Correlation Between Inflammatory Parameters and Thyroid Axis in Patients With COVID-19

doi:10.21203/rs.3.rs-563531/v1

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Correlation Between Inflammatory Parameters and Thyroid Axis in Patients With COVID-19

https://doi.org/10.21203/rs.3.rs-563531/v1

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Purpose: Inflammation plays a critical role in the progression of COVID-19. Nonthyroidal illness syndrome (NTIS) has been increasingly recognized in affected patients. We aim to evaluate the correlation of thyroid hormones with markers of inflammation and association with disease outcome in hospitalized patients with COVID-19, and in two profiles of NTIS (low T3-normal/low FT4 vs low T3-high FT4).

Methods: prospective study of 55 patients (50.9% men, median age 56 years) admitted to a non-intensive care unit for COVID-19. Infection was mild in 22%, moderate in 27.1% and severe in 50.8%; 7.41% died. T4, T3, FT4, FT3 and their ratios (T3/T4, FT3/FT4) were correlated with albumin, ferritin, fibrinogen, erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], lactate dehydrogenase [LDH] and D-dimer.

Results: Albumin correlated positively with T3 and hormones ratios, but negatively with FT4. T3, FT3, T3/T4 and FT3/FT4 ratios correlated inversely with ferritin, fibrinogen, ESR, CRP, LDH and D-dimer. FT4 showed direct correlation with fibrinogen and ESR. T3/T4 ratio was lower in severe compared to mild/moderate disease [7.5 (4.5-15.5) vs 9.2 (5.8-18.1); p=0.04], and lower in patients who died than in those discharged [5 (4.53-5.6) vs 8.1 (4.7-18.1); p=0.03]. A lowT3/high FT4 profile was associated with lower albumin, higher ferritin, and severity.

Conclusion: In this cohort, thyroid hormones correlated with inflammation and outcome. T3 and T3/T4 ratio correlated inversely with inflammatory markers; a low T3/T4 ratio was associated with severity and poor prognosis. Patients with low T3 but high FT4 had higher ferritin, lower albumin, and more severe disease at presentation.

General Biochemistry

Molecular Biology

Endocrinology & Metabolism

COVID-19

inflammatory markers

thyroid hormones

nonthyroidal illness syndrome

The outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), has rapidly spread worldwide and led to the declaration of Public Health Emergency of International Concern by the World Health Organization (WHO) [1–2]. SARS-CoV-2 has a wide spectrum of clinical severity, ranging from a- or pauci-symptomatic presentation to disease-specific mortality [3]. COVID-19 has the potential to cause upper respiratory tract, pulmonary and systemic inflammation, determining multi-organ dysfunction especially in frail patients [4].

Both direct (i.e., caused by the virus infection of the target cells) and indirect injury (i.e., through abnormal immune inflammatory responses to the virus and likely involving the coagulation, cytokine and complement systems) have been linked to the wide clinical expression spectrum and multisystem organ failure of COVID-19 and SARS [5–9]. Angiotensin-converting enzyme 2 (ACE2), the functional receptor for SARS-CoV-2, plays a role in the pathogenesis of COVID-19. ACE2 expression is present in many endocrine organs, including the thyroid gland [10]. Increasing evidence suggests that COVID-19 affects thyroid function [11].

The nonthyroidal illness syndrome (NTIS) comprises a constellation of alterations in the central component of the hypothalamus–pituitary–thyroid (HPT) axis and changes in thyroid hormones (TH) metabolism in a variety of TH target organs [12]. NTIS can occur in several acute or chronic systemic diseases including cardiovascular, respiratory, infectious diseases and cancer [13]. The most typical hormonal changes are low plasma T3, low or normal plasma T4, or elevated plasma reverse (rT3), in the presence of normal or slightly decreased TSH [13]. Cytokines, released during illness, are considered a major determinant of NTIS since they affect a variety of genes involved in TH metabolism [12]. Chen reported that NTIS could underlie the hormonal changes of at least 30% (15/50) of hospitalized patients with COVID-19 [14]. A study by Khoo et al [15] detected that patients with COVID-19 had lower admission TSH and FT4 levels compared to those without COVID-19. Ten patients with COVID-19 in a study by Lui and colleagues [16] were found to have isolated low FT3, with normal TSH and FT4 levels, suggesting a possible NTIS; FT3 in the study showed a decreasing trend with worsening clinical severity of the disease. Furthermore, an independent inverse correlation between erythrocyte sedimentation rate and FT3/FT4 ratio was also demonstrated in the study by Lui, which suggested the potential effect of systemic inflammation on deiodinase activity [17]. Our group studied a population of hospitalized patients with COVID-19 and found low T3 in 42/ 57 (73, 7%). Most of them represented classic NTIS profile, with low/normal FT4 and normal TSH, but 11/42 (26%) of the patients with low T3 had high FT4 (data submitted for publication). Whether this represents a new NTIS profile is not yet fully clarified.

In the present study, we aimed to evaluate the correlation of thyroid hormones with biochemical markers of inflammation and association with disease outcome in hospitalized patients with COVID-19. We also evaluated these parameters in the two profiles of NTIS (low T3-normal/low FT4 vs low T3-high FT4).

