Granulomatous hyperinflammatory state induced by dupilumab treatment for eosinophilic esophagitis.

We present the first case of a dupilumab-induced hyperinflammatory state in the setting of underlying eosinophilic esophagitis characterized by multisystem granulomatous inflammation. Although clinical trial data and subsequent real-world experience support dupilumab as a highly effective therapy for eosinophilic esophagitis, close monitoring for development of adverse symptoms following initiation remains paramount.

Heterogeneity in immune cell composition is associated with Mycobacterium tuberculosis replication at the granuloma level.

The control of bacterial growth is key to the prevention and treatment of tuberculosis (TB). Granulomas represent independent foci of the host immune response that present heterogeneous capacity for control of bacterial growth. At the whole tissue level, B cells and CD4 or CD8 T cells have an established role in immune protection against TB. Immune cells interact within each granuloma response, but the impact of granuloma immune composition on bacterial replication remains unknown. Here we investigate the associations between immune cell composition, including B cell, CD4, and CD8 T cells, and the state of replicating Mycobacterium tuberculosis (Mtb) within the granuloma. A measure of ribosomal RNA synthesis, the RS ratio®, represents a proxy measure of Mtb replication at the whole tissue level. We adapted the RS ratio through use of in situ hybridization, to identify replicating and non-replicating Mtb within each designated granuloma. We applied a regression model to characterize the associations between immune cell populations and the state of Mtb replication within each respective granuloma. In the evaluation of nearly 200 granulomas, we identified heterogeneity in both immune cell composition and proportion of replicating bacteria. We found clear evidence of directional associations between immune cell composition and replicating Mtb. Controlling for vaccination status and endpoint post-infection, granulomas with lower CD4 or higher CD8 cell counts are associated with a higher percent of replicating Mtb. Conversely, changes in B cell proportions were associated with little change in Mtb replication. This study establishes heterogeneity across granulomas, demonstrating that certain immune cell types are differentially associated with control of Mtb replication. These data suggest that evaluation at the granuloma level may be imperative to identifying correlates of immune protection.

Macrophage polarization in human periapical lesions in relation to histopathological diagnosis, clinical features and lesion volume: An ex vivo study.

AIM: To evaluate M1 and M2 macrophage polarization in radicular cysts and periapical granulomas through an immunohistochemical analysis and the correlation between macrophage polarization and histopathological diagnosis, clinical characteristics and lesion volume using cone-beam computed tomography. METHODOLOGY: Periapical biopsies diagnosed as radicular cysts (n = 52) and periapical granulomas (n = 51) were analysed by immunohistochemical method. Teeth with periapical lesion with no history of root canal treatment (primary lesion) and lesions persistent to root canal treatment (persistent lesions) were included. Pathological diagnosis, patients' age, gender and clinical characteristics were obtained from treatment records. A cone-beam computed tomographic periapical volume index (CBCTPAVI) score was assigned to each periapical lesion based on the volume of the lesion. Immuno-expressions of CD68 and CD163 were quantified. The CD68/CD163 ratio was adopted to represent M1 or M2 macrophage polarization. Mann-Whitney U test was used to determine the different CD68/CD163 ratio between groups of radicular cyst and periapical granuloma. Spearman's correlation test was performed to assess the correlation between the CD68/CD163 ratio and lesion volume and CBCTPAVI score. RESULTS: Radicular cysts and periapical granulomas had CD68/CD163 median of 2.05 (IQR = 1.33) and 1.26 (IQR = 0.81), respectively. A significantly higher CD68/CD163 ratio was observed in radicular cysts (p < .001). In contrast, periapical granulomas had significantly lower median of CD68/CD163 ratio. Larger lesions had a higher median of CD68/CD163 ratio, while smaller lesions had lower median of CD68/CD163 ratio (p = .007, rs = .262). CD68/CD163 ratio was significantly correlated with the CBCTPAVI score in the overall periapical lesions (p = .002, rs = .306). The higher CD68/CD163 ratio in larger lesions indicated a higher degree of M1 polarization compared to smaller lesions. Regarding the pathological diagnosis, there was a significant positive correlation between CBCTPAVI score and CD68/CD163 ratio in periapical granulomas (p < .001, rs = .453), whereas the negative correlation was observed for radicular cysts (p < .001, rs = -.471). CONCLUSIONS: Periapical granulomas are characterized by a M2-dominant macrophage polarization, while radicular cysts have significantly higher M1 macrophages. The higher degree of M1 macrophage polarization was significantly correlated with larger volume and higher CBCTPAVI scores of overall periapical lesion and periapical granuloma.

