Bronchial Asthma and Its Associated Risk Factors Among Adults with Thyroid Nodules

Imad R Musa

Royal Commission Hospital at AL Jubail Industrial City, Al Jubail, Kingdom of Saudi Arabia

*Corresponding author: Imad R Musa, Royal Commission Hospital at AL Jubail Industrial City, Al Jubail, Kingdom of Saudi Arabia.

Received: 18 October 2023; Accepted: 26 October 2023; Published: 03 November 2023

1. Introduction

Bronchial asthma (BA) is a chronic inflammatory condition of the airways characterised by bronchial hyperreactivity and evidence of a variable degree of airway obstruction [1]. Diagnosis of BA depends on the clinical history, physical findings, and pulmonary function tests: reversibility testing and measurement of bronchial reactivity [1]. In 2019, the estimated global prevalence of BA is 9.8% in those aged 5-69 years, with the highest prevalence reported in Africa (11.3%) and the lowest documented in Southeast Asia (8.8%).[2]. Different prevalence of BA have been demonstrated in different regions worldwide [2-7]. Moreover, the burden of treating BA has continued to rise, with approximately 262.41 million cases reported across the globe in 2019 [8]. Several studies have pointed to an association between BA and pulmonary function tests and thyroid status and thyroid hormones [9,10]. In addition to the increased risk of hypothyroidism, hyperthyroidism and goitre among patients with BA [11-14]. Additionally, large goitres—particularly retrosternal goitre may mimic BA [15,16]. Similarly, symptomatic ectopic intratracheal thyroid is associated with breathing difficulty, cough, stridor and dysphagia [17]. Several risk factors for BA have been identified, including age, male gender, high body mass index (BMI), occupational asthmagens, smoking and thyroid dysfunction [8,11,18,19]. Nevertheless, TN is a growing global health problem that indicates the presence of an abnormal lesion within the thyroid gland tissue [20]. Females (36.51%) are more vulnerable to the condition than males (23.47%), and the estimated overall global prevalence of TNs is 24.83%, regardless of the diagnostic method adopted, based on a systematic review and meta-analysis study, conducted on 2022 [21]. Moreover, variations in the prevalence of TNs have been documented in different global regions [22]. TN malignancy risk warrants targeted and timely assessment and follow-up that will result in a better prognosis and a high cure rate [23]. Fortunately, the risk of malignancy in TNs is not markedly higher (27.5%) as most these nodules were benign [24]. Moreover, assessment of TNs has been improved considerably by thyroid ultrasound [25,26], sonography-guided fine needle aspiration cytology (FNAC) for TNs [26,27], the adoption of scoring systems for both thyroid ultrasound [27] and thyroid FNAC [28] in addition to the development of the facilities required to perform genetic and molecular testing [29]. Diagnostic accuracy and procedural safety have thus been achieved by reducing the rate of unindicated FNAC and thyroid surgeries [27,28].

TNs are identified as a growing medical and health problem in the KSA that may pose potential malignancy risks [24,30,31]: thyroid cancer has been identified as the third most common cancer among the Saudi population [32] and the second most common malignancy among Saudi women behind breast cancer [33]. TNs are linked to significant morbidity and mortality burdens in KSA [31]. Moreover, managing TNs is associated with higher financial costs in particular, those associated with aggressive thyroid cancer [34]. BA is considered a health challenge with a higher prevalence that is considerably higher than the prevalence reported in most countries using the European Community Respiratory Health Survey questionnaire [18]. It is more prevalent among children, with an overall prevalence of 8-25% [35], and males are more vulnerable to the condition than females [36]. A higher prevalence of BA was observed in southern Saudi Arabia (6.9%-19.5%) and in the capital Riyadh (11.3%-19.6%)[18,36]. In fact, the household out-of-pocket spending burden in KSA for chronic non-communicable diseases, including BA, remains high, with several disparities such as age, gender, education, employment and marital status [37]. Moreover, a higher percentage of adult patients with BA had uncontrolled disease (64%) [38]. Considering the significance of BA and TNs as growing medical health problems and the poor availability of published data on the coexistence of both medical conditions in the region, the present study aimed to investigate the prevalence and associated risk factors of BA among adult patients with TNs in the KSA.

2. Methods

A retrospective study was conducted at the Royal Commission Hospital in Al Jubail Industrial City between January 1, 2015 and December 31, 2021. The electronic medical files of adult patients (men and women) aged 18 years and older were retrieved. The study included those with documented TNs based on an ultrasound procedure performed in the hospital’s radiology department of the hospital. Medical files with incomplete data or thyroid ultrasound reports for thyroid ultrasounds performed outside the hospital were excluded. The sociodemographic data, including each patient’s age, gender, weight and height, were recorded. Common comorbidities were identified using a data collection sheet: thyroid status [euthyroid, hypo- or hyperthyroidism], diabetes mellitus (DM), hypertension and BA, obesity and anaemia. Similarly, laboratory tests performed simultaneously with TN evaluated were collected: complete blood count (WBCc, haemoglobin, PLTc and other haematological indices), vitamin D levels, lipid profiles [total cholesterol, low-density lipoprotein, high-density lipoprotein and triglycerides] and thyroid function [TSH, FT3 and FT4]. Each thyroid ultrasound procedure was performed by a radiology specialist in the hospital’s radiology department. Each report was then reviewed and finally approved by a radiology consultant. The radiological department in the hospital adopted the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) for evaluating TNs (Table 1) [39].

