Persistent symptoms of postcoronavirus disease-2019 (COVID-19) have recently attracted increased attention[1–3] and yet most studies concentrate on mild or/and moderate COVID-19, i.e., noncritical cases,[4–6] regardless of the type of study. The focus of this article is solely on persistent symptoms resulting from severe and critical COVID-19. The World Health Organization (WHO) guidance for the clinical management of COVID-19 defines a severe case as one in which the patient shows clinical signs of pneumonia (fever, cough, dyspnea, and fast breathing) plus one of the following: respiratory rate >30 breaths/min, severe respiratory distress, or SpO2 <90% in room air, whereas it defines a critical case as one in which the patient develops acute respiratory distress syndrome, sepsis, or septic shock.
Mandal et al. performed a cross-sectional study of persistent symptoms over the median of 54 days, including severe cases; they identified persistent symptoms and radiological abnormalities without determining the degree of severity. Peghin et al. conducted research over 6 months period and patients were classified based on the WHO interim guidance. They showed that 40.2% of patients experienced post-COVID-19 syndrome.
The aim of this study was to identify persistent symptoms among survivors of severe and critical COVID-19, including the possible impact of chronic diseases.
MATERIALS AND METHODS
Study design, populations, and data collections
This is a single-center, cross-sectional, epidemiological study that focuses solely on a recovered patient from severe and critical COVID-19. The study was carried out at King Khalid University (KKU) Hospital, Riyadh, Saudi Arabia, with patients who were admitted between March 4 and December 1, 2020. These patients were diagnosed using the confirmed real-time reverse transcriptase-polymerase chain reaction (PCR) test for severe acute respiratory-coronavirus-2 through a nasopharyngeal swab and were considered to be in either the severe or critical category according to definitions given in the WHO guidance for clinical management of COVID-19.
All of the data for this study were collected between April 1 and May 31, 2021, i.e., 60 days. During this period, all eligible patients recovered and were discharged from the hospital to resume a normal life. It had been more than 120 days since the onset of the first symptoms; the minimum day was 121 for some patients and the maximum was 453 for other patients. The initial personal and clinical data of the participants were first collected from the KKU hospital electronic system. A total of 588 patients had been admitted with severe and critical COVID-19 and after applying our study criteria (discussed below), this number was reduced to 125. The authors of this article all work in the infectious diseases unit of the hospital and were in charge of collecting the data and contacting the potential study participants through telephone. A specific telephone questionnaire [Supplementary Material] was developed based on symptoms discussed by Garrigues et al. and it also asked participants to report any other symptoms since this current study was conducted over a long time period than the work of Garrigues et al. In addition, we asked about chronic diseases, especially hypertension (HTN), diabetes mellitus, and asthma, and whether patients had been in the intensive care unit (ICU) during their hospital stay. As the interviews were conducted over the phone, the identity of the patients was first confirmed and their verbal consent was then given before they continued to participate in the study. The authors abided by survey questions and sometimes telephoned the participants more than once in case of no answer the first time. All of the participants collaborated with the interview. The body mass index (BMI) was missing only for seven patients where there was either no clinical record or the patients were not able to provide a clear answer.
The inclusion criteria were: all adult patients (≥18 years old) who were diagnosed with severe and critical COVID-19 at the time of admission; the diagnosis was confirmed by PCR from nasal swab and the minimum day since the first symptom onset was 121 and the maximum was 453. Exclusion criteria were: patients who were <18 years old, or who had mild or moderate COVID-19, or admitted to the hospital for another reason than COVID-19 then it was detected incidentally. Furthermore, deceased patients (even if they had severe or critical COVID-19), recovered patients who did not complete the period of our study or those who were unable to answer a phone questionnaire and who decline to participate.
Persistent symptoms outcome in our study
The main persistent symptoms were the presence of at least one of the following: breathlessness, hair loss, forgetfulness, chest pain, difficulty in concentrating, cough, and lack of energy. Other persistent symptoms that were less common were: weakness when climbing stairs, anosmia, headache, insomnia, and malaise. All of the persistent symptoms were associated with ICU admission or fever (temperature >38°) or diarrhea at symptom onset.
Descriptive statistics included frequency analysis (percentages) for categorical variables. We used comparative analysis with Chi-square and Fisher’s tests. The analyses were done by IBM SPSS Statistics version 22.214.171.124. P < 0.05 was considered statistically significant.
All patients were informed about the aims and design of the study and consent was taken verbally with an emphasis on the participants’ right to decline or drop out. King Saud University represented by the institutional review board for Health Science Colleges’ research on human subjects approved the study project Ref. No. 21/0253/IRB on March 2021.
Patients’ baseline characteristics
For the study and out of a total of 588 patients who were admitted to the academic KKU Hospital, only 125 met our criteria [Materials and Methods]. The remaining 463 were excluded for the following reasons: 260 were diagnosed with mild and moderate COVID-19, 8 were deceased, 66 had no contact phone number, 43 did not answer our calls, 78 were unable to communicate due to their ages or/and language barrier, and 8 were children.