This was a prospective single center cohort study performed between August and November 2020. Fifty-five consecutive adult patients (> 18 years old) were recruited. The presence of SARS-CoV2 was confirmed in all patients by RT-PCR from the nasopharyngeal swab. All of them were initially admitted to a non-intensive care unit. Clinical and demographic data were extracted from patient records. Data regarding major comorbidities, vital signs, baseline oxygen saturation by pulse oximetry, chest X-ray and chest CT scan, when performed, were registered.

Each patient had blood tests upon admission before the initiation of treatments of COVID-19. Complete blood count and biochemical parameters such as urea, creatinine, fasting glucose, total cholesterol, aspartate and alanine aminotransferase, albumin (Reference range [RR] 3.5–5.2 g/dl), ferritin (RR 20–159 ng/ml), fibrinogen (RR 150–450 mg%), erythrocyte sedimentation rate (ESR) (RR 1–15 mm/h), C-reactive protein (CRP) (RR 0–5.0 mg/l), lactate dehydrogenase (LDH) (RR 230–480 UI/l), D-dimer (RR 0-500 ng/ml) were analyzed after a 12 h fasting. Thyroid hormones [thyrotropin (TSH: 0.5-4.0 mIU /ml), total T4 (T4: 5–11,5 ug/dl), free T4 (FT4: 0,8 − 1,4 ng/dl), total T3 (T3: 85–175 ng/dl), free T3 (FT3: 1.9–4.1 pg/ml)], and thyroid peroxidase antibody (TPOAb: <20 IU / ml) were measured with chemiluminescence assay IMMULITE 2000. Samples were obtained within 48 hours of admission.

COVID-19 severity was classified according to the ‘Chinese Clinical Guidance for COVID-19 Pneumonia Diagnosis and Treatment (7th edition)’ published by the Chinese National Health Commission [18]. Mild disease was defined by mild clinical symptoms without manifestations of pneumonia on imaging. Moderate disease was defined by fever and respiratory symptoms, and manifestations of pneumonia on imaging. Severe disease was defined by any of the following: respiratory rate ≥ 30/min, SpO2 ≤ 93% at rest, and > 50% progression in 48 hours on imaging. A favorable evolution was considered when patients did not have high oxygen requirements or were not admitted to the intensive care unit.

The study followed the principles in the Declaration of Helsinki and was approved by the Institutional Review Board of the Jose Maria Ramos Mejia Hospital. All patients provided written informed consent.

Statistical analysis

All data were analyzed using Statistical Package for Social Sciences (SPSS) version 21.0 software (SPSS Inc., Chicago, IL, United States); any p value < .05 was regarded as statistically significant. Categorical data were described using frequencies and percentages. Continuous data were described using median and range. The distribution of baseline characteristics across categories of the exposure variable was evaluated using nonparametric statistics. The proportions were compared with chi-square test or Fisher's exact test. Continuous variables were tested by Wilcoxon rank-sum test. Spearman correlations were used to assess the relationship between continuous variables.

The final study population included 55 patients: 28 (50.9%) men and 29 (49.1%) women, with a median age of 56 years (range 21-89y). Patients were classified according to the severity of the infection as mild in 22% of the cases, moderate in 27.1% and severe in 50.8%. 84.7% were considered to have a favorable evolution, while 3.4% had high oxygen requirements and 11.9% were admitted to the intensive care unit for mechanical ventilation. Four patients (7.41%) of the total population died.

We found correlation between thyroid hormones and thyroid hormones ratios (T3/T4, FT3/FT4) with several inflammatory parameters (Table 1). Serum albumin correlated positively with T3 and thyroid hormones rations, but negatively with FT4. We observed an inverse correlation between ferritin, fibrinogen, ESR, CRP, LDH and D-dimer with T3, FT3. The magnitude of this correlation was even more important with T3/T4 and FT3/FT4 ratios. On the other hand, T4, and specially FT4, showed a direct correlation with fibrinogen and ESR.

Table 1. Correlation between thyroid hormones and inflammatory parameters. In light blue, direct correlations. In orange, inverse correlations.

When we analyzed thyroid hormones levels according to severity of the disease and to clinical evolution of the patients, we observed that T3/T4 ratio was significantly lower in those patients with a severe form of the disease compared with those with mild/moderate infection [7.5 (4.5–15.5) vs 9.2 (5.8–18.1); p = 0.04] (Fig. 1a). Also, T3/T4 ratio was significantly lower in patients who died than in patients who were finally discharged [5 (4.53–5.6) vs 8.1 (4.7–18.1); p = 0.03] (Fig. 1b).

Forty patients (72.7%) had low T3 levels. Thirty of them had normal or low levels of FT4, with normal TSH, corresponding to a classic NTIS profile, whereas 10 had high FT4 levels with normal TSH. We observed that those with high FT4 had lower albumin [3.4 g/dl (3–4) vs 3.7 g/dl (3–4); p = 0.03], higher ferritin [1202 ng/ml (930–7127) vs 435 ng/ml (101–2232); p < 0.05] (Fig. 2a and b) and tendency to higher fibrinogen [681 mg% (583–798) vs 508 mg% (307–807); p = 0.06] than those with normal/low FT4. Also, no patient with mild disease at presentation had high FT4.