Table 1: (TI-RADS) Category definitions

ACR TI-RA

DS: American College of Radiology Thyroid Imaging Reporting and Data System.

2.1 Definition of variables

TNs: TNs were diagnosed based on the definition of the American Thyroid Association (ATA) Guidelines [20].

Body mass index: BMI was calculated as body mass divided by the square of the body height; it is expressed in units of kg/m², resulting from mass in kilograms and height in metres [40].

Vitamin D deficiency: Vitamin D deficiency is defined by a (25(OH)D) level of < 30 ng/mL; levels equal to or above this cutoff point are considered normal [41].

Bronchial asthma: This variable includes individuals diagnosed with BA based on the documentation of their medical records.

DM: DM diagnoses is considered for those with documentation of DM (type 1 and 2), whether they were on diet control or on glucose-lowering drugs, during TN assessment.

Hypertension: This variable includes patients who had been diagnosed with hypertension and were receiving treatment during TN assessment.

Thyroid dysfunction: Indicates the documented diagnosis of hypothyroidism or hyperthyroidism based on thyroid function tests as documented in their medical records and as part of their treatment during TN assessment.

2.2 Statistical analysis

Data were input into a computer using IBM Statistical Package for the Social Sciences^® (SPSS^®) for Windows, version 22.0 (SPSS Inc., New York, United States). The proportions were expressed as frequencies (%). The Shapiro-Wilk test was used to determine the normality of continuous data (age, BMI, vitamin D levels, thyroid function test, haematological indices and lipid profile) and revealed a non-normal distribution. The non-normally distributed variables were expressed as the median (interquartile range [IQR]). A univariate analysis was performed for BA as the dependent variable with sociodemographic demographics (age, sex, age, BMI, vitamin D levels, thyroid function test, haematological indices, lipid profile, hypertension and DM) as independent variables. A multivariate analysis was also conducted for all variables with p < 0.2 to control for confounding variables. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were calculated as they were applied, and a two-sided p < 0.05 was considered statistically significant.

3. Results

A total of 391 patients with documented TNs were enrolled in the study, and most of them were females (84.9%). The median (IQR) of the age was 46.00 (20.0) years, the median (IQR) of BMI was 30.27 (7.71) kg/m² and 25[OH)] D level was 14.5 (12.0) nmol/L. The median (IQR) for the thyroid function test was TSH 1.71 (2.43) mmol/L, FT4 1.12 (0.45) ng/dL FT3 2.69 (0.40) nmol/L. The median (IQR) for haematological indices was haemoglobin 12.6 (1.7) gm/dl, PLTc 276.15 (95.80) 10⁹/L, WBCc was 7.01 (2.63) µL, neutrophil count 10³/µL 3.740 (1.77), lymphocyte count 10³/µL 2.500 (0.94), RDW (fL) 13.400 (3.10) haematocrit (L/L) 38.680 (5.50) and MPV (fL) 9.800 (2.83). The median (IQR) of lipid profile, total cholesterol, low-density lipoprotein, high-density lipoprotein and triglyceride were 5.8 (3.89) mmol/L, 3.76 (0.80) mmol/L, 3.00 (1.71) mmol/L and 1.78 (1.11) mmol/L, respectively. The prevalence of BA among adult patients with TNs was 7.9%. The outcome of thyroid ultrasound reports based on (ACR TI-RADS): ACR TI-RADS-1(2.6%), ACR TI-RADS-2 (18.4%) ACR TI-RADS-3 (40.7), ACR TI-RADS-4 (36.3%) and ACR TI-RADS-5 (2%) table (2).

Table 2: general characteristics of patients who had documented TNs in eastern region 2015-2021

The univariate analysis revealed no significant association between BA in adult patients with TNs and gender, BMI, thyroid status, (25[OH)] D), white blood cell count, haemoglobin, red cell distribution width, total cholesterol, triglyceride, TSH or FT4. However, a significant association was observed between BA in these patients and age (AOR = 1.037, 95% CI = 1.009 -1.067), PLTc (AOR = 1.005, 95% CI = 0.275-0.881), neutrophil count (AOR = 1.217, 95% CI = 1.0161.457), lymphocyte count (AOR = 0.611, 95% CI = 0.3721.004), mean platelet volume AOR = 0.872, 95% CI = 0.275-0.881), haematocrit (AOR = 1.006, 95% CI = 1.001-1.012), FT3 (AOR = 1.197, 95% CI = 1.017-1.409), low-density lipoprotein (AOR = 1.040, 95% CI = 0.994-1.089) and high-density lipoprotein (AOR = 0.721, 95% CI = 0.481-1.081) (see Table 3).

Table 3: Univariate analysis of the predictors associated with bronchial Asthma among adult patients with TNs in eastern region, 2015-2021.

The multivariate analysis indicated that DM, hypertension, neutrophils, haematocrit, mean platelet volume, low-density lipoprotein and high-density lipoprotein were not significantly associated with BA in patients with TNs. However, increased age (AOR = 1.046, 95% CI = 1.015-1.079), a higher PLTc, (AOR = 1.006, 95% CI 1.002-1.011), a lower lymphocyte count (AOR = 0.492, 95% CI = 0.275-0.881), and elevated FT3 (AOR = 1.242, 95% CI = 1.043-1.480), were highly significantly associated with BA in adult patients with TNs (Table 4).