The male/female ratio was 0.60 (male 62.4%, 78/125); the mean age was years. 94.4% (118/125) of patients had BMI records; 32.2% (38/118) had normal BMI (18.5–24.9 kg/m2). About 33.9% (40/118) were overweight, (BMI 25–29.9 kg/m2), whereas 33.9% (40/118) were suffering from obesity regardless of the class, (BMI >30 kg/m2) [Table 1].
In brief, most of our patients had a BMI above 23 kg/m2 yet we found no correlation between high BMI and persistent symptoms. The same applied to gender and age.
About 70.4% (88/125) of the patients had chronic diseases; 25.6% (32/125) had three or more, 20% (25/125) had two, and 24.8% (31/125) had one. The two most common were diabetes mellitus 49.6% and HTN 41.2%. Other chronic diseases comprised < 10% except for cardiovascular diseases at 15.2%. More information is summarized in Table 2. Importantly, we found that chronic diseases were not responsible for persistent symptoms of COVID-19.
The persistent symptoms
About 42.4% (53/125) of patients had at least one or more persistent symptoms that can be divided into two groups. The first group of persistent symptoms comprises symptoms that were detected from the 1st day of the COVID-19 infection and continued after more than 120 days. The second group was reported after passing more than 120 days from the symptom onset and had not been detected from the first presentation. Breathlessness, cough, and chest pain belong to the first group and were found to be the main persistent symptoms. Ninety-six percent of patients suffered from breathlessness in the first presentation; however, 27.2% of patients had breathlessness after more than 120 days from symptom onset. It was also found that 80% of patients developed a cough in the first presentation compared to 5.6% who had a persistent cough after more than 120 days. Yet the decline in cough (74.4%) is slightly higher than breathlessness (68.8%) after more than 120 days from symptom onset. Chest pain only increased by 1.6%.
For the second group, hair loss was reported by 14.4%, followed by forgetfulness (8%), difficulty in concentrating (6.4%), and lack of energy (4%) [Table 3].
There were some symptoms that were detected at the first presentation, but which did not persist. The most significant symptoms were fever in 40.8% (51/125) of patients, followed by the need for ICU admission by 35.2% (44/125) and diarrhea in 14.4% (18/125). The latter three symptoms were the major reasons for the persistence of other symptoms [Table 3]. Other, less significant symptoms are summarized in the same table.
It is worth mentioning that the length of ICU admissions varied among patients. ICU stays last between 1 and 30 days, with the mean at 10.75 ± 7.2. Yet there appears to be no correlation between the duration of ICU admission and persistent symptoms, as the P = 0.05. Another finding is that 78.6% (33/44) of patients who were admitted to the ICU were on a high-flow nasal cannula, 21.4% (9/44) were intubated, and there were no records for two patients. Again, this had no correlation with persistent symptoms as the P = 0.05.
This study focuses on persistent symptoms resulting solely from severe and critical COVID-19. The main strength of our study was to investigate the possible influence of chronic disease along with age, gender, and BMI, on the persistence of symptoms. The immunopathogenesis of persistent symptoms is still not fully understood. However, there are various hypotheses that suggested several mechanisms depending on the type of system which can be summarized into three main mechanisms. First, inflammatory damage is due to inflammation that could lead to neurocognitive impairment and/or microvascular and macrovascular thrombosis, etc. Second, virus-specific pathophysiological changes, for example, the COVID-19 virus could lead to a downgrade of angiotensin-converting enzyme 2 receptors. Third, an expected squeal after a critical illness which is related to the pathophysiology of postintensive care syndrome.
In our study, COVID-19 symptoms had to have been recorded in the early stages, as well as after more than 120 days since the symptom onset, to determine the persistence of symptoms. Breathlessness, cough, and chest pain were the most frequent symptom reported. This is different compared to mild and moderate cases, in which anosmia/ageusia and fever were the most reported symptoms during a 60-day follow-up study. Anosmia/ageusia has also been reported in mild COVID-19. In our study, anosmia was reported by only three patients at the first presentation, but this did not persist [Table 3]. The same result was found for fever although 51 patients reported it. However, we found that fever has a significant influence on the persistence of other symptoms.
Findings suggest that there is no connection between persistent symptoms and chronic diseases but as De Almeida-Pititto et al. pointed out diabetes, HTN, and cardiovascular disease are hazard factors for severity and mortality in COVID-19-infected people. We observed other chronic diseases in patients with severe and critical COVID-19, although these were not highly widespread [Table 2]. Age, gender, and BMI were also not associated with persistent symptoms and our finding agrees with Gao et al. regarding that severe and critical COVID-19 affects people with a high BMI [Table 1].
This study has several limitations. It is cross-sectional in nature since the clinical follow-up of individuals over time was not possible. In addition, it was performed at a single center and relied on the self-reporting of symptoms by patients.
This research found that 42.4% (53/125) of patients suffered at least one or more persistent symptoms. Breathlessness and cough were the main persistent symptoms. Planning rehabilitation or follow-up should be considered for patients who reported fever and diarrhea, and those who were admitted to ICU in the first presentation.
The data that support the findings of this study are available from the corresponding author upon the request.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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