not one of Mackall Bonefede, Liptsen, nor Goldberg expressed hope their long COVID-19 would be cured—whether because they didn’t believe it to be possible or if it just wasn’t as important as feeling symptomatically better. They each described a desire to resume normalcy at work, their social lives, in their exercise and hobbies. The holistic and over-the-counter tips they trade across their forums are short-term salves to a chronic condition that is currently undermet by the standards of the US pharmaceutical development and health benefit industries.

But there are developments in research that could eventually bring them hope.

As described by Alcendor, long COVID-19 is heterogenous, but research has highlighted its impact on the immune system and the gut microbiome as key drivers of disease. Teams including the Palmer Lab at the University of Colorado Denver Anschutz Medical Campus are characterizing the disease further.

The laboratory recently published research showing up to 100-fold greater counts of cytotoxic CD8 T cells in patients with PCC versus former COVID-19 patients who fully recovered. The team also identified a negative correlation between the frequency of COVID-19-targeting T cells from blood samples and pulmonary function in patients.

In a statement regarding the findings, Brent Palmer, PhD, also highlighted recent discoveries into the correlation between gut microbiome and elevated inflammation blood markers in patients with PCC.

“What we hypothesize is that there’s residual virus somewhere in the body, but it’s not detected by a nasal swab,” Palmer said. “It has been shown that individuals who died of severe acute COVID had virus all over their body. When they do autopsies on these individuals, they can find virus in the brain, the kidney, the lung, and the gut.”

Study coauthor Kate Littlefield, BS, research services senior professional in the Palmer Lab, told 

 that long COVID-19 needs to be understood as an “umbrella term” for various physiologies. As such, their team’s investigations into it are variable—from lingering virus in reservoir tissue, to the gut microbiome, to scarring in the lung tissue, and more.

A number of factors may predetermine how PCC persists in a patient—from acute disease severity, to variant type of SARS-CoV-2 at infection, to patients’ vaccination status and treatment for acute COVID-19. Littlefield and colleagues are identifying potential subpopulations based on factors such as these, as well inflammatory levels in the blood and stool that may insinuate reservoirs of COVID-19 still in the body, and how those locations result in the symptoms patients have.

Though Littlefield acknowledged long COVID-19 research has fixed on symptom relief strategies, previous breakthroughs in treating the viral reservoirs of patients with HIV elucidate the potential of targeted antiviral therapies to help provide more long-term relief in patients.

“I wouldn't say that that's the route of curing,” Littlefield said. “But at least there's some hope for individuals, if that is what's causing their long-term symptoms, that this is a route that we already have a wide variety and good knowledge of these antivirals that could be used.”

Before pharmaceuticuals can be researched and advanced though, science has ground to make up on PCC diagnostics. Littlefield noted long COVID-19 is still a “disease of exclusion”—a condition that patients are often self-determining. Based on their team’s research, they would be interested to see FDA-approved assays that seek out virus-specific T cells to confirm COVID-19 reservoirs that may be treated with appropriate antivirals.

All of these advances may be years away, though. In the interim, Littlefield stressed the importance of communication between patients and physicians on new COVID-19 diagnoses and new PCC presentation—and between physicians and study team sites and PCC clinics, to facilitate long COVID-19 patient referrals.

Littlefield empathized with patients who feel left behind while waiting for research and development. They stressed the importance of understanding a disease, classifying its subtypes and pathology, before identifying treatments. The reality is in 2023—3 years since COVID-19 first changed the world—those questions are still being answered.

It may be another 5 – 10 years until long COVID-19 is defined and treated, but hope persists.

“I think that people should stay strong,” Littlefield said, “and to continue advocating for themselves, to continue advocating for the government to make sure that we're well-funded and that we can do the research needed to help a significant amount of people who are having long-term and really detrimental outcomes of this virus.”

Rodriguez A. Dr. Anthony Fauci aims to answer 'a lot of important questions' about 'COVID long-haulers' in new nationwide initiative. 

. Published Feb 24, 2021. Accessed March 25, 2023.
https://www.usatoday.com/story/news/health/2021/02/24/covid-19-long-haulers-fauci-announces-launch-nationwide-initiative/4572768001/

Logue JK, Franko NM, McCulloch DJ, et al. Sequelae in Adults at 6 Months After COVID-19 Infection. JAMA Netw Open. 2021;4(2):e210830. doi:10.1001/jamanetworkopen.2021.0830

Post COVID-19 condition (Long COVID). World Health Organization. Updated Dec 7, 2021. Accessed March 25, 2023.
https://www.who.int/europe/news-room/fact-sheets/item/post-covid-19-condition#:~:text=Definition,months%20with%20no%20other%20explanation.

