By Betty Tran, MD, MSc

Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago

SYNOPSIS: In this prospective uncontrolled cohort study of COVID-19 survivors performed four months after their hospitalization, many patients reported at least one symptom not previously present, and abnormalities on lung computed tomography scan were common.

SOURCE: Writing Committee for the COMEBAC Study Group; Morin L, Savale L, Pham T, et al. Four-month clinical status of a cohort of patients after hospitalization for COVID-19. JAMA 2021;325:1525-1534.

The COMEBAC (Consultation Multi-Expertise de Bicêtre Après COVID-19) was a prospective uncontrolled cohort study of adult patients admitted to a university hospital near Paris for COVID-19 (diagnosed via reverse transcriptase-polymerase chain reaction [RT-PCR], typical computed tomography [CT] lung scan, or both) from March 1 to May 20, 2020. Inclusion criteria were survival to four months post-hospital/intensive care unit (ICU) discharge and hospitalization for at least 24 hours primarily for COVID-19.

At three to four months post-hospital or ICU discharge, telephone assessments asked patients about respiratory, cognitive, and neurologic symptoms. All ICU patients and those who were symptomatic were further evaluated in the ambulatory setting with a general physical exam, bloodwork, and several tests assessing quality of life (36-Item Short-Form Health survey questionnaire), fatigue (Multidimensional Fatigue Inventory scale), and dyspnea (modified Medical Research Council scale, 6-minute walk test, pulmonary function tests, Nijmegen questionnaire, and hyperventilation provocation test). All patients had a high-resolution lung CT and a transthoracic echocardiogram performed if they were an ICU patient or had a pulmonary embolism or cardiac symptoms. In addition, all patients underwent psychometric testing (Montreal Cognitive Assessment, McNair self-questionnaire, and d2-R test) and were evaluated for anxiety, depression, and insomnia symptoms (Hospital Anxiety and Depression Scale, 13-item Beck Depression Inventory score, Insomnia Severity Index, and Posttraumatic Stress Disorder Checklist).

Among the 1,151 patients admitted because of COVID-19, 834 were eligible for telephone consultation, and 478 (57%; 142 ICU patients and 336 non-ICU patients) consented to be part of the study. Of 294 patients eligible for ambulatory assessment, 177 consented (97 ICU patients, 80 non-ICU patients). Median time to telephone assessment was 113 days (interquartile range [IQR] 94-128 days) post-discharge, and median time to ambulatory assessment was 125 days (IQR 107-144 days).

Of the 478 patients assessed via telephone, 244 (51%) reported at least one symptom that was not present pre-COVID-19 infection, most commonly fatigue (31.1%), memory difficulties (17.5%), dyspnea (16.3%), and persistent paresthesia (12.1%). During the ambulatory assessment, cognitive impairment was confirmed in 38.4% of patients, more commonly in patients 75 years of age. In ICU patients, symptoms of anxiety (23.4%), depression (18.1%), and significant posttraumatic stress (7.4%) were notable. ICU neuromyopathy was identified in 27.5% of previously intubated patients. Lung abnormalities were noted in a majority of both previously intubated patients (75.5%) and nonintubated ones (58.2%), most commonly persistent ground glass opacities (42.4%) and fibrotic lesions (19.4%), particularly in patients who had acute respiratory distress syndrome. Among the 78 patients assessed in the ambulatory setting with reports of new-onset dyspnea, the dyspnea was attributed to lung CT abnormalities in 56.4% and to hyperventilation provocation test-confirmed dysfunctional breathing in 17.9%. Of the patients who had echocardiograms performed, 9.6% had an ejection fraction of less than 50%; all had been ICU patients. Among the 95 of 478 patients who had acute kidney injury, two displayed persistent kidney dysfunction at four months.

COMMENTARY

There have been few systematic comprehensive evaluations of the long-term clinical consequences of COVID-19 infection thus far. Anecdotally, many patients have presented to our outpatient clinics with reports of persistent symptoms post-COVID-19 infection. This cohort study reports that at least half of patients who were hospitalized for COVID-19 infection had at least one persistent symptom that was not present pre-infection. Although persistent cardiac and renal dysfunction was uncommon, lung CTs frequently revealed persistent abnormalities, although fibrosis was less common (19%). Interestingly, many patients exhibited dysfunctional breathing not attributable to parenchymal lung findings as confirmed on hyperventilation provocation testing. Not surprisingly, psychological sequelae were common, as they have been described previously in ICU survivors.1

However, it is important to note that the findings of this study cannot confirm that COVID-19 was the direct causative agent, since there was no non-COVID-19 control group or pre-COVID-19 assessments done on the same patients. Furthermore, this study was conducted prior to more widespread use of corticosteroids, higher doses of anticoagulation, and many immunomodulator therapies, all of which may (or may not) have an impact with regard to the persistence of symptoms.

Despite its limitations, this study, in addition to our anecdotal experience, highlights the need for comprehensive COVID-19 clinics to address persistent symptoms post-infection. Given the wide range of symptoms, engaging multiple subspecialties in treating these patients is key. In the May 2021 issue of Critical Care Alert, Dr. Radigan nicely summarized a diagnostic approach to evaluating post-COVID-19 patients in follow-up clinics.2 These clinics also will be valuable in collecting further data on the longer-term outcomes of these patients and how those outcomes are associated with COVID-19 disease. 

REFERENCES

  1. Jackson JC, Pandharipande PP, Girard TD, et al. Depression, post-traumatic stress disorder, and functional disability in survivors of critical illness in the BRAIN-ICU study: A longitudinal cohort study. Lancet Respir Med 2014;2:369-379.
  2. Radigan K. Post-COVID-19: The crisis after the crisis. Critical Care Alert 2021;29:9-13.