Cholesterol granuloma of the maxillary sinus: a case report.

BACKGROUND: Cholesterol granuloma is not a common entity in the paranasal sinuses. It is a foreign body reaction to the cholesterol crystal deposition. Mostly associated with chronic middle ear diseases. CASE PRESENTATION: This article reports a case of cholesterol granuloma in the maxillary sinus. A 23-year-old Asian man presented with cough, nasal obstruction, and postnasal discharge. On endoscopy, there was a mass protruding from the right maxillary ostium. On computed tomograpy imaging, there was a polypoidal mass in the right maxillary sinus. Endoscopic sinus surgery was performed, the cholesterol granuloma was removed from the right maxillary sinus, and the tissue was submitted for histopathological examination, which showed foreign body giant cell reaction to cholesterol crystals. CONCLUSION: Cholesterol granuloma of maxillary sinus is not common and often missed by clinicians. It is necessary to consider the cholesterol granuloma of maxillary sinus in the differential diagnosis sinonasal lesions. Histopathological analysis is required for confirmation and should be removed surgically. This case may help as a reference for clinician to approach these kinds of cases.

Debulking surgery after muscular paraffin oil injections: Effects on calcium homeostasis and patient satisfaction.

OBJECTIVE: Cosmetic paraffin oil injections can lead to granuloma formation causing hypercalcemia and kidney failure. This study explores whether debulking surgery is an effective treatment for improving calcium homeostasis, inflammation and clinical symptoms. MATERIALS AND METHODS: In a retrospective study, we reviewed 33 patients undergoing debulking surgery. Changes in calcium, inflammatory markers, and renal function from baseline up to twelve months post-surgery were assessed. Patients were interviewed post-surgery. RESULTS: The patients were 34.6 years (SD 6.9) and had 1,104 grams (SD 591) of granuloma tissue removed following injection of 1,329 mL (SD 803) paraffin oil 7.9 years (SD 3.2) earlier. Seventeen patients had hypercalcemia and experienced a significant decline in ionized calcium from 1.48 mmol/L (SD 0.16) at baseline to 1.33 mmol/L (SD 0.03) at twelve months (p<0.002), although only four men (23.5%) became normocalcemic. Serum ferritin was reduced by 50% after twelve months (p=0.048). Sixteen patients were normocalcemic and had no change in calcium homeostasis but experienced a 20% drop in serum ferritin levels (p=0.025) after surgery. Fifteen patients completed all their planned surgeries within the study period and experienced a decline in serum ionized calcium (p=0.031), ferritin (p=0.011), and interleukin 2-receptor (p=0.037). A patient satisfaction survey showed that 55% of patients reported post-operative satisfaction scores of 10/10, and 59% of the patients reported reduced pain. CONCLUSION: Surgery improved calcium homeostasis in a fraction of patients, reduced inflammation and subjective symptoms such as pain and mental well-being in a patient group left with few treatment options except high-dose prednisolone.

Subcutaneous granuloma annulare: a systematic review of a rare and underdiagnosed disease.

