Bronchitis, COPD, and pneumonia after viral endemic of patients with leprosy on Sorok Island in South Korea

Viral respiratory diseases (VRDs) cause lung inflammation and inflammatory cytokine production. We study whether dapsone is responsible for its observed preventive treatment effects of the sustained viral RNA interferon response. Around 2008 and 2012, Korea’s Dementia Management Act stipulated drastic changes in the administration of dementia medication by medical staff. Participants were randomized and we compared leprosy patients with VRDs after prescribing dapsone as a standard treatment from 2005 to 2019. Significance was evaluated based on the dapsone-prescribed (+) subgroup and the dapsone-unprescribed (−) subgroup of the VRD diagnosed (+) and VRD undiagnosed (−) subgroup. We analyzed VRD ( +)/(− with dapsone (+)/(−) group and used a T-test, and designed the equation of acetylation with dapsone and acetylcholine (AA) equation. The 6394 VRD participants who received the dapsone intervention compared to the 3255 VRD participants in the control group demonstrated at T2 VRD (+) dapsone (−) (mean (M) = 224.80, SD = 97.50): T3 VRD (−) dapsone (+) (M = 110.87, SD = 103.80), proving that VRD is low when dapsone is taken and high when it is not taken. The t value is 3.10, and the p value is 0.004395 (significant at p < 0.05). After an increase in VRDs peaked in 2009, bronchitis, COPD, and pneumonia surged in 2013. The AA equation was strongly negatively correlated with the prevalence of bronchitis and chronic obstructive pulmonary disease (COPD): with bronchitis, r(15) =  −0.823189, p = 0.005519, and with COPD, r(15) =  −0.8161, p = 0.000207 (significant at p < 0.05). Dapsone treated both bronchitis and COPD. This study provides theoretical clinical data to limit acetylcholine excess during the VRD pandemic for bronchitis, COPD, and pneumonia. Supplementary Information The online version contains supplementary material available at 10.1007/s00210-023-02407-7.


Introduction
Sorok Island was established in May 1916 to quarantine leprosy patients. The public health report filed on June 4, 1946, increased the capacity of Sorokdo Leper Colony to between 8000 and 9000, making it the largest leprosarium in the world (Kim 2012;Jane 2010). Sister M. Stoeger and Sister M. Pissarek cared for the patients from 1962 to 2005 (Anthony 2019).
The antibiotic dapsone (4,4′-diaminodiphenyl sulfone, DDS) is predominantly associated with treating leprosy and is both an antibiotic and ANTI-inflammatory agent (Wolf et al. 2002). Dapsone has been used for leprosy, malaria, toxoplasmosis, and Pneumocystis pneumonia in persons with human immunodeficiency virus infection. Moreover, dapsone is prescribed for dermatitis herpetiformis, linear IgA dermatosis, bullous pemphigoid, subcorneal pustular dermatosis, erythema elevatum diutinum, bullous systemic lupus erythematosus, and other chronic inflammatory Complete blinded randomized controlled trial (RCT) study

