COVID-19 is an acute respiratory disease caused by severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2). Since the first case was identified,
1
the rapid emergence of new cases, admissions to hospital, and deaths required that
public health officials focus on prevention through infection control measures, clinicians
focus on diagnosis and supportive care, and medical scientists focus on the development
of new vaccines and therapeutics. Attention is now turning towards understanding the
natural course of COVID-19 in survivors and optimising follow-up to prevent, identify,
and treat any undesirable long-term sequelae.
Distinct patterns of disease progression were documented in early clinical descriptions
of the first COVID-19 cases.
2
Many patients with acute COVID-19 have involvement of their respiratory system, characterised
by dry cough, dyspnoea, hypoxaemia, and abnormal imaging results.
3
Although most patients had mild-to-moderate disease, 5–10% progress to severe or critical
disease, including pneumonia and acute respiratory failure.4, 5 Severe cases can occur
early in the disease course but clinical observations typically describe a two-step
disease progression, starting with a mild-to-moderate presentation, followed by a
secondary respiratory worsening 9–12 days after the first onset of symptoms.4, 6,
7 Respiratory deterioration is concomitant with extension of ground-glass lung opacities
on chest CT scans, lymphocytopenia, and high prothrombin time and D-dimer levels.
4
Early evidence supports the hypothesis that some survivors might develop long-term
respiratory sequelae. Fibrotic abnormalities of the lung have been detected as early
as 3 weeks after the onset of symptoms regardless of whether the acute illness was
mild, moderate, or severe.3, 8, 9, 10 Abnormal lung function (ie, restrictive abnormalities,
reduced diffusion capacity, and small airways obstruction) has also been identified
at the time of discharge from hospital and 2 weeks after discharge.11, 12, 13 These
lung function abnormalities appear to be more common among patients whose acute COVID-19
was severe with high levels of inflammatory markers, and are often accompanied by
evidence of pulmonary fibrosis including interstitial thickening, coarse reticular
patterns, and parenchymal bands.
12
It is too soon to determine which patients with COVID-19 are at greatest risk for
developing long-term pulmonary abnormalities, if such sequelae will resolve, improve,
or become permanent, and how the pulmonary abnormalities might be affected by therapeutics
such as remdesivir, dexamethasone, and others under investigation. We hypothesise
that most COVID-19 survivors will manifest early pulmonary abnormalities, which could
range from being asymptomatic, to mild to severe, and debilitating. We further hypothesise
that among patients without pre-existing lung disease, the duration of pulmonary abnormalities
will be related to the severity of their acute COVID-19 course, with complete or near
complete resolution within 6 months in patients who had a mild course (ie, did not
require admission to hospital) and within 12 months in patients who had a moderate
course (ie, admitted to hospital but did not require intensive care). However, persistent
lung function abnormalities, including restrictive lung disease, decreased diffusing
capacity, and fibrosis, are expected in patients who had a severe course, particularly
those who required mechanical ventilation. These hypotheses need to be tested, which
requires a systematic approach. We call on the pulmonary community to work together
to develop a uniform and systematic approach to follow-up of COVID-19 survivors. Such
an approach should facilitate research and knowledge generation and, ultimately, improve
patient outcomes.
An approach to deciding when it is safe to schedule COVID-19 survivors for elective
in-person visits has been published.
14
However, no empirical evidence or consensus exists on how patients should be followed-up.
Here, we propose an approach for consideration, which is based upon evolving clinical
knowledge, clinical experience and rationale.
The initial in-person visit should target the establishment of a patient's baseline
after COVID-19. This process would require a thorough investigation of present and
past medical, social, and family history, physical examination, and blood testing,
including the following: a complete blood count; comprehensive metabolic panel; coagulopathy
studies (prothrombin time, partial thromboplastin time, D-dimers, and fibrinogen);
serology for antiphospholipid and anticardiolipin antibodies; SARS-CoV-2 IgG antibody
levels; and cryopreservation of serum and plasma, including RNA and DNA for genotype
research studies. Additionally, a baseline non-contrast high-resolution CT scan (HRCT),
pulmonary function tests (spirometry, lung volumes, and diffusion capacity), 6-min
walk test, assessment of quality of life (including fatigue, anxiety and depression)
by patient reported outcomes, pulse oximetry on room air at rest and during the 6-min
walk test, pulse oximetry with supplemental oxygen if the pulse oximetry on room air
is less than 88%, and an echocardiogram should be considered, if resources permit.
Once the COVID-19 survivor's baseline has been established, a follow-up evaluation
during a structured protocol visit should aim to better understand the natural course
of disease and identify new abnormalities early. A reasonable plan would be to follow-up
patients with mild impairment of lung function by phone visits or videoconferencing,
or both, at 1, 2, and 4 months and in-person at 3 and 6 months, and subsequently at
9, 12, 18, 24, 30, and 36 months based on the degree and extent of lung involvement
and impairment on a case-by-case basis (figure
). During the initial 12 months of follow-up, the in-person visits could be accompanied
by repeat testing for COVID-19 infectivity, repeat pulmonary testing, 6-min walk test,
monitoring of quality of life, fatigue, and some blood testing (eg, complete blood
count, comprehensive metabolic panel, coagulopathy studies, and SARS-CoV-2 IgG antibody
levels). Imaging by non-contrast HRCT of the chest at the 6-month and 12-month in-person
visits could be done to assess improvement, resolution, persistence, or worsening
of any fibrosis. Beyond 12 months, most tests could be ordered on a case-by-case basis,
although patients with fibrosis on their 6-month or 12-month HRCT of the chest might
warrant additional scans at 24 and 36 months to understand long-term sequelae of interstitial
pneumonia or pulmonary fibrosis.
Figure
Suggested follow-up care for COVID-19 survivors
HRCT=high-resolution CT. SARS-CoV-2= severe acute respiratory syndrome coronavirus
2. *Nasal swab testing during the 3–5 days before visit is to make sure that the survivors
are not shedding the virus particles and thus ascertain the status of infectivity
at baseline and during follow-up visits. The intended in-person baseline and follow-up
visits could then be converted to telemedicine visits if found to be positive for
SARS-CoV-2, on a case-by-case basis, or appropriate precautionary measures could be
taken with personal protective equipment by health-care workers. †Quality of life
assessment via patient reported outcomes with standard questionnaires used for respiratory
diseases, fatigue, anxiety, and depression.
In summary, the varying extent of pulmonary fibrosis and lung function impairment
among survivors of COVID-19, and the unknown course of such abnormalities, highlight
the need for pulmonary clinicians to closely monitor disease course in survivors.
Such follow-up will generate knowledge about the natural course of disease and facilitate
enrolment in clinical trials assessing the treatment of abnormalities with immune
modulating drugs and antifibrotic drugs.
15
A standard approach from institution to institution will facilitate research and could
improve outcomes.
© 2020 Lea Paterson/Science Photo Library
2020
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