Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares

Abstract Background Heme oxygenase-1 (HMOX1) catalyzes the metabolism of heme into carbon monoxide, ferrous iron, and biliverdin. Through biliverdin reductase, biliverdin becomes bilirubin. HMOX1-deficiency is a rare autosomal recessive disorder with hallmark features of direct antibody negative hemolytic anemia with normal bilirubin, hyperinflammation and features similar to macrophage activation syndrome. Clinical findings have included asplenia, nephritis, hepatitis, and vasculitis. Pulmonary features and evaluation of the immune response have been limited. Case presentation We present a young boy who presented with chronic respiratory failure due to nonspecific interstitial pneumonia following a chronic history of infection-triggered recurrent hyperinflammatory flares. Episodes included hemolysis without hyperbilirubinemia, immunodeficiency, hepatomegaly with mild transaminitis, asplenia, leukocytosis, thrombocytosis, joint pain and features of macrophage activation with negative autoimmune serologies. Lung biopsy revealed cholesterol granulomas. He was found post-mortem by whole exome sequencing to have a compound heterozygous paternal frame shift a paternal frame shift HMOX1 c.264_269delCTGG (p.L89Sfs*24) and maternal splice donor HMOX1 (c.636 + 2 T > A) consistent with HMOX1 deficiency. Western blot analysis confirmed lack of HMOX1 protein upon oxidant stimulation of the patient cells. Conclusions Here, we describe a phenotype expansion for HMOX1-deficiency to include not only asplenia and hepatomegaly, but also interstitial lung disease with cholesterol granulomas and inflammatory flares with hemophagocytosis present in the bone marrow.

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Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares

10.21203/rs.3.rs-17045/v1 ◽

2020 ◽

Author(s):

Alice S Chau ◽

Bonnie L Cole ◽

Jason S Debley ◽

Kabita Nanda ◽

Aaron BI Rosen ◽

...

Keyword(s):

Interstitial Lung Disease ◽

Lung Disease ◽

Heme Oxygenase ◽

Macrophage Activation ◽

Autosomal Recessive Disorder ◽

Clinical Findings ◽

Heme Oxygenase 1 ◽

Compound Heterozygous ◽

Biliverdin Reductase ◽

Frame Shift

Abstract Background: Heme oxygenase-1 (HMOX1) catalyzes the metabolism of heme into carbon monoxide, ferrous iron, and biliverdin. Through biliverdin reductase, biliverdin becomes bilirubin. HMOX1-deficiency is a rare autosomal recessive disorder with hallmark features of direct antibody negative hemolytic anemia with normal bilirubin, hyperinflammation and features similar to macrophage activation syndrome. Clinical findings have included asplenia, nephritis, hepatitis, and vasculitis. Pulmonary features and evaluation of the immune response have been limited.Case presentation: We present a young boy who presented with chronic respiratory failure due to nonspecific interstitial pneumonia following a chronic history of infection-triggered recurrent hyperinflammatory flares. Episodes included hemolysis without hyperbilirubinemia, immunodeficiency, hepatomegaly with mild transaminitis, asplenia, leukocytosis, thrombocytosis, joint pain and features of macrophage activation with negative autoimmune serologies. Lung biopsy revealed cholesterol granulomas. He was found post-mortem by whole exome sequencing to have a compound heterozygous paternal frame shift a paternal frame shift HMOX1 c.264delCTGG (p.L89Sfs*24) and maternal splice donor HMOX1 (c.636+2 T>A) consistent with HMOX1 deficiency. Western blot analysis confirmed lack of HMOX1 protein upon oxidant stimulation of the patient cells. Conclusions: Here, we describe a phenotype expansion for HMOX1-deficiency to include not only asplenia and hepatomegaly, but also interstitial lung disease with cholesterol granulomas and inflammatory flares with hemophagocytosis present in the bone marrow that can mimic systemic-onset juvenile arthritis.

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Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares

10.21203/rs.3.rs-15456/v1 ◽

2020 ◽

Author(s):

Alice S. Chau ◽

Bonnie L. Cole ◽

Jason S. Debley ◽

Kabita Nanda ◽

Aaron B.I. Rosen ◽

...