WHO Coronavirus (COVID-19) Dashboard. World Health Organization. Updated March 21, 2023. Accessed March 25, 2023.
https://covid19.who.int/

Diamond J. White House to disband Covid-19 response team in May. CNN. Published March 22, 2023. Accessed March 25, 2023.

Littlefield KM, Watson RO, Schneider JM, et al. SARS-CoV-2-specific T cells associate with inflammation and reduced lung function in pulmonary post-acute sequalae of SARS-CoV-2. PLOS Pathogens. 18(5): e1010359. https://doi.org/10.1371/journal.ppat.1010359

Glasgow G. CU School of Medicine Researcher Identifies Potential Cause of ‘Long COVID’. News release. CU School of Medicine. Published Feb 10, 2023. Accessed March 24, 2023.

Articles

As the US tries to move on from the pandemic, patients with long COVID-19 are fighting to regain normalcy while clinicians improve care plans and researchers search for answers.

No One Left Behind: The Long COVID Crisis in 2023

 condition, or “long COVID-19,” is more commonly associated with female sex, older age and clinical characteristics including cigarette use and body mass index (BMI), according to new data.

In a new systematic review and meta-analysis from a team of UK-based investigators, demographic and clinical characteristics were associated with increased risk of developing the long-term condition after SARS-CoV-2 infection and recovery. The could help elucidate individual risk of post-COVID-19 conditions and better prioritize such patients to timely screening and treatment strategies.

Led by Vasiliki Tsampasian, MD, MSc, of the department of cardiology at Norfolk and Norwich University Hospital, investigators conducted an assessment to identify clinical and epidemiologic risk factors linked to the development of long COVID-19 via available literature. They stressed the impact of interpreting individual risk not only to optimize follow-up care strategies, but to provide more refined public health measures in the long-term management of the pandemic.

“The World Health Organization (WHO) defined post−COVID-19 condition as having symptoms usually 3 months from the onset of COVID-19 with a duration of at least 2 months,” investigators wrote. “Typical clinical symptoms include dyspnea, fatigue, autonomic dysfunction, headache, and persistent loss of smell and/or taste—although a wide range of symptoms has been described. Given that individuals with post-COVID-19 condition may need long-term clinical support, the economic consequences have been estimated to be substantial.”

Tsampasian and colleagues conducted their meta-analysis using all published trials that assessed risk factors and predictors of long COVID-19 among adult patients ≥18 years old. They synthesized data to generate odds ratios (ORs) for each determined risk factor from the trial data. Selected risk factors included patient age, sex, BMI, smoking status, previous hospitalization or intensive care unit (ICU) admission due to COVID-19, COVID-19 vaccination status, and comorbidities including the following:

Their final assessment included 41 published studies including 860,783 patients who met inclusion criteria.

Female sex was associated with a 56% increased risk of post-COVID-19 condition (OR, 1.56; 95% CI, 1.41 – 1.73). When comparing 3 age groups—18-40 years, 40-69 years and ≥70 years—investigators observed the 2 older groups had significantly greater risk of post-COVID-19 condition as well (OR, 1.21; 95% CI, 1.11 – 1.33).

Patients with high BMI (≥30) defining obesity were additionally at significant risk of long COVID-19 (OR, 1.15; 95% CI, 1.08 – 1.23), as was current smoking status (OR, 1.10; 95% CI, 1.07 – 1.13).

Patients who were previously hospitalized due to COVID-19 were associated with the greatest risk of long COVID-19 development relative to all observed factors (OR, 2.48; 95% CI, 1.97 – 3.13). A further meta-analysis showed patients who required ICU admission during acute infection were at a similar risk (OR, 2.37; 95% CI, 2.18 – 2.56).

All but 1 of the clinical comorbidities were linked to an increased risk of long COVID-19; the highest-risk comorbidities included immunosuppression, COPD, and ischemic heart disease. The odds ratios for each comorbidities were as follows:

Anxiety and/or depression (OR, 1.19; 95% CI, 1.02 – 1.40)

Diabetes (OR, 1.06; 95% CI, 1.03 – 1.09)

Immunosuppression (OR, 1.50; 95% CI, 1.05 – 2.15)

Ischemic heart disease (OR, 1.28; 95% CI, 1.19 – 1.38)

Patients who had received 2 doses of a COVID-19 vaccine had a 43% reduced risk of developing post-COVID-19 condition than those who had not (OR, 0.57; 95% CI, 0.43 – 0.76).

