Case ReportClinical Studies
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Molecular Hydrogen as a Promising Therapy Could Be Linked With Increased Resting Treg Cells or Decreased Fas+ T Cell Subsets in a IgG4-PF-ILD Patient: A Case Report

SHAN-WEN LUI, JENG-WEI LU, YI-JUNG HO, SHIH-EN TANG, KAI-HSIUNG KO, TING-YU HSIEH and FENG-CHENG LIU
In Vivo May 2024, 38 (3) 1512-1518; DOI: https://doi.org/10.21873/invivo.13600

Abstract

Background/Aim: Progressive fibrosing interstitial lung disease (PF-ILD) refers to a group of chronic lung conditions commonly associated with immunoglobulin G4-related disorders. It is characterized by progressive scarring (fibrosis) within the pulmonary interstitium, resulting in respiratory failure and early mortality. Some patients do not respond to standard therapeutic interventions. Numerous studies have confirmed the anti-inflammatory and antioxidant properties of molecular hydrogen in various disease models. Case Report: In this report, we present a case study of an 85-year-old female diagnosed with suspected IgG4-related PF-ILD complicated by hospital-acquired pneumonia. On the fourth day of hydrogen-assisted therapy, a noticeable improvement in lung infiltrations was observed in chest X-rays as the patient gradually progressed towards weaning off mechanical ventilation. To assess treatment responses, we compared immune phenotypes before and after hydrogen treatment. A marked increase was observed in resting regulatory T cell levels after treatment, accompanied by a notable decrease in Fas+ helper T cell and cytotoxic T cell subtypes. Conclusion: This case study highlights the effectiveness of hydrogen-assisted therapy in managing PF-ILD complicated by pneumonia, warranting further research in the future.

Key Words:

Immunoglobulin G4-related disease (IgG4-RDs), otherwise known as hyper-IgG4 or IgG4-related autoimmune disease, refers to a class of fibroinflammatory disorders, which can affect any organ (1). The various pulmonary manifestations of IgG4-RD often resemble lung carcinoma, pneumonia, or interstitial lung disease (ILD) (2, 3). ILDs are rare disorders presenting a range of etiologies and prognoses (4). Many patients with ILDs develop progressive fibrotic ILD (PF-ILD) (4), which is characterized by fibrotic changes within the pulmonary interstitium, resulting in respiratory failure and early mortality (5). Note that hospital-acquired infectious pneumonia is a common complication among patients with pulmonary disorders.

Current clinical interventions include pharmacological and non-pharmacological therapies. Pharmacotherapy involves anti-fibrotic treatments, such as nintedanib or pirfenidone, to mitigate the decline in lung function. Immunosuppression is applicable to specific subtypes of PF-ILD, such as connective tissue disease-associated ILD and hypersensitivity pneumonitis. Among the non-pharmacological therapies, lung transplantation is the sole curative option; however, oxygen therapy and the management of complications also play pivotal roles in the treatment of PF-ILD (5). Note that a substantial number of patients are unresponsive to standard therapy, underscoring the need for novel and efficacious interventions.

When used as a therapeutic gas, hydrogen exhibits potent cytoprotective, anti-inflammatory, and antioxidant effects (6). Evidence from animal models indicates that molecular hydrogen can alleviate inflammation through the inhibition of mitochondrial oxidation and nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome activation (7). Hydrogen-assisted therapy has considerable potential in safeguarding the lungs from a range of diseases, including acute lung injury, chronic obstructive pulmonary disease, asthma, lung cancer, pulmonary arterial hypertension, and pulmonary fibrosis (8, 9).

