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If one word describes Eladio (“Lad”) Braganza, age 77, it’s “tenacious.” For 28 days, he clung to life on a ventilator in a Seattle ICU. Now ― after a 46-day hospitalization for SARS-CoV-2 infection — he’s making progress in inpatient rehab, determined to regain function.
“We were not sure if he was going to make it through his first night in the hospital, and for a while after that. We were really prepared that he would not survive his ventilator time,” his daughter, Maria Braganza, told Medscape Medical News just 5 days after her father had been transferred to inpatient rehab.
In many ways, Braganza’s experience is typical of seriously ill COVID-19 patients. Many go from walking and talking to being on a ventilator within 10 hours or less. Braganza was admitted to the hospital on March 21 and was intubated that day. To keep him on the ventilator, he was heavily sedated and unconscious at times. In the ICU, he experienced bouts of low blood pressure, a pattern of shock that occurs in COVID-19 patients and that does not always respond to fluids.
Doctors have quickly learned to treat these patients aggressively. Many patients in the ICU with COVID-19 develop an inflamed, atypical form of acute respiratory distress syndrome (ARDS), in which the lung’s compliance, or stiffness, does not match the severity of hypoxia. These patients require high levels of oxygen and high ventilator settings. Many develop pneumothorax, or collapsed lungs, because of the high pressures needed to deliver oxygen and the prolonged time on ventilation.
“The vast majority of COVID patients in the ICU have lung disease that is quite severe, much more severe than I have seen in my 20 years of doing this,” said critical care specialist Anna Nolan, MD, an associate professor of medicine at New York University School of Medicine.
After about 2 weeks, some of these patients can come off the ventilator, or they may undergo a tracheostomy, a hole in the neck through which a tube is placed to deliver oxygen. By this time, many have developed ICU-acquired weakness and muscle wasting. Some may be so debilitated that they cannot walk. Even the respiratory muscles that help them breath may have weakened as a result of the ventilator doing the work for them.
These patients “get sick very fast, and it takes a long time for them to heal. What’s not really well appreciated is how much rehab and how much recovery time these patients are going to need,” said David Chong, MD. He is medical director of the ICU at New York–Presbyterian Hospital/Columbia University Medical Center, and he has been on the front lines during the COVID-19 surge in New York City.
The Road to Recovery
Regardless of the cause, many people who have a prolonged stint in the ICU face an even longer convalescence. Still-unanswered questions concern whether recovery time will be longer for those with COVID-19 compared to other illnesses and whether some of the damage may be permanent. A number of small studies in Hong Kong and China, as well as studies of SARS patients’ recoveries, have promoted speculation about possible long-lasting damage to lungs and other organs from COVID-19.
Yet some of these reports have left out important details about ARDS in COVID-19 patients, who also may be most at risk for long-lasting damage. To clear up some of the confusion, the Pulmonary Fibrosis Foundation said on April 6 that some but not all of COVID-19 patients who develop ARDS may go on to develop lung fibrosis — scarring of the lungs — which may be permanent.
“Post-ARDS fibrosis typically is not progressive, but nonetheless can be severe and limiting. The recovery period for post-ARDS fibrosis is approximately one year and the residual deficits persist, but generally do not progress,” the Foundation noted.
Emerging Research on Lung Damage in COVID-19
Because the pandemic is only a few months in, it’s unclear as yet what the long-term consequences of severe COVID-19 may be. But emerging data are enabling researchers to venture an educated guess about what may happen in the months and years ahead.
The key to understanding the data is knowing that ARDS is a syndrome ― the end product of a variety of diseases or insults to the lung. Under the microscope, lung damage from ARDS associated with COVID-19 is indistinguishable from lung damage resulting from other causes, such as vaping, sepsis, or shock caused by a motor vehicle accident, said Sanjay Mukhopadhyay, MD, director of pulmonary pathology at Cleveland Clinic.
