Patterns of thyroid gland dysfunction among hospitalized patients with COVID-19 pneumonia

Background Since the onset of the COVID-19 pandemic, multiple studies have reported a bidirectional between COVID-19 and dysfunction of the thyroid gland. These studies have identified various forms of thyroid dysfunction that have been found to affect the severity and outcome of COVID-19 infection. However, the data from these studies have been inconsistent and conflicting. Our objective was to assess the prevalence of various types of thyroid dysfunction among moderate to severe cases of COVID-19 pneumonia. In addition, the study aimed to evaluate the outcome of thyroid dysfunction after recovery from COVID-19 infection. Patient and methods In this observational prospective study data on the clinical features of individuals with moderate to severe COVID-19 pneumonia who were admitted to Zagazig University isolation hospitals from April to December 2022 and their laboratory results were gathered and examined. Thyroid function tests, including TSH, FT3, and FT4, were conducted for all patients upon admission. Follow-up testing was performed on patients who initially had aberrant thyroid lab results 90 days after recovering from COVID-19 infection. Results The study comprised a total of 136 patients who had moderate (44.1%) to severe (55.9%) COVID-19 infection. Sick euthyroid syndrome was the most prevalent form of thyroid dysfunction, accounting for 58.7% of patients with thyroid disorders on admission. After 90 days of post-COVID-19 examination, thyroid dysfunction recovery was observed in 61% of cases. A statistically significant correlation was noted between the severity of COVID-19 and the levels of TSH, free T3, and the ratio of free T3 to T4. A large percentage of patients who showed complete recovery had sick euthyroid syndrome. All patients diagnosed with primary hypothyroidism maintained their hypo-thyroidism condition, whereas those with hyperthyroidism showed complete recovery. Conclusion COVID-19 patients may experience several patterns of thyroid dysfunction, including nonthyroidal illness syndrome. These dysfunctions are associated with the intensity of the inflammatory response and the severity of the COVID-19 infection. Nevertheless, these alterations are predominantly reversible upon recovery from a COVID-19 infection.


Background
Following the global COVID-19 pandemic, there has been a significant focus on examining its impact on various body systems, particularly the endocrine system.It has been observed that SARS-COVID-19 can lead to various metabolic and endocrinal changes, such as disruptions in thyroid function, lipid profile, and blood glucose levels.These alterations have significant implications for affected patients' prognosis [1].The COVID-19 virus can affect the functioning of the thyroid gland at several stages of its pathway.This includes changes in the release of thyroxin hormones and TSH, their binding to plasma proteins, as well as their transportation and effects on peripheral tissues [2].
COVID-19 has the potential to impact the thyroid gland either indirectly (via the hypothalamic-pituitary axis) or directly (through several methods).The primary route of entry for the SARS-COVID-2 virus into host cells involves angiotensin-converting enzyme 2 receptors (ACE2), which serve as the functional receptors for the virus.The ACE receptors are extensively expressed on the vascular endothelium of several tissues, particularly thyroid tissues [3].
Another possible mechanism is the occurrence of autoimmune thyroiditis in COVID-19 patients due to inflammatory damage caused by the production of inflammatory mediators during a cytokine storm.Postmortem examination of thyroid tissue in COVID-19 patients showed severe harm to the parafollicular and follicular cells, as well as decreased staining for thyrotropin (TSH) in these patients' anterior pituitary cells [4].This study attempted to assess the prevalence of various types of thyroid dysfunction among individuals with moderate to severe conditions of COVID-19 pneumonia, as well as to examine the impact of thyroid dysfunction on COVID-19 infection recovery.

Study design
This observational prospective study was carried out between April and December 2022, involving 136 patients with moderate to severe COVID-19 pneumonia < 18 years admitted to Zagazig University Isolation Hospitals.Patients aged < 18 years old and patients with well-known thyroid gland dysfunction have been excluded from the study.COVID-19 pneumonia was diagnosed by evaluating clinical symptoms, radiological findings from a chest CT scan, and detecting SARS-CoV2 RNA using real-time PCR (RT-PCR) from a nasopharyngeal swab.The severity of the COVID-19 infection was also assessed according to the management protocol issued by the Egyptian Ministry of Health and Population (2021).
Thyroid dysfunction variable patterns were defined as follows: Primary hypothyroidism: characterized by low serum T4 levels as well as elevated serum thyroid stimulating hormone (TSH) levels; subclinical hypothyroidism: when serum TSH level is upregulated, while serum T4 is within the normal range; primary hyperthyroidism: characterized by elevated serum thyroxine (T4) and triiodothyronine (T3) levels along with downregulated serum thyroid-stimulating hormone (TSH) levels; and sick euthyroid syndrome: characterized by downregulated or slightly below normal TSH serum levels while both T3 and T4 serum levels are low [5].

