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Article

Long COVID with Symptoms Persisting for More than Six Months in Unvaccinated Patients: Investigation of Biochemical Changes Associated with Chronic Manifestations

by
Matheus Torres
1,†,
Giulia Davanço
1,†,
Isabela de Paula Destro
1,
Neif Murad
1,
Glaucia Luciano da Veiga
1,*,
Pedro Henrique Alves Reis
1,
Renata de Lion Botero Martins
1,2,
Beatriz da Costa Aguiar Alves
1,
Rodrigo Daminello Raimundo
1,
Juliana Zangirolami-Raimundo
1 and
Fernando Luiz Affonso Fonseca
1,3
1
Laboratório de Análises Clínicas, Centro Universitário Faculdade de Medicina do ABC (FMABC), Santo André 09060-870, Brazil
2
Campus do Centro Universitário São Camilo, São Paulo 04263-200, Brazil
3
Departamento de Ciências Farmacêuticas, Universidade Federal de São Paulo (UNIFESP), Diadema 09972-270, Brazil
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
COVID 2026, 6(3), 39; https://doi.org/10.3390/covid6030039
Submission received: 8 October 2025 / Revised: 31 October 2025 / Accepted: 3 November 2025 / Published: 28 February 2026
(This article belongs to the Section COVID Clinical Manifestations and Management)
Browse Figure
Versions Notes

Abstract

Long COVID is a complex condition characterized by persistent symptoms following SARS-CoV-2 infection. Understanding its biochemical mechanisms is essential for effective management and treatment strategies. Objective: This study investigated biochemical alterations associated with long COVID in unvaccinated individuals presenting symptoms persisting for more than six months, highlighting the prolonged nature of the condition and its systemic and neurological manifestations. A cross-sectional study was conducted with 60 unvaccinated patients at least six months post-COVID-19 infection. Serum biomarkers, including C-reactive protein (CRP), interleukin-6 (IL-6), N-terminal pro-brain natriuretic peptide (NT-proBNP), and irisin, were analyzed. Correlations between these biomarkers and persistent symptoms were assessed using statistical regression models. Elevated CRP levels were significantly associated with persistent respiratory and musculoskeletal symptoms, suggesting ongoing inflammation. Increased IL-6 levels correlated with fatigue and musculoskeletal complaints. NT-proBNP elevations were linked to cardiovascular manifestations, including dyspnea and chest pain. A positive correlation between irisin and persistent sensory impairments, such as anosmia and dysgeusia, indicates potential neuroinflammatory mechanisms. This study highlights that persistent inflammation plays a critical role in long-term (>6 months) post-COVID manifestations. Monitoring biomarkers such as CRP, IL-6, NT-proBNP, and irisin may enhance understanding and management of prolonged post-COVID conditions.

1. Introduction

COVID-19, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is a respiratory disease first reported in Wuhan, China, on 31 December 2019. It was officially named COVID-19 in February 2020 [1].
SARS-CoV-2 utilizes the angiotensin-converting enzyme 2 (ACE2) as its primary cellular receptor, enabling viral entry and replication. ACE2, a membrane protein, plays a crucial role in blood pressure regulation via the renin–angiotensin–aldosterone system [2]. It is highly expressed in type II pneumocytes, which serve as the main entry point for the virus, but it is also found in the heart, intestines, kidneys, oral mucosa, and tongue [3].
Although SARS-CoV-2 primarily causes acute respiratory illness, many patients experience lingering symptoms for weeks or months post-infection, a condition referred to as “long COVID” or “post-COVID syndrome” [4]. The World Health Organization (WHO) recognizes that some individuals, regardless of hospitalization status, continue to experience symptoms such as fatigue, cardiovascular, respiratory, and neurological issues. According to the U.S. Department of Health and Human Services, long COVID encompasses signs, symptoms, and conditions that persist beyond four weeks after the initial infection [5].
Long COVID manifests with diverse symptoms, including shortness of breath, chest pain, neurocognitive impairment, anosmia, dysgeusia, profound fatigue, musculoskeletal pain, gastrointestinal disturbances, headaches, and dermatological issues [6]. Fatigue is one of the most prevalent symptoms, often exacerbated by physical or mental exertion (post-exertional malaise) [4,7,8,9]. It is frequently associated with non-restorative sleep, cognitive dysfunction (“brain fog”), and pain exacerbations [7,10]. Persistent respiratory symptoms, particularly dyspnea, are more common among hospitalized individuals, although they can occur in any patient [11].
Several pathological mechanisms are implicated in long COVID. Three key mechanisms supported by current evidence include: (1) persistence of viral components (e.g., S and N proteins) in tissues, causing direct tissue damage [12,13,14]; (2) dysregulated immune responses leading to inflammation and functional impairment [15,16]; and (3) endothelial inflammation and immune thrombosis [17]. Additionally, complement cascade dysregulation, protein misfolding, gut microbiome alterations, mitochondrial gene downregulation, circadian rhythm disruption, autonomic dysfunction, endocrine abnormalities, and blood–brain barrier disruption have been proposed as contributing factors [18,19,20].
Long COVID incidence varies: 50–85% among unvaccinated hospitalized patients, 10–35% among unvaccinated non-hospitalized individuals, and 8–12% among vaccinated individuals [21,22]. Vaccination is associated with a reduced risk and severity of long COVID [23].
This study aims to investigate long COVID symptoms in unvaccinated patients and their associated biochemical changes.