Subcutaneous granuloma annulare (SGA) is a rare clinicopathologic subtype of granuloma annulare characterized by the presence of subcutaneous nodules. There are no present reviews synthesizing the clinical features and treatment modalities in SGA. We conducted a systematic review following PRISMA guidelines [CRD42022344672] on all peer-reviewed English-language studies that reported one or more cases of SGA. A total of 97 studies, comprising 26 case series and 71 case reports with 324 patients, were included for analysis. Most cases were predominantly pediatric, with 78.9% of the cases identified being age 16 or lower and a median age of diagnosis of 6. There was no overall gender predisposition. Although over two-thirds of patients did not have any comorbidities, diabetes mellitus was the most common comorbidity present in 4% of cases. The most common feature of SGA was nodules, which were present in 99.6% of patients. Pain or tenderness was reported in 15.4%, and erythema of overlying skin in 11.0% of cases. Surgical excision was performed in 96/141 (68.1%) patients. Among the 27/141 (18.0%) patients who were conservatively managed, 87.0% spontaneously improved, including 60.0% who completely self-resolved. Topical and intralesional steroids were used in 3.40% and 1.85% of patients, respectively, resulting in complete or partial resolution in 54.6% and 100%. Among patients who were followed up, 83/324 (25.6%) patients experienced recurrence after a median duration of 26 weeks. SGA is predominantly a pediatric disease that frequently occurs on the limbs and the head. Juxta-articular lesions are more commonly observed in adults than in children. Surgical excision is common and effective in most patients. Spontaneous improvement occurs in most untreated cases, and intralesional steroids but not topical steroids may be beneficial for non-resolving cases and to reduce time to resolution.

Sarcoid-Like Reactions in Breast Cancer Patients: A Report of Two Cases.

Sarcoid-like reactions (SLR) in patients with malignancies are a relatively common finding. Defined by the presence of non-caseating granulomas, SLR does not meet the clinical criteria for classic sarcoidosis. In cancer patients, SLR often presents a challenging differential diagnosis, as it must be distinguished from disease progression due to malignancy. We present two cases of SLRs associated with breast cancer, underscoring the need for heightened vigilance among physicians. SLR should always be considered a potential diagnosis in these patients, with histological confirmation being essential for accurate identification.

Causes of Oral Granulomatous Disorders: An Update and Narrative Review of the Literature.

Granulomatous diseases include a diverse range of chronic inflammatory disorders with a wide variety of pathologies and clinical characteristics. In particular, the orofacial region can be affected by granulomatous conditions-whether as an isolated disease or as part of a systemic disorder. Regardless of the nature of the disease or its mechanism of development, precise diagnosis can be challenging, as etiopathogenesis may be driven by several causes. These include reactions to foreign bodies, infections, immune dysregulation, proliferative disorders,, medications, illicit drugs, and hereditary disorders. Granulomas can be identified using histopathological assessment but are not pathognomonic of a specific disease, and therefore require correlation between clinical, serological, radiographical, and histopathological findings. The purpose of this review is to provide a summary of the etiopathogenesis, clinical and histopathologic characteristics, and treatment of oral granulomatous disorders.

Juvenile trabecular ossifying fibroma associated with central giant cell granuloma and aneurysmal bone cyst like changes - A triple hybrid tumour? Or a pathologic sequelae?

Hybrid tumours encompass lesions containing two or more pathologic entities. The pathogenesis of these lesions is barely understood and described. Juvenile trabecular ossifying fibroma (JTOF) is a benign but locally aggressive fibro-osseous neoplasm commonly affecting the maxilla of the adolescent age group. Hybrid lesions of JTOF have been reported along with central giant cell granuloma (CGCG), aneurysmal bone cyst (ABC) and traumatic bone cyst, respectively. However, the co-occurrence of JTOF with CGCG and ABC in a single patient has not yet been reported in the literature, hence, making ours the first case report of this kind. Theories describing the pathogenesis of this rare phenomenon have also been proposed and elaborated.

Paediatric oral hyaline ring granuloma associated with an impacted tooth and its management preserving the tooth germ: A case report.