Mukhopadhyay, who specializes in lung pathology, performed one of the first complete autopsies of a COVID-19 patient in the United States. In most autopsy series published to date, he said, the most common lung finding in patients who have died from COVID-19 is diffuse alveolar damage (DAD), a pattern of lung injury seen in ARDS from many other causes.
In DAD, the walls of the alveoli — thinly lined air sacs that facilitate gas exchange in the lung — develop a pink, hyaline membrane composed of damaged cells and plasma proteins that leak from capillaries in the wall of the alveolus. This hyaline membrane gets plastered against the wall of the alveolus and interferes with diffusion of oxygen into the body.
“We know what happens in ARDS from other causes. If you follow people who have been on a ventilator long term, some of their respiratory function goes back to normal,” Mukhopadhyay said. “But there are other people in whom some degree of respiratory impairment lingers. In these patients, we think the DAD progresses to an organizing stage.”
Organizing pneumonia refers to a family of diseases in which fibroblasts (cells involved in wound healing) arrive and form scar tissue that forms hyaline membranes and fibrin balls (tough proteins) that fill up the alveoli, making gas exchange very difficult.
Also called BOOP (bronchiolitis obliterans organizing pneumonia), this condition is sensitive to steroids. Early aggressive steroid treatment can prevent long-term lung damage. Without steroids, damage can become permanent. A variant of this condition is termed acute fibrinous and organizing pneumonia (AFOP), which is also sensitive to steroids. A report from France demonstrates AFOP in some patients who have died from COVID-19.
The trick is identifying who is developing BOOP and who is not, and beyond that, who might be most amenable to treatment. Use of steroids for patients with certain other problems, such as a bacterial infection on top of COVID-19, could be harmful. Chong and colleagues at Columbia University Medical Center are investigating this to determine which COVID-19 patients may benefit from early steroid therapy.
“It’s not clear if there is a predominant histologic type or if we are catching people at different phase of their disease, and therefore we’re seeing different lung pathology,” Chong said.
He thinks that many patients with severe COVID-19 probably will not develop this pattern of lung scarring.
“We’re speculating that lung damage from severe COVID-19 is probably going to behave more like lung damage from regular ARDS, which is often reversible. We think the vast majority of these patients probably have DAD that is similar to most patients with ARDS from other etiologies,” Chong said.
That would be consistent with information from China. In an April interview with Chinese domestic media, Zhong Nanshan, MD, a pulmonologist at the head of China’s COVID-19 task force, stated that he expects that the lungs in most patients with COVID-19 gradually recover. He was responding to a widely publicized small study that found evidence of residual lung abnormalities at hospital discharge in most patients (94%, 66/70) who suffered from COVID-19 pneumonia in Wuhan, China, from January to February 2020.
Tough Research Conditions
Experts say that follow-up in this Chinese study and others to date has not nearly been long enough to allow predictions about lasting lung damage in COVID-19.
They also highlight the tough conditions in which researchers are working. Few autopsies have been performed so far — autopsies take time, extra precautions must be taken to avoid spread of COVID-19, and many patients and families do not consent to an autopsy. Furthermore, autopsy data from patients who died of COVID-19 may not extrapolate to survivors.
“I would not hang my hat on any of the limited data I have seen on autopsies,” said Lina Miyakawa, MD, a critical care and pulmonary medicine specialist at Mount Sinai Hospital in New York City.
“Even though we have answers about how the lungs are damaged at the end stage, this does not elucidate any answers about the earlier lung damage from this disease,” she continued. “It would be informative to have pathological data from the early or transitional phase, to see if that may translate into a treatment modality for COVID-19 patients.”
The problem is that these patients often experience a large amount of sloughing of airway cells, along with mucous plugging (collections of mucous that can block airflow and collapse alveoli). Bronchoscopy, which is used to view the inside of the lungs and sometimes to retrieve biopsy specimens for microscopic evaluation, is too risky for many COVID-19 patients.
In addition, few CT data exist for severely ill COVID-19 patients, who can be so unstable that to transport them to undergo a CT scan can be dangerous, not to mention the concern regarding infection control.