Methods
Informed consent was obtained for each patient.In addition, the patients included in the study underwent a comprehensive assessment that involved obtaining a detailed medical history, with particular on medications, age and comorbidities.Additionally, a thorough physical examination was conducted, along with laboratory testing that encompassed the following: 1) Routine Lab (Kidney function test, CBC, coagulation profile, and liver function test).2) Thyroid function tests, including TSH, FT3, and FT4 upon admission.Furthermore, patients who initially had abnormal thyroid laboratory results underwent follow-up testing on day 90 after recovering from COVID-19 infection.

Statistical analysis
Data were analyzed utilizing the 22nd version of the SPSS software (USA).Percentages and numbers are used to represent data (percent) or mean ± SD.The Chi square (X2) test was used to analyze several qualitative variables.All comparisons conducted were two-tailed, with P-value < 0.05 indicating significant difference (S), P ≥ 0.05 indicates a nonsignificant difference (NS), and p < 0.001 indicates a highly significant difference (HS).

Results
The total number of patients enrolled in this study was 136: 82 (60.3%) were females, and 54 (39.7%) were males, with a mean age of 62.25 years.Patients were categorized depending on the severity of the infection as moderate 60 (44.1%) and severe 76 (55.9%).About 65% of patients had comorbid hypertension, 24.3% had comorbid diabetes, and 14.7% had no associated comorbidities (Table 1).
The findings of this study indicate that Sick euthyroid syndrome was the most prevalent thyroid dysfunction observed in the study participants, followed by primary hyperthyroidism and subclinical hypothyroidism (Table 2).
After a 3-month follow-up, approximately 62% of patients with thyroid dysfunction were recovered, whereas 27.5% were lost during the follow-up period.Additionally, 6.9% continued to have hypothyroidism, and 0.7% continued to have subclinical hypothyroidism (Table 3).
In this study there was significant statistical positive correlation between free T3/T4 ratio and BMI, and temperature.There was a statistically significant negative correlation between free T3/T4 ratio and ALT, AST, procalcitonin and D-dimer (Table 4).
A statistically significant correlation was noted between the severity of COVID-19 and the levels of TSH, free T3, and the ratio of free T3 to T4.Specifically, individuals with severe disease had substantially upregulated levels of TSH, while those with severe disease had considerably lower levels of both free T3 and the free T3/T4 ratio.However, there was no marked correlation between disease severity and either free T4 levels or the prevalence of thyroid dysfunction during infection or on follow-up (Table 5).
A substantial correlation was noted between thyroid malfunction patterns and outcomes.A large percentage of patients who showed complete recovery had sick euthyroid syndrome.All patients diagnosed with primary hypothyroidism maintained their hypothyroidism condition, whereas those with hyperthyroidism showed complete recovery (Table 6).

