The Long Haul

For some people infected with COVID-19, the disease does not end with the swift resolution of all symptoms.

Last year, Sudipto Mukherjee, MD, MPH, a hematologist at Cleveland Clinic working with patients who have recovered from COVID-19 infection, recalls seeing a man in his early 40s who was sick with COVID for four months. The patient had developed pneumonia and respiratory failure severe enough to require ventilation. He also developed hemophagocytic lymphohistiocytosis (HLH) during his second month in the hospital.

Dr. Mukherjee said the case was unique because, while “a variety of viral infections are known to trigger HLH, the surprising fact … was this occurred in the setting of SARS-CoV-2, a recently diagnosed virus.”

The patient was first treated with dexamethasone and etoposide, but when he developed “profound cytopenias,” his care team switched him to the immunosuppressive drug anakinra. Eventually, he transitioned back to dexamethasone, but with the addition of ruxolitinib, and managed to recover from his complications.

Unfortunately, Dr. Mukherjee’s patient is not unique. For some people infected with COVID-19, the disease does not end with the swift resolution of all symptoms.

The long-term sequelae revealed themselves soon after the initial reports of COVID-19, as cases multiplied and hospitals gained experience with treating patients with the novel coronavirus. Many other infections, including influenza, have been known to cause post-viral syndrome characterized by lingering fatigue and other symptoms. Some, such as Epstein-Barr virus, increase a person’s risk for a variety of ailments like certain cancers for the rest of their lives.1

With COVID-19, the varied litany of symptoms that last far longer than the initial infection goes by many names – long COVID, persistent COVID, or long-haul COVID.

Patient groups have popped up on social media, now with hundreds of thousands of members sharing their experiences of COVID-19 symptoms that just won’t go away. One of the earliest groups, started by patient Amy Watson, is called the “Long Haul COVID Fighters.” The name, she told NBC News, was a nod to the trucker hat she’d worn to get a COVID test back in April of 2020 – followed by more than 137 days dealing with symptoms such as burning sensations on her arms, torso, head, and neck.2

In August 2020, The Atlantic reported that the Centers for Disease Control and Prevention (CDC) had not yet mentioned the issue on its website.3 By November 2020, the CDC published a page describing persistent COVID-19 symptoms in people who had ostensibly recovered from the infection.4

Months before the CDC acknowledged the urgency of the issue, hospitals were already building interdisciplinary clinics to treat, in a coordinated manner, the myriad symptoms COVID-19 survivors experience. These “post-COVID clinics” are designed to streamline patients’ care, replacing repeated visits to multiple specialists with a visit to a single clinic where they can be seen by a team of pulmonologists, neurologists, hematologists, and other specialists who can treat the various manifestations of long-haul COVID.

“We see patients who have had symptoms more than 30 days out from their initial infection,” said Zijian Chen, MD, an endocrinologist who runs Mount Sinai Health System’s Center for Post-COVID Care in New York City. “Patients report to us that they have neurologic symptoms, like forgetfulness and fatigue, and we are seeing patients experiencing cardiovascular symptoms like tachycardia or bradycardia – randomly fast or slow heartbeats – all the way to symptoms like blood clots and difficulty with circulation.”

ASH Clinical News spoke with Drs. Mukherjee, Chen, and several other physicians working with COVID-19 long-haulers about what they are seeing in clinics, how they are approaching treatment, and the many questions that still require research.

Who Gets It?

COVID-19 infection is known to wreak havoc on organs and systems throughout the body. The ACE2 receptors that the virus uses to enter cells are particularly prevalent in the lungs, but are also found in cells in the intestines, kidneys, liver, blood vessels, heart, and even the brain. The most distinctive characteristics of the disease are respiratory; patients often experience coughs, difficulty breathing, and anosmia, but many also experience constellations of symptoms all throughout the body, such as muscular pain, gastrointestinal discomfort, headaches, neurologic symptoms, and kidney failure.

A segment of the patient population will continue to experience these symptoms months after testing negative for the virus. In some cases, people seem to recover from the infection, only to see new symptoms emerge. The spectrum of possible symptoms and range of combinations is just as diverse with long-term COVID-19 infection as it is during the acute disease phase.

“We’ve come to realize that COVID-19 recovery doesn’t end as soon as someone is stable and leaves the hospital. A wide range of medical issues can persist and impair function and overall quality of life in these patients,” said Benjamin Abramoff, MD, a physical rehabilitation specialist working at the University of Pennsylvania’s Post-COVID Assessment and Recovery Clinic in Philadelphia.5

“Probably the most common sequelae are lingering pulmonary complaints, meaning shortness of breath, cough or shortness of breath with exertion, as well as fatigue and loss of endurance with activities,” Dr. Abramoff told ASH Clinical News. Other common symptoms include cognitive changes, insomnia, difficulty concentrating, and anxiety and depression.