In reviewing the data, Tsampasian and colleagues noted the findings confirm post-COVID-19 condition to be a “complex clinical syndrome.”

“Individuals with PCC may experience long-lasting adverse effects requiring long-lasting support. It has been reported that 15% of individuals with post-COVID-19 condition were absent from work owing to illness,” investigators wrote. “Follow-up outpatient services may be needed to manage this condition and to better understand the possible association between symptoms and residual organ impairment.”

The team concluded a holistic approach supported by integrated care pathways may improve the support available for patients with long COVID-19, as well as enable physicians to better prepare to manage patients at higher risk of long COVID-19 development.

“Moreover, in addition to preventing and diminishing the acute phase of the infection, COVID-19 vaccination may protect against post-COVID-19 , giving vaccination additional evidence of benefit,” they wrote.

Tsampasian V, Elghazaly H, Chattopadhyay R, et al. Risk Factors Associated With Post−COVID-19 Condition: A Systematic Review and Meta-analysis. JAMA Intern Med. Published online March 23, 2023. doi:10.1001/jamainternmed.2023.0750

New meta-analysis show patient demographics—as well as their pre-existing comorbidities and COVID-19 vaccination status—may significantly define their risk of long-term conditions.

Long COVID-19 Risk Linked to Women, Older Age, Higher BMI

The May 2022 mpox (formerly known as monkeypox) outbreak generated a storm of worry and mass speculation over the risk of “twindemics” amid the ongoing COVID-19 pandemic.

Though the scope and scale of the mpox outbreak has paled to match the comprehensive and global burden of COVID-19, the ongoing crisis has provided unique challenges to infectious disease specialists, epidemiologists—and even dermatologists now treating the characteristic and stigmatizing lesions associated with the virus.

In the second segment of an interview with 

 during the American Academy of Dermatology (AAD) 2023 Annual Meeting in New Orleans last week, Esther Ellen Freeman, MD, PhD, associate professor of dermatology at Harvard Medical School, discussed key disparities between the dermatologic manifestation of COVID-19 and mpox infection.

Put plainly, it’s a night-and-day comparison: about 98% of patients with mpox present with skin lesions, versus just 10% of patients with COVID-19.

Even when compared to earlier outbreaks of mpox in Africa years ago, clinicians are observing changes in skin manifestation today: current iterations of infection are resulting in lesions spreading from the genital and groin area to the rest of the body, whereas it previously began facially then spread to total body.

“We’re also seeing patients with 1-5 lesions—and certainly a majority of patients with less than 20 lesions,” Freeman explained. “This is in contrast to prior outbreaks when you’d might see lesion counts of 200 - 1000, much much higher.”

As the outbreak is ongoing, it’s been difficult for investigators to fully interpret the consistency of disease—as Freeman noted, these current cases of mpox being reported among US patients would maybe not have been reported at all in Africa, where the standard for disease has been more severe. And because presentation has been different from the textbook standard, so has the treatment strategy.

Freeman discussed her involvement on on an AAD task force dedicated to documenting and setting precedent for care of mpox, in collaboration with the Centers for Disease Control and Prevention (CDC). Thus far, the task force has generated 2 different guidances, Freeman said: one for caring for lesions as either a physician or patient, and the other for managing severe mpox lesions.

The former consists of patient-centric advisory around gentle cleansing practice, emollients, transmission risk reduction and the use of sun protection to avoid scarring and hyperpigmentation.

The latter addresses more long-term and burdensome forms of the common lesions.

“One thing that we’re seeing especially in our immunocompromised patients—such as those with HIV—they can have these really substantial, tricky wounds that are very large, very deep, very oxidative,” Freeman said.

Regarding the risk of scarring, Freeman conceded that current data is limited in understanding long-term impact.

“If you look at prior outbreaks…about 10% of people who had mpox had some sort of long-term scarring,” Freeman siad. “We don’t know what that percentage is going to be with this (2022) outbreak.”

Videos

The current pox virus outbreak has become closely synonymous with fewer lesions than past mpox—but dermatology guidance is needed all the same.