Discussion
The study revealed a prevalence rate of 21.3% for thyroid-related disorders among hospitalized patients with COVID-19-associated pneumonia.The predominant form of thyroid dysfunction observed was sick euthyroid syndrome (also known as non-thyroidal illness), which accounted for approximately 58.6% of cases with thyroid dysfunctions.This condition is characterized by abnormal thyroid function tests without any thyroid dysfunction.It is typically characterized by low levels of FT3, occasionally accompanied by low levels of FT4 or TSH.The prevalence of primary hyperthyroidism was 17.2%, primary hypothyroidism was 6.9%, and subclinical hypothyroidism was 17.2%.A study conducted by Jiyeon et al. [6] revealed that the prevalence of thyroid dysfunction was 36.1%.The most prevalent manifestation was nonthyroidal illness syndrome (18.5%), followed by subclinical thyrotoxicosis (14.3%) among patients with thyroid dysfunction and subclinical hypothyroidism (3.3%).The   study conducted by Lania et al. [7] revealed that 5.2% (15/287) of patients acquired primary hypothyroidism.Among these cases, 90% were classified as subclinical, while the remaining 10% were overt.Additionally, 20.2% (58/287) developed thyrotoxicosis.In a study by Dabas et al. [8], which included 185 patients, 111 (67.7%) had an abnormal thyroid profile, 88 (53.7%) had sick euthyroid syndrome, 14 (8.53%) had overt hypothyroidism, and 9 (5.5%) had thyroiditis.The precise mechanisms by which the thyroid is involved in COVID-19 are still not fully understood, and there are various potential explanations.ACE-2 and TMPRSS2, which are recognized as viral entry points, are predominantly present in thyroid follicular cells.Consequently, viral infiltration has the potential to impair these cells.Additionally, the immunological reaction triggered by a virus may lead to the autoimmune destruction of thyroid follicles.Ultimately, changes in the hypothalamic-pituitary-thyroid axis may play a role [9].Our investigation revealed a substantial relationship between the severity of COVID-19 and levels of TSH, free T3, and the ratio of free T3 to T4.Specifically, individuals with severe disease had considerably higher levels of TSH.These findings were controversial compared to the data documented by Gong et al. [10] and Chen Y et al. [11], who found a decrease in TSH levels in severe cases of COVID-19.The controversy can be attributed to the high occurrence of nonthyroidal illness (NTI) in our study sample.NTI is the most frequent form of thyroid malfunction, defined by low FT3 and normal TSH levels, with fewer cases of low TSH levels.Conversely, individuals with severe illness exhibited considerably lower free T3 and free T3/T4 ratio levels.Similarly, Gao et al. [12] found that free T3 concentration was significantly lower in patients with severe COVID-19 than in non-severely ill cases.Likewise, Verónica et al. [13] found that the free T3/T4 ratio was lower in severe compared to mild and moderate disease and in patients who died compared to those discharged.
This study revealed a marked negative correlation between the free T3/T4 ratio and ALT, AST, procalcitonin, and D-dimer.Similarly, Verónica et al. [13] found that FT3/FT4 is inversely correlated with ferritin, fibrinogen, ESR, CRP, LDH, and D-dimer.Similar results reported by Gong J et al. [10] identified increased levels of leucocytes, neutrophils, CRP, and procalcitonin and decreased levels of lymphocytes in the thyroid  dysfunction group.These findings can be elucidated by the potential impact of systemic inflammation on deiodinase enzyme activity.Systemic inflammation, which occurs alongside systemic tissue injury, results in reduced deiodinase activity.This led to a decrease in the conversion of T4 to T3, leading to a low level of FT3, as demonstrated by Mancini et al. [14].In this study, there was a substantial correlation between the patterns of thyroid malfunction and outcomes.A significant proportion of patients who experienced full recuperation exhibited sick euthyroid syndrome.Patients diagnosed with primary hypothyroidism maintained their hypothyroid state, whereas those with hyperthyroidism experienced full remission.The findings were consistent with Muller et al. [15], who illustrated that Covid-19-induced thyroid dysfunction was transient, with nearly all patients recovering to normal thyroid function as soon as three months post-infection.This also was observed in other short-term follow-up studies of patients surviving moderate-to-severe Covid-19 disease [16][17][18].Chronic inflammation of the thyroid gland, leading to reduced hormone secretion, is a potential cause of hypothyroidism following COVID-19 infection.A descriptive cross-sectional study reported that 60.53% (23 of 38) of patients with COVID-19 pneumonia had subclinical hypothyroidism, suggesting a link between infection severity and the risk of developing hypothyroidism [19].

Limitations
Our work had some limitations as this study was a single-center study with a relatively small sample size.Furthermore, this study did not assess other factors that may impact thyroid function, such as pituitary function, reverse triiodothyronine (rT3) levels, and glucocorticoid therapy.

Conclusion
COVID-19-affected patients may experience several patterns of thyroid dysfunction, including NTI.These dysfunctions are associated with the intensity of the inflammatory response and the severity of the COVID-19 infection.However, these changes are mostly reversible after recovery from COVID-19 infection.

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Morsi et al.The Egyptian Journal of Bronchology (2024) 18:53 Spearman' rank correlation coefficient or Pearson' correlation coefficient were computed to determine the correlation between the examined variables.(-) sign indicate inverse correlation, whereas (+) sign indicates direct correlation.In addition, values near 0 indicate a weak correlation, whereas values near 1 indicate a strong correlation.

Fig. 1
Fig. 1 Distribution of the studied patients demonstrating abnormal thyroid functions

Table 1
The studied patients' baseline data as regards demographic distribution and medical history

Table 2
The studied patients' baseline data as regards the laboratory results, severity of COVID-19 infection, and thyroid disorder patterns TLC Total lecucytic count, CRP C reactive protein, ALT Alanine transaminase, TSH Thyroid stimulating hormone, FT4 Free thyroxine, FT3 Free triiodothyronine

Table 4
Correlation between thyroid function and the studied parameters

Table 5
The relation between thyroid profile and COVID severity

Table 6
Correlation between thyroid malfunction patterns and outcomes