Recovery after COVID-19. Persistent symptoms beyond acute infection

A high rate of persistent and multiorgan symptoms, beyond the acute phase of severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2), has been observed. Given the large number of confirmed cases of acute coronavirus disease 2019 (COVID-19) in Australia (over 29,000 confirmed infections to date)¹ being followed in the community by GPs, this represents a novel disease and health concern for which we recommend careful assessment and multidisciplinary follow up. 

How and why does the patient present with this problem?

COVID-19 is characterised by symptoms such as fever, dry cough, myalgias, anosmia and gastrointestinal disturbance.^2-4 Persistent symptoms, affecting multiple organ systems and lasting for months after resolution of acute infection, have been reported in a number of studies. This syndrome has been termed ‘long COVID’ or the ‘post-COVID-19 syndrome’ and refers to the long-term effects of COVID-19; however, a precise consensus definition is lacking. 

As part of the ADAPT study, a prospective Australian cohort of adult patients at St Vincent’s Hospital Sydney, is being followed to characterise the long-term effects of COVID-19. At two to three months after COVID-19 infection, a considerable proportion of patients (39.7%) reported persistent symptoms including fatigue, shortness of breath and chest tightness.⁵ The proportion of patients with symptoms at initial infection and follow up are summarised in Figure 1. The proportion of individuals with persistent symptoms was highest in those hospitalised for initial infection, but a third of patients with community-managed COVID-19 reported persistent symptoms; this is of particular relevance to GPs. 

In other international cohorts, fatigue is a commonly reported persistent symptom but multiple other symptoms are also described, in particular referrable to the pulmonary, cardiovascular and neuropsychiatric systems.^6-8 Ongoing research priorities include the identification of predictive factors for ‘long COVID’, defining its natural history and identifying clinically-effective interventions.⁹ Additional work is needed to understand whether long-term symptoms represent persistence of initial COVID-19 infection or a post-viral complication. 

What are the likely causes of 'long COVID' syndrome?

Residual pulmonary radiological changes (ground-glass opacities and parenchymal bands) and abnormalities in pulmonary function testing during recovery have been reported and may explain persistent cardiothoracic symptoms in patients recovered from COVID-19.¹⁰ Figure 2 demonstrates post-viral parenchymal bands and volume loss in coronal slices of a chest CT of a recovering patient in the ADAPT study. Patients in this study showed reduced total lung capacity and abnormalities in the diffusion capacity for carbon monoxide (DLCO) on complex lung function testing, especially those requiring hospitalisation for viral pneumonia.⁵ Long-term abnormalities were also reported after severe acute respiratory distress syndrome (SARS) including reduced DLCO and exercise capacity, chronic fatigue and psychiatric morbidity.^11-15 Long-term illness has also been reported after Middle-East Respiratory Syndrome (MERS) and other viral infections including infectious mononucleosis and influenza.^16-18  

Persistent morbidity is well established after sepsis and intensive care admission.^19,20 A wide range of cardiac complications has been observed in people with COVID-19 including fulminant myocarditis, acute heart failure and arrhythmias.^21,22 Assessment for myocardial damage is an area for ongoing evaluation in those with persistent cardiothoracic symptoms.

Given the systemic effects of SARS-CoV-2, including reports of neurological manifestations such as large vessel stroke, encephalitis and delirium, neurocognitive impairment remains a concern.^23-25 Abnormalities have been observed in the quality of life of people recovering from COVID-19 and include new problems in mobility, self-care and activities of daily living.²⁶ Mental health disturbances may include post-traumatic stress disorder, anxiety and depression.²⁷ Several factors could be driving these abnormalities including the experience of recent illness, uncertainty of recovery, general concerns over COVID-19 and its global effects and exacerbation of pre-existing conditions. Increased mental health disturbance in the Australian community in the immediate post-COVID period has been reported, and issues around stigma and discrimination of people with or recovering from COVID-19 may also be factors contributing psychological decline.^28-31 

Some cohorts have reported persistently elevated D-dimer, C-reactive protein, interleukin 6 (IL-6), ferritin and brain natriuretic peptide concentrations in recovering patients.³² In relation to the specific symptom of fatigue after COVID-19, there is no established association with routine laboratory markers of inflammation and cell turnover or pro-inflammatory molecules.⁶ 

What initial investigations should be considered if you suspect 'long COVID' in your patient?

A variety of health resources may be required to adequately manage persistent symptoms after COVID-19. We recommend a clinical review by a GP at four weeks after COVID-19 infection and we urge that GPs be aware of the potential long-term symptoms (Box). Full lung function testing and pulmonary imaging should be considered to investigate thoracic symptoms, especially in patients with oxygen desaturation or physical signs of respiratory disease by 12 weeks after acute infection. Cardiology investigations such as an echocardiogram may be required to investigate those with persistent cardiothoracic symptoms or physical signs of cardiac disease. Blood tests, including a full blood count and kidney, liver function and C-reactive protein tests, may be offered. Pulmonary rehabilitation may assist to improve exercise capacity and breathlessness.³³ Neurocognitive testing and imaging may be required to investigate cognitive symptoms. Mental health symptoms should be specifically asked about and early referral for liaison psychiatry specialist support may be required. Shared care by GPs and specialists is likely required to care for patients with persistent symptoms after COVID-19. 

Does 'long COVID' differ from other post-viral syndromes and if so, how?

A number of viral infections have been associated with longer term symptoms after the resolution of an initial infection. SARS-CoV-1, a novel coronavirus that caused a pandemic outbreak in 2002, results in SARS illness and has been associated with pain, fatigue, psychological symptoms and disturbed sleep up to three years after infection.³⁴ Viral infection has been considered a possible causal factor for chronic fatigue/myalgic encephalomyelitis and Guillain-Barré syndrome, the neurological illness mediated by an aberrant immune response to prior infection, including viral infections.^35,36 It is too early in the pandemic to fully establish the nature of ‘long COVID’. A better understanding of this syndrome will depend on further careful clinical and research evaluation of patients after infection. 

Conclusion

A considerable proportion of patients experience persistent symptoms beyond acute SARS-CoV-2 infection that may impact physical function, mental health and quality of life. Systematic assessment is recommended to monitor recovery, assess the need for rehabilitation and to detect complications. This is particularly relevant for GPs, given the significant number of patients undergoing follow up in the community.    RMT

COMPETING INTERESTS: The authors’ research is supported by funding from  St Vincent’s Curran Foundation and St Vincent’s Clinic Foundation. 

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