2. Materials and Methods

2.1. Study Design and Participants

This cross-sectional study was conducted from February to October 2021 at Hospital Estadual Mário Covas and Centro Universitário FMABC, in accordance with the STROBE guidelines for observational studies [24]. Ethical approval was obtained from the Research Ethics Committee of Centro Universitário ABC/FMABC (#4,875,433), and all participants provided informed consent.
Participants aged 18–80 years, at least six months post-SARS-CoV-2 infection, confirmed via RT-PCR or serology, were included. Exclusion criteria comprised autoimmune, oncologic, or infectious comorbidities. Blood samples were analyzed for CRP, IL-6, NT-proBNP, and irisin levels. Patients with autoimmune diseases, HIV, hepatitis B or C, or cancer were excluded. A cardiologist assessed all participants.

2.2. Biochemical Analysis

Peripheral blood samples were collected for biochemical testing. Complete blood counts were performed using flow cytometry (HORIBA ABX SAS® PENTRA120, Montpellier, France). Immunoenzymatic assays and high-sensitivity C-reactive protein (hs-CRP) analysis were conducted.

2.3. Statistical Analysis

The normality of data distribution was assessed using the Shapiro–Wilk test (significance threshold: p > 0.05). Continuous variables are presented as mean ± standard deviation when normally distributed, or as median with interquartile range (IQR) for non-normally distributed data. Correlation analyses were performed using Pearson’s correlation coefficient for normally distributed variables and Spearman’s rank correlation coefficient for non-normally distributed variables. Statistical significance was defined as p < 0.05. All analyses were conducted using GraphPad Prism software (version 10.1.4, GraphPad Software, San Diego, CA, USA).

