Chronic Granulomatous Disease Research Articles

Chronic Granulomatous Disease; Experience of a Rare Primary Immunodeficiency from a Tertiary Care Center in Pakistan

Objective: To determine the clinical parameters, consanguinity of parents, previous family history of primary immunodeficiency (PID) and Neutrophil oxidative index (NOI) of Dihydrorhodamine (DHR) assay in chronic granulomatous disease (CGD). Study Design: Cross-sectional study. Place and Duration of Study: Immunology Department, Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from Jan 2015 to Dec 2020. Methodology: A total of 18 patients with chronic granulomatous disease were diagnosed over six years by Dihydrorhodamine assay on flow cytometry, in our institute. Results: The mean age of patients at the time of symptoms was 4.0±3.01 months, while diagnosis was made at the mean age of 42.02±46.00 months. In 6 years, 13(72%) males and 5(28%) females were diagnosed with chronic granulomatous disease by DHR assay on flow cytometry. Parents of fifteen patients (83%) had consanguineous marriages, and 8(44%) patients had positive family history of PIDs. DHR assay showed two mothers had carrier states. The commonest clinical presentation noted was recurrent respiratory tract infections in 16 (89%) patients, repeated abscesses were seen in 13 (72%) and 5(28%) patients had a history of tuberculosis. Conclusion: Chronic granulomatous disease should be suspected in patients with repeated chest infections (especially with catalase-positive organisms), abscesses, diarrhoea and death of siblings at an early age with undiagnosed PID.

Rhinosporidiosis of Male Urethra - Case Report of a Rare Disease

Rhinosporidiosis is a chronic granulomatous disease caused by the fungus commonly affecting anterior nares and nasopharynx. Other sites of involvement included the larynx, hard palate, vagina, vulva, and anus. It may occur very rarely at urethra. This disease generally acquired by bathing in ponds contaminated by animal feces. It is a benign condition where the organisms are limited to the lesion and regional lymph nodes. Adjacent tissues are not usually involved. The infection is very slow to develop with little discomfort; it is often difficult to ascribe age at onset. Males account for 70% to 90% of cases mostly from the rural environment. The lesion causes pressure and obstructive symptoms when they enlarge. Diagnosis usually confirmed by histopathology of excised mass. J Com Med Col Teachers’ Asso July 2023; 27(2): 83-84

Type II Reaction Erythema Nodosum Leprosum: A Case Report

Leprosy, or Hansen's disease, is a chronic granulomatous infectious disease caused by Mycobacterium leprae. This is a case of a 25-year-old male from Micronesia who presented to a hospital in the Midwest with a two-week history of a widespread, nodular, erythematous, painful rash most severe on his lower extremities and sparing only his hands and feet. In addition to the cutaneous manifestations, the patient met the criteria for Systemic Inflammatory Response Syndrome (SIRS) due to his presentation of tachycardia, tachypnea, leukocytosis, and elevated inflammatory markers. A short course of antibiotics, including Piperacillin-Tazobactam and Vancomycin, and IV steroids were started on admission. A skin biopsy taken from the center and edge of a lesion on the patient’s right arm demonstrated acute and chronic granulomatous superficial and deep inflammation with abundant acid-fast bacilli consistent with lepromatous leprosy from a Mycobacterium leprae infection. Once the National Hansen's Disease Center was contacted previous therapies were stopped and a multidrug therapy, consisting of Rifampin, Moxifloxacin, Minocycline, Methotrexate, and Prednisone was started. The multidrug therapy promptly resulting in substantial clinical improvement over the subsequent months. This case emphasizes the significance of early recognition, accurate diagnosis, and timely initiation of appropriate treatment in leprosy management, even in unlikely regions such as the Midwestern United States.