Keyword(s):

Interstitial Lung Disease ◽

Lung Disease ◽

Heme Oxygenase ◽

Autosomal Recessive Disorder ◽

Clinical Findings ◽

Heme Oxygenase 1 ◽

Compound Heterozygous ◽

Biliverdin Reductase ◽

Frame Shift ◽

Whole Exome

Abstract Background Heme oxygenase-1 (HMOX1) catalyzes the metabolism of heme into carbon monoxide, ferrous iron, and biliverdin. Through biliverdin reductase, biliverdin becomes bilirubin. HMOX1 -deficiency is an exceedingly rare autosomal recessive disorder with hallmark features of direct antibody negative hemolytic anemia with normal bilirubin, hyperinflammation and features indicating hemophagocytosis lymphohistiocytosis. Clinical findings have included asplenia, nephritis, hepatitis, and evidence of vasculitis. Pulmonary features and evaluation of the immune response have been limited. Results Here, we present the fifth reported case in literature of a young boy who remarkably also presented with chronic respiratory failure due to nonspecific interstitial pneumonia in addition to infection-triggered recurrent hyperinflammatory flares notable for hemolysis without hyperbilirubinemia, immunodeficiency, hepatomegaly with mild transaminitis, asplenia, leukocytosis, thrombocytosis, joint pain and features of macrophage activation with negative autoimmune serologies. Lung biopsy revealed cholesterol granulomas. He was found post-mortem by whole exome sequencing to have a compound heterozygous paternal frame shift a paternal frame shift HMOX1 c.264delCTGG (p.L89Sfs*24) and maternal splice donor HMOX1 (c.636+2 T>A) consistent with HMOX1 deficiency. Western blot analysis confirmed lack of HMOX1 protein upon oxidant stimulation of the patient cells. Conclusions Here, we describe a phenotype expansion for HMOX1-deficiency to include not only asplenia and hepatomegaly, but also interstitial lung disease with cholesterol granulomas and inflammatory flares with hemophagocytosis present in the bone marrow.

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Heme oxygenase-1 in patients with interstitial lung disease: A review of the clinical evidence

The American Journal of the Medical Sciences ◽

10.1016/j.amjms.2021.02.009 ◽

2021 ◽

Author(s):

Yu Hara ◽

Kentaro Nakashima ◽

Ryo Nagasawa ◽

Kota Murohashi ◽

Yoichi Tagami ◽

...

Keyword(s):

Interstitial Lung Disease ◽

Lung Disease ◽

Heme Oxygenase ◽

Clinical Evidence ◽

Heme Oxygenase 1

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Serum heme oxygenase-1 measurement is useful for evaluating disease activity and outcomes in patients with acute respiratory distress syndrome and acute exacerbation of interstitial lung disease

BMC Pulmonary Medicine ◽

10.1186/s12890-020-01341-1 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Ryo Nagasawa ◽

Yu Hara ◽

Kota Murohashi ◽

Ayako Aoki ◽

Nobuaki Kobayashi ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Respiratory Distress Syndrome ◽

Interstitial Lung Disease ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Lung Disease ◽

Acute Exacerbation ◽

Heme Oxygenase ◽

Distress Syndrome ◽

Heme Oxygenase 1

Abstract Background Oxidative stress plays an important role in acute lung injury, which is associated with the development and progression of acute respiratory failure. Here, we investigated whether the degree of oxidative stress as indicated by serum heme oxygenase-1 (HO-1) is clinically useful for predicting prognosis among the patients with acute respiratory distress syndrome (ARDS) and acute exacerbation of interstitial lung disease (AE-ILD). Methods Serum HO-1 levels of newly diagnosed or untreated ARDS and AE-ILD patients were measured at diagnosis. Relationships between serum HO-1 and other clinical parameters and 1 and 3-month mortality were evaluated. Results Fifty-five patients including 22 of ARDS and 33 of AE-ILD were assessed. Serum HO-1 level at diagnosis was significantly higher in ARDS patients than AE-ILD patients (87.8 ± 60.0 ng/mL vs. 52.5 ± 36.3 ng/mL, P < 0.001). Serum HO-1 correlated with serum total bilirubin (R = 0.454, P < 0.001) and serum LDH (R = 0.500, P < 0.001). In both patients with ARDS and AE-ILDs, serum HO-1 level tended to decrease from diagnosis to 2 weeks after diagnosis, however, did not normalized. Composite parameters including serum HO-1, age, sex, and partial pressure of oxygen in arterial blood/fraction of inspired oxygen (P/F) ratio for prediction of 3-month mortality showed a higher AUC (ARDS: 0.925, AE-ILDs: 0.892) than did AUCs of a single predictor or combination of two or three predictors. Conclusion Oxidative stress assessed by serum HO-1 is persistently high among enrolled patients for 2 weeks after diagnosis. Also, serum HO-1 levels at the diagnosis combined with age, sex, and P/F ratio could be clinically useful for predicting 3-month mortality in both ARDS and AE-ILD patients.