Highlights
After an increase in viral respiratory diseases (VRDs) peaked in 2009, bronchitis, COPD, and pneumonia surged in 2013.Dapsone prescribed group has a lower prevalence of VRDs.The acetylationacetylcholine (AA) equation, ㅣSum of dapsone prescribed group − the sum of increased acetylcholine groupㅣ, was strongly correlated with the prevalence of bronchitis and COPD, not bacteria origin pneumonia.We rediscovered in humans that type 1 interferon production reduced inhibitory M2 muscarinic receptor function and gene expression in cultured airway parasympathetic neurons by VRDs.Acetylcholine excess appears to inhibit acetylcholine receptors for interferon production against virus invasion. diseases characterized by the infiltration of neutrophils or eosinophils (Wozel 2010).
Acetylation of dapsone showed genetic polymorphism and reproducible individual characteristics. Acetylation of dapsone and deacetylation of monoacetyl dapsone occurred concurrently, and plasma ratios of acetylated to parent drug were attained constantly but characteristic for the individual (Gelber et al. 1971). Acetylation of aspirin inhibits cyclic GMP-AMP synthase (cGAS)-mediated interferon production, and cGAS acetylation on Lys384, Lys394, or Lys414 contributes to keeping cGAS inactive (Dai et al. 2019). The gut microbiota drives systemic antiviral immunity of type I interferon (IFN-I) priming. DNA-containing membrane vesicles from the gut microbiota were found in circulation. They promoted the clearance of both herpes simplex virus type 1 of DNA virus and vesicular stomatitis virus of RNA virus in a GAS-STING-IFN-I axis (Erttmann et al. 2022).
We investigated Hansen's disease (HD) patients with dapsone following the Dementia Management Act (DMA), enacted in 2011, in Sorokdo National Hospital. We analyzed the medical records of Sorokdo National Hospital from 2005 to 2020. We compared the incidence of viral respiratory diseases (VRDs) with dapsone prescriptions for persistent lung inflammation, inflammatory cytokine production, viral RNA, and sustained IFN response; indeed, these responses are recapitulated and contribute to the pathology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Study design
Medical data on the correlation between DDS and respiratory diseases were then analyzed by the International Classification of Diseases (ICD) codes of VRDs. There was no significant change and no statistical correlation (Lee et al. 2020a). However, in the study of the dapsone effect in antihistamine refractory chronic idiopathic urticaria, VRDs occurred in only three patients in the placebo group (Morgan et al. 2014). A higher dose of dapsone was required when the patient developed a tracheal infection, but the patient had no similar VRDs (Zheng et al. 2021). We correlated dapsone to compete with the NLRP3 inflammasome (Lee et al. 2020a). As NLRP3 plays a critical role in viral immunopathology (Malinczak et al. 2021), we analyzed the relationship between bacterial respiratory diseases (RDs) and VRDs (Fig. S1).
HD patients took dapsone for their lives but did not take dementia symptom improvement drugs. We included a control cohort from February 1962 to November 21, 2005 (Lee 2022b). Around 2008 and 2012, Korea's Dementia Management Act (DMA) stipulated drastic changes in the administration of dementia medication by medical staff . It facilitated the EDI code-based cohort studies, randomized the cohort at a complete-blinded state, and made the RCT study provide causality .
DMA separated the dapsone-prescribing (+) group from the dapsone non-prescribing (−) group. Psychiatrists prescribed AAD instead of dapsone to treat mild cognitive impairment (MCI) or Alzheimer's disease (AD). We connected the EMR database of the Sorokdo National Hospital, archived from January 2005 to June 2019, and searched the ICD-10 codes of RDs with dapsone. This cohort study is the second to be validated by RCT methodology because the intervention was performed for dementia treatment.

Eligibility criteria
According to the Infectious Disease Control and Prevention Act, all Hansen subjects on Sorok Island have been registered and treated at Sorokdo National Hospital. This cohort consisted of HD patients, dapsone, and respiratory diseases in all Hansen subjects, according to the data received from Sorokdo National Hospital by South Korea's Official Information Disclosure Act. We searched all medical records of the Sorokdo National Hospital with ICD-10 codes in South Korea from 2005 when the government computerized the codes.
Study Setting for ICD Code of Korean Diseases and Medicines (ICD-10 Version: 2019).

Complete blinded study and randomization
HD patients have taken dapsone for their life or four types of dementia symptom improvement drugs: acetylcholinesterase inhibitors (AChEIs) and the NMDA antagonist memantine since 2008. The Korean government has established compulsory long-term care insurance (Chon 2014). The government successively established Community Dementia Reassurance Centers at all public Health Centers according to the National Duty for Dementia (Youn and Jeong 2018). In addition, medical teams reinforced the dementia management programs that administer AAD to MCI or AD patients as a preventive treatment (Lee et al. 2009;Ahn et al. 2015). The current mainstays of dementia treatment include AChEIs and memantine (Lee 2022b;Lee et al 2022). Ahn et al. (2015) insisted that the 1-year persistence rate of AChEIs should be precisely monitored to optimize treatment persistence for AD patients because patients are more likely to stop therapy than those in other countries. As a result, prescriptions for effective medications have increased. It overlaps with the enactment of the 2011 DMA. DMA significantly influenced the diagnosis and treatment of dementia. Medical staff treated HD patients with VRD or dementia, while no one knew about dapsone's relationship with viral inflammasomes. This is a complete blinded randomized study by DMA.