In this prospective study, we observed that, among patients with COVID-19 infection, thyroid hormones and their ratios correlated with different parameters of inflammation. T3, FT3, T3/T4 and FT3/FT4 showed an inverse correlation with ferritin, fibrinogen, ESR, CRP, LDH and D-dimer, whereas FT4 was directly correlated with fibrinogen and ESR.

Accumulating evidence has suggested that inflammatory responses play a critical role in the progression of COVID-19. Inflammatory responses triggered by rapid viral replication of SARS-CoV-2 and cellular destruction can recruit macrophages and monocytes and induce the release of cytokines and chemokines. These cytokines and chemokines then attract immune cells and activate immune responses, leading to cytokine storms and aggravations. Several inflammatory markers such as procalcitonin, CRP, ESR, IL-6 have been reported to be significantly associated with the severity of COVID-19 [19]. Nonthyroidal illness syndrome presents as abnormal thyroid function in serious diseases other than thyroid disorders, including infection [13]. It is well established that NTIS is a consequence of an acute phase response to severe systemic illness or macronutrient restriction and usually presents as decreased plasma T3 level, or low or normal T4 and TSH levels. Cytokines, released during illness, are considered a major determinant of NTIS since they affect a variety of genes involved in TH metabolism [12].

Some studies have analyzed the thyroid function in COVID-19 patients and found patterns suggestive of NTIS [14–16, 20], but very few have reported an association with markers of inflammation. Lui et al found that higher CRP level was independently associated with low FT3. FT3 and FT3/FT4 ratio showed an inverse correlation with CRP, similar to our findings [16]. Wang et al identified increased levels of leucocytes, neutrophils, CRP and procalcitonin, and decreased level of lymphocytes in thyroid dysfunction group [20]. They defined thyroid dysfunction as any abnormality in TT3, TT4, or TSH. These findings, along with ours, suggest the potential effect of systemic inflammation on deiodinase activity. Systemic inflammation, (represented by higher inflammatory markers), which in turn is associated with systemic tissue injury, lead to reduce deiodinase activity. This results in decreased conversion of T4 to T3, leading to low FT3 [12, 21].

Data have shown that IL-6 levels are also significantly higher in COVID-19-patients with a severe status compared with those with a non-severe condition, so IL-6 is a prognostic marker in serious COVID-19 cases [22]. Moreover, serum IL-6 is also often elevated in NTIS (the exact mechanism is not defined yet), and its level is inversely related to T3 levels in NTIS patients. Lania and colleagues [23] also found that thyroid dysfunction, particularly thyrotoxicosis, was associated with a high level of IL-6 in patients with SARS-CoV-2 infection. Unfortunately, we were not able to determine IL-6 levels in our cohort.

Reduced T3 concentration has been related to mortality in patients with chronic renal failure, acute myocardial infarction, liver failure and surgical sepsis. In COVID-19 patients, low FT3 may also have prognostic significance. A previous retrospective study showed that COVID-19 patients who died had lower FT3 on admission compared with the survivors [4]. Chen reported that the degree of the decreases in TT3 levels was positively correlated with the severity of the disease [14], while Gao and colleagues informed that reduced FT3 independently predicted all-cause mortality of patients with severe COVID-19 [24]. In a similar way, we observed that T3/T4 ratio was significantly lower in those patients with a severe form of the disease and in patients who eventually died. Interestingly, we also noticed that a group of patients with low FT3 had high FT4. None of them presented with a mild form of the disease and FT4 showed positive correlation with some inflammatory parameters. Mercke et al. demonstrated that low FT3 levels and high FT4 were associated with higher all-cause and cardiovacular mortality in Caucasians undergoing angiography, independent of age and sex [25]. A possible explanation could be more profound alterations in deiodinase activity associated with inflammation.

Some strengths of this study include its prospective nature, and that all patients were evaluated before starting any specific medication that could affect thyroid hormone axis such as steroids. Limitations could be related that it was a single-center protocol, and the lack of a control group without COVID-19 infection.

In conclusion, in this cohort of hospitalized patients with COVID-19 infection, both thyroid hormones (T3, T4 and free fractions) correlated, in a opposite way, with inflammation parameters and worse clinical outcome. In particular, T3 and T3/T4 ratio correlated inversely with markers of inflammation, whereas a low T3/T4 ratio was associated with severity and poor prognosis. Of note, those with low FT3 and high FT4 profile showed lower albumin, higher ferritin, and more severe disease at presentation. Further longitudinal studies are needed to determine the full impact of COVID-19 on the hypothalamic-pituitary-thyroid axis.

Funding: No funds, grants or other support was received for conducting this study or preparing this manuscript.

Conflicts of interests: The authors have no conflicts of interest to declare that are relevant to the content of this article.

Ethics approval: All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Bioethics Committee of the Jose Maria Ramos Mejia Hospital. All patients provided written informed consent.

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Correlation Between Inflammatory Parameters and Thyroid Axis in Patients With COVID-19

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