Abstract

Introduction

The most frequent symptoms of coronavirus disease 2019 (COVID-19) at disease onset are cough, fever, asthenia, myalgia and altered smell or taste, including anosmia/ageusia. Respiratory distress can occur, mostly between 7 to 10 days after symptom onset [[1], [2], [3], [4]].

Recent studies investigating predictors of poor prognosis at an early stage identified potential risk factors for severe COVID-19 [1,5,6]. One recent study in Italy by Carfi et al. [7] described persistent symptoms after hospitalization for COVID-19. Such evidence has not been reported for mild to moderate COVID-19. Our objective was to describe the clinical evolution and predictors of symptom persistence at D30 and D60 in patients with initial noncritical COVID-19. The aim was to highlight the initial key symptoms of COVID-19 to alert practitioners and patients of the risk of longer symptom duration in individuals with noncritical COVID-19.

Materials and methods

Results

Over the first 6 weeks of the epidemic, 293 patients sought care at our hospital as inpatients or outpatients with RT-PCR–confirmed COVID-19. After excluding 64 ICU patients, 36 residents of nursing home or long-term care facilities or patients transferred to another healthcare facility, 24 lost to follow-up at D30 and 19 deaths, we finally included 150 patients with noncritical COVID-19 presentation. Between D30 and D60, 20 more patients were lost to follow-up (Fig. 1 ).

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Fig. 1

Flowchart of study design. OCEC, outpatient clinical evaluation centre.

The male/female ratio was 0.79 (female, 56%, 84/150); the mean age was 49 ± 15 years. More than half of the patients (54%, 80/150) had at least one comorbid condition, and half were healthcare professionals (75/150). Despite the 20 patients lost to follow-up, demographic characteristics at D30 and D60 were similar (Supplementary Material S3).

The most common symptoms at disease onset were flulike symptoms (87%, 129/150), anosmia/ageusia (59%, 89/150) and fever (51%, 76/150) (Table 1 ).

For the follow-up at D30 and D60, phone calls were performed at a mean of 32.7 ± 2.5 days (range, 27–37 days) and 59.7 ± 1.7 days (range, 57–67 days) after symptom onset. At D30, 103 (68%) of 150 patients reported at least one symptom compared to 86 (66%) of 130 at D60 (Table 2 ). However, each symptom was less frequently reported at D60 than D30, except for arthralgia. At D30, 46% (73/150) of patients still felt ill or were in a worse clinical condition than at COVID-19 onset versus 37% (48/130) at D60.

The most frequent symptom reported at D30 and D60 was anosmia/ageusia (Table 1). On an analogue scale (from 0, total anosmia/ageusia, to 10, normal), at the worse moment of the disease, the mean anosmia and ageusia scores were 1.5 ± 2.1 (range, 0–8) and 1.9 ± 2.5 (range, 0–8) respectively; at D30, the mean scores were 7 ± 2.9 (range, 0–10) and 7.7 ± 2.3 (range, 0–10); and at D60, they were 7.1 ± 2.3 (range, 0–10) and 8.3 ± 1.6 (range, 5–10) respectively.

Symptoms persisting at D30 were significantly associated with hospital admission at symptom onset, initial clinical presentation, dyspnoea and abnormal auscultation (Fig. 2 ). Persisting clinical symptoms at D30 were associated with age class 40 to 60 years old but not with preexisting comorbid conditions. At D60, the associations remained for hospital admission and abnormal auscultation at symptom onset as well as the same age class 40 to 60 years old.

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Fig. 2

Predictors of persistent coronavirus disease 2019 (COVID-19) symptoms.

Discussion

This study showed that the medium-term course of 150 patients with mild or moderate COVID-19 was unfavourable: two-thirds of patients still reported symptoms at D30 and D60, and more than one third felt still ill or in a worse clinical condition at D60 than at onset of COVID-19. These prolonged symptoms were significantly associated with age 40 to 60 years old, hospital admission at symptom onset, severe COVID-19 and dyspnoea or abnormal auscultation.