Oral hyaline ring granuloma is an unusual granulomatous lesion affecting the jaws characterized by the presence of numerous eosinophilic rings with multinucleated giant cells. The lesion can be of central or peripheral variety, caused by the impaction of foreign particles in the oral cavity. While literature describes this lesion in association with dentures, carious teeth and extraction socket, this paper reports the first case of an oral hyaline ring granuloma associated with an impacted premolar tooth and its surgical management.

A Comprehensive Multi-drug Strategy for the Management of Foreign Body Granuloma Following Mesotherapy.

BACKGROUND: Mesotherapy is a medical technique that administers cosmetic nutrients directly to the dermis through microdrop injections for aesthetic purposes. Its application has become increasingly widespread. However, there have also been a growing number of reported cases of multiple foreign body granulomas following mesotherapy. It is crucial to find an effective and safe treatment. METHODS: In this study, 31 patients with facial foreign body granuloma after mesotherapy were included. A mixture of 5-fluorouracil, lidocaine injection , and normal saline was prepared in a ratio of 1:1:4 and injected subcutaneously. Triamcinolone acetonide, 5-fluorouracil, lidocaine injection, and normal saline were prepared in a ratio of 2:5:3:10. Subcutaneous injections were administered to each papule using a 34G needle. The treatments were scheduled at intervals of 10-14 days. Color Doppler ultrasound was used to evaluate the condition before the initial treatment and after the final treatment. RESULTS: The preoperative ultrasonography revealed diffuse hypoechoic areas in the dermis of the facial skin. After an average of 2-4 treatment sessions, a significant improvement was observed in all patients' appearance, with reduced redness and swelling, softened nodules, absence of pain and itching symptoms, and no evident abnormal echo on ultrasound examination. During a follow-up period ranging from 1 to 8 months, no recurrence or adverse reactions were reported. CONCLUSION: This technique demonstrates clear efficacy. And this formulation effectively reduces the dosage of triamcinolone acetonide and minimizes the risk of adverse reactions such as skin atrophy. Therefore, it can be considered an effective treatment for multiple foreign body granulomas following mesotherapy. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Therapeutic success of tofacitinib in granuloma annulare: A retrospective case series of 15 patients.

Background Granuloma annulare (GA) is a necrobiotic granulomatous disorder that may sometimes be resistant to treatment, especially the generalised form. Tofacitinib has recently shown promise in the treatment of non-infective granulomatous dermatosis. Objectives In this study, we aimed to evaluate the response of generalised GA to oral tofacitinib. Methods This was a retrospective case series in patients of generalised GA who were treated with oral tofacitinib 5 mg twice a day in a tertiary care centre in north India. Baseline clinical details and histopathological findings were reviewed. Treatment response was noted in the form of clearance of lesions (complete or partial) along with the time taken to achieve the maximum response. Results A total of 15 patients of generalised GA were included in this study, amongst whom nine patients were resistant to conventional therapies whilst the remaining were treatment naïve. Complete clearance of lesions was noted in 11 patients at a mean treatment duration of 4.4 ± 2.1 months whereas clearance was partial in four, with a mean follow-up duration post- treatment in patients who had partial clearance, which is 7.3 ± 2.8 month, with a reduction in erythema and infiltration in those lesions. Adverse effects in the form of hyperlipidemia were observed in two patients. Conclusion Tofacitinib, a JAK-STAT inhibitor is beneficial in treating GA, especially in those with generalised and recalcitrant disease.

Peripheral giant cell granuloma in a child with ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome: a case report.

BACKGROUND: Ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC) syndrome mainly affects ectodermal and mesodermal tissues. It is usually manifested as split hands and feet, ectodermal dysplasia, and orofacial clefting, along with other signs and symptoms. A multidisciplinary approach to treatment is required, in which dentists play an important role in identifying and treating various oral conditions that may be genetically linked to or may be the result of EEC syndrome. CASE PRESENTATION: The present case describes the oral condition of a young child suffering from EEC syndrome and presenting with peripheral giant cell granuloma (PGCG) in the mandibular anterior region. After obtaining a thorough medical and family history and a clinical examination, the lesion was surgically excised under local anesthesia. The patient was followed up at periodic intervals for the next twenty four months, during which no recurrence of the lesion was observed. CONCLUSION: This report highlights the role of a dentist in the management of the oral conditions of patients suffering from EEC syndrome.