3. Results

In this study, 60 patients were evaluated, 38 (63.3%) women and 22 (36.7%) men. The mean age was 46 ± 13 years.
Patients reported 43 different signs and symptoms during infection. Among the symptoms, the following stand out: altered taste, fever, myalgia, altered smell, cough altered appetite, headache, diarrhea, nausea, weight loss, dizziness and throat pain/irritation. Table 1 consists of the frequency of the aforementioned symptoms and their distribution according to sex. The following stand out: asthenia/fatigue, dyspnea, chest pain, palpitation and lower limb edema as cardiovascular symptoms. The frequency of cardiovascular symptoms is described in Table 2.
Forty-six symptoms were reported, signs of distinct diseases that emerged after infection. The main symptoms and general signs were: memory loss, cognitive loss, alopecia, myalgia, psychiatric complaints, increased incidence of new infections, ophthalmological changes, olfactory changes, glycemic uncontrolled and hormonal changes. The frequency of each symptom and its distribution according to sex can be found in Table 3. In addition, cardiovascular symptoms (tachycardia, paroxysmal nocturnal dyspnea, angina and fatigue), cardiovascular signs (lower limb edema) and cardiovascular diseases (hypertension, heart failure) have been reported (Table 4).
From the analyses of the blood samples of the 60 patients, 18 showed changes in serum hs-CPR levels, 8 showed suggestive alteration of NT-proBNP and 23 showed changes in IL-6 levels. Table 5 describes the values of the hs-CPR, NT-proBNP and IL-6 markers. The biochemical analysis revealed mean hs-CRP levels of 5.223 ± 7.806 mg/L (median: 2.92 mg/L), slightly above the threshold of 3 mg/L [25], which is indicative of increased cardiovascular risk or chronic low-grade inflammation. The mean NT-proBNP concentration was 71.501 ± 130.836 pg/mL (median: 35.05 pg/mL), the normal reference range for adults (<125 pg/mL) [26]. The mean IL-6 level was 3.276 ± 2.748 pg/mL (median: 2.56 pg/mL), the cutoff is >10 pg/mL [27]. Irisin expression showed a mean value of 0.0179 ± 0.053 (median: 0.0026), for which no standardized reference range is currently established for gene or protein expression analyses (Figure 1).
Table 1. General symptoms experienced by patients during infection and persistent after infection [28].
Table 1. General symptoms experienced by patients during infection and persistent after infection [28].
SymptomsN (%)Affected Women (%)Affected
Men (%)		N
Persistent
(%)		Persistent Symptoms
Women
(%)		Persistent
Symptoms
Men
(%)
Altered Taste44 (73.33)55.2631.8227 (45.00)52.6331.82
Fever41 (68.33)57.8986.360 (0.00)0.000.00
Myalgia40 (66.67)63.1672.7312 (20.00)28.954.55
Altered Smell39 (65.00)71.0554.5524 (40.00)47.3727.27
Cough37 (61.67)60.5363.646 (10.00)13.164.55
Altered appetite28 (46.67)55.2631.823 (5.00)7.890.00
Headache27 (45.00)47.3740.9114 (23.33)36.840.00
Diarrhea24 (40.00)44.4731.820 (0.00)0.000.00
Nausea20 (33.33)31.5836.361 (1.67)2.630.00
Weight loss16 (26.67)26.3227.271 (1.67)2.630.00
Sneeze15 (25.00)28.9518.182 (3.33)5.260.00
Dizziness14 (23.33)31.589.094 (6.67)10.530.00
Throat pain/irritation13 (21.67)23.6818.180 (0.00)0.000.00
Asthenia/fatigue49 (81.67)76.3290.9130 (50.00)52.6345.45
Table 2. Cardiovascular symptoms presented by patients during infection and persistent after infection.
Table 2. Cardiovascular symptoms presented by patients during infection and persistent after infection.
SymptomsN (%)Affected Women (%)Men
Affected (%)		N
Persistent
(%)		Persistent
Symptoms
Women
(%)		Persistent
Symptoms
Men
(%)
Dyspnea35 (58.33)63.1650.0019 (31.67)39.4718.18
Chest pain2 (3.33)2.634.550 (0.00)0.000.00
Palpitation1 (1.67)04.550 (0.00)0.000.00
Lower limb edema1 (1.67)04.551 (1.67)0.004.55
Table 3. General symptoms and new diseases presented by patients after infection.
Table 3. General symptoms and new diseases presented by patients after infection.
SymptomsN (%)Affected
Women (%)		Affected
Men (%)
Memory loss32 (53.33)55.2650.00
Cognitive Loss31 (51.67)55.2645.45
Alopecia22 (36.27)52.639.09
Myalgia11 (18.33)21.0513.64
Psychiatric complaints9 (15.00)15.7913.64
Increase/New infections7 (11.67)13.169.09
Ophthalmic changes5 (8.33)10.534.55
Smell Alteration3 (5.00)5.264.55
Glycemic uncontrolled3 (5.00)5.264.55
Hormonal changes2 (3.33)5.260.00
Table 4. Symptoms and new diseases presented by patients after infection.
Table 4. Symptoms and new diseases presented by patients after infection.
SymptomsN (%)Affected
Women (%)		Affected
Men (%)
Hypertension5 (8.33)7.899.09
Tachycardia3 (5.00)5.264.55
Paroxysmal nocturnal dyspnea1 (1.67)0.004.55
Lowe limb edema1 (1.67)2.630.00
Heart failure1 (1.67)2.630.00
Angina1 (1.67)2.630.00
Fatigue1 (1.67)0.004.55
Table 5. Cardiovascular serological markers.
Table 5. Cardiovascular serological markers.
hs-CPR (mg/L)N-Terminal-ProBNP (pg/mL)IL-6
(pg/mL)
Number of patients606060
Minimum0.405.001.50
25% percentile1.4218.001.83
Median2.7436.002.57
75% percentile5.7272.003.83
Maximum49.17913.0020.40
Range48.77908.0018.90
Mean5.1671.506.94
Standard Deviation7.75130.833.27
Standard error of the mean1.0016.890.42
Lower estimate of confidence interval (95%)3.238.396.12
Upper estimate of confidence interval (95%)7.12104.607.77
When persistent musculoskeletal and neurological symptoms were evaluated after the resolution of the acute infection, we identified that neurological manifestations were reported by a subset of participants. Headache was observed in one participant (25.0%), representing a common complaint in post-COVID-19 conditions, often associated with neuroinflammatory mechanisms. Cognitive impairment, also reported by one participant (25.0%), manifested as difficulties in attention and memory, consistent with the clinical description of post-COVID “brain fog.” Paresthesia was identified in one participant (25.0%), suggesting possible peripheral or central nervous system involvement. Finally, dizziness or vertigo occurred in one participant (25.0%), which may reflect vestibular dysfunction or autonomic imbalance frequently described in long COVID cases.
Linear regression analysis showed a relationship between the biomarkers measured and the symptoms reported by the patients, and there was a significant relationship between the CRP, IL-6 and irisin markers with persistent symptoms after infection. Table 6 shows the biomarkers that showed significant correlation (p < 0.05) with patient-reported symptoms.