This paper presents a case study of an 85-year-old female suspected of having IgG4-related PF-ILD complicated by hospital-acquired infectious pneumonia. A failure of standard treatments prompted the initiation of hydrogen therapy as an adjuvant treatment, which was shown to induce a substantial increase in the levels of resting regulatory T (resting Treg) cells (CD3+CD4+CD25highFoxP3lowCD45RA+) and notable decreases in all Fas+ T helper (Th) cell subsets as well as Fas+ cytotoxic T (Tc) cell subsets. Within days of treatment initiation, chest X-rays (CXR) revealed marked improvements in the patient’s condition, which led to respiratory weaning and subsequent transfer from the intensive care unit (ICU). This study was approved by the Institutional Review Board (IRB) of Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, and complied with relevant guidelines (IRB: B202105106, date of approval 18 July 2023). Patient informed consent was obtained in written form (No. B202105106-29). This study involving human participants was in accordance with the ethical standards of the institutional and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Case Report

An 85-year-old female patient presented with persistent respiratory distress, coughing, and chronic ILD during a scheduled outpatient follow-up visit for the management of atrial fibrillation with non-vitamin K antagonist oral anticoagulants. In late 2021, the patient was referred to the Department of Rheumatology and Immunology, due to an antinuclear antibody (ANA) titer of 1:320. Initial laboratory data from January 2022 revealed elevated levels of IgA (544) and IgG (2171) as well as an antineutrophil cytoplasmic antibody (ANCA) titer of 1:320 and ANA titer of 1:640. Subsequent follow-up assessments revealed a gradual increase in IgE (reaching 504) and IgG4 (reaching 369.30) levels (Figure 1A). Physicians suspected that the ILD was associated with a rheumatologic disorder. From September to October 2022, the patient was hospitalized in the gastroenterology department, due to epigastric pain and nausea. During hospitalization, the patient developed dyspnea and a productive cough with sputum. CXR images revealed rapid bilateral lung progression of lung disease with coarse reticulation and consolidation within three days (Figure 1B and C). High-resolution computed tomography (HRCT) scans obtained at the same time revealed patchy ground-glass opacities in peribronchial and subpleural regions of both lungs, accompanied by traction bronchiectasis and honeycomb changes (Figure 1D and E). IgG4-related PF-ILD was suspected (3, 10, 11). Due to the patient's advanced age and unstable condition, a lung biopsy to confirm the IgG4-RD diagnosis (12) or forced vital capacity measurements were not feasible.

Figure 1.
Figure 1.

Clinical course of the patient. (A) IgE and IgG-4 levels before and after progressive fibrosing-interstitial lung disease (PF-ILD) diagnosis. IgG-4 levels are marked in red, and IgE levels are marked in blue with the highest values indicated by green arrows; (B, C) Chest X-ray (CXR) images showing PF-ILD. (B) CXR image from September 12, 2022, showing decreased lung volume and basal predominant coarse reticulation. (C) CXR image from September 15, 2022, showing progression with reticulation and consolidation in bilateral lungs (triangle). (D, E) High-resolution computed tomography (HRCT) images taken on September 15, 2022. (D) Axial view of the HRCT revealing fibrosing ILD and associated acute exacerbation with traction bronchiectasis (arrow) and honeycomb changes (triangle). (E) Coronal view at the corresponding horizontal level revealing bilateral ground-glass opacity (triangle). (F to H) Remarkable differences between CXR images taken before and after molecular hydrogen therapy. (F) CXR taken prior to molecular hydrogen therapy (May 12, 2023) showing airspace consolidations with interstitial infiltration over bilateral lungs. (G) CXR taken on day 2 of molecular hydrogen therapy (May 13, 2023) showing significant improvements, characterized by prominent resolution of airspace consolidations and decreased interstitial infiltration over bilateral lungs. (H) CXR taken on day 4 (May 15, 2023) showing further improvements, with reductions in the patchy areas of ground glass opacities and interstitial infiltration.