Management and outcomes of pilonidal patients with secondary sinuses-a cohort study.

BACKGROUND: Patients with pilonidal disease (PD) can present with concurrent draining secondary sinus at the superior gluteal cleft. The natural disease course in the setting of this severe phenotype is poorly characterized. We present the largest cohort of patients with PD and concurrent secondary sinus. METHODS: Patients with PD and concurrent secondary sinus who underwent Gips procedure with secondary sinus excision from 2019 to 2023 were prospectively followed. Patient demographics, drainage recurrence, symptom resolution, treatment, and follow-up period were recorded. Recurrent drainage from previous secondary sinus site was defined as isolated painless serous drainage after the wound had closed for > 3 weeks; recurrent PD was characterized as recurrent pain and bloody drainage after excision. RESULTS: One hundred and five patients (seventy-one males) with a median age of 17.2 years [interquartile range (IQR):15.4-19.0] underwent excision of their disease and were followed for a median of 367.0 days (IQR: 173.2-658.8). Without regular epilation, six patients (5.7%, five males, one female) had recurrent PD. With regular epilation, three patients (2.8%, three males) had recurrent PD. Eight patients (7.5%, six males, two females) had recurrent secondary sinus site drainage. Median time to recurrent drainage was 75.5 days (IQR: 65.2-216.2) after excision and for recurrent drainage to resolve was 72 days (IQR: 49-81). Recurrent secondary sinus site drainage was treated with antibiotics, silver nitrate, debridement, or no treatment. CONCLUSION: Patients who present with PD in the setting of concurrent secondary sinus have a unique, more severe disease phenotype. Excision can be complicated by recurrent drainage from the secondary sinus site that can resolve without repeat surgical excision.

Liver biopsy revealing anti-neutrophil cytoplasmic antibody-associated vasculitis: a tale for a challenging diagnosis.

A 62-year-old woman presented with a chronic fever and fatigue. Biological investigations showed leukocytosis and elevation of acute phase markers. Liver blood tests showed deterioration with both cholestatic and hepatocellular patterns (there were, respectively, elevations in serum alkaline phosphatase levels as well as in serum alanine and aspartate aminotransferases). Viral serologies were negative. Mycobacterial infection and endocarditis were excluded. Results from blood cultures were negative. Autoantibody tests including ANCA (anti-neutrophil cytoplasmic antibody), anti-nuclear, anti-smooth muscle and anti-mitochondria were all negative. A liver biopsy revealed epithelioid granulomatous necrotizing vasculitis. Subsequently, immunological testing was repeated revealing MPO-ANCA (myeloperoxidase-ANCA). A diagnosis of ANCA-associated vasculitis with liver involvement was then made. The patient was started on steroids and her clinical state gradually improved.

A 62-year-old woman presented to the internal medicine department of our university hospital with chronic unresolved fever and an increase in liver function tests. Liver biopsy was performed. Microscopic examination revealed epithelioid granulomatous necrotizing vasculitis. Immunological testing revealed a perinuclear anti-neutrophil cytoplasmic antibody (ANCA) staining pattern with the presence of MPO-ANCA (Myeloperoxidase-ANCA). A diagnosis of ANCA-associated vasculitis with liver involvement was then made. The patient was started on steroids and her clinical state gradually improved.

Review of the Adverse Effects Associated with Dermal Filler Treatments: Part I Nodules, Granuloma, and Migration.