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Serum heme oxygenase-1 measurement is useful for evaluating disease activity and outcomes in patients with acute respiratory distress syndrome and acute exacerbation of interstitial lung disease

10.21203/rs.3.rs-39746/v2 ◽

2020 ◽

Author(s):

Ryo Nagasawa ◽

Yu Hara ◽

Kota Murohashi ◽

Ayako Aoki ◽

Nobuaki Kobayashi ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Respiratory Distress Syndrome ◽

Interstitial Lung Disease ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Lung Disease ◽

Acute Exacerbation ◽

Heme Oxygenase ◽

Distress Syndrome ◽

Heme Oxygenase 1

Abstract Background: Oxidative stress plays an important role in acute lung injury, which is associated with the development and progression of acute respiratory failure. Here, we investigated whether the degree of oxidative stress as indicated by serum heme oxygenase-1 (HO-1) is clinically useful for predicting prognosis among the patients with acute respiratory distress syndrome (ARDS) and acute exacerbation of interstitial lung disease (AE-ILDs).Methods: Serum HO-1 levels of newly diagnosed or untreated ARDS and AE-ILD patients were measured at diagnosis. Relationships between serum HO-1 and other clinical parameters and 1 and 3-month mortality were evaluated. Results: Fifty-five patients including 22 of ARDS and 33 of AE-ILD were assessed. Serum HO-1 level at diagnosis was significantly higher in ARDS patients than AE-ILD patients (87.8 ± 60.0 ng/mL vs. 52.5 ± 36.3 ng/mL, P < 0.001). Serum HO-1 correlated with serum total bilirubin (R = 0.454, P < 0.001) and serum LDH (R = 0.500, P < 0.001). In both patients with ARDS and AE-ILDs, serum HO-1 level tended to decrease from diagnosis to 2 weeks after diagnosis, however, did not normalized. Composite parameters including serum HO-1, age, sex, and partial pressure of oxygen in arterial blood/fraction of inspired oxygen (P/F) ratio for prediction of 3-month mortality showed a higher AUC (ARDS: 0.925, AE-ILDs: 0.892) than did AUCs of a single predictor or combination of two or three predictors. Conclusion: Oxidative stress assessed by serum HO-1 is persistently high among enrolled patients for 2 weeks after diagnosis. Also, serum HO-1 levels at the diagnosis combined with age, sex, and P/F ratio could be clinically useful for predicting 3-month mortality in both ARDS and AE-ILD patients.

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AB0660 COVID-19 SHARES CLINICAL FEATURES WITH ANTI-MELANOMA DIFFERENTIATION ASSOCIATED PROTEIN 5 POSITIVE DERMATOMYOSITIS AND ADULT STILL’S DISEASE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.1031 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1362.1-1362

Author(s):

Y. Kondo ◽

Y. Kaneko ◽

H. Takei ◽

H. Tamai ◽

T. Takeuchi

Keyword(s):