Interventions
According to the DMA, the medical staff of Sorokdo National Hospital started a full investigation in 2011 for the treatment of dementia for all HD patients on Sorok Island. As a result, AAD was prescribed for Hansen subjects diagnosed with dementia, and doctors stopped prescribing dapsone for inactive HD patients. They have followed up on all HD patients since 2011.
As a result, DMA administered dapsone to the trial group, and we classified dapsone (−) subjects as the control group.

Outcomes
Significance was evaluated based on a p-value of 0.05 in the DDS (+) subgroup and the DDS (−) subgroup of the VRD-diagnosed (+) subgroup and the VRD-undiagnosed (−) subgroup.

Statistical analysis
We used the software programs Object-Relational DBMS and Google spreadsheet with SPSS. The Mann-Whitney U test, one-way repeated-measures ANOVA calculator, and post hoc Tukey honestly significant difference (HSD) test were applied. A significant T test was performed among the

Results
Nine thousand six hundred forty-nine participants were randomized from 2005 to 2020 on Sorok Island. We performed primary (Tables S4-S4-11, Figs. S2-S6) and secondary (Tables S5-2-S5-13, Figs. S7-S11) analyses based on the p value. Because all the results were significant, we used primary data to report the results (Fig. 1). The f-ratio value is 8.52. The p value in the one-way ANOVA calculator for independent measures is 0.000094 (Table S4-1). However, there were caveats to post hoc Tukey's honestly significant difference. The pairwise comparisons (T1:T3, T1:T4, T2:T3, T2:T4, and T3:T4) were applicable except for T1:T2 and T2:T4 (Table S4-2) ( Table 1) stopped taking dapsone, their condition would deteriorate because of exacerbated VRDs, and be hospitalized. We can find that the number of VRD patients was comparable (148 in 2005 and 155 in 2019). Very few people have been hospitalized for VRD in the group taking dapsone since 2013. The t value is 3.21, and the p value is 0.003287 (significant at p < 0.05) (Table S4-  The chi-square is 281.826 The p value is <0.00001. I t is significant at p < 0.05 Bold means significant; italic, non-significant * Four groups were classified: T1 group is DDS-prescribed (+) with VRD-diagnosed (+) subjects, T2 group is DDS-unprescribed (−) with VRDdiagnosed (+) subjects, T3 group is DDS-prescribed (+) with VRD-undiagnosed (−) subjects, and T4 group is DDS-unprescribed (−) with VRD-undiagnosed (−) subjects ** Chi-square, e indicates a p value <0.05, f standard deviation (SD), g confidence interval (CI) dapsone is taken and very high when not taken. The t value is 3.10, and the p value is 0.004395 (significant at p < 0.05) (  (2015), and SARS-CoV-2 (2020) on Sorok Island. In addition, the T1:T3, T1:T4, T2:T3, and T2:T4 tests indicate that as of 2010, the group with dapsone (+) and the group without dapsone (−) were separated, and the group taking dapsone should have milder symptoms of VRD. SARS-CoV-2 as RNA-virus activates cGAS-stimulator of interferon genes (STING) signaling in endothelial cells through mitochondrial DNA release, which leads to type I IFN production, and pharmacological inhibition of STING reduces severe lung inflammation and disease severity (Domizio et al. 2022). This provides evidence that dapsone inhibits interferon, which is an exacerbation of the viral respiratory disease (Fig. 2).
Immune-related inflammatory diseases showed a sharp increase in prevalence from 2008 to 2015, followed by a decrease. COPD increased slowly from 2008 to 2011, rapidly increased in 2012 and 2013, and decreased. Bronchitis levels rose rapidly from 2012 to 2014 and then decreased. Pneumonia increased sharply in 2013 compared to previous years.
Since 2008, immune-related inflammatory diseases have increased rapidly. It is a period of viral respiratory disease: 2008-2010 endemic on Sorok Island. Since 2012, COPD has increased, as have bronchitis and pneumonia frequencies. We observed a decrease in the average age of death in the group taking AAD and psychotropic drugs from 2008 to 2015 (Lee 2022b) (Fig. S12). We investigated asthma and lung function trajectories leading to COPD from the ICD-10 codes asthma (J45), predominantly allergic asthma (J45.0), nonallergic asthma (J45.1), asthma, unspecified (J45.9), and status asthmaticus (J46) and COPD patients: other chronic obstructive pulmonary disease (J44), chronic obstructive pulmonary disease, unspecified (J44.9), and bronchiectasis (J47) to identify the prevalence of asthma-COPD relationships. The prevalence of asthma-COPD was not associated at all. However, we only observed a much higher prevalence of COPD than asthma. Asthma and lung function trajectories did not lead to COPD (Fig. S13).