Initial treatment using steroids and rituximab led to a reduction in IgE and IgG4 levels (Figure 1A) and decreases in other immune markers (IgA: 400, IgG: 1,454, ANA: negative, ANCA: negative); however, upper respiratory symptoms persisted. Subsequent use of antibiotics, steroids, and an immunosuppressant (Myfortic) failed to control the disease. A tracheostomy was performed on December 8, 2022, followed by a five-day course of intravenous immunoglobulin (IVIG) in mid-December. Nonetheless, persistent respiratory distress and instability persisted. On February 5, 2023, the symptoms intensified, prompting transfer to the ICU. Antifibrotic treatment (Pirespa) and antifungal therapy (Cresemba) were initiated following the detection of fungal growth in sputum cultures. The patient showed no improvements, despite treatments including rituximab, IVIG, steroids, antibiotics, and antifibrotic treatment. On April 28, 2023, the patient experienced a shock episode necessitating emergent measures. CXR images revealed severe lung infiltration (Figure 1F), and the patient remained dependent on a ventilator.

Molecular hydrogen therapy (1 capsule/day) was initiated on May 12, 2023. Hydrogen capsules (PURE HYDROGEN) were purchased from HoHo Biotech Co., Ltd. (Taipei, Taiwan, ROC). Each capsule contained 170 mg of hydrogen-rich coral calcium containing 1.7×1021 molecules of hydrogen, which is equivalent to 24 cups of water with 1,200 ppb of hydrogen or 0.6 mM of hydrogen per 200 ml of water. By the 2nd day of hydrogen therapy, there was a noticeable improvement in lung infiltration (Figure 1G). By the 4th day, physicians observed marked improvement in the patient’s overall condition (Figure 1H). Note that the patient was initially unable to speak due to severe dyspnea and tracheostomy. By the 7th day of hydrogen therapy, the patient was able to sit up and communicate with family members, and the entire family regarded the effects of hydrogen therapy as highly effective. At this point, respiratory weaning training was initiated. There were no adverse reactions or events observed following the administration of hydrogen capsules. The patient was ventilator-free for 10 h on the 14th day and 18 h on the 23rd day, while awaiting transfer out of the ICU. The disease progression is illustrated in Figure 2.

Figure 2.
Figure 2.

Disease progression and clinical treatment course. The gray line indicates overall disease progression. The hollow arrows indicate the time points for symptom persistence and improvement, changes in laboratory data, and scheduled examinations. The green line and arrow denote the medical treatments and hospitalization status. The blue line indicates the time points for whole-blood analysis.

Flow cytometry was used for whole-blood analysis aimed at assessing changes in immune cells before and after hydrogen therapy. For subsequent whole-blood analysis, blood samples were prepared using standard fluorescent dye preparation methods and fluorescent antibody reagent kits with dried reagents (Beckman Coulter, Brea, CA, USA). The methods, steps, immunophenotypic analysis, and cell gating were performed as previously described (13). The detailed setting and the cells gating are listed in Supplementary Data 1 to 5, Figure 1, Figure 2, and Figure 3. Our analysis of immunophenotypic markers before and after hydrogen therapy revealed a dramatic increase in resting Treg cells and a notable decrease in Fas+ Th and Tc cell subtypes after treatment (Figure 3). Furthermore, the reporting of this study conforms to the CARE reporting guidelines (2013 CARE Checklist).

Figure 3.
Figure 3.

Immunophenotypic changes after molecular hydrogen therapy. Whole-blood analysis was conducted six times: prior to molecular hydrogen therapy (November 1, 2022; December 5, 2022; December 15, 2022; December 29, 2022; May 1, 2023) and post-therapy (May 19, 2023). (A) Percentage changes in resting Treg cells before and after molecular hydrogen therapy. (B to F) Changes in Fas+ Th cell subsets, including Th Fas+, Naive Th Fas+, CM Th Fas+, Effector Th Fas+, and EM Th Fas+ cells after molecular hydrogen therapy. (G to K) Changes in Fas+ Tc cell subsets, including Tc Fas+, naive Tc, CM Tc Fas+, effector Tc Fas+, and EM Tc Fas+ cells after molecular hydrogen therapy. Tc: T Cytotoxic; CM: central memory; EM: effector memory.

Discussion

This case study underscores the urgent need for novel interventions to treat cases of suspected IgG4-related PF-ILD complicated by hospital-acquired pneumonia. Despite eight months of pharmacological and non-pharmacological interventions, including rituximab, antibiotics, steroids, and an immunosuppressant (Myfortic), pulmonary infiltration continued (Figure 1C and F) and symptoms remained unrelieved, eventually necessitating emergency measures due to shock.