Interstitial Lung Disease ◽

Lung Disease ◽

Clinical Features ◽

Serum Ferritin ◽

Rheumatic Diseases ◽

Macrophage Activation ◽

Cytokine Storm ◽

Still’S Disease ◽

Still's Disease ◽

Adult Still's Disease

Background:The coronavirus disease 2019 (COVID-19), caused by a novel corona virus named SARS-CoV-2, has emerged as a global pandemic. Severe inflammatory process is one of main pathogenesis of COVID-19 and this involves cytokine storm along with overactivation of macrophage. On another front, cytokine storm with macrophage activation is frequently observed in various connective tissue diseases including dermatomyositis with positive antimelanoma differentiation-associated protein 5 (anti-MDA5) autoantibodies and adult Still’s disease. Macrophage activation during inflammatory states is partially characterized by an increased serum ferritin levels and hyperferritinaemia and characteristics shared by the three diseases are a topic of interest to rheumatologists, however, no study has evaluated anti-MDA5-positive dermatomyositis and adult Still’s disease in comparison to COVID-19.Objectives:The aim of this study was to highlight the homology and heterogeneity of COVID-19, anti-MDA5 dermatomyositis, and adult Still’s disease by comparing clinical pictures of each disease in order to discuss their respective pathogeneses.Methods:We reviewed consecutive, newly diagnosed, untreated patients with COVID-19, anti-MDA5 dermatomyositis, or adult Still’s disease. We compared their clinical, laboratory, and radiological characteristics, including the prevalence of macrophage activation syndrome and lung involvement in each disease.Results:The numbers of patients with COVID-19, anti-MDA5 dermatomyositis, and adult-onset Still’s disease with hyperferritinaemia (serum ferritin ≥ 500ng/dL) who were included for main analysis were 22, 14, and 59, respectively. COVID-19 and adult Still’s disease both featured hyperinflammatory status, such as high fever and elevated serum C-reactive protein, whereas COVID-19 and anti-MDA5 dermatomyositis both presented with severe interstitial lung disease and hypoxaemia. While two-thirds of the patients in each group met the criteria for macrophage-activated syndrome that is used in systemic juvenile idiopathic arthritis, the HScore, an indicator of haemophagocytic lymphohistiocytosis, was low in anti-MDA5 dermatomyositis and COVID-19 even in severe or critical cases. The findings of chest computed tomography were similar between COVID-19 and anti-MDA5 dermatomyositis (Figure 1).Conclusion:COVID-19 shared clinical features with rheumatic diseases characterised by hyperferritinaemia, including anti-MDA5 dermatomyositis and adult Still’s disease. These findings should be investigated further in order to shed light on the pathogenesis of not only COVID-19 but also the aforementioned rheumatic diseases.References:[1]Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. (2020) 395: 1033-4.[2]Gono T, Sato S, Kawaguchi Y, et al. Anti-MDA5 antibody, ferritin and IL-18 are useful for the evaluation of response to treatment in interstitial lung disease with anti-MDA5 antibody-positive dermatomyositis. Rheumatology (Oxford). 2012; 51(9):1563-70.Figure 1.Imaging characteristics of chest CT scans in patients with COVID-19, anti-MDA5 dermatomyositis, and adult Still’s disease A)Bilateral ground-glass and consolidative opacities with peripheral distribution in COVID-19. B)Bilateral ground-glass opacities with peripheral consolidations in anti-MDA5 dermatomyositis. C)Pleural effusion with pleural thickening on the left side in adult Still’s disease.Disclosure of Interests:Yasushi Kondo: None declared., Yuko Kaneko: None declared., Hisoshi Takei: None declared., Hiroya Tamai: None declared., Tsutomu Takeuchi Grant/research support from: received research grants outside the submitted work from Abbvie, Astra Zeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eisai Pharmaceutical, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Novartis, Takeda Pharmaceutical, Abbott Japan Co., Ltd., Astellas Pharma, Ltd., Daiichi Sankyo, Pfizer, Sanofi–Aventis, Santen Pharmaceutical, Teijin Pharma Ltd., Asahikasei Pharma Corp., SymBio Pharmaceuticals Ltd., Celtrion, Nipponkayaku Co. Ltd., Eli Lilly Japan, and Taisho Toyama Pharmaceutical.

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Products of heme oxygenase and their potential therapeutic applications

AJP Renal Physiology ◽

10.1152/ajprenal.00220.2005 ◽

2006 ◽

Vol 290 (3) ◽

pp. F563-F571 ◽

Cited By ~ 148

Author(s):

Kristin A. Kirkby ◽

Christopher A. Adin

Keyword(s):

Heme Oxygenase ◽

Heme Oxygenase 1 ◽

Inexpensive Method ◽

Waste Products ◽

Biliverdin Reductase ◽

Therapeutic Applications ◽

Beneficial Effects ◽

Tissue Protection ◽

Organ Systems ◽

Dose Dependent

Heme oxygenase 1 (HO-1) is induced in response to cellular stress and is responsible for converting the prooxidant heme molecule into equimolar quantities of biliverdin (BV), carbon monoxide (CO), and iron. BV is then converted to bilirubin (BR) by the enzyme biliverdin reductase. Experimental evidence suggests that induction of the HO system is an important endogenous mechanism for cytoprotection and that the downstream products of heme degradation, CO, BR, and BV, may mediate these powerful beneficial effects. These molecules, which were once considered to be toxic metabolic waste products, have recently been shown to have dose-dependent vasodilatory, antioxidant, and anti-inflammatory properties that are particularly desirable for tissue protection during organ transplantation. In fact, recent work has demonstrated that administration of exogenous CO, BR, or BV may offer a simple, inexpensive method to substitute for the cytoprotective effects of HO-1 in a variety of clinically applicable models. This review will attempt to summarize the relevant biochemical and cytoprotective properties of CO, BR, and BV, and will discuss emerging studies involving the therapeutic applications of these molecules in the kidney and other organ systems.

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