There has been a long evolution of the Coronavirus disease 2019 (covid-19) pandemic caused by the SARS-CoV-2 virus, but currently, covid-19 still causes between 300 and 500 deaths per day in the United States, which equates to a higher annual mortality burden than that associated with a bad influenza season; In addition, many people continue to face severe short- or long-term illness from covid-19, including people without access to vaccines or treatment and those with underlying conditions that affect their immune response to vaccines or make them especially vulnerable [1]. The long-term health consequences following SARS-CoV-2 infection, collectively described as Post-covid-19 conditions, are recognized to have a significant negative impact on human health [2]. A review of the state of knowledge on these conditions estimates that 10% of people infected with SARS-CoV-2 will experience lasting symptoms [3]. Multiple hypotheses have been proposed to connect acute covid-19 and post-covid-19 conditions, including chronic inflammation driven by persistent viral reservoirs, autoimmunity, microbiome or virome dysbiosis, and lasting tissue damage [5]. Currently, research on the symptoms of Long covid-19 continues. Thus, scientists have found three types of Long covid-19, which have their own symptoms [6, 7]. However, relatively little is known about the differences between the symptoms of covid-19 in acute phase of infection and the symptoms of Long covid-19, and in relation to this, about the clinical course of covid-19 and the return to health or the transition to Long covid-19 for people with milder outpatient illnesses [8]. In this context, we present a study to try to clarify the differences between covid-19 acute phase and Post-covid-19 conditions. Thus, clinical characteristics of patients with Long covid-19 (presence of prolonged symptoms for at least 12 weeks) were compared with covid-19 acute phase, in a population of a general medicine outpatient clinic.

Design and Emplacement

Comparison of secondary data among two previous studies:

• Symptoms in covid-19 acute phase which were taken from another previous study: an observational, longitudinal and prospective study of patients from March 15, 2020 to March 31, 2021 [9].
• Symptoms in Long covid-19 which were taken from another previous study: An observational, longitudinal and prospective study of patients with Long covid-19 from March 15, 2020 to October 31, 2022 [10].

Both studies were carried out in the same population of patients treated in a general medicine office in the Health Center Santa Maria de Benquerencia, Toledo (Spain), which has a list of 2,000 patients> 14 years of age (in Spain, the general practitioners [GPs] care for people > 14 years of age, except for exceptions requested by the child's family and accepted by the GP).

To compare clinical characteristics of covid-19 in acute infection phase with Long covid-19 (presence of prolonged symptoms for at least 12 weeks, lasting at least 2 months, after acute covid-19 infection, and that are not explained by an alternative diagnosis).

Diagnosis of covid-19

The diagnosis was performed with reverse transcriptase polymerase chain reaction (PCR) oropharyngeal swab tests or antigen testing. A symptomatic confirmed case with active infection was considered to be any person with a clinical picture of sudden onset acute respiratory infection of any severity that occurs, among others, with fever, cough or feeling of shortness of breath. Other symptoms such as odynophagia, anosmia, ageusia, muscle pain, diarrhea, chest pain or headache, among others, were also considered symptoms of suspected SARS-CoV-2 infection according to clinical criteria; and a positive PCR or rapid antigen test positive.

Criteria of Long-covid-19

The diagnostic criteria for Long covid-19 have already been published [11]. Basically Long-covid-19 was diagnosed by the presence of prolonged symptoms for at least 12 weeks, lasting at least 2 months, after acute covid-19 infection that are not explained by an alternative diagnosis)

Statistic Analysis

The bivariate comparisons were performed using the Chi Square test (X2) with Yates correction or Fisher Exact Test when necessary, (according to the number the expected cell totals) for percentages.

33 covid-19 cases in acute phase, with 138 symptoms and 27 Long covid-19 cases with 44 symptoms were included. Respiratory symptoms predominated in both groups. Symptoms in Long covid-19 cases were significantly lower in general symptoms [discomfort, asthenia, myalgia, fever, arthralgia] (X2= 5.9539. p= .014), and higher in Circulatory system [peripheral venous insufficiency, tachycardia on exertion] and Genitourinary [Lower urinary tract symptoms] (Fisher exact test= 0.05, in both). In Long covid 19 vs. covid-19 phase acute, ENT symptoms also predominated (anosmia / ageusia, odynophagia, rhinorrhea, pharyngeal dryness-mucus, epixtasis, epistaxis), Neurological (headache, dizziness, paresthesias, mental confusion -brain fog) and Psychiatric (anxiety/depression, insomnia), but without statistical significance (Table 1, Figure 1).

Main Findings

The main finding of our study was that although respiratory symptoms predominate in both acute phase covid-19 and Long covid-19, there are clinical differences between the two. The symptoms of long-term covid-19 versus covid-19 in the acute phase are more specific, clinically more relevant, and more heterogeneous, being frequent in almost all organs and systems, significantly in the Circulatory and Genitourinary system.