Even if sufficient data did exist, findings from chest x-rays, CTs, pathology studies, and lung function tests do not always match up. A patient who has lung abnormalities on CT may not necessarily have clinically impaired lung function or abnormal pathologic findings, according to Ali Gholamrezanezhad, MD, an emergency radiologist and assistant professor of clinical radiology with Ketch School of Medicine at the University of Southern California.
Together with colleagues at USC, Gholamrezanezhad has started a long-term study of patients who were hospitalized with COVID-19. The researchers will follow patients for at least 1 year and will use chest x-ray, chest CT, and exercise testing to evaluate lung recovery over time.
“In the acute phase, we have acute inflammation called ground glass opacities, which usually happen bilaterally in COVID-19. That is totally reversible damage that can return to normal with no scarring,” Gholamrezanezhad said.
On the basis of data from survivors of other severe pneumonias, such as MERS, SARS-CoV-1 infection, and H1N1 influenza, Gholamrezanezhad thinks that most survivors of COVID-19 will be able to return to work and normal life, although some may show residual lung dysfunction. Age, underlying medical conditions, smoking, length of hospital stay, severity of illness, and quality of treatment may all play a role in how well these people recover.
The lung has a remarkable capacity to recover, he added. Critical illness can destroy type one pneumocytes — the cells that line the alveoli in the lung — but over time, these cells grow back and reline the lungs. When they do, they can also help repair the lungs.
On top of that, the lung has a large functional reserve, and when one section becomes damaged, the rest of the lung can compensate.
However, for some people, total maximum exercise capacity may be affected, he commented.
Mukhopadhyay said: “My feeling is you will get reversal to normal in some patients and you will get long-term fibrosis from ARDS in some survivors. The question is, how many will have complete resolution and how many will have fibrosis? To know the answer, we will need a lot more data than we have now.”
Convalescence of COVID-19 Patients
Like many who become seriously ill with COVID-19, Braganza had underlying medical problems. Before becoming ill, he had had a heart attack and stroke. He walked with a walker and had some age-related memory problems.
Five days after transfer to inpatient rehab, Braganza was walking up and down the hallway using a walker. He was still shaking off the effects of being heavily sedated for so long, and he experienced periods of confusion. When he first came off the ventilator, he mixed up days and nights. Sometimes he did not remember being so sick. A former software engineer, Braganza usually had no problem using technology, but he has had to relearn how to use his phone and connect his iPad to Wi-Fi.
“He is still struggling quite a bit with remembering how to do basic things,” Maria Braganza said. “He has times of being really depressed because he feels like he’s not making progress.”
Doctors are taking note and starting to think about what lies ahead for ICU survivors of COVID-19. They worry about the potential for disease recurrence as well as readmission for other problems, such as other infections and hip fractures.
“As COVID-19 survivors begin to recover, there will be a large burden of chronic critical illness. We expect a significant need for rehabilitation in most ICU survivors of COVID-19,” said Steve Lubinsky, MD, medical director of respiratory care at New York University Langone Tisch Hospital.
Thinking about her father, Maria Braganza brings an extra dimension to these concerns. She thinks about depression, loneliness, and social isolation among older survivors of COVID-19. These problems existed long before the pandemic, but COVID-19 has magnified them.
The rehab staff estimates that Braganza will spend 10 to 14 days in their program, but discharge home creates a conundrum. Before becoming ill, Braganza lived in an independent senior living facility. Now, because of social distancing, he will no longer be able to hang out and have meals with his friends.
“Dad’s already feeling really lonely in the hospital. If we stay on a semipermanent lock down, will he be able to see the people he loves?” Maria Braganza said. “Even though somebody is older, they have a lot to give and a lot of experience. They just need a little extra to be able to have that life.”
Nolan, Chong, Mukhopadhyay, Miyakawa, Gholamrezanezhad, and Lubinsky report no relevant financial relationships.
Veronica Hackethal, MD, MSc, is a freelance medical journalist in Manhattan with expertise in public health. Her work has appeared in the New York Times, Scientific American, Nature Medicine News, Reuters Health, and others.