4. Discussion

COVID-19 has emerged not only as an acute infectious disease but also as a condition with long-term systemic consequences, collectively referred to as post-COVID-19 syndrome or long COVID. These manifestations involve complex and overlapping pathophysiological processes, including persistent inflammation, immune dysregulation, endothelial dysfunction, and neuroinflammatory responses. In this context, the present study provides new evidence linking inflammatory and metabolic biomarkers—such as CRP, IL-6, NT-proBNP, and irisin—to the persistence of respiratory, musculoskeletal, cardiac, and sensory symptoms in unvaccinated individuals. Rather than interpreting each biomarker in isolation, these findings should be understood as interconnected components of a sustained inflammatory network that contributes to the chronic symptom burden observed in long COVID. This integrative perspective underscores the multifactorial nature of the syndrome and aligns with emerging evidence that persistent immune activation may underlie the broad spectrum of clinical manifestations seen after SARS-CoV-2 infection.
C-reactive protein (CRP) was correlated with persistent respiratory and musculoskeletal symptoms. CRP is a widely used inflammatory marker, often elevated in COVID-19 patients, and associated with disease severity [29] and long-term complications such as post-COVID syndrome [30]. During the acute phase of infection, CRP reflects the intensity of the systemic inflammatory response triggered by SARS-CoV-2 [31]. In the context of long COVID, persistently elevated CRP levels have been linked to ongoing respiratory symptoms, such as dyspnea, cough, and respiratory difficulty [32,33]. This suggests that chronic inflammation plays a key role in the pathogenesis of long-term respiratory symptoms observed in some patients after acute infection [15,20,34]. Additionally, studies indicate that severe acute-phase disease, reflected by higher CRP levels [35], may increase the risk of developing post-COVID-19 syndrome and persistent respiratory symptoms [36]. Patients who experienced severe COVID-19 requiring hospitalization or intensive care are more likely to develop long-term respiratory complications [28,37]. Thus, the elevated CRP levels detected in this study’s patients indicate a persistent inflammatory state, which correlates with the presence of long COVID symptoms.
IL-6, a pro-inflammatory cytokine, was also significantly correlated with persistent musculoskeletal symptoms. The literature highlights IL-6 as a crucial component of the inflammatory response during infectious processes, with elevated levels frequently observed in severe COVID-19 cases [38,39]. Persistently high IL-6 levels post-infection may contribute to chronic inflammation, manifesting as fatigue and pain, both commonly associated with post-COVID-19 syndrome [40]. Furthermore, the correlation between IL-6 and musculoskeletal symptoms suggests that inflammation may be a key driver of the pain and physical discomfort experienced by these patients.
Recent neuroimaging studies have provided compelling evidence that supports the biological plausibility of the associations observed between inflammatory biomarkers and neurological sequelae in post-COVID-19 syndrome. Elevated IL-6 and CRP levels, as observed in our study, have been linked to persistent neuroinflammatory activity and metabolic brain alterations detected by advanced imaging techniques. MRI and PET studies have demonstrated cortical and subcortical hypometabolism, particularly in the frontal and limbic regions, as well as microstructural white matter changes consistent with ongoing inflammation and gliosis [41,42,43]. These alterations correlate with clinical symptoms such as cognitive impairment, mental fatigue, and emotional dysregulation, supporting the concept that systemic inflammation contributes to CNS dysfunction in PACS. The convergence of biochemical and neuroimaging findings strengthens the hypothesis that long-term neurological symptoms in post-COVID-19 patients arise from persistent neuroinflammatory and metabolic disturbances rather than isolated psychological factors [41].
Beyond the acute phase, elevated NT-proBNP levels in post-COVID-19 patients may not solely represent a residual effect of prior cardiac injury but could also indicate a sustained pathophysiological process characteristic of long COVID [44,45]. Evidence from cardiac magnetic resonance and echocardiographic studies has shown persistent myocardial inflammation, microvascular dysfunction, and subtle ventricular remodeling months after recovery from acute SARS-CoV-2 infection [46,47]. These findings suggest that chronic low-grade inflammation and endothelial injury may contribute to ongoing myocardial stress and neurohormonal activation, leading to prolonged NT-proBNP elevation. Moreover, autonomic dysregulation and impaired baroreceptor sensitivity, commonly described in long COVID, may further exacerbate cardiac workload. Therefore, in the context of post-COVID syndrome, increased NT-proBNP levels likely reflect a combination of residual myocardial damage from the acute phase and persistent pathophysiological mechanisms involving inflammation, endothelial dysfunction, and autonomic imbalance [48,49,50].