According to the Centers for Disease Control and Prevention (CDC), the most commonly reported long-term symptoms of COVID-19 include:

  • fatigue
  • dyspnea
  • cough
  • arthralgia
  • chest pain

Less frequently reported long-term symptoms include:

  • difficulty with thinking and concentration (sometimes referred to as “brain fog”)
  • depression
  • myalgia
  • headache
  • intermittent fever
  • heart palpitations

The CDC also notes more serious long-term complications are possible, but appear to be less common. These have been noted to affect different organ systems, including:

  • cardiovascular: inflammation of the heart muscle
  • respiratory: lung function abnormalities
  • renal: acute kidney injury
  • dermatologic: rash, hair loss
  • neurologic: smell and taste problems, sleep issues, difficulty with concentration, memory problems
  • psychiatric: depression, anxiety, changes in mood

“Fatigue is the main thing I’ve seen [among patients recovering from COVID-19],” noted David Avigan, MD, a hematologist and oncologist at Beth Israel Deaconess Medical Center in Boston. That has led some researchers to draw comparisons between COVID-19 and chronic fatigue syndrome, a condition without a specific diagnostic test or cure. Treatments for chronic fatigue syndrome revolve around alleviating symptoms like insomnia and depression using medication, exercise, and counseling.

There is some good news on the horizon: In a March report from The Washington Post, patients with long-term symptoms have found some relief after receiving a COVID-19 vaccine.6 One woman, who endured long-haul COVID-19 for eight months, said that, 36 hours after receiving her second vaccine shot in February, her symptoms disappeared. Researchers are working to understand the connection – some have posited that the vaccine triggers a strong enough immune response to eliminate any lingering virus that may be causing long-term COVID-19 symptoms, and none have ruled out the placebo effect.

Hematologic Concerns and Interactions

Physicians and researchers suspected early on that COVID-19 somehow interacted with the blood. Many patients seemed to be dying from blood clots and National Institutes of Health (NIH) guidelines questioned the value of giving patients higher doses of anticoagulants when they arrived in the hospital to prevent such complications.7 As of February 2021, the NIH recommended against prophylactic anticoagulation and antiplatelet therapy for non-hospitalized patients with COVID-19 who show no other indications for the therapy, but noted that there are insufficient data to recommend either for or against routine thrombolytics or venous thromboembolism (VTE) prophylaxis among hospitalized patients.

A meta-analysis from November 2020 added evidence for an interaction between the disease and blood. Across a total of 42 studies of more than 8,000 patients, 20% of hospitalized patients experienced VTE. Experiencing VTE nearly doubled the risk of death, with pooled mortality rates of 23% in patients with COVID-19 and 13% among those without COVID-19.8

There also seems to be a connection between immune thrombocytopenia (ITP) and COVID-19. Physicians who spoke with MedScape described two patients who developed the disorder after recovering from COVID-19 infection, and a third who died after developing ITP while still fighting COVID-19.9 In a systematic review of 45 patients who developed ITP secondary to COVID-19, the onset of ITP occurred at least three weeks after the onset of COVID-19 symptoms in 20% of cases, and ITP was most likely to emerge after recovery.10

Moreover, a preprint posted in early February suggested that COVID-19 is more fatal in patients with hematologic cancers than in the general population. Patients with CD8 T cell depletion and a high viral load had the highest mortality rate, at 71%.11

How Long Is the Long Haul?

Several studies have attempted to estimate how many patients will have health issues that persist after recovering from acute COVID-19 infection. Two reports from European research groups found that more than three-quarters of hospitalized patients had symptoms at least two to three months after symptom onset.12,13

In another study of 100 patients who had recovered from COVID-19, ranging in severity from asymptomatic to requiring ventilation, 78 had cardiac involvement.14 Patients with mild and moderate disease showed cardiac involvement just as frequently as those who experienced severe disease. The researchers also found that 60 patients had ongoing cardiac inflammation and scarring that persisted after the patients cleared the infection.

With tens of millions of confirmed COVID-19 cases worldwide, the number of patients who will need ongoing treatment is substantial. Less clear, though, is whether these symptoms will last for months, years, or even the rest of patients’ lives.

“There are very limited studies out there showing the percentages or prevalence of these symptoms,” Allison Navis, MD, from the Division of Neuro-Infectious Diseases at Icahn School of Medicine at Mount Sinai, said in a webinar on long-lasting COVID-19 symptoms for the Infectious Diseases Society of America in February.15 “But, based on available research and anecdotal data, fatigue seems to be the most common thing. It’s a little unclear as to what’s causing the fatigue, as that can have many different etiologies.”

Also at Mount Sinai, neuroscientist and rehabilitation specialist David Putrino, PhD, and his team have been tracking long COVID since March 2020. So far, they have surveyed more than 1,400 long-haulers. As he told The Atlantic, most of these patients are women, their average age is 44, and most were fit and healthy when they contracted COVID-19.3

What Causes Long-Haul COVID?