Mycobacterium avium Subspecies paratuberculosis Infection and Immunopathological Changes in Animals: A Review

Mycobacterium avium subspecies paratuberculosis (MAP) is a chronic granulomatous intestinal disease and causative agent of Johne’s disease (JD) in domestic and wild ruminants. This study explores the intricate dynamics of the host immune response in MAP infection and its implications for disease progression and control. Our investigation revealed the pivotal role of interleukin-10 (IL-10) in mediating the communication between the host’s innate and adaptive immunological responses. IL-10 inhibits interferon-gamma (IFN-γ) secretion, altering the balance between Th1 and Th2 responses. In the early stages, a robust Th1 response marked by increased IFN-γ production is observed, but as the disease progresses, a shift towards a humoral Th2 response occurs. Furthermore, we found that IL-10 exerts suppressive effects on macrophage (Mφ) anti-mycobacterial action, leading to increased intracellular survival of mycobacteria. IL-10 also hampers Mφ antimicrobial activity by suppressing the production of essential cytokines such as IL-12 and tumor necrosis factor alpha (TNF-α), crucial for activating natural killer (NK) cells and inducing differentiation of CD4+ T lymphocytes into Th1 effector cells. Importantly, our study sheds light on the intricate interplay between past infections or concurrent active co-infections and their influence on the immune response to unrelated pathogens in the context of paratuberculosis. This review underscores the multifaceted role of IL-10 in the immunopathological manifestation of MAP infection and host immunomodulation. These findings provide valuable insights for both animal and human research in the fight against MAP infection, emphasizing the importance of balancing immune responses and considering the influence of concurrent infections in disease progression.

Inflammatory Complications in Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) is a rare inborn error of immunity that typically manifests with infectious complications. As the name suggest though, inflammatory complications are also common, often affecting the gastrointestinal, respiratory, urinary tracts and other tissues. These can be seen in all various types of CGD, from X-linked and autosomal recessive to X-linked carriers. The pathogenetic mechanisms underlying these complications are not well understood, but are likely multi-factorial and reflect the body's attempt to control infections. The different levels of neutrophil residual oxidase activity are thought to contribute to the large phenotypic variations. Immunosuppressive agents have traditionally been used to treat these complications, but their use is hindered by the fact that CGD patients are predisposed to infection. Novel therapeutic agents, like anti-TNFa monoclonal antibodies, anakinra, ustekinumab, and vedolizumab offer promise for the future, while hematopoietic stem cell transplantation should also be considered in these patients.

Overview of Leprosy Reactions at Universitas Sumatera Utara Medical Faculty Hospitals between 2017 and 2021

BACKGROUND: Leprosy, or Morbus Hansen, is a chronic granulomatous disease caused by Mycobacterium leprae that involves the skin and peripheral nerves, with or without motor disorders. Leprosy reactions are immune-mediated acute or subacute inflammatory episodes that interfere with chronic disease and are classified into three types: type 1 (RR), type 2 (ENL), and the Lucio phenomenon. AIM: The purpose of the study is to describe the epidemiology of leprosy reactions at Universitas Sumatera Utara (USU) teaching hospitals and provide a description of factors associated with the reactions that might provide valuable information for future studies. METHODS: This is a cross-sectional analytic study with total sampling on medical records of patients in the Dermatology and Venereology Polyclinic at H. Adam Malik Hospital Medan and USU Education Hospital in 2017–2021. RESULTS: The incidence of leprosy reactions at the USU Medical Faculty Education Hospital in 2017–2021 was 41 cases. The majority of reaction types were type 2 reactions (68.3%). Risk factors for type 1 reactions were a history of reactions, being elderly, multiple lesions or nerve involvement, and co-infections, whereas the risk factors for type 2 reactions were LL, younger age, bacterial index >4+, stress, and co-infections. The highest age group proportion was 18–59 years (95.1%) and was more common in men (70.7%), which mostly appeared before treatment (39.1%). The incidence of leprosy reactions was 26 new cases per 100 patients. CONCLUSION: The highest proportion of leprosy reactions was type 2, within the adult age group (18–59 years), males, and before treatment.

TNFα: TNFR1 signaling inhibits maturation and maintains the pro-inflammatory programming of monocyte-derived macrophages in murine chronic granulomatous disease.