NT-proBNP was selected in this study as a cardiac biomarker due to its superior biochemical stability and longer plasma half-life compared to BNP, making it a more reliable indicator of subclinical myocardial stress and chronic cardiac dysfunction. Unlike BNP, which is rapidly cleared from circulation, NT-proBNP remains stable for longer periods, allowing a more consistent assessment of cardiac overload and neurohormonal activation, even in patients with mild or subclinical manifestations. Its robust analytical properties and prognostic value have been widely demonstrated in cardiovascular research, consolidating NT-proBNP as the preferred biomarker for detecting and monitoring cardiac involvement in post-COVID-19 conditions [48,51].
Regarding irisin, a positive correlation was identified between this biomarker and persistent sensory symptoms, including anosmia (loss of smell) and dysgeusia (altered taste). These associations may be attributed to a chronic inflammatory response and damage to neural pathways responsible for sensory perception [42,52]. Irisin, a hormone produced by skeletal muscle in response to physical exercise, has demonstrated beneficial effects on cognitive function, neuroprotection, and inflammation control. Irisin has shown potential for modulating inflammation and promoting neuroplasticity, suggesting that adequate levels of this biomarker may aid in recovering impaired sensory functions. Studies indicate that physical exercise, which increases irisin release, can help reduce inflammation and improve cognitive and sensory function [53,54]. Additionally, irisin is associated with increased brain-derived neurotrophic factor (BDNF), which plays a crucial role in neuronal health and the recovery of cognitive and sensory functions [55]. The positive correlation between irisin and persistent sensory symptoms found in this study suggests it may act as a regulatory mechanism promoting neuronal recovery during post-COVID syndrome.
Recent studies and international clinical guidelines have adopted the term brain fog as an umbrella concept that encompasses both cognitive dysfunction and mental fatigue in individuals with post-COVID-19 condition. In accordance with the definitions proposed by the World Health Organization (WHO) and the National Institute for Health and Care Excellence (NICE), the present study refers to brain fog as a neurocognitive and neuroinflammatory phenomenon characterized by difficulties in attention, memory, and information processing, often accompanied by a persistent sense of mental exhaustion. This terminology provides a more comprehensive and standardized framework for describing cognitive alterations associated with COVID-19, highlighting their biological and neurological basis rather than attributing them solely to subjective perception [28].
In summary, this study concluded that long COVID symptoms in unvaccinated patients correlate with altered CRP, IL-6, and NT-proBNP levels and a positive correlation with irisin as a modulatory biomarker. These findings highlight the significant role of COVID-19 vaccination in mitigating post-COVID symptoms. The literature supports that immunization not only reduces acute infection severity but also lowers the incidence of persistent symptoms after infection [56,57].
Several studies confirm that pre-infection COVID-19 vaccination reduces acute disease severity and the incidence of persistent symptoms. One study found that the probability of persistent symptoms post-infection was 60% in vaccinated individuals, compared to 79.1% among the unvaccinated [58]. A meta-analysis demonstrated that pre-infectious vaccination is associated with an 18% to 40% reduction in persistent symptoms compared to unvaccinated individuals [58,59]. Vaccination can reduce viral burden, inflammatory responses, and immune activation contributing to symptom persistence [60]. Furthermore, vaccinated individuals exhibit a more robust immune response, leading to lower levels of inflammatory biomarkers such as CRP and IL-6. Immunization has also been linked to a decreased risk of developing post-COVID-19 syndrome, as it mitigates viral burden and inflammatory responses associated with infection [61]. Thus, the high incidence of post-COVID manifestations identified in this study is directly related to the fact that only unvaccinated patients were included. These findings underscore the importance of CRP, IL-6, NT-proBNP, and irisin in understanding the pathogenesis of long COVID and their correlation with post-COVID manifestations.

