In this study, we described the main characteristics of discharged patients (n = 797) from a cohort of 969 patients who required hospitalization during the first months of the COVID-19 pandemic in four hospitals in southern Spain. We provided a detailed list of SPS during the 6 months after discharge and described which of these SPS are associated with negative outcomes (return to Emergency Services, hospital readmission and post-discharge death).
Characteristics of the cohort
The characteristics of our sample are consistent with other cohorts of patients hospitalized during the first wave of the COVID-19 pandemic in different countries. Therefore, the mean age of our sample (63.0) and the sex distribution (53.7% of men) are similar to previous studies such as the recently published Mediterranean cohort study , studies conducted in Italy  and Brazil  and other Spanish multicentre studies , although slightly different from other national reports . For example, Carfi et al. showed 56.5 mean age and 63% of men  and Garrigues et al. showed 58 mean age and 63% of women .
Our higher mean age could be partially explained by the high life expectancy in our country and by an ageing reference population in South Spain . Also, during the first weeks of the pandemic in Spain, a high number of elderly patients from residential care homes were hospitalized , given that exhaustive prevention and control measures had not yet been established. The in-hospital mortality of our cohort was 17.8%, data similar to those reported in other studies in the same period performed in New York  but lower than in other studies performed in Wuhan  and Spain . Similarly, the proportion of patients requiring intensive care was 12.1%, which is consistent with large patient cohorts in the USA (14.2%) .
Since the sample of our study is composed of the most severe COVID-19 cases (those requiring hospitalization), they presented a high frequency of previous diseases, polymedication and dependency for daily living activities, as shown in Table 1.
Frequency of SPS
We showed 63.9% of SPS during the 6 months after discharge, similar to other studies. A study conducted in Spain with 14 weeks of follow-up showed 50% post-acute COVID-19 syndrome . Another study conducted in France showed 55% persistent symptoms after a mean of 110 days of follow-up  and 62.5% of SPS was present 50 days after discharge . However, other series have reported up to 68% at 2 months , 87% at 2 months  and 87% at 3 months .
Table 2 lists all reported SPS and their prevalence stratified by sex. The most relevant were as follows.
Dyspnoea was the most frequent specific SPS in our cohort (28.0%). These data are lower than other reported frequencies, 31.4%  and 43.4% . All reported series concur that dyspnoea and fatigue are the most frequent SPS after COVID-19 [12, 18, 20, 30]. A possible explanation for these symptoms could be the persistence of fibrotic residual pulmonary areas. Furthermore, fibrosis would be the result of an ineffective organization stage after the initial acute inflammatory response . Thoracic pain (6.6%) was associated with return to the Emergency Services. Therefore, the presence of this symptom could warn of potential severity.
The high prevalence of fatigue (22.1%) is consistent with previous series [20, 30, 32]. A high frequency of musculoskeletal pain (15.3%) was also observed. Both symptoms could be explained by the systemic inflammatory response generated by COVID-19 [33, 34] and by natural recovery after hospitalization processes . Persistent fever (7.0%) and pressure ulcers (1.8%), generally occurring in patients with longer hospitalization time, were associated with negative outcomes. Therefore, the presence of these signs could be related to particularly vulnerable patients that require more intense monitoring.
Digestive SPS were very frequent (26.2%), especially diarrhoea (10.3%) and abdominal pain (5.4%), according to previous series . Some digestive SPS, such as vomiting (2.0% in our cohort), diarrhoea, nausea, hepatitis or abdominal pain, have been associated with COVID-19 treatment, as adverse drug reactions . According to other studies, hepatic injuries may also be associated with COVID-19 .
