INTRODUCTION

The coronavirus disease 2019 (COVID-19) pandemic has ravaged parts of the United States and, as of this publication, continues its devastation around the world. While it claimed the lives of hundreds of thousands of Americans, it left even more survivors in its wake. As the medical community learns more about the natural history of COVID-19, our focus has shifted from simply survival to ensuring recovery.

Here, we discuss the care of the post-COVID-19 patient: the symptoms and workup described in the literature as well as our own center's experience. We pay special attention to care of post-ICU patients, who are at risk for postintensive care syndrome (PICS) in addition to long-term sequelae of COVID-19. 

RESPIRATORY SYMPTOMS

Long-term respiratory sequelae can develop following COVID-19, even after mild infection ^[1]. We describe three common respiratory complications seen in COVID-19 survivors: dyspnea without hypoxemia, organizing pneumonia, and pulmonary fibrosis.

Dyspnea without hypoxemia

Persistent dyspnea without hypoxemia is frequently seen following COVID-19 infection, often in the setting of a normal computed tomography (CT) scan of the chest and a normal transthoracic echocardiogram (TTE). Existing data, although limited, report that exertional dyspnea without hypoxemia was present in 15–40% of patients with mild to moderate COVID-19 nearly 3 months into their recovery ^[2▪,3].

In the face of a paucity of data regarding the long-term sequelae of COVID-19 infection, we can turn to data from other viral respiratory pandemics for guidance. Multiple studies from the severe acute respiratory syndrome (SARS) pandemic reported that survivors had limited exercise capacity without exertional hypoxemia when compared with the general population ^[4,5]. The functional disability appeared out of proportion to the degree of lung function impairment, which was considered mild, and it was thus postulated that dyspnea without hypoxemia in this population could be secondary to global deconditioning, critical illness myopathy, or steroid myopathy.

We routinely order pulmonary function testing (PFT) and 6-min walk testing (6MWT) on patients with prolonged respiratory symptoms. If these studies are unrevealing, we recommend a detailed evaluation for alternative causes for dyspnea, such as pulmonary embolism, and often refer for cardiopulmonary exercise testing. Many will benefit from pulmonary rehabilitation and an exercise regimen, with close monitoring of their oxygen saturation at home and frequent follow-up. It has been our experience that with this supportive care and time, many patients eventually experience resolution of dyspnea.

Organizing pneumonia

The imaging findings of organizing pneumonia and subacute COVID-19 infection are strikingly similar. Classic CT chest findings for organizing pneumonia from any cause include peripheral, bilateral, lower lobe predominant consolidation associated with ground-glass opacities ^[6]. The most commonly reported radiographic findings in acute COVID-19 infection include lower lobe and subpleural ground-glass and consolidative opacities ^[7,8]. As the disease progresses (days 12–17), the ground glass opacities become more consolidative and architectural distortion appears, suggesting a secondary organizing pneumonia ^[7,9,10]. Secondary organizing pneumonia following viral pneumonia was reported in the Middle Eastern respiratory syndrome (MERS) epidemic, as well, and was successfully treated with corticosteroids ^[11].

In our practice, patients recovering from COVID-19 with persistent dyspnea, hypoxemia, or cough who have ground-glass opacities on CT chest are treated with steroids. Anecdotally, these patients respond very similarly to those treated for organizing pneumonia from other causes, with robust and rapid clinical and radiographic improvement. We typically repeat the CT scan of the chest after the steroid course to ensure improvement or resolution of the ground glass opacities, but the most recent American Thoracic Society/European Respiratory Society International Task Force guidance on the management of COVID-19 did not recommend for or against the use of repeat CT chest following acute infection ^[1].

Pulmonary fibrosis

The most feared complication of COVID-19 is pulmonary fibrosis. If we again turn to the SARS pandemic for guidance, pulmonary fibrosis was present in over half of survivors at day 35 ^[12]. Similarly, 33% of MERS survivors had pulmonary fibrosis on follow-up chest CT at approximately day 45 ^[13]. An early study out of the COVID-19 pandemic in Wuhan revealed the presence of a reticular pattern associated with bronchiolectasis and irregular interlobular or septal thickening at week 3, suggesting the development of pulmonary fibrosis in survivors ^[14]. Another retrospective study of 32 confirmed COVID-19 patients found that 43% had pulmonary fibrosis on CT chest approximately 10 days after discharge ^[15]. While these small, retrospective studies can help us recognize that pulmonary fibrosis may complicate COVID-19 recovery, there are no large, prospective studies or randomized control trials to date.

Patients with pulmonary fibrosis following COVID-19 infection are referred to our specialty interstitial lung disease clinic. We routinely obtain PFTs and a 6MWT in this population. If ground glass is present in addition to fibrosis on CT of the chest, we treat with steroids, as detailed above. However, if fibrosis is the only radiographic finding, we do not initiate steroids. We routinely repeat a CT scan of the chest at 3 months to assess for disease improvement or progression. We offer pulmonary rehabilitation and supplemental oxygen, if needed. While the use of antifibrotics in patients with post-COVID fibrosis has been debated, we do not routinely prescribe pirfenidone or nintedanib given the lack of available data and medication side effects. Finally, we enroll patients in clinical trials whenever possible, and in a very select population, we have referred patients for lung transplant evaluation.