Loss of NADPH oxidase activity results in proinflammatory macrophages that contribute to hyperinflammation in Chronic Granulomatous Disease (CGD). Previously, it was shown in a zymosan-induced peritonitis model that gp91phox-/- (CGD) monocyte-derived macrophages (MoMacs) fail to phenotypically mature into pro-resolving MoMacs characteristic of wild type (WT) but retain the ability to do so when placed in the WT milieu. Accordingly, it was hypothesized that soluble factor(s) in the CGD milieu thwart appropriate programming. We sought to identify key constituents using ex vivo culture of peritoneal inflammatory leukocytes and their conditioned media. MoMac phenotyping was performed via flow cytometry, measurement of efferocytic capacity and multiplex analysis of secreted cytokines. Addition of exogenous TNFα, TNFα neutralizing antibody and TNFR1-/- MoMacs were used to study the role of TNFα: TNFR1 signaling in MoMac maturation. More extensive phenotyping defined normal MoMac maturation and demonstrated failure of maturation of CGD MoMacs both ex vivo and in vivo. Protein components, and specifically TNFα, produced and released by CGD neutrophils and MoMacs into conditioned media was identified as critical to preventing maturation. Exogenous addition of TNFα inhibited WT MoMac maturation, and its neutralization allowed maturation of cultured CGD MoMacs. TNFα neutralization also reduced production of IL-1β, IL-6 and CXCL1 by CGD cells though these cytokines played no role in MoMac programming. MoMacs lacking TNFR1 matured more normally in the CGD milieu both ex vivo and following adoptive transfer in vivo. These data lend mechanistic insights into the utility of TNFα blockade in CGD and to other diseases where such therapy has been shown to be beneficial.

Relationship between Leprosy Suspicion Questionnaire with IgM anti-PGL-1 antibody levels in household contacts of leprosy

Introduction: Leprosy is a chronic granulomatous disease affecting mainly the skin and peripheral nerves caused by the obligate intracellular pathogen Mycobacterium leprae. This study aimed to determine the relationship between Leprosy Suspicion Questionnaire (LSQ) and anti-PGL-1 IgM antibody levels in household contacts of leprosy patients. Methods: This research was an observational analytical study with a cross-sectional design. The sample consisted of 30 subjects who were household contacts of leprosy patients. Anti-PGL-1 IgM antibody levels were examined using the ELISA method at the Cito Laboratory, Yogyakarta. Results: Regarding demographic characteristics, there were 18 female subjects (60%) and 12 male subjects (40%). LSQ+ results were found in 22 (73.3%) subjects, while LSQ- results were found in 8 (26.7%) subjects. The results of the anti-PGL-1 IgM examination were classified into three categories, namely seronegative (<605 U/ mL) totaling 25 people (83.3%), low titer seropositivity (605–1000 U/mL) totaling four people (13.3 %), and high titer seropositivity (>1000 U/mL) was one person (3.3%). The mean value of IgM anti-PGL-1 was 383.63 U/mL, with the lowest value being 0 and the highest being 1593 U/mL. Using Fischer's Exact showed no relationship between LSQ and IgM Anti-PGL-1 (p=0.287). Conclusions: No relationship was found between LSQ and anti-PGL-1 IgM antibody levels in household contacts of leprosy patients. The results of the LSQ answers correlated with anti-PGL-1 IgM antibodies found in only five subjects.

Effect of allogeneic hematopoietic stem cell transplantation for chronic granulomatous disease in children: A multicentre, retrospective cohort study in China

Chronic granulomatous disease (CGD) in children is a rare primary immunodeficiency disorder that can lead to life-threatening infections and inflammatory complications. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is increasingly being used to treat severe CGD in children. We conducted a multicenter retrospective analysis of children with CGD who were treated with allo-HSCT at four pediatric hematopoietic stem cell transplant centers in China from September 2005 to December 2019. The study included a total of 171 patients (169 males and 2 females). The median age at the time of transplantation was 6.1 (0–16.4) years. Among them, 154 patients had X-linked recessive inheritance caused by CYBB gene mutations, 12 patients were autosomal recessive, 1 patient had DNAH11 and HYDIN gene mutations, and 4 patients had no gene mutations. The median follow-up period was 36.3 (1.9–79) months. All participating patients were applied to myeloablative conditioning (MAC) regimens. The rates of OS, EFS, and GEFS within three years were 87.5%, 85.3%, and 75.2%, respectively. The total graft failure and the total mortality rate were 5.3% and 11.1%. The cumulative incidence of acute GVHD was 53.8% and the incidence of chronic GVHD was 12.9%, The incidence of chronic GVHD was higher for patients who received unrelated donor cord blood stem cell transplantation (UD-CB) (P = 0.001). Chronic GVHD and coinfections are the risk factors for OS and EFS in patients with CGD after receiving allo-HSCT. UD-CB is a risk factor for EFS and the presence of pneumonia before transplantation is a risk factor for OS. In conclusion, through this study, we have demonstrated that allo-HSCT has excellent efficacy in the treatment of CGD in children, especially, RD-haplo is associated with a lower rate of graft failure incidence and mortality than the treatment modalities of other donor type. Therefore, allo-HSCT is strongly recommended when a well-matched donor is available. If a well-matched donor is not available, the HLA-mismatched donor should be carefully evaluated, and the conditioning regimen modified accordingly.