Factors from the number of diagnosed Alzheimer's disease patients and dapsone use group
Because pharmaceutical companies that produce AChEI reported its frequent side effects like pharyngitis, pneumonia, increased cough, and bronchitis (Lee et al. 2020b), and AAD use in dementia-related disorders increased mortality (Stone 2005; Jong Hoon 2022), we used the pile-up data from Sorok Island_Cohort-Lee, Jong Hoon (2022), "Basic cohort study: dapsone is an anticatalysis for AD exacerbation," Mendeley Data, V2 (Data S1).
We formulated the factor to calculate the relationship between acetylation and acetylcholine.
[Acetylation-acetylcholine (AA) equation]: A total was calculated for all the people taking dapsone and all the individuals diagnosed with AD taking AAD, subtracting 1 from the other, processing the data as an absolute value (Table S6). We used the Pearson correlation coefficient calculator and Spearman's rho calculator to correlate the factors and the prevalence of bronchitis, pneumonia, and COPD.
Our calculations can be summarized as follows: Pearson correlation coefficient calculator The AA equation and bronchitis were strongly negatively correlated, r(15) = − 0.823189, p = 0.005519. The result is significant at p < 0.05.
The AA equation and pneumonia variables were weakly and negatively correlated, r(15) = − 0.4402, p = 0.100742. Therefore, the result is not significant at p < 0.05.
The AA equation and COPD were found to be strongly negatively correlated, r(15) = − 0.8161, p = 0.000207. The result is significant at p < 0.05.
Spearman's rho calculator gave the same result: the association between the two variables of bronchitis and COPD with the AA equation was considered statistically significant by normal standards. Pneumonia would not be considered statistically (Supplement S6.1, S6.2, and S6.3) (Fig. 3).
The AA equation was correlated with the prevalence of bronchitis and COPD. This means that dapsone treated and AAD exacerbated them, but dapsone not with pneumonia caused by bacteria. Ameliorating viral disease with dapsone (Lee et al. 2020a;Kanwar et al. 2021Kanwar et al. , 2022 or the downstream IFN-stimulated cascade with anti-IFNAR2 in the onset stages of disease (Lee 2022a) must attenuate overactive immune-mediated respiratory inflammatory diseases. (1) The Dapsone IFN1 factor = | DDS (+) − sum AD (+) |

Limitations
The limitation is that this study was conducted in an island area and on HD patients. Since dapsone's maximal allowance price in South Korea was very low in 2016, pharmaceutics, which produced it in Korea, stopped the production of dapsone except for the supply for HD patients (Lee 2021). More studies are required to compare COVID-19 survival rates later.

We recommend taking dapsone continuously for Hansen's disease patients if there are no side effects
Dapsone activates specific T cells of hypersensitive patients expressing the risk allele HLA-B* 13: 01.
HLA-B*13:01-CD8 + T cells (cytotoxic T lymphocytes) induce a dapsone-responsive immune response . The multidrug therapy containing rifampin and clofazimine with dapsone was decisive for treating leprosy (Ramos-e-Silva and Rebello 2001). According to our survey, some HD patients on Sorok Island have taken dapsone for over 20 years. Remarkably, we noted that some people took dapsone for more than 50 years (Lee 2022b;Lee et al. 2022;Kanwar et al. 2021). Therefore, if there are no dapsone side effects, we recommend taking dapsone continuously.