Questions about what causes ongoing COVID-19 symptoms abound. Chances are, there are multiple causes and different patients are experiencing symptoms related to prolonged infection, inflammation, organ damage, or a combination of these factors.

“I would be surprised if it is the same thing going on with everybody,” said Dr. Abramoff. “Some preliminary evidence suggests there is an autoimmune component, and it has also been suggested that, even though a patient is no longer contagious, viral particles someplace in the body lead to persistent inflammation.”

Several studies have pointed to a prolonged immune response as a possible cause of long-haul COVID.

In one study of 15 postmortem brains, one-third had megakaryocytes stuck in the cerebral vasculature, suggesting a mechanism by which some patients experience brain fog.16 “By occluding flow through individual capillaries, these large cells could cause ischemic alteration in a distinct pattern, potentially resulting in an atypical form of neurologic impairment,” the authors wrote, noting that, prior to this pandemic, they had never observed megakaryocytes in brain vessels.

A group of researchers at Emory University pointed to higher levels of autoreactive antibodies in patients with severe COVID-19 infection, similar to those that cause damage in patients with autoimmune diseases.17

Another possible source of damage is scar tissue, particularly in the lungs, that takes time to heal long after the infection is gone. Ali Gholamrezanezhad, MD, a radiologist from the Keck School of Medicine of the University of Southern California, told Nature that, after tracking computed tomography scans of patients who had cleared their COVID-19 infection, his team found that one-third of patients had lung scarring more than one month later.18 This could cause a range of pulmonary issues, such as difficulty breathing during exercise. The damage may take months or even decades to heal. For example, in a study of 71 people who were hospitalized with SARS, 38% still had reduced lung function 15 years later.19

Lastly, even if a patient tests negative on a nasal swab, that only means there isn’t much virus in his or her nose. The patient could still have small amounts of virus elsewhere in the body that the immune system is still fighting. “There has been some documentation over a few months that some patients, particularly those that are immunocompromised, may have chronic shedding of the virus,” noted Dr. Avigan.

Post-COVID Care

COVID-19 was first identified in the U.S. in January 2020 and, by spring of that year, patients who had seemingly recovered were returning to doctors’ offices and hospitals with complaints of all varieties of ongoing symptoms.

“Some were seeing cardiology, some were seeing pulmonology, some were seeing neurologists,” said Dr. Abramoff, recounting his experience at the University of Pennsylvania. “The pulmonologists were saying, ‘We can address their lung issues, but they’re also having headaches and fatigue and functional impairments.’ These multisystem complaints didn’t really have a home within the medical system to guide their care.”

“COVID-19 recovery doesn’t end as soon as someone is stable and leaves the hospital. A wide range of medical issues can persist and impair function and overall quality of life in these patients.”

—Benjamin Abramoff, MD

So, in June 2020, Penn Medicine opened its Post-COVID Assessment and Recovery Clinic. As of February 2021, Dr. Abramoff said they have seen about 250 patients.

The post-COVID assessment process begins with a standard telehealth screening to determine patients’ personal, health, and rehabilitation needs. Colleagues in rehabilitation medicine, pulmonology, critical care, and other specialties share a single spreadsheet in which they jointly interpret the patient’s status and determine what care the person needs before bringing them in for regular testing and therapy.

Penn Medicine is not alone. Several hospitals around the U.S. have formed such clinics. The goal is not just to streamline care, but also to streamline research.

“When you don’t know the mechanism and you don’t know why patients are having their symptoms, it feels like you’re putting a Band-Aid on it,” said Dr. Abramoff. At his clinic, the team is also creating a registry to track patients’ data over time in hopes of learning more about how COVID-19 progresses and evolves to post-COVID syndrome.

On a larger scale, entire nations are working to create registries. For example, the U.K. has launched the Post-hospitalisation COVID-19 study (PHOSP-COVID) to understand and improve long-term health outcomes for COVID-19 survivors. Its goal is to recruit and follow 10,000 patients hospitalized with COVID-19 using blood tests and other assessments for one year post-discharge.20 Similar efforts began over the summer in the U.S., with the National Institute of Neurological Disorders and Stroke (NINDS) launching a database to track neurologic symptoms associated with COVID-19. The COVID-19 Neuro Databank/Biobank (NeuroCOVID) is being maintained by NYU Langone Health in New York City, and will serve as a resource of clinical information and biospecimens from people of all ages who have experienced neurologic problems associated with SARS-CoV-2 infection.21

Dr. Chen says that, at his COVID recovery clinic at Mount Sinai, it is standard practice to take blood samples from patients and store them for later testing for insights into the causes of long COVID. Even a year into the pandemic, he said, “it is still so early that we don’t know what the questions are.” —By Emma Yasinski


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