This case study also demonstrates the feasibility of hydrogen-assisted therapy in treating PF-ILD patients with concomitant infectious pneumonia. Within a week of the first dose of hydrogen-assisted therapy, improvements were observed in symptoms and lung infiltration (see CXR images in Figure 1F-H), and the patient regained the ability to speak. This prompted mechanical ventilation weaning, and on the 23rd day of hydrogen-assisted therapy, the patient was able to breathe autonomously for 18 h, while awaiting transfer from the ICU.

The mechanisms underlying the therapeutic effects of hydrogen therapy have yet to be fully elucidated. Existing research suggests that molecular hydrogen possesses anti-inflammatory and antioxidant properties (8), which allow the selective scavenging of hydroxyl radicals generated within mitochondria as well as the inhibition of NLRP3 inflammasome activation (7). Hydrogen can influence various systems and processes (e.g., the immune system and cellular apoptosis), indicating its therapeutic potential for a range of systemic diseases (14). Molecular hydrogen has also been proposed as a potential protective agent for the treatment of acute lung injury (15), having demonstrated protective effects in a variety of pulmonary conditions, including acute lung injury, chronic obstructive pulmonary disease, and pulmonary fibrosis (8). Hydrogen therapy can be administered via inhalation, oral hydrogen capsules, hydrogen baths, hydrogen saline injections (including intraperitoneal and intravenous administration), and topical eye drops (8). In the current study, we selected oral capsules for the treatment of PF-ILD complicated by infectious pneumonia. Hydrogen-assisted therapy provides a promising new option for similar cases.

We conducted analysis on immune cell phenotypes before and after treatment with the aim of characterizing responses and assessing the effectiveness of hydrogen-assisted therapy (Figure 3). Our results revealed a noticeable decrease in all Fas+ Th and Tc cell subtypes accompanied by a dramatic increase in resting Treg cell levels after the initiation of hydrogen-assisted therapy. In healthy individuals, Treg cells perform distinct immunoregulatory functions and exhibit anti-inflammatory properties in the peripheral blood and the spleen. Dysregulation at any level of the various molecular pathways within the regulatory cell population can lead to an overactive immune system, contributing to the development of inflammatory lung disease (16). Note that the proportions of Treg cells in bronchoalveolar lavage and peripheral blood are lower than average in individuals with autoimmune pulmonary fibrosis. In these cases, Treg cells also exhibit limited inhibitory activity, which is inversely correlated with disease severity (16). As a transcription factor, the forkhead box P3 (FOXP3) gene plays a crucial role in regulating Treg cell differentiation, and its expression is tightly controlled by various epigenetic enhancers and promoters. Dysregulation of FOXP3 has been associated with the development of various immune-related diseases. FOXP3+ Treg cells are known to exhibit the strongest suppressive function with the widest range of inhibitory targets. In addition, FOXP3+ Treg cells prevent the activation of autoreactive T cells, suppress the occurrence of autoimmune and allergic diseases, exhibit anti-inflammatory functions, and maintain autoimmune tolerance. Reduced FOXP3 expression can lead to a loss of Treg cell-mediated inhibition of infections and tumors (17). Researchers have suggested that an increase in the proportion of resting Treg cells within the Treg population could exacerbate systemic lupus erythematosus and lead to aberrant inflammatory states (18). It has also been suggested that the impaired functionality of resting Treg cells is associated with type 2 diabetes (19). Some research has indicated that hydrogen therapy can mitigate immune system hyperactivity by restoring Treg cells (14). In the current study, we detected an increase in the resting Treg cell count concurrent with marked improvements in symptoms and CXR findings following the initiation of hydrogen-assisted therapy (Figure 1F-H).