5. Conclusions

This study demonstrates that long COVID in unvaccinated individuals with symptoms persisting beyond six months is characterized by chronic inflammatory and metabolic dysregulation. Elevated levels of C-reactive protein (CRP) and interleukin-6 (IL-6) were significantly associated with persistent systemic, respiratory, and musculoskeletal symptoms, underscoring the central role of sustained inflammation in the pathophysiology of post-acute sequelae of SARS-CoV-2 infection. Additionally, increased NT-proBNP concentrations suggest subclinical cardiac involvement and ongoing cardiopulmonary stress in this population. Notably, a positive association was observed between the myokine irisin and sensory symptoms such as anosmia and dysgeusia, potentially reflecting a compensatory or neuroprotective mechanism linked to neuronal repair processes. Collectively, these findings highlight that the persistence of long COVID symptoms is closely tied to chronic inflammatory burden and metabolic imbalance, and they position irisin as a potential modulatory biomarker in this context. The exclusive inclusion of unvaccinated participants further emphasizes the protective role of vaccination, which has been shown to mitigate both the acute inflammatory response and the risk of developing long-term complications.
Accordingly, monitoring biomarkers such as CRP, IL-6, NT-proBNP, and irisin may enhance clinical stratification, deepen pathophysiological understanding, and inform targeted management strategies for long COVID. Future longitudinal studies with control groups—including vaccinated individuals—are essential to establish causal relationships and evaluate post-vaccination differences in the trajectory and severity of long COVID syndrome.

Author Contributions

Conception and design of the research: G.D., M.T., N.M., G.L.d.V. and F.L.A.F. Acquisition of data: N.M., G.L.d.V., G.D., M.T., R.d.L.B.M. and F.L.A.F. Analysis and interpretation of the data: G.L.d.V., G.D., M.T., R.d.L.B.M., R.D.R. and J.Z.-R. Statistical analysis: G.L.d.V., R.D.R. and J.Z.-R. Obtaining financing: G.D., M.T. and F.L.A.F. Writing of the manuscript: I.d.P.D., G.L.d.V., G.D., M.T., B.d.C.A.A., R.D.R. and F.L.A.F. Critical revision of the manuscript for important intellectual content: G.L.d.V., N.M., G.D., M.T., I.d.P.D., P.H.A.R., B.d.C.A.A. and F.L.A.F. All authors have read and agreed to the published version of the manuscript.

Funding

This study was funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) #2021/15162-2.