NONRESPIRATORY COMPLICATIONS

While the lower respiratory tract is the site of most interest for COVID-19 infection, many other organ systems can be affected.

Neurologic complications

Headache

Persistent and refractory headache is reported by 13–38% of patients with acute COVID-19 infection and can continue to cause significant morbidity well into the recovery phase of the illness ^[16–19]. The existing literature does not recommend a standardized approach to the treatment of persistent headache in COVID survivors. If headaches persist despite standard treatment, referral to a neurologist is recommended.

Stroke

Acute stroke has been described in hospitalized patients with COVID-19. In one New York City-based study, ischemic stroke was found in 1.6% of hospitalized patients with COVID-19, significantly more than the 0.2% who had ischemic stroke while hospitalized with influenza infection ^[20]. While less common, intracranial hemorrhage was also described, but in some cases was secondary to anticoagulation in the setting of thrombosis ^[21].

Patients who suffered acute stroke during COVID-19 infection should follow with a neurologist and should receive the standard workup and preventive therapies to prevent further strokes. All stroke survivors should be evaluated for impairments in swallowing, mobility, and physical function. Referral to rehabilitation services should be made if necessary.

Anosmia and ageusia

The loss of smell (anosmia) and taste (ageusia) are well known symptoms of COVID-19, found in up to 40.2% of patients ^[22]. These symptoms can last for weeks to months and can be debilitating for many patients, often decreasing their appetite ^[19]. Ageusia in COVID-19 infection is thought to be due to loss of retronasal olfaction rather than loss of gustation, so olfactory training can be tried if symptoms last more than 2 weeks, as this treatment has been validated in postinfectious olfactory dysfunction ^[23]. Intranasal steroids have not shown to be of benefit, but other medications such as intranasal sodium citrate or intranasal vitamin A may be used ^[23]. A referral to an otolaryngologist is recommended.

Cardiovascular complications

Chest pain

Persistent chest pain following COVID-19 infection affects up to 22% of patients ^[19]. One German study performed cardiac MRI on nearly 100 patients who had recently recovered from COVID-19 infection; 78% were found to have cardiac involvement and 60% were found to have ongoing myocardial inflammation, independent of preexisting conditions and severity of illness ^[24].

When evaluating COVID-19 survivors with persistent chest pain, a low threshold should be used to order a troponin, brain-natriuretic peptide, ECG, and TTE, with referral to cardiology if results are abnormal.

Thrombosis

Patients with COVID-19 are at a significantly increased risk of venous thromboembolism (VTE) ^[25]. In one study, the prevalence of ultrasound-confirmed deep venous thrombosis (DVT) in ICU patients with COVID-19 was 27% ^[26]. In another, the incidence of thrombosis was 47% in COVID-19 ICU patients versus 3.2% in non-ICU hospitalized patients ^[27]. In addition, pulmonary embolism was found to be the cause of death in multiple autopsies of COVID-19 patients ^[28,29]. Finally, arterial thromboses have been reported in COVID patients and can be catastrophic ^[30,31].

We recommend evaluating COVID survivors for potential undiagnosed thrombotic complications, including myocardial infarction, stroke, DVT, and pulmonary embolism, if warranted based on their current symptom profile. In patients with proven DVT or pulmonary embolism who have no persistent risk factors, anticoagulation may be discontinued after 3 months. If concern for recurrent VTE persists, a lower extremity ultrasound and d-dimer can be obtained at 3 months to help guide anticoagulation course. Those with arterial thromboses are typically continued on lifelong anticoagulation ^[32]. Evaluation by hematology is recommended in select cases, such as those with recurrent VTE and in those with arterial thromboses.

SPECIAL CONSIDERATIONS: THE POSTINTENSIVE CARE PATIENT

While the majority of COVID-19 survivors had mild-to-moderate disease, a considerable number will have survived critical illness from acute respiratory distress syndrome (ARDS). PICS is increasingly recognized and comprises new or worsened physical, cognitive, and/or mental health impairments after an ICU stay ^[36]. Special attention should be paid to the following conditions in COVID-19 ICU survivors.

Physical impairment

Weakness

Patients with ARDS often require mechanical ventilation for a prolonged period of time, necessitating high doses of sedatives, systemic paralysis, and prone positioning. These standards of care contribute to profound muscle loss and weakness that impact the physical functioning of ICU survivors for years ^[37]. 6MWT can remain abnormal for years, and patients lose an average of 18% of their baseline body weight during critical illness ^[38].

Early implementation of physical and occupational therapy while admitted to the hospital is essential in combating weakness. With few exceptions, all COVID-19 ICU survivors should be discharged with ongoing physical and occupational therapy. At a post-ICU clinic visit, we assess patients’ ability to ambulate and to perform activities of daily living with validated screening questionnaires. We routinely perform 6MWT and evaluate grip strength. We make referrals to physical therapy, occupational therapy, and physical medicine and rehabilitation (PM&R) as needed.