The main strength of our study was a well-documented prospective follow-up of patients with a noncritical COVID-19 presentation at the early stage and at D30 and D60. Indeed, the recent international literature has provided evidence of the clinical presentation and evolution of COVID-19 patients [2,[12], [13], [14], [15]], although mainly regarding the most severe cases in ICUs and predictors of initial deterioration. The WHO has stated that median time from illness onset to recovery is about 2 weeks for mild cases and 3 to 6 weeks with severe or critical disease [16]. Small-scale studies in Wuhan, China, showed that survivors continued to have poor lung and heart function [1].

The initial clinical presentation for patients with mild or moderate COVID-19 (frequent respiratory and flulike symptoms) was similar to that of previous studies [17,18] including patients with more severe clinical presentation at symptom onset described in New York (USA), the United Kingdom or Italy. However, the patients included in our study were younger (mean age 49, vs. 62 to 73 years in severe cases) [[13], [14], [15]], and health professionals were overrepresented because of the national recommendations at this date and their prioritizing access to diagnostic tests [19].

For patients with mild or moderate COVID-19, different symptoms such as anosmia/ageusia, myalgia or headache persisted. In a recent study, Lechien et al. [17] reported persistent olfactory dysfunction in 37.5% of patients at least 7 days after the end of mild to moderate COVID-19. The precise mechanism of this symptom is unknown. Patients should be informed of this anomaly and referred to a specialist.

In our study, at D30, half of the patients still felt ill or in a worse clinical condition than before symptom onset, and 7% reported severe asthenia (3.1% at D60). One third of the patients had dyspnoea and approximately one sixth had chest pain. This situation is particularly frightening for patients. Rigorous studies with chest explorations seem necessary. Indeed, the evaluation at D30 and D60 was declarative over a phone call, without available physical, biological or imaging assessment. We controlled for this potential reporting bias by using standardized questionnaires administrated by trained investigators (Supplementary Data S1 and S2). However, subjective complaints are worth the attention and focus of the medical community and need to be taken into account in medical care. Moreover, several infectious diseases such as primary cytomegalovirus or Epstein-Barr virus infection are known to be associated with persistent symptoms, without necessarily any obvious anomaly at physical examination [[20], [21], [22]].

Marked inflammatory response associated with symptomatic COVID-19 could promote such prolonged convalescence and persisting symptoms. Some authors also suggest the possibility of posttraumatic stress disorder after COVID-19, which could contribute to a more prolonged experience of symptoms such asthenia or poor well-being [23,24]. These complex tardive psychological disorders have already been shown after acute respiratory distress syndrome [25,26]. This hypothesis could not be detailed in our study because of a lack of a reproducible psychological assessment but should probably be explored.

We found prolonged symptoms to be significantly associated in bivariate analysis with age 40 to 60 years, hospital admission at symptom onset, severe COVID-19 and dyspnoea or abnormal auscultation. Because patients' baseline characteristics were partially retrospectively collected, data for potentially contributive factors were missing, thereby preventing multivariate modelling, as the main contributive factors in bivariate analysis (dyspnoea, abnormal auscultation) had up to 29% of data missing. However, the findings of the bivariate analysis were clinically relevant. Patients' smoking status was not available; it would have been interesting to look for an association with duration of symptoms (especially anosmia/ageusia or chronic dyspnoea).

With this observational study allowing the prospective follow-up of 150 patients with noncritical COVID-19, we were able to assess the evolution of the disease and demonstrate that even the mildest presentation was associated with medium-term symptoms requiring follow-up. Thus, the COVID-19 pandemic will involve a care burden long after its end.

Transparency declaration

All authors report no conflicts of interest relevant to this article.

Acknowledgements

Notes

Editor: L. Leibovici

Footnotes

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