Comparison with Other Studies

The disease caused by the SARS-CoV-2 virus, covid-19, is characterized by a respiratory condition made up of different symptoms and signs that have been described as the pandemic has developed. Covid-19 has a wide range of clinical presentations ranging from general nonspecific symptoms to severe respiratory and cardiovascular complications, including acute respiratory distress syndrome and multiple organ failure leading to mortality. The most frequently reported symptoms in the acute phase are cough, myalgia, headache and fever, but dyspnea, fatigue, joint pain, sore throat, diarrhea, nausea and vomiting, anosmia, ageusia, nasal congestion, chest pain, and neuropsychiatric symptoms such as anxiety disorder, dementia, and insomnia [12, 13]. On the other hand, the symptoms of Long covid-19 vary, but can include severe fatigue, brain deterioration and nervous system dysfunction, as well as nausea and shortness of breath [3, 14]. However, patients with post covid-19 condition experience a wide range of physical and mental/psychological symptoms. More than 50 symptoms possibly associated with Long covid-19 have been described, including: fatigue, muscle weakness, alopecia, anosmia, dyspnea, gastrointestinal disorders, difficulty concentrating, insomnia, and anxiety [15]. Pooled prevalence data showed that the 10 most prevalent reported symptoms were fatigue, dyspnoea, muscle pain, joint pain, headache, cough, chest pain, altered odor, altered taste, and diarrhoea. Other common symptoms included temporary or even long-lasting cognitive dysfunction (impaired attention, executive functioning, language, processing speed, and memory, symptoms collectively referred to as "brain fog," along with increased incidence of anxiety, depression, sleep disorders, and chronic headache [16-22]. Dyspnea, fatigue, and anxiety were the most frequent symptoms 12 months after discharge [23], and fatigue and joint pain were the most frequent ninety days after discharge [24]. In addition, attention has been drawn to the abundance of cardiac symptoms among patients with Long covid-19 (25). These patients have been reported to be at increased risk of cardiovascular diseases such as heart failure and stroke just one year after contracting covid-19, regardless of the severity of the initial infection [3, 13, 14]. Our study shows results in line with these data. However, it must be borne in mind that the symptoms of covid-19 have changed throughout the pandemic. Different variants could also generate different symptoms of Long covid-19. In addition, the implementation of vaccination has changed the intensity of symptoms. That is, the new variants could show changing clinical pictures, not only with respect to the severity and symptoms of the acute disease, but possibly also with respect to the sequelae [26]. The initial virus infection caused quite severe cardiorespiratory or mainly respiratory symptoms in the acute phase with other symptoms as well, such as mental confusion. The alpha variant was associated with increased risk of muscle pain, insomnia, brain fog, anxiety/depression. When alpha was dominant, the prevalence of myalgia, dyspnea, brain fog/confusion, and anxiety/depression increased significantly in relation to the original variant, while anosmia, dysgeusia, and hearing impairment were less frequent. The runny nose had become more common during the delta wave. Omicron's BA.1 and BA.2 subvariants cause mainly upper respiratory symptoms, fever, myalgia, fatigue, sneezing, sore throat, and cough. The BA.4 and BA.5 subvariants are more likely to cause a sore throat and hoarse voice; Night sweats and insomnia are also symptoms that have emerged more frequently in the recent BA.5 era. Skin involvement during the Omicron wave was less frequent than during the Delta wave. More neurological and psychiatric disorders have been observed with the delta variant than with the alpha variant, and omicron was associated with similar neurological and psychiatric risks; Neurological symptoms after acute covid-19 appear to be a fairly dominant feature in patients with the older variants: the wild-type, alpha, and delta variants [27-29]. These variations between 2020 and 2022 in the symptoms of covid-19 have also been found in the population of our study [30]. In this same sense, three different profiles have been identified, with long-term symptoms centered on neurological, respiratory or physical conditions. As well as different patterns between people infected with the original strain of the coronavirus, the alpha variant and the delta variant. The largest group had a cluster of nervous system symptoms, such as fatigue, brain fog, and headaches. It was the most common subtype between the alpha variant, which was dominant in the winter of 2020-2021, and the delta variant, which was dominant in 2021. The second group had respiratory symptoms, such as chest pain and severe shortness of breath, which could suggest lung damage; this was the largest cluster of the original strain of coronavirus in the spring of 2020, when people were not vaccinated. The third group included people who reported a wide range of physical symptoms, including heart palpitations, muscle aches and pains, and skin and hair changes; this group had some of the most severe and debilitating multi-organ symptoms. Furthermore, while all three subtypes were present in all variants, other symptom groups had subtle differences between variants, such as symptoms in the stomach and intestines [6, 7]. In our study, the symptoms of covid-19 acute phase were collected from March 15, 2020 to March 31, 2021 and those of Long covid-19 from March 15, 2020 to October 31, 2022. During 2020, variants of original Wuhan virus were dominated in Spain [31-33]. In January 2021 alpha variant predominated, and from the summer-autumn of 2021 the delta variant was predominant [34, 35]. And from January 2022 to October 2022, the omicron variant predominated .

Limitations and Strengths of the Study

• The use of databases collected for specific purposes in the primary analysis, other than the secondary analysis, limits the analysis and interpretation of results.
• The population and the investigator was the same in both studies, which could allow the findings to be generalizable to similar populations.
• The number of cases was small, which may hide differences between the groups.
• Comparison of non-identical dates (from March 15, 2020 to March 31, 2021 versus from March 15, 2020 to October 31, 2022 can make interpretation of symptom differences difficult, as different virus variants can lead to different frequencies of predominant symptoms

Both in Long covid-19 and in covid-19 acute phase respiratory symptoms predominate. The symptoms of Long covid-19 are less general than those of covid-19 acute phase, and present more symptoms of almost all organs and systems, those of the Circulatory and Genitourinary system being significant. The symptoms of Long covid-19 vs. acute phase are more debilitating and clinically heterogeneous.

Table 1: Comparison of Symptoms in Covid-19 Acute Phase and Long Covid-19.

Figure 1: Comparison of Symptoms in Covid-19 Acute Phase and Long Covid-19.

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