The increase in the use of filler treatments within minimally invasive cosmetic surgery has correspondingly escalated the variety and frequency of associated side effects. Initially, unregulated procedures led to primary side effects such as infections, foreign body reactions, and granuloma formation. However, severe vascular complications like skin and tissue necrosis and blindness have emerged as recognized risks. Side effects from filler treatments can range from mild to life-threatening, including edema, pain, tenderness, numbness, bleeding, bruising, hematoma, redness, erythema, pigmentation, allergic reactions, itching, pruritus, the Tyndall effect, asymmetry, irregularity, migration, skin and soft tissue infections, nodules, granulomas, and vascular compromise. These side effects are categorized into early and delayed types. Many complications, particularly those related to vascular abnormalities, are frequently linked to procedural issues, emphasizing the importance of understanding filler properties, injection techniques, and facial anatomy. Preventing side effects is ideal, but early detection and treatment are crucial. Recognizing potential side effects based on their timing and understanding appropriate preemptive treatment methods is essential. This discussion addresses non-vascular side effects, highlighting their onset, symptoms, and management strategies. The comprehensive understanding and careful management of these side effects are vital for minimizing complications and ensuring patient safety in filler treatments.

Multisystemic Beryllium Disease: An Exceptional Case Revealed by a Urinary Tract Granulomatosis.

Chronic beryllium disease (CBD), or berylliosis, is an interstitial lung disease caused by the chronic inhalation of finely particulate beryllium, frequently mistaken for sarcoidosis. It is rarely associated with skin nodular lesions, asymptomatic granulomatous hepatitis or calcium nephrolithiasis. To date, it has never been reported as a diffused multi-organ granulomatous disease. A 60-year-old Pakistani man, a former excavation worker with ancient history of suspected sarcoidosis, underwent a left nephroureterectomy for suspected papillary kidney carcinoma. The histopathological analysis showed a benign non-necrotic granulomatous infiltration of the renal pelvis and ureter. Six months later, he suffered from two consecutive episodes of acute kidney failure. Bladder biopsies found similar noncaseous granulomatosis and kidney biopsies showed interstitial nephritis. Known for suspected asthma, sleep apnea, and usual interstitial pneumonia, the patient would regularly consult for episodes of pyrexia, chills, nocturnal coughing, and wheezing. As kidney function gradually worsened, he ultimately started hemodialysis and was transferred to our facility. A positive blood beryllium lymphocyte proliferation test confirmed the diagnosis of CBD. This original report is the first description of multi-organ berylliosis with diffused urothelial granulomatosis and pseudo-tumor. The patient's pulmonary disease is minimal compared with renal and urinary tract involvement, eventually responsible for end-stage kidney disease. Berylliosis usually responds to glucocorticoids. This case report highlights the importance of evoking the diagnosis of CBD in the presence of any granulomatosis, even extra-thoracic, especially if associated with pulmonary symptoms, however atypical.

CD4+ T cells re-wire granuloma cellularity and regulatory networks to promote immunomodulation following Mtb reinfection.

Immunological priming-in the context of either prior infection or vaccination-elicits protective responses against subsequent Mycobacterium tuberculosis (Mtb) infection. However, the changes that occur in the lung cellular milieu post-primary Mtb infection and their contributions to protection upon reinfection remain poorly understood. Using clinical and microbiological endpoints in a non-human primate reinfection model, we demonstrated that prior Mtb infection elicited a long-lasting protective response against subsequent Mtb exposure and was CD4+ T cell dependent. By analyzing data from primary infection, reinfection, and reinfection-CD4+ T cell-depleted granulomas, we found that the presence of CD4+ T cells during reinfection resulted in a less inflammatory lung milieu characterized by reprogrammed CD8+ T cells, reduced neutrophilia, and blunted type 1 immune signaling among myeloid cells. These results open avenues for developing vaccines and therapeutics that not only target lymphocytes but also modulate innate immune cells to limit tuberculosis (TB) disease.

Idiopathic hyalinizing fibrosclerosis: A systemic steroid-resistant condition distinct from IgG4-related disease.

Since the concept of IgG4-related disease (IgG4-RD) was proposed, that diagnosis has been considered in idiopathic fibroinflammatory diseases in various organs, particularly in cases with multi