Several recent studies pointed the high frequency of neurological SPS after COVID-19 [37, 38]. In our cohort (20.8%), the most prevalent SPS was persistent anosmia or dysgeusia (7.2%), which showed a protective association with negative outcomes. Headache (5.3%) was associated with the outcomes, and disorientation or confusion (2.6%) was associated with hospital readmission. The presence of these symptoms could predict a worse evolution and, therefore, require timely preventive measures. Finally, the high prevalence of paraesthesia (3.4%) and movement (3.4%) disorders, such as dystonia or tremor, was surprising. These SPS were recently pointed out as potentially involved in COVID-19 complications . A wide variety of neurological manifestations (e.g. encephalopathy, encephalitis, seizures, cerebrovascular events, acute polyneuropathy, etc.) have been associated with COVID-19 , some of them also confirmed at the neuropathological level . Apart from symptoms, COVID-19 has also been linked to a variety of severe neurological complications, especially Guillain-Barré syndrome .
Mental health SPS
The high frequency of mental health symptoms in our cohort (12.2%) reflects the alarm expressed by several authors [42, 43] on the importance of preventing and identifying mental health SPS after hospitalization for COVID-19. These symptoms could be overestimated due to isolation during the hospitalization period and lockdown measures during the first wave of the pandemic [44, 45], but also due to other simultaneous familiar cases and admissions as well as high uncertainty during the first months. We found a high frequency of anxiety (6.8%), sleep disturbances (4.9%) and depressive symptoms (4.4%), especially higher in women.
This group represented 9.3% of our cohort. Although a high prevalence of dermatological symptoms related to COVID-19 has been reported since the beginning of the pandemic , we did not find any studies reporting these frequencies in follow-up cohorts. In our study, these symptoms were associated with return to the Emergency Services, possibly because they are visible and worrying to patients, but we found no association with mortality or hospital readmission. The most frequent SPS in our study was exanthema (3.1%). The high presence of alopecia (3.0%) in our study, especially higher in women, is noteworthy.
One of the most intriguing findings of our study was the high prevalence of superinfection (7.9%) during the 6 months after discharge from COVID-19 and its strong association with negative outcomes. It is possible that COVID-19 produces medium-term immunosuppression leading to superinfection, especially pneumonia, as reported in other works [33, 34]. This is consistent with other viral infections such as influenza, especially bacterial respiratory superinfections. The most frequent SPS in our cohort were urinary tract infection (3.9%) and mycosis (1.4%), which were not associated with negative outcomes. However, the presence of pneumonia (0.8%) led to negative outcomes in the adjusted analyses, thus becoming one of the main alarm symptoms proposed in our study. We were able to identify Streptococcus pneumoniae as one of the agents involved in 2 of the 6 cases of pneumonia, but no other etiological diagnosis was available.
Several authors have reported the potential cardiovascular effects of COVID-19 [47, 48], as occur with other systemic viral infections like influenza . Longitudinal studies reported frequencies of cardiovascular SPS higher than 10% . In our sample, 5.8% of patients reported some cardiovascular SPS. Specifically, arrythmia or palpitations (3.1%) and hypotension or syncope (2.9%) were also associated with negative outcomes.
We present the highest frequency of reported ophthalmological SPS in a cohort of hospitalized patients (4.6%), including conjunctivitis and vision loss, among others. Although not associated with negative outcomes, our results suggest that COVID-19 may be implicated in ophthalmic outcomes, as noted by other authors .
In our cohort, 4.5% of patients presented nephrological SPS and 0.9% showed de novo renal insufficiency. It is possible that some nephrological SPS might be related to the nephrotoxicity of COVID-19 treatment. However, this has been mainly associated with remdesivir , which was not involved in therapeutic approaches in our cohort during the first wave of the pandemic. The most important aspect of these SPS is their strong association with negative outcomes in our study. Therefore, patients who develop nephrological symptomatology after discharge should be especially monitored, as these SPS could signal a particularly vulnerable patient profile .
In agreement with other studies that reported this relationship very early [54, 55], our study shows thrombotic manifestations (4.4%), namely deep vein thrombosis, acute pulmonary embolism or cerebral stroke as the main haematological SPS in our cohort.
Urological SPS were present in 4.3% of the patients followed. Symptoms of voiding syndrome such as dysuria, oliguria or nocturia, but also haematuria were relatively frequent in our cohort. Although the impact of the pandemic on urological services has been studied , these symptoms have not been consistently associated with COVID-19.