Nerve injury

Peroneal injury resulting in foot drop is a common manifestation of critical illness polyneuropathy, which can affect 30–70% of critically ill patients ^[39]. Patients with unilateral or bilateral foot drop are prescribed physical and occupational therapy, but full resolution requires time. Referral to neurology for MRI or electromyography is appropriate, as is referral to PM&R for brace fitting.

Brachial plexus injuries are the most common nerve injuries that occur with prone positioning, which was used frequently in managing ARDS from COVID-19 ^[40]. For brachial plexus injuries, referral to PM&R, and/or neurology is appropriate, as well as referral to occupational therapy for hand-centered therapy.

Finally, in our anecdotal experience, many COVID survivors report new peripheral neuropathy. We often prescribe a trial of gabapentin, but more research is needed to determine the best preventive and therapeutic interventions for both nerve injury and pain.

Vocal cord injury

Persistent hoarse voice due to unilateral or bilateral vocal cord paresis, weeks to months after extubation or decannulation, is a common complaint in ICU patients who were mechanically ventilated. These patients should be evaluated by otolaryngology and often require direct flexible laryngoscopy for visualization of defects. If indicated, otolaryngology can perform therapeutic interventions such as injection therapy.

Dysphagia

Patients often suffer from persistent dysphagia after critical illness, some requiring percutaneous gastrostomy (PEG) placement. Referral to a speech-language pathologist and a nutritionist are recommended to optimize recovery and assess for removal when no longer necessary. Anecdotally, the majority of our COVID-19 ICU survivors who were discharged with a PEG have recovered sufficiently to have them removed.

Cognitive impairment

Cognitive impairment is a well documented complication of ARDS, with one study reporting an incidence of 82% in ARDS survivors versus 48% in a mixed ICU population at time of hospital discharge ^[41]. In another study, 40% of ICU survivors had global cognition scores 1.5SD below population means at 3 months postdischarge, and 26% had scores 2.5SD below the population means ^[42]. Cognitive impairment contributes to one's ability to return to work; in one study, only 77% of patients who were working prior to developing ARDS had returned to work 5 years after their illness ^[43].

To assess cognitive impairment, the Montreal Cognitive Assessment (MoCA) should be administered. The MoCA-BLIND can be used during a tele-health visit. If cognitive impairment is detected, referral to a neuropsychologist or occupational therapist for further assessment and cognitive rehabilitation is recommended.

Mental health

The COVID-19 pandemic has resulted in increased rates of depression and anxiety across our society, regardless of whether one was infected with COVID-19 ^[33,34]. Among those infected, a study from China reported that patients with COVID-19 had higher rates of anxiety, depression and insomnia ^[35]. Mental health disorders are known to disproportionately impact ARDS survivors, with the BRAIN ICU study revealing that one third of patients reported depressive symptoms at 3 and 12 months after critical illness, and 7% had evidence of posttraumatic stress disorder (PTSD) ^[44]. Furthermore, in a study of 90 patients with SARS, the post-SARS cumulative incidence of psychiatric disorders recognized in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), was 59% ^[45]. COVID-19 survivors will likely face similarly high rates of mental illness in the aftermath of critical illness.

Recognition of these comorbidities is essential in caring for the ICU survivor, especially as individuals are reintegrated into homes, school, work, and society at large. All COVID survivors should be screened for anxiety, depression, and PTSD; if positive, referral to a mental health provider is recommended. Communication with primary care physicians is also key in establishing long-term support for these vulnerable patients.

Post-ICU clinics

The post-COVID ICU population is remarkably complex and requires a multidisciplinary approach to care ^[46▪]. Post-ICU clinics are uniquely poised to deliver this care, as they are staffed by physicians specializing in ICU recovery and often have preexisting relationships with important collaborators such as physical and occupational therapy, rehabilitation medicine, nutrition, mental health providers, and pharmacists. Finally, we strongly recommend the use of telemedicine to reach the most debilitated ICU survivors who are unable to physically transport to clinic appointments. Offering video visits substantially improved the no-show rate in our practice.

CONCLUSION

Much remains unknown about the complications that COVID-19 survivors will face. Yet what we have already learned is striking: hundreds of thousands of survivors could suffer long-lasting complications of nearly every organ system. Rates of post-ICU syndrome could reach unprecedented levels as the almost insurmountable social and financial implications of survivorship accumulate. More data are needed to guide practitioners as we attempt to care for COVID-19 survivors in the wake of this pandemic.

Acknowledgements

We would like to thank Drs Edward Schenck, Christopher Parkhurst, and Jamuna Krishnan for their assistance in caring for our post-COVID population. We would also like to acknowledge Ryan Burslem, Liz Ramos, Ariel Muscente, and Dora Kanellopoulos, our colleagues in nutrition, pharmacology, social work, and psychology whose expertise and care is invaluable to our ICU survivors.

Financial support and sponsorship

None.

Conflicts of interest

The authors have no conflicts of interest.