Mitral Valve Mass in a Patient with Positive Tuberculosis Wound Pathology: Successful Medical Management and Regression of Cardiac Mass

Introduction: Tuberculosis (TB) is a chronic granulomatous disease, ranking as the second cause of death by infectious agents in 2021. Tuberculosis affects millions worldwide, with valvular TB being a rare manifestation, accounting for less than 1% of extrapulmonary TB cases. Valvular TB is often diagnosed through imaging and laboratory evaluations, and the treatment involves prolonged antibiotic therapy and might require surgical intervention for damaged cardiac valves. Case Presentation: A 60-year-old female patient with diabetes mellitus and rheumatoid arthritis was referred for a cardiac assessment prior to hand wound debridement surgery. Transthoracic echocardiography (TTE) revealed a mass on the mitral valve, and subsequent transesophageal echocardiography (TEE) confirmed a large, mobile mass with abscess-like density. A blood culture study was negative for infective endocarditis, and a biopsy of the wound revealed necrotizing granuloma positive for Mycobacterium tuberculosis. Anti-TB medication was initiated, resulting in a significant improvement in the valve mass. No cardiac complications were reported during the follow-up. Conclusions: In suspected cardiac TB patients with a high risk of surgery or patients reluctant to undergo an operation, quadruple chemotherapy can serve as a diagnostic and therapeutic tool.

Hematopoietic stem cell transplantation in children with chronic granulomatous disease: the Spanish experience.

Hematopoietic stem cell transplantation (HCT) can cure chronic granulomatous disease (CGD). However, transplant-associated morbidity or mortality may occur, and it is still controversial which patients benefit from this procedure. The aim of this retrospective study was to evaluate the outcome of pediatric patients who received HCT in one of the Spanish pediatric transplant units. Thirty children with a median age of 6.9 years (range 0.6-12.7) were evaluated: 8 patients received a transplant from a sibling donor (MSD), 21 received a transplant from an unrelated donor (UD), and 1 received a haploidentical transplant. The majority of the patients received reduced-intensity conditioning regimens based on either busulfan plus fludarabine or treosulfan. Relevant post-HCT complications were as follows: i) graft failure (GF), with a global incidence of 28.26% (CI: 15.15-48.88), 11.1% in patients with MSD (1.64-56.70) and 37.08% in unrelated donors (19.33-63.17); and ii) chronic graft-versus-host disease (GVHD), with an incidence of 20.5% (8.9-43.2), 11.1% in patients with MSD (1.64-56.70) and 26.7% in unrelated donors (10.42-58.44). Post-HCT infections were usually manageable, but two episodes of pulmonary aspergillosis were diagnosed in the context of graft rejection. The 2-year OS was 77.3% (55.92-89.23). There were no statistically significant differences among donor types. HCT in patients with CGD is a complex procedure with significant morbidity and mortality, especially in patients who receive grafts from unrelated donors. These factors need to be considered in the decision-making process and when discussing conditioning and GVHD prophylaxis.

Chinese guideline for the diagnosis and treatment of Takayasu's arteritis(2023)

Takayasu's arteritis (TAK) is a chronic granulomatous inflammatory disease that involves the aorta and its primary branch arteries. It is characterized by wall thickening,stenosis or aneurysm formation of involved arteries,leading to ischemia of related organs. The clinical diagnosis and treatment of TAK is challenging. In order to further improve the level of diagnosis and treatment of TAK in China and standardize the diagnosis and treatment of TAK, a clinical practice guidelines based on evidence-based medicine evidence was developed under the leadership of the National Clinical Medical Research Center for Dermatologic and Immunologic Diseases. Eleven recommendations for 11 clinical questions problems that are important to the diagnosis and treatment of TAK were developed based on the latest research evidence and expert opinions, combined with real clinical practice in China.