Institutional Review Board Statement

Ethical approval was obtained from the Research Ethics Committee of Centro Universitário ABC/FMABC (protocol #4,875,433, approved on 21 June 2021), and all participants provided written informed consent prior to inclusion in the study. All procedures were conducted in accordance with the ethical standards of the institutional and national research committees and with the principles outlined in the Declaration of Helsinki.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author (Glaucia Veiga: grlveiga@gmail.com) upon reasonable request. Data sharing is subject to ethical and privacy restrictions in accordance with institutional guidelines.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
ACE2Angiotensin-Converting Enzyme 2
BDNFBrain-Derived Neurotrophic Factor
COVID-19Coronavirus Disease 2019
CRPC-Reactive Protein
FMABCFaculdade de Medicina do ABC
HIVHuman Immunodeficiency Virus
hs-CRPHigh-Sensitivity C-Reactive Protein
IgGImmunoglobulin G
IgMImmunoglobulin M
IL-6Interleukin 6
NT-proBNPN-terminal pro-B-type Natriuretic Peptide
RNARibonucleic Acid
RT-PCRReverse Transcription Polymerase Chain Reaction
SARS-CoV-2Severe Acute Respiratory Syndrome Coronavirus 2
STROBEStrengthening the Reporting of Observational Studies in Epidemiology
WHOWorld Health Organization

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Covid 06 00039 g001
Figure 1. Distribution of serum biomarker concentrations in long COVID patients. Boxplots illustrate the variability and median values of high-sensitivity C-reactive protein (hs-CRP), N-terminal pro–B-type natriuretic peptide (NT-proBNP), and interleukin-6 (IL-6). Outliers are represented as open circles. The orange dots indicate the reported median values for each biomarker.
Figure 1. Distribution of serum biomarker concentrations in long COVID patients. Boxplots illustrate the variability and median values of high-sensitivity C-reactive protein (hs-CRP), N-terminal pro–B-type natriuretic peptide (NT-proBNP), and interleukin-6 (IL-6). Outliers are represented as open circles. The orange dots indicate the reported median values for each biomarker.
Covid 06 00039 g001
Table 6. Evaluation of the relationship of biomarkers with persistent symptoms after infection.
Table 6. Evaluation of the relationship of biomarkers with persistent symptoms after infection.
Persistent Respiratory Symptoms
(r2)		pPersistent Musculoskeletal Symptoms
(r2)		pPersistent Sensory Symptoms
(r2)		p
hs-CRP0.2880.0260.5610.000--
NT-pro-BNP--−0.2290.078-
IL-6--0.4420.000--
Irisin--- 0.4640.001
Note: Data obtained from linear regression analysis. GraphPad Prism software version 6.
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Torres, M.; Davanço, G.; de Paula Destro, I.; Murad, N.; da Veiga, G.L.; Reis, P.H.A.; de Lion Botero Martins, R.; da Costa Aguiar Alves, B.; Raimundo, R.D.; Zangirolami-Raimundo, J.; et al. Long COVID with Symptoms Persisting for More than Six Months in Unvaccinated Patients: Investigation of Biochemical Changes Associated with Chronic Manifestations. COVID 2026, 6, 39. https://doi.org/10.3390/covid6030039

AMA Style

Torres M, Davanço G, de Paula Destro I, Murad N, da Veiga GL, Reis PHA, de Lion Botero Martins R, da Costa Aguiar Alves B, Raimundo RD, Zangirolami-Raimundo J, et al. Long COVID with Symptoms Persisting for More than Six Months in Unvaccinated Patients: Investigation of Biochemical Changes Associated with Chronic Manifestations. COVID. 2026; 6(3):39. https://doi.org/10.3390/covid6030039

Chicago/Turabian Style

Torres, Matheus, Giulia Davanço, Isabela de Paula Destro, Neif Murad, Glaucia Luciano da Veiga, Pedro Henrique Alves Reis, Renata de Lion Botero Martins, Beatriz da Costa Aguiar Alves, Rodrigo Daminello Raimundo, Juliana Zangirolami-Raimundo, and et al. 2026. "Long COVID with Symptoms Persisting for More than Six Months in Unvaccinated Patients: Investigation of Biochemical Changes Associated with Chronic Manifestations" COVID 6, no. 3: 39. https://doi.org/10.3390/covid6030039

APA Style

Torres, M., Davanço, G., de Paula Destro, I., Murad, N., da Veiga, G. L., Reis, P. H. A., de Lion Botero Martins, R., da Costa Aguiar Alves, B., Raimundo, R. D., Zangirolami-Raimundo, J., & Fonseca, F. L. A. (2026). Long COVID with Symptoms Persisting for More than Six Months in Unvaccinated Patients: Investigation of Biochemical Changes Associated with Chronic Manifestations. COVID, 6(3), 39. https://doi.org/10.3390/covid6030039

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