Fas is a member of the tumor necrosis factor receptor family expressed in various cells and tissues. Fas ligand (FasL) is a cell surface molecule that binds to its receptor (Fas) to induce cell apoptosis. Researchers have obtained evidence indicating that in patients with idiopathic pulmonary fibrosis, the expression of Fas and FasL is upregulated in bronchial and alveolar epithelial cells as well as in infiltrating lymphocytes or granulocytes. Excessive cell apoptosis in dysregulated Fas-FasL pathways plays a pivotal role in the development of pulmonary fibrosis. Excessive cell apoptosis and increased FasL expression have also been observed in pulmonary fibrosis animal models (20). After hydrogen-assisted therapy, we observed a noticeable decrease in Fas+ Th and Tc cell subtypes as well as dramatic improvements in lung infiltration in CXR images (Figure 1F-H).

Note that after hydrogen-assisted therapy, we also observed a decrease in nucleosome count from 15 to 7 as well as an increase in hemoglobin level from 8.1 to 10.6. The nucleosome serves as a general gene repressor affecting all types of transcription (genic, intragenic, and intergenic) (21). In one study, plasma nucleosome levels were significantly higher in patients with severe COVID-19 than in healthy controls (22). Elevated nucleosome levels have also been observed in the bronchoalveolar lavage fluid of mice with methicillin-resistant Staphylococcus aureus pneumonia (23). The literature lacks a comprehensive exploration of the relationship between hydrogen therapy and nucleosomes. The marked reduction in the nucleosome count observed in the current study coincided with a marked improvement in pulmonary infiltration. The primary function of hemoglobin is to transport oxygen from the lungs to the tissues, via cooperative binding and oxygen release. Researchers have demonstrated the effectiveness of a hydrogen-rich solution in accelerating hematological and immunological recovery in mice with aplastic anemia, suggesting its potential as a clinical therapeutic agent for this condition (24). In the current study, we observed an increase in hemoglobin levels after hydrogen treatment; however, further research will be required to explore the relationship between hydrogen and nucleosomes as well as between hydrogen and hemoglobin.

Conclusion

In conclusion, this case study demonstrates the efficacy of hydrogen-assisted therapy for patients with PF-ILD accompanied by infectious pneumonia. Hydrogen-assisted therapy is a promising treatment option; however, due to the limited sample size, future studies with an expanded sample size and long-term follow-up will be necessary to validate its efficacy and establish the association between hydrogen therapy and resting Treg cells, as well as Fas+ T cell subsets.

Acknowledgements

This study was supported by the Undergraduate research fellowship, Ministry of Science and Technology (110-2813-C-016-003-B), Ministry of Science and Technology (MOST 109-2314-B-016-052 and MOST 111-2314-B-016-026), National Science and Technology Council (NSTC 112-2314-B-016-033) and Tri-Service General Hospital (TSGH-E-111215) in Taiwan.

Footnotes

  • Authors’ Contributions

    SWL: Conceptualization, methodology, writing – original draft, writing – review and editing. JWL: Conceptualization, methodology, writing – original draft, writing – review and editing. YJH: Conceptualization, methodology, project administration, writing – original draft, writing – review and editing. SET: Methodology, project administration, writing – review and editing. KHK: Methodology, project administration, writing – review and editing. TYF: Methodology, project administration, writing – review and editing. FCL: Conceptualization, investigation, supervision, writing – review and editing.

  • Supplementary Material

    Supplementary material can be found at: https://figshare.com/s/d9d07a254182e33211de

  • Conflicts of Interest

    The Authors declare that they have no conflicts of interest or competing interests in relation to this study.

  • Received January 6, 2024.
  • Revision received February 8, 2024.
  • Accepted February 9, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Molecular Hydrogen as a Promising Therapy Could Be Linked With Increased Resting Treg Cells or Decreased Fas+ T Cell Subsets in a IgG4-PF-ILD Patient: A Case Report
SHAN-WEN LUI, JENG-WEI LU, YI-JUNG HO, SHIH-EN TANG, KAI-HSIUNG KO, TING-YU HSIEH, FENG-CHENG LIU
In Vivo May 2024, 38 (3) 1512-1518; DOI: 10.21873/invivo.13600
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