Esther Ellen Freeman, MD, PhD: Current Mpox Impact on the Skin

An investigative oral JAK inhibitor has shown capability to repigment patients’ 

 skin for the first time in new phase 2b trial data.

In outcomes presented during the late-breaking sessions at the American Academy of Dermatology (AAD) 2023 Annual Meeting in New Orleans last week, investigators reported that povorcitinib, a small-molecule selective JAK1 inhibitor in development as an oral medication by Incyte, was associated with statistically significantly improved total and facial Vitiligo Area Scoring Index (T-VASI; F-VASI) metrics versus placebo at 24 weeks.

Across the 3 different dosages, a notable proportion of treated patients with the pigmentation disease achieved ≥50% facial vitiligo clearance by 24 weeks.

Led by Amit G. Pandya, MD, adjunct professor in the department of dermatology at University of Texas Southwestern Medical Center, investigators sought to assess the efficacy and safety of povorcitinib on the basis of early-stage trials showing “potential activity in the treatment of nonsegmental vitiligo.”

The team randomized 171 adults with vitiligo to either once-daily oral povorcitinib doses of 15, 45, or 75 mg, or placebo, for 24 weeks. All patients were then administered 45 or 75 mg povorcitinib during a 28-week extension period. Eligible trial patients had nonsegmental vitiligo affecting ≥8% of their body surface area. The primary outcomes were T-VASI and F-VASI improvements versus placebo.

From baseline, investigators observed the following mean T-VASI percent changes with each treatment arm at 24 weeks:

Outcomes for mean F-VASI percent changes at 24 weeks were as follows:

Both primary efficacy end points were deemed statistically significant. Pandya and colleagues additionally observed 16.3%, 34.9%, and 23.8% of patients receiving each povorcitinib dose, respectively, achieved F-VASI 50 at 24 weeks—versus just 7.0% of placebo patients.

Investigators observed continued improvement in vitiligo area severity score improvement in treated patients through the 36-week extension period:

Povorcitinib 15 mg to 75 mg (T-VASI, -30.5%; F-VASI, -41.5%)

Povorcitinib 45 mg (T-VASI, -28.4%; F-VASI, -51.1%)

Povorcitinib 75 mg (T-VASI, -28.8%; F-VASI, -54.3%)

Placebo to povorcitinib 75 mg (T-VASI, -5.3%; F-VASI, -26.1%)

In the new extension treatment arms, 40.0%; 58.6%; 63.6%; and 30.3% achieved F-VASI 50, respectively, by 36 weeks.

The most common treatment-emergent adverse events observed at 24 weeks included COVID-19 (16.7%), headache (10.3%), fatigue (9.5%), increased blood creatine phosphokinase (7.9%) and acne—however none were serious in severity, and no new safety signals were observed after 24 weeks.

In a statement accompanying the new data, Pandya stressed the difficulty to manage vitiligo, which as of March 2023 has only 1 approved therapy—Incyte’s ruxolitinib cream (Opzelura)

—from the US Food and Drug Administration (FDA).

“As vitiligo can impact patients in different ways, I am encouraged by the continued focus on expanding medical treatment options, and I believe these data highlight the potential of this investigational oral treatment for patients with extensive nonsegmental vitiligo,” Pandya said.

Pandya AG, et al. Efficacy and Safety of Povorcitinib in Extensive Vitiligo: Results from a Phase 2, Placebo-Controlled, Dose Ranging Study. Paper presented at: American Academy of Dermatology 2023 Annual Meeting; March 17 – 21. New Orleans, LA. Accessed March 22, 2023.

Butera A. FDA Approves Ruxolitinib Cream 1.5% for Nonsegmental Vitiligo. HCPLive. Published July 18, 2022. Accessed March 22, 2023. https://www.hcplive.com/view/fda-approves-ruxolitinib-cream-for-nonsegmental-vitiligo

Incyte. Incyte Announces Data from Phase 2b Study Evaluating Povorcitinib (INCB54707) in Patients with Extensive Nonsegmental Vitiligo. News release. Published March 18, 2023. Accessed March 22, 2023. https://www.businesswire.com/news/home/20230318005041/en/Incyte-Announces-Data-from-Phase-2b-Study-Evaluating-Povorcitinib-INCB54707-in-Patients-with-Extensive-Nonsegmental-Vitiligo

New phase 2b findings support the oral JAK1 inhibitor's capability to improve  repigmentation versus placebo.