435 - Infant with a rare XP22.2 chromosomal duplication and concomitant chronic granulomatous disease

435 - Infant with a rare XP22.2 chromosomal duplication and concomitant chronic granulomatous disease

In adult X-CGD patients, regulatory T cells are expanded while activated T cells display a NOX2-independent ROS increase

The X-linked chronic granulomatous disease (X-CGD), a rare genetic disease characterised by recurrent infections, is caused by mutations of NOX2. Significant proportions of X-CGD patients display signs of immune dysregulation. Regulatory T cells (Tregs) are CD4+T lymphocytes that expand in active inflammation and prevent autoimmune disorders. Here we asked whether X-CGD is associated to Treg dysfunctions in adult patients. To this aim, the frequency of Tregs was analysed through intracellular flow cytometry in a cohort of adult X-CGD patients, carriers and controls. We found that Tregs were significantly expanded and activated in blood of adult X-CGD patients, and this was associated with activation of conventional CD4+T cells (Tconvs). T cell activation was characterised by accumulation of intracellular ROS, not derived from NOX2 but likely produced by cellular metabolism. The higher TNF production by Tconvs in X-CGD patients might contribute to the expansion of Tregs through the TNFR2 receptor. In summary, our data indicate that Tregs expand in adult X-CGD in response to immune activation, and that the increase of NOX2-independent ROS content is a feature of activated T cells.

Allogeneic hematopoietic cell transplantation is effective for p47phox chronic granulomatous disease: A Primary Immune Deficiency Treatment Consortium study

BackgroundP47phox deficiency is the most common cause of autosomal recessive chronic granulomatous disease (CGD) and is considered to be associated with a milder clinical phenotype. Allogeneic hematopoietic cell transplantation (HCT) for p47phox CGD is not well-described. ObjectivesTo study HCT for p47phox CGD in North America. MethodsThirty patients with p47phox CGD who received allogeneic HCT at Primary Immune Deficiency Treatment Consortium (PIDTC) centers since 1995 were included. ResultsResidual oxidative activity was present in 66.7% of patients. In the year before HCT, there were 0.38 CGD-related infections/person-years. Inflammatory diseases, predominantly of the lungs and bowel, occurred in 36.7% of the patients. The median age at HCT was 9.1 years (range 1.5-23.6 years). Most HCTs (90%) were performed after using reduced intensity/toxicity conditioning. HCT sources were HLA-matched (40%) and -mismatched (10%) related donors, or HLA-matched (36.7%) and -mismatched (13.3%) unrelated donors. CGD-related infections after HCT decreased significantly to 0.06/person-years (p=0.038). The frequency of inflammatory bowel disease and the use of steroids also decreased. The cumulative incidence of graft failure and second HCT was 17.9%. The 2-year overall and event-free survival were 92.3% and 82.1%, respectively, while at 5 years they were 85.7% and 77.0%, respectively. In the surviving patients evaluated, >95% donor myeloid chimerism at 1 and 2 years after HCT was 93.8% and 87.5%, respectively. ConclusionPatients with p47phox CGD suffer from a significant disease burden that can be effectively alleviated by HCT. Similar to other forms of CGD, HCT should be considered for patients with p47phox CGD.

Xp21 DNA microdeletion syndrome in a Chinese family: clinical features show retinitis pigmentosa and chronic granuloma.

Xp21 DNA microdeletion syndrome is a very rare disease characterized by retinitis pigmentosa (RP), chronic granulomatous disease (CGD), and McLeod syndrome (MLS). Due to the complex and diverse clinical manifestations, early diagnosis remains a challenge for many physicians. In this study, for the purpose of determining the pathogenic gene variants and definitive diagnosis in a patient medically backgrounded with RP and CGD from a normal Chinese family, whole-exome sequencing (WES) was performed in this proband and copy number variation (CNV) was further verified in other family members by qPCR. A genetic evaluation revealed that the short arm of the X chromosome in the proband had a deletion CNV Xp21.1p11.4 (37431123-38186681) of approximately 0.755Mb in size, and contained three contiguous OMIM genes as X-linked Kx blood group antigen (XK), cytochrome b-245 beta chain (CYBB), and RP GTPase regulator (RPGR). The qPCR results confirmed the copy number loss in Xp21.1p11.4 present in the proband and his unaffected mother. According to the American College of Medical Genetics and Genomics (ACMG) guidelines for the CNV interpretation, the deletion of this segment was a pathogenic variant. Our results provided evidence that CNV deletion of Xp21.1p11.4 in the short arm of the X chromosome was a pathogenic variant in such Chinese RP and CGD family, and the McLeod phenotype was not yet available. This study suggests that genetic testing is essential for a definitive diagnosis, which should better assist physicians in prediction, diagnosis, genetic counseling, and guidance for Xp21 DNA microdeletion syndrome.