COPD was associated with AChEIs and IFN1
COPD was associated with incident nonamnestic MCI in a dose-dependent manner in the Mayo Clinic Study on Aging (Singh et al. 2014). The risk of COPD exacerbation may increase in the first 90 days of AChEI therapy in patients with dementia and COPD (Mahan and Blaszczyk 2016). Virus infection and interferon treatment decreased the M2 muscarinic receptor gene expression on the parasympathetic nerve endings by causing the release of IFN-gamma, which inhibits M2 receptor gene expression (Jacoby et al. 1998). Acetylcholine excess appears to inhibit acetylcholine receptors for interferon production against virus invasion. The genesis of acetylcholine receptor needs interferon (Balasa et al. 1997). The muscarinic and nicotinic acetylcholine receptors play critical roles in regulating immune function (Kawashima et al. 2012). This study elucidates the correlation between donepezil and acetylcholine and suggests that acetylcholine excess negatively affects acetylcholine receptor gene expression.
An asthma component might facilitate the identification of COPD patients with no previous diagnosis of obstructive lung disease. The prevalence of asthma-COPD overlap syndrome was only 6% of the COPD patients who fulfilled both criteria (Baarnes et al. 2017). Our study also corresponds to previous results. Asthma and lung function trajectories did not lead to COPD.
The molecule neuropilin-1 (NRP1) plays an important and complex role in the secondary CD8 T-cell response to control viral infections and tumors (Hwang et al. 2019). We can divide innate lymphoid cells (ILCs) into three groups based on distinct cytokine secretion profiles and dependent transcription factors. Group 3 ILCs (ILC3s) are present in smokers and patients with COPD.  (4) We calculated that all Hansen's disease patients were taking dapsone, and all the individuals diagnosed with Alzheimer's disease (AD) * were taking anti-Alzheimer's disease (AAD) ** . Then, we subtracted one from the other, processed the data as an absolute value, and illustrated these data graphically. Our results were strongly negatively correlated with COPD and bronchitis, not pneumonia ILC3s with NRP1 produce higher levels of cytokines than ILC3s without NRP1 (Shikhagaie et al. 2017). NRP1 + ILC3s play a potential role in inflammation and vascularization (Meininger et al. 2020). Dapsone might control the NRP1-ILC inflammatory pathway with the IFN1 or cGAS-STING cascade pathways through acetylation-deacetylation.

Conclusion
This study provides theoretical clinical data to limit acetylcholine excess during the VRD pandemic for bronchitis, COPD, and pneumonia. Author contribution J.L conceptualized, methodologically investigated, and wrote the original draft. B.K., A.K., E.A., C.S., S.J.L., S.C., J.P., M.C., and J.B. examined the methodology and analyzed its results.
Data availability All data are available in the main text or the supplementary materials. Additional data supporting this study's findings are available from the corresponding author upon reasonable request. In addition, the complete detailed survey is provided as a separate file. Lee, Jong Hoon (2022), "Data of viral respiratory diseases on Sorok Island during the pandemic", Mendeley Data, V1, https:// doi. org/ 10. 17632/ cwxsw njnb2.1.

Declarations
Ethical approval The National Agency approved this study for the Management of Life-sustaining Treatment, which certified that lifesustaining treatments were managed properly (Korea National Institute for Bioethics Policy (KoNIBP) approval number P01-202007-22-006). The KoNIBP approved the observational study of patients ethically based on FDA guidelines following the World Medical Association Declaration of Helsinki. Therefore, we carried out all methods following relevant ethical guidelines and regulations and reported the study results. Sorokdo National Hospital provided the necessary information in accordance with Article 13 of the "Act on Information Disclosure of Public Institutions." Sorokdo National Hospital obtained informed consent from all participants or, if participants were under 18, from a parent and/or legal guardian. All consent to participate and consent to publish.

Competing interests The authors declare no competing interests.
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