Table 4: Multivariate analysis of the predictors associated with bronchial asthma in patient with thyroid nodules in eastern region 2015-2021

4. Discussion

Among the study’s main findings is the higher prevalence (7.9%) of BA among adult patients with TNs. The prevalence obtained in this study is considerably higher than that reported by a national household survey conducted among the general population in 2013 (4.05 %) and in the eastern region of KSA (4.15-4.36%), where this study was conducted [42]. Meanwhile, a markedly higher prevalence of BA was observed among the Saudi population in the southern region of KSA (19.5%) and in Riyadh (11.3%-19.6%) [18,36]. The prevalence reported in the present study is significantly lower than the global prevalence of BA in the general population aged 5-69 years (9.8%), with the highest prevalence recorded in Africa (11.3%) and the lowest in Southeast Asia (8.8%) [2]. Moreover, it is within the range of prevalence that was documented in the Gulf region (4.7% to 30.0% ), with the highest prevalence recorded in the United Arab Emirates and the lowest in KSA [43]. The current prevalence, as documented in the present study, is close to that recorded among adults in America (7.0-7.7%) [3,5], higher than that reported in Germany (5.35%) [4] and lower than that demonstrated in Finland (10.3-11.2%) [6,7].

The difference in prevalence of BA among adults with TNs may be explained by the variation across KSA’s different regions [42] as well as the fact that the prevalence of BA among Saudi adults is under-investigated [18]. The higher prevalence of BA in this group of patients may reflect a close association between the two medical conditions. Several studies have reported that patients with BA have a higher risk of developing thyroid dysfunction, including thyroiditis, hypothyroidism, hyperthyroidism and diffuse or nodule thyroid goitre [11-13]. A recently published study demonstrated a significant relationship between serum total immunoglobulin E (IgE) levels and TN formation [44]. This corroborates the finding that IgE production is a primary marker for the diagnosis and monitoring of allergic asthma, and higher levels of IgE are associated with poor prognosis: persistent symptoms, exacerbations of BA and a poor quality of life [45]. Moreover, hypothyroidism increases BA episodes, diminishes the possibility of remission, and exacerbates BA due to the lack of thyroid hormones [14]. Hyperthyroidism similarly impacts BA remission and increases the serum IgE and interleukins (IL4/IL1) ratio, leading to deterioration of BA control as a result of Type 2 helper T (Th2)-response excessive stimulation [14].

Moreover, thyroid functions varied in patients with BA without impairing pulmonary function [10]. Although hyperthyroidism and hypothyroidism clinically represent different thyroid function entities, the pathogenesis of Graves’ disease and Hashimoto thyroiditis involves the Th-17 pathway and the IL-17 family cytokines pathway [46,47] as well as non-type 2 asthma and airway remodelling in patients with BA [11,48]. This accords with the present study’s finding that a higher prevalence of thyroid dysfunction (hypo-hyperthyroidism) among patients with TNs (36%) and BA (38.7%). Interestingly, the severity of BA and goitre are significant predictors for the risk of developing cancers in general, and in particular, thyroid papillary cancer among patients with BA [49]. Additionally, certain medications used to control BA, such as Dupilumab, a fully human monoclonal antibody that blocks IL-4 and IL-13 are associated with painless thyroiditis, leading to transient hyperthyroidism and hypothyroidism and recovery without anti-thyroid treatment [50]. Similarly, nonspecific β blockers used to control palpitation of overactive thyroid may exacerbate BA attacks [51].

The present study identified a significant association between increased age and BA in adult patients with thyroid nodular diseases, corroborating several studies that have identified increased age as a significant predictor for risk of developing BA [3,4,6,19,52]. Ageing is associated with a decline in lung function owing to a reduction in compliance, elastic recoil of the lung, a reduction in respiratory muscle strength and increased residual volumes [53]. Furthermore, increased prevalence of airway hyper-responsiveness may occur in elderly patients with BA compared to younger subjects as a result of differences in the pathophysiological determinants of airway hyper-responsiveness with ageing [54]. Moreover, the signification association between ageing and BA may relate to elderly people’s vulnerability to asthma induced by non-IgE-mediated allergy [52]. Similarly, ageing is associated with a chronic low-grade inflammation called inflamm-ageing [55] and altered adipokine levels in patients with BA [56]. Additionally, the multimorbidity associated with asthma, such as gastro-oesophageal reflux, chronic rhino-sinusitis, obstructive sleep apnoea and heart conditions, increases with age [57].

Some of these comorbidities in the elderly and the medications required to treat them may increase asthma exacerbation’s and negatively affect its control [19]. Meanwhile, TNs in advanced age are related to changes in the thyroid gland that accompany ageing: the degeneration of thyroid cells, leading to fibrosis; infiltration of inflammatory cells; thyroid follicle alteration; and eventually thyroid nodular diseases [58]. The prevalence of both medical conditions (BA and TNs) is expected to increase with age to justify its significant association in this study.

The present study demonstrated a significant association between elevated FT3 and BA, as reported in several earlier clinical trials [9,59,60]. Interestingly, elevated FT3 in patients with BA is reversible, and it is a protective mechanism against stress response [9]. Low FT3 was significantly associated with higher mortality rates and a significantly longer duration of mandatory ventilation[59,60]. Moreover, the correlation between FT3 and pulmonary function is directly related to changes in thyroid enzymology: hypoxia reduces step-up deiodinase activity, and the retention of carbon dioxide markedly reduces thyroid hormone levels [9].