Gene regulation in inborn errors of immunity: Implications for gene therapy design and efficacy.

Inborn errors of immunity (IEI) present a unique paradigm in the realm of gene therapy, emphasizing the need for precision in therapeutic design. As gene therapy transitions from broad-spectrum gene addition to careful modification of specific genes, the enduring safety and effectiveness of these therapies in clinical settings have become crucial. This review discusses the significance of IEIs as foundational models for pioneering and refining precision medicine. We explore the capabilities of gene addition and gene correction platforms in modifying the DNA sequence of primary cells tailored for IEIs. The review uses four specific IEIs to highlight key issues in gene therapy strategies: X-linked agammaglobulinemia (XLA), X-linked chronic granulomatous disease (X-CGD), X-linked hyper IgM syndrome (XHIGM), and immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX). We detail the regulatory intricacies and therapeutic innovations for each disorder, incorporating insights from relevant clinical trials. For most IEIs, regulated expression is a vital aspect of the underlying biology, and we discuss the importance of endogenous regulation in developing gene therapy strategies.

Bifocal malakoplakia in a patient living with HIV: case report

BackgroundMalakoplakia is a rare chronic granulomatous disease characterized by the presence of Michaelis-Gutmann bodies (MGBs) within histiocytic aggregates. It predominantly affects immunocompromised individuals, including those living with Human Immunodeficiency Virus (HIV).Case PresentationWe present a unique case of bifocal malakoplakia in a 49-year-old man, previously with Coronavirus disease 2019 (COVID-19) and HIV positive, presented with respiratory symptoms, weight loss, and lymphadenopathy. He had various infections including Non-Tuberculous Mycobacteria (NTM), Cytomegalovirus (CMV), and Candida, with evolving lung and gastrointestinal issues. Despite treatment attempts, he deteriorated due to respiratory distress, multi-organ failure, and coagulopathy, leading to his unfortunate demise.ConclusionThis report presents a distinctive and complex case of malakoplakia in an HIV-positive patient, a rare inflammatory disorder originally described by Michaelis and Gutmann in 1902. The hallmark Michaelis-Gutmann organisms were observed, confirming the diagnosis. While typically affecting the urinary tract, this case demonstrates the exceptional ability of malakoplakia to manifest in various organ systems, including pulmonary, gastrointestinal, and more. Although Escherichia coli is a prevalent associated pathogen, the exact cause remains elusive. Treatment, often involving surgical excision and antibiotic therapy, underscores the challenging nature of managing this condition in immunocompromised individuals.

Macrophage Activation Syndrome Secondary to Histoplasmosis in an Adult Female Carrier of X-linked Chronic Granulomatous Disease with Extreme Lyonization.

not applicable to a Letter to the Editor.

Biomarkers and molecular endotypes of sarcoidosis: lessons from omics and non-omics studies.

Sarcoidosis is a chronic granulomatous disorder characterized by unknown etiology, undetermined mechanisms, and non-specific therapies except TNF blockade. To improve our understanding of the pathogenicity and to predict the outcomes of the disease, the identification of new biomarkers and molecular endotypes is sorely needed. In this study, we systematically evaluate the biomarkers identified through Omics and non-Omics approaches in sarcoidosis. Most of the currently documented biomarkers for sarcoidosis are mainly identified through conventional "one-for-all" non-Omics targeted studies. Although the application of machine learning algorithms to identify biomarkers and endotypes from unbiased comprehensive Omics studies is still in its infancy, a series of biomarkers, overwhelmingly for diagnosis to differentiate sarcoidosis from healthy controls have been reported. In view of the fact that current biomarker profiles in sarcoidosis are scarce, fragmented and mostly not validated, there is an urgent need to identify novel sarcoidosis biomarkers and molecular endotypes using more advanced Omics approaches to facilitate disease diagnosis and prognosis, resolve disease heterogeneity, and facilitate personalized medicine.