We present 3.1% of otorhinolaryngological SPS. To the best of our knowledge, these are not well-known SPS of COVID-19, although some authors have pointed out their possible implications . We observed 1.9% of vertigo SPS reported (rotatory dizziness, tinnitus, etc.) after discharge. More data are still necessary to draw conclusions about this association.
The last group of SPS identified in our cohort were endocrinological SPS (1.5%), especially uncontrolled glycaemia (0.9%) in diabetic patients. This group was the only one that presented higher frequencies in men.
Return to the Emergency Services
This outcome has not yet been analysed in depth in previous studies. However, given the increasing number of patients discharged from COVID-19, the healthcare costs and the current saturation of the Emergency Services, it is important to detect which SPS cause patients to return to these services. Although we found a high frequency of patients who returned to the Emergency Services (20.3%), it is possible that these data are even underestimated, given the high concern for seeking healthcare at the onset of the pandemic. In our cohort, it was interesting to find that previous diseases, dependency, living in residential care homes or prognostic scores showed no association with this return. However, visible or easily identifiable symptoms like dermatological SPS and persistent anosmia or dysgeusia (which did not increase the risk of mortality or hospital readmission in our cohort) were strongly associated with return to the Emergency Services. It is possible that these SPS could be appropriately addressed by primary care telephone consultations. SPS that showed association with other negative outcomes, such as thoracic pain, arrhythmia, fever and pneumonia, which are undoubtedly alarming symptoms, were also associated with necessary return to the Emergency Services. Recognition of the severity of COVID-19 symptoms is crucial for correct therapeutic management , which should also improve follow-up treatment. We believe that more information on the potential alarming symptoms of patients discharged from COVID-19 could be provided to patients and their caregivers to improve follow-up and preventive measures in primary care.
We present the prevalence of SPS during the 6 months after discharge of patients hospitalized for COVID-19. No distinctions were made between early or long-term SPS and any interpretation of the results of this study should take into account that our exposures are SPS during the 6 months after discharge, at any time point. Since the data assessment was collected retrospectively and no prior standardization of SPS was designed, analytical associations through OR are of limited value and should be interpreted with caution. However, we present these results as potential risk factors to be considered in future longitudinal studies. Also, we cannot confirm that these SPS are a consequence of COVID-19, as there is no available comparison group (prevalence of all SPS in patients that did not suffer from COVID-19). We attempted to minimize this limitation by suggesting only potential risk factors to be taken into account during patient follow-up and analysing their relationship with potential negative outcomes in adjusted models. However, the adjusted models could not be well optimized for two outcomes: hospital readmission and death after discharge, given their small sample size (35 and 8, respectively). Therefore, both models were adjusted for a small number of variables and the validation criteria were not always optimal. Given this limitation, associations on post-discharge death are only presented as Additional file 2: Table S5. In addition, obesity and smoking could not be adequately collected and, therefore, models were not adjusted for these important variables. The aim of this study, however, is to describe SPS and propose (but not corroborate or conclude) possible risk factors on negative outcomes.
Our study is also conducted in a sample of high-risk COVID-19 patients (i.e. those who required hospitalization). Therefore, the results regarding SPS frequencies and association with outcomes could not be extrapolated to all COVID-19 patients, but only to those who required hospital care. Also, the SPS reported by this cohort could be attributable to COVID-19 or could be partially explained by the hospitalization process and the treatment received.
The study was conducted during the first wave of COVID-19, when diagnostic and therapeutic protocols were different from the current ones. This bias was addressed by adjusting all associations for diagnostic and therapeutic variables.
Finally, our study was conducted in Spain. External validity may be biased given that the life expectancy, health care and baseline characteristics of Spanish patients cannot be extrapolated to other countries. We tried to minimize this effect by designing a multicentre study including 4 different hospitals and 969 patients. The results of this study could be applied to the Spanish population but should be included in systematic reviews and compared with international samples to optimize accurate conclusions.