This indicates that hypoxia leads to type 1 thyroid allostasis via different mechanisms that are unrelated to the negative effect of hypothyroidism on pulmonary function [9]. On the other hand, elevated FT3 levels may be associated with hot nodules of toxic adenomas and multinodular goitre [61]. Moreover, inflammation accelerates the development of TN disease by means of an indirect effect, inhibiting the synthesis of thyroid hormones, which eventually leads to elevated TSH [62]. Not only is elevated FT3 protective against BA but it is also associated with a reduced risk of thyroid cancer [63] and lowers the risk of recurrence [64]. A significant association was observed between PLTc and BA among TN patients in the present study. A similar significant association with elevated PLTc was observed among patients with BA compared to the control group [65][66]. Similarly, significantly high PLTc was observed among the patients during exacerbation and asymptomatic periods compared with the control group [67].

Moreover, a higher PLTc was reported in thyroid nodular diseases and is an independent predictor for severity of inflammation and the presence of papillary thyroid cancer [66,68,69]. Not only was elevated PLTc documented during episodes of BA but the platelet indices were also altered during the exacerbation phase, compared with the stable phase and control group [70]. This may point to the role of platelets in the inflammation process during BA attacks [71]. The potential mechanism may be attributablee to IL-6-induced thrombocytosis associated with increased thrombopoietin level, which is a platelet production stimulator [72]. Another possibility is that paraneoplastic thrombocytosis results from the stimulation of malignant cells to increase platelet production and platelet activation and aggregation [68,69]. Both plasma levels of platelet factor 4 and platelet-activating factor among patients with an asthma attack were significantly higher than those of the controls [73], which results in the release of platelets from bone marrow haematopoietic stem or via a spleen-dependent mechanism, respectively [74,75].

The present study identified a significant association between low lymphocyte counts and BA among adult patients with TNs. Other studies have observed a similar significant association [76,77]. Likewise, a significant decrease in the lymphocyte subgroup—human peripheral blood gamma delta T cells—was reported in adult patients with both mild and severe BA [78,79]. The lower lymphocyte count in patients with BA is of prognostic significance, as it is negatively associated with the severity of BA and normalized after remission of asthmatic events [77]. This may be explained by the role that B and T lymphocyte attenuator (BTLA) plays in the proliferation, recruitment and survival of T cells in response to inhaled allergen; hence, the regulation of cell death through BTLA signalling is the main determinant of the inflammatory response in the lung[80]. The newly approved biological agents may be associated with lymphopenia, as the lymphocyte count before the biological agent treatment was statistically higher than the value at 3 and 6 months of treatment [81]. Similar CD4+ T-cell lymphopenia was observed with alefacept therapy, which inhibits the activation and proliferation of T cells by blocking LFA-3/CD2 interaction and induction of apoptosis in activated memory T cells [82].  Nevertheless, a recently published study reported a significant association with lower lymphocyte count and TNs [83,84]. Moreover, it is a predictor for TN cancer, as a lower lymphocyte count was observed in malignant TNs than in benign samples [84].

Likewise, T-cell lymphopenia in patients with thyroid cancer was considered a significant indicator for the aggressiveness of tumour behaviour and might determine future therapeutic options [85]. T-cell lymphopenia may be due to increased T-cell apoptosis, which was associated with head and neck cancer [86] or possibly concomitant decreased homeostatic proliferation of T cells, reduced thymic output and redistribution of T cells to the tumour site [85]. The other variables assessed in this study demonstrated a non-significant association with BA among patients with TNs. This may be explained by the fact that BA is a complicated, multifactorial illness with hereditary and environmental influences [87] as well as thyroid nodular diseases [88]. The study’s main limitation is that it was retrospective and collected data from only one centre. Other factors, such as thyroid antibodies, iodine levels, smoking, alcohol consumption, physical activity, nutritional patterns, drug history, genetic analysis and environmental factors, were not assessed.

5. Conclusion

A higher prevalence of BA was observed among adult patients with TNs than among the general population in eastern KSA. Older age, elevated FT3, a higher PLTc and lower lymphocyte count were significant predictors of BA in this group of patients.

Declarations

Availability of data and Material

Data are available upon request.

Ethics approval and consent to participate

The study was approved by the Institutional Review Board of the Royal Commission Hospital, KSA (IB-RCH-012), which waived verbal or written consent from the participants. It was conducted in compliance with the ethical standards of the responsible institution on human subjects as well as with the Helsinki Declaration.

Consent for publication

Not applicable.

Conflicts of Interest

The author has no conflicts of interest to declare.

Disclosure

No funding received.

ORCID iD: Imad R. Musa   https://orcid.org/0000-0002-1138-0710

References

1. Ukena D, Fishman L, Niebling WB. Bronchial Asthma: Diagnosis and Long-Term Treatment in Adults. Dtsch. Arztebl. Int 105 (2008).
2. Song P, Adeloye D, Salim H, Dos Santos JP, Campbell H, Sheikh A, et al. Global, Regional, and National Prevalence of Asthma in 2019: A Systematic Analysis and Modelling Study. J. Glob. Health 12 (2022): 04052.
3. Oraka E, Kim HJE, King ME, Callahan DB. Asthma Prevalence among US Elderly by Age Groups: Age Still Matters. J. Asthma 49 (2012): 593-599.
4. Langer S, Horn J, Kluttig A, Mikolajczyk R, Karrasch S, Schulz H, et al. [Occurrence of Bronchial Asthma and Age at Initial Asthma Diagnosis-First Results of the German National Cohort]. Bundesgesundheitsblatt. Gesundheitsforschung. Gesundheitsschutz 63 (2020): 397-403.
5. Loftus PA, Wise SK. Epidemiology of Asthma. Curr. Opin. Otolaryngol. Head Neck Surg 24 (2016): 245-249.
6. Pakkasela J, Ilmarinen P, Honkamäki J, Tuomisto LE, Andersén H, Piirilä P, et al. Age-Specific Incidence of Allergic and Non-Allergic Asthma. BMC Pulm. Med 20 (2020): 1-9.
7. Honkamäki J, Ilmarinen P, Hisinger-Mölkänen H, Tuomisto LE, Andersén H, Huhtala H, et al. Nonrespiratory Diseases in Adults Without and With Asthma by Age at Asthma Diagnosis. J. allergy Clin. Immunol. Pract 11 (2023): 555-563.
8. Wang Z, Li Y, Gao Y, Fu Y, Lin J, Lei X, et al. Global, Regional, and National Burden of Asthma and Its Attributable Risk Factors from 1990 to 2019: A Systematic Analysis for the Global Burden of Disease Study 2019. Respir. Res 24 (2023).
9. Bingyan Z, Dong W. Impact of Thyroid Hormones on Asthma in Older Adults. J. Int. Med. Res 47 (2019): 4114-4125.
10. Huang D, Wu D, He J, Chen M, Zhao X, Li D, et al. Association Between Thyroid Function and Acute Exacerbation of Chronic Obstructive Pulmonary Disease. Int. J. Chron. Obstruct. Pulmon Dis 16 (2021): 333.
11. Huang SC, Gau SY, Huang JY, Wu WJ, Wei JCC. Increased Risk of Hypothyroidism in People with Asthma: Evidence from a Real-World Population-Based Study. J. Clin. Med 11 (2022).
12. Settipane GA, Hamolsky MW. Status Asthmaticus Associated with Hyperthyroidism. N. Engl. Reg. Allergy Proc 8 (1987): 323-326.
13. Gau SY, Huang JY, Yong SB, Cheng-Chung Wei J. Higher Risk of Hyperthyroidism in People with Asthma: Evidence from a Nationwide, Population-Based Cohort Study. J. allergy Clin. Immunol. Pract 10 (2022): 751-758.
14. Kamaeva I, Shaporova N. Possible Mechanisms of Worsening Bronchial Asthma Coexisting with Thyroid Gland Pathology. Eur. Respir. J 42 (2013).
15. Eugenia Y. Retrosternal Goiter Mimicking Asthma: A Diagnostic Challenge more Information (2020).
16. Loo GH, Wan Mat WR, Muhammad, R, Azman, M. Obstructive Retrosternal Goitre Mimicking Severe Bronchial Asthma in Pregnancy. BMJ Case Rep 12 (2019).
17. Rahman W, Arimbrathodi NI, Abdulkader F, Al-Enazi H, Dogan ZA. Ectopic Intratracheal Thyroid: A Rare Cause of Airway Obstruction. Case Rep. Otolaryngol (2018): 1-4.
18. Al Ghobain MO, Algazlan SS, Oreibi TM. Asthma Prevalence among Adults in Saudi Arabia. Saudi Med. J 39 (2018): 179-184
19. Boulet L-P. Asthma in the Elderly Patient. Asthma Res. Pract 2 (2016): 3.
20. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, et al. Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 19 (2009): 1167-1214.
21. Mu C, Ming X, Tian Y, Liu Y, Yao M, Ni Y, et al. Mapping Global Epidemiology of Thyroid Nodules among General Population: A Systematic Review and Meta-Analysis. Front. Oncol 12 (2022).
22. Sajisevi M, Caulley L, Eskander A, Du Y, Auh E, Karabachev A, et al. Evaluating the Rising Incidence of Thyroid Cancer and Thyroid Nodule Detection Modes: A Multinational, Multi-Institutional Analysis. JAMA Otolaryngol. Head Neck Surg 148 (2022).
23. Uppal N, Collins R, James B. Thyroid Nodules: Global, Economic, and Personal Burdens. Front. Endocrinol. (Lausanne) 14 (2023).
24. Alqahtani SM. Cytological Patterns of Thyroid Lesions in Najran, Saudi Arabia: A 5-Year Retrospective Study. Saudi Med. J 43 (2022): 735-742.
25. Alyousif H, Ahmed MAS, Khair AM, Alharbi FH, Hassan S, Elbadwi NM, et al. The Prevalence and Associated Predictors for Diabetes Mellitus in Adult Patients with Thyroid Nodules. J. Clin. Med Res 15 (2023): 166-173.
26. Yang X, Zhai D, Zhang T, Zhang S. Use of Strain Ultrasound Elastography versus Fine-Needle Aspiration Cytology for the Differential Diagnosis of Thyroid Nodules: A Retrospective Analysis. Clinics (Sao Paulo) 75 (2020): 1-8.
27. Al-Ghanimi I, Al-Sharydah A, Al-Mulhim S, Faisal S, Al-Abdulwahab A, Al-Aftan M, et al. Diagnostic Accuracy of Ultrasonography in Classifying Thyroid Nodules Compared with Fine-Needle Aspiration. Saudi J. Med. Med. Sci 8 (2020): 25.
28. Pandya A, Caoili EM, Jawad-Makki F, Wasnik AP, Shankar PR, Bude R, et al. Retrospective Cohort Study of 1947 Thyroid Nodules: A Comparison of the 2017 American College of Radiology TI-RADS and the 2015 American Thyroid Association Classifications. AJR. Am. J. Roentgenol 214 (2020): 900-906.
29. Livhits MJ, Zhu CY, Kuo EJ, Nguyen DT, Kim J, Tseng CH, et al. Effectiveness of Molecular Testing Techniques for Diagnosis of Indeterminate Thyroid Nodules: A Randomized Clinical Trial. JAMA Oncol 7 (2021): 70-77.
30. Hussain F, Iqbal S, Mehmood A, Bazarbashi S, ElHassan T, Chaudhri N. Incidence of Thyroid Cancer in the Kingdom of Saudi Arabia, 2000-2010. Hematol. Oncol. Stem Cell Ther 6 (2013): 58-64.
31. Flemban AF, Kabrah S, Alahmadi H, Alqurashi RK, Turaes AS, Almaghrabi R, et al. Patterns of Thyroid Cancer Mortality and Incidence in Saudi Arabia: A 30-Year Study. Diagnostics (Basel, Switzerland) 12 (2022).
32. Alqahtani WS, Almufareh NA, Domiaty DM, Albasher G, Alduwish MA, Alkhalaf H, et al. Epidemiology of Cancer in Saudi Arabia Thru 2010-2019: A Systematic Review with Constrained Meta-Analysis. AIMS Public Heal 7 (2020): 679.
33. Alshehri B. Descriptive Epidemiological Analysis of Thyroid Cancer in theSaudi Population (2001-2013). Asian Pac. J. Cancer Prev 18 (2017): 1445-1451.
34. Nejadghaderi SA, Moghaddam SS, Azadnajafabad S, Rezaei N, Rezaei N, Tavangar SM, et al. Burden of Thyroid Cancer in North Africa and Middle East 1990-2019. Front. Oncol 12 (2022).
35. Al-Moamary M, Alhaider S, Idrees M, Al Ghobain M, Zeitouni M, Al-Harbi A, et al. The Saudi Initiative for Asthma - 2016 Update: Guidelines for the Diagnosis and Management of Asthma in Adults and Children. Ann. Thorac. Med 11 (2016): 3.
36. Al Ghobain MO, Al-Hajjaj MS, Al Moamary MS. Asthma Prevalence among 16- to 18-Year-Old Adolescents in Saudi Arabia Using the ISAAC Questionnaire. BMC Public Health 12 (2012).
37. Almalki ZS, Alahmari AK, Alqahtani N, Alzarea AI, Alshehri AM, Alruwaybiah AM, et al. Households’ Direct Economic Burden Associated with Chronic Non-Communicable Diseases in Saudi Arabia. Int. J. Environ. Res. Public Health 19 (2022).
38. Al-Jahdali HH, Al-Hajjaj MS, Alanezi MO, Zeitoni MO, Al-Tasan TH. Asthma Control Assessment Using Asthma Control Test among Patients Attending 5 Tertiary Care Hospitals in Saudi Arabia. Saudi Med. J 29 (2008).
39. Tessler FN, Middleton WD, Grant EG, Hoang JK, Berland LL, Teefey SA, et al. ACR Thyroid Imaging, Reporting and Data System (TI-RADS): White Paper of the ACR TI-RADS Committee. J. Am. Coll. Radiol 14 (2017): 587-595.
40. NHLBI Obesity Education Initiative Expert Panel on the Identification, Evaluation, and Treatment of Obesity in Adults (US). Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: The Evidence Report. Bethesda (MD): National Heart, Lung, and Blood Institute (1998).
41. Alzaheb RA. The Prevalence of Hypovitaminosis D and Its Associated Risk Factors Among Women of Reproductive Age in Saudi Arabia: A Systematic Review and Meta-Analysis. Clin. Med. insights. Women’s Heal 11 (2018): 1179562X1876788.
42. Moradi-Lakeh M, El Bcheraoui C, Daoud F, Tuffaha M, Kravitz H, Al Saeedi M, et al. Prevalence of Asthma in Saudi Adults: Findings from a National Household Survey 2013. BMC Pulm. Med 15 (2015).
43. Al Busaidi N, Alweqayyan A, Al Zaabi A, Mahboub B, Al-Huraish F, Hameed M, Al-Ahmad M, et al. Gulf Asthma Diagnosis and Management in Adults: Expert Review and Recommendations. Open Respir. Med. J 16 (2022).
44. Kalkan I, Atmaca U, Akbas F. Total Serum IgE Level and Metabolic Parameters in Patients with Hashimoto Thyroiditis. Istanbul Med J 22 (2021): 218-240.
45. Pelaia G, Canonica GW, Matucci A, Paolini R, Triggiani M, Paggiaro P. Targeted Therapy in Severe Asthma Today: Focus on Immunoglobulin E. Drug Des. Devel. Ther 11 (2017): 1979-1987.
46. Esfahanian F, Ghelich R, Rashidian H, Jadali Z. Increased Levels of Serum Interleukin-17 in Patients with Hashimoto’s Thyroiditis. Indian J. Endocrinol. Metab 21 (2017): 551-554.
47. Qin J, Zhou J, Fan C, Zhao N, Liu Y, Wang S, et al. Increased Circulating Th17 but Decreased CD4+Foxp3+ Treg and CD19+CD1dhiCD5+ Breg Subsets in New-Onset Graves’ Disease. Biomed Res. Int (2017).
48. Margelidon-Cozzolino V, Tsicopoulos A, Chenivesse C, de Nadai P. Role of Th17 Cytokines in Airway Remodeling in Asthma and Therapy Perspectives. Front. allergy 3 (2022).
49. Salameh L, Mahboub B, Khamis A, Alsharhan M, Tirmazy SH, Dairi Y, et al. Asthma Severity as a Contributing Factor to Cancer Incidence: A Cohort Study. PLoS One 16 (2021).
50. Narantsatsral D, Junko T, Hideyuki I, Daisuke I, Hiroyuki T, Yuka N, et al. Painless Thyroiditis in a Dupilumab-Treated Patient. Endocrinol. diabetes Metab. case reports (2020): 1-4.
51. Sabih D, Inayatullah, M. Managing Thyroid Dysfunction in Selected Special Situations. Thyroid Res 6 (2013).
52. Mitsunobu F, Mifune T, Hosaki Y, Ashida K, Tsugeno H, Okamoto M, et al. IgE-Mediated and Age-Related Bronchial Hyperresponsiveness in Patients with Asthma. Relationship to Family History of the Disease. Age Ageing 29 (2000): 215-220.
53. Ducharme ME, Prince P, Hassan N, Nair P, Boulet LP. Expiratory Flows and Airway Inflammation in Elderly Asthmatic Patients. Respir. Med 105 (2011): 1284-1289.
54. Hardaker KM, Downie SR, Kermode JA, Farah CS, Brown NJ, Berend N, et al. Predictors of Airway Hyperresponsiveness Differ between Old and Young Patients with Asthma. Chest 139 (2011): 1395-1401.
55. Sharma G, Goodwin J. Effect of Aging on Respiratory System Physiology and Immunology. Clin. Interv. Aging 1 (2006): 253-260.
56. Aydin M, Koca C, Ozol D, Uysal S, Yildirim Z, Kavakli HS, et al. Interaction of Metabolic Syndrome with Asthma in Postmenopausal Women: Role of Adipokines. Inflammation 36 (2013): 1232-1238.
57. Boulet LP, Boulay MÈ. Asthma-Related Comorbidities. Expert Rev. Respir. Med 5 (2011): 377-393.
58. Saad AG, Kumar S, Ron E, Lubin JH, Stanek J, Bove KE, et al. Proliferative Activity of Human Thyroid Cells in Various Age Groups and Its Correlation with the Risk of Thyroid Cancer after Radiation Exposure. J. Clin. Endocrinol. Metab 91 (2006): 2672-2677.
59. Bello G, Pennisi MA, Montini L, Silva S, Maviglia R, Cavallaro F, et al. Nonthyroidal Illness Syndrome and Prolonged Mechanical Ventilation in Patients Admitted to the ICU. Chest 135 (2009): 1448-1454.
60. Plikat K, Langgartner J, Buettner R, Bollheimer LC, Woenckhaus U, Schölmerich J, et al. Frequency and Outcome of Patients with Nonthyroidal Illness Syndrome in a Medical Intensive Care Unit. Metabolism 56 (2007): 239-244.
61. Holzheimer RG, Mannick JA, eds. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt (2001).
62. Li Z, Huang Y, Chen X, Wei C, Yang P, Xu W. The Effect of Inflammation on the Formation of Thyroid Nodules. Int. J. Endocrinol (2020).
63. Wang Z, Lin Y, Jiang Y, Fu R, Wang Y, Zhang Q. The Associations between Thyroid-Related Hormones and the Risk of Thyroid Cancer: An Overall and Dose-Response Meta-Analysis. Front. Endocrinol. (Lausanne) 13 (2022).
64. Liu Y, Huang Y, Mo G, Zhou T, Hou Q, Shi C, et al. Combined Prognostic Value of Preoperative Serum Thyrotrophin and Thyroid Hormone Concentration in Papillary Thyroid Cancer. J. Clin. Lab. Anal 36 (2022).
65. Gresele P, Dottorini M, Selli ML, lannacci L, Canino S, Todisco T, et al. Altered Platelet Function Associated with the Bronchial Hyperresponsiveness Accompanying Nocturnal Asthma. J. Allergy Clin. Immunol 91 (1993): 894-902.
66. Kemona-Chetnik I, Bodzenta-Lukaszyk A, Butkiewicz A, Dymnicka-Piekarska V, Kemona H. Thrombocytopoesis in Allergic Asthma. Pol. Arch. Med. Wewn 117 (2007): 9-13.
67. Nacaroglu HT, Isguder R, Bahceci SE, Ceylan G, Korkmaz HA, Karaman S, et al. Can Mean Platelet Volume Be Used as a Biomarker for Asthma? Postep. dermatologii i Alergol 33 (2016): 182-187.
68. Martin S, Mustata T, Enache O, Ion O, Chifulescu A, Sirbu A, et al. Platelet Activation and Inflammation in Patients with Papillary Thyroid Cancer. Diagnostics (Basel, Switzerland) 11 (2021).
69. Mizrak S, Kucuk S. Platelet Levels and Neutrophil to Lymphocyte Ratio in Thyroid Nodules with and without Cancer Diagnosis (2020).
70. Hafez MR, Eid HA, Elsawy SB, Eldin NE, El Madbouly AA. Assessment of Bronchial Asthma Exacerbation: The Utility of Platelet Indices. Egypt. J. Bronchol 1365 (2020): 623-629.
71. Sullivan PJ, Jafar ZH, Harbinson PL, Restrick LJ, Costello JF, Page CP. Platelet Dynamics Following Allergen Challenge in Allergic Asthmatics. Respiration 67 (2000): 514-517.
72. Kaser A, Brandacher G, Steurer W, Kaser S, Offner FA, Zoller H, et al. Interleukin-6 Stimulates Thrombopoiesis through Thrombopoietin: Role in Inflammatory Thrombocytosis. Blood 98 (2001): 2720-2725.
73. Tutluoglu B, Gurel CB, Ozdas SB, Musellim B, Erturan S, Anakkaya AN, et al. Platelet Function and Fibrinolytic Activity in Patients with Bronchial Asthma. Clin. Appl. Thromb. Hemost 11 (2005): 77-81.
74. Castro-Faria-Neto HC, Bozza PT, Martins MA, Dias PMFL, Silva PMR, Cordeiro RSB. Platelet Mobilization Induced by PAF and Its Role in the Thrombocytosis Triggered by Adrenaline in Rats. Thromb. Haemost 62 (1989): 1107-1111.
75. Pucci F, Rickelt S, Newton AP, Garris C, Nunes E, Evavold C, et al. PF4 Promotes Platelet Production and Lung Cancer Growth. Cell Rep 17 (2016): 1764-1772.
76. Schuyler MR, Bondarevsky E, Schwartz HJ, Schmitt D. Corticosteroid-Sensitive Lymphocytes Are Normal in Atopic Asthma. J. Allergy Clin. Immunol 68 (1981): 72-78.
77. Pan R, Ren Y, Li Q, Zhu X, Zhang J, Cui Y, et al. Neutrophil-Lymphocyte Ratios in Blood to Distinguish Children with Asthma Exacerbation from Healthy Subjects. Int. J. Immunopathol. Pharmacol 37 (2023).
78. Mota-Pinto A, Todo A, Alves V, Santos A, Santos M. Regulatory T Cells in Elderly Patients with Asthma. J. Investig. Allergol. Clin. Immunol 21 (2011): 199-206.
79. Huang Y, Jin N, Roark CL, Aydintug MK, Wands JM, Huang H, et al. The Influence of IgE-Enhancing and IgE-Suppressive Gammadelta T Cells Changes with Exposure to Inhaled Ovalbumin. J. Immunol 183 (2009): 849-855.
80. Deppong C, Degnan JM, Murphy TL, Murphy KM, Green JM. B and T Lymphocyte Attenuator, BTLA, Regulates T Cell Survival in the Lung1. J. Immunol 181 (2008): 2973.
81. An I, Ucmak D, Ozturk M. The Effect of Biological Agent Treatment on Neutrophil-to-Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio, Mean Platelet Volume, and C-Reactive Protein in Psoriasis Patients. Postep. dermatologii i Alergol 37 (2020): 202-206.
82. Redelman-Sidi G, Michielin O, Cervera C, Ribi C, Aguado JM, Fernández-Ruiz M, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the Safety of Targeted and Biological Therapies: An Infectious Diseases Perspective (Immune Checkpoint Inhibitors, Cell Adhesion Inhibitors, Sphingosine-1-Phosphate Receptor Modulators and Proteasome Inhibitors). Clin. Microbiol. Infect 24 (2018): S95-S107.
83. Liu J, Li C, Du J, Fan J, Liu K, Zhang B, et al. The Neutrophil-to-Lymphocyte Ratio Correlates with Age in Patients with Papillary Thyroid Carcinoma. ORL. J. Otorhinolaryngol. Relat. Spec 77 (2015): 109-116.
84. Zhang J, Gong Z, Li S, Fan P, Yue G, Zou G, et al. The Value of Neutrophil-to-Lymphocyte Ratio Combined with the Thyroid Imaging Reporting and Data System in the Diagnosis of the Nature of Thyroid Nodules. J. Clin. Lab. Anal 36 (2022).
85. Rabold K Gielen PR, Kers-Rebel ED, Netea MG, Smit JWA, Adema GJ, et al.T-Cell Lymphopenia in Patients with Advanced Thyroid Carcinoma Is Associated with Poor Prognosis. Oncologist 24 (2019): e106-e110.
86. Hoffmann TK, Dworacki G, Tsukihiro T, Meidenbauer N, Gooding W, Johnson, J.T, Whiteside, T.L. Spontaneous Apoptosis of Circulating T Lymphocytes in Patients with Head and Neck Cancer and Its Clinical Importance. Clin. Cancer Res. 2002, 8, 2553-2562.
87. Kulkarni A, Kediya DA. A Multi-Point View of Genetic Factors Affecting Hereditary Transmissibility of Asthma. Cureus 2 (2022).
88. Paschke R. Molecular Pathogenesis of Nodular Goiter. Langenbeck’s Arch. Surg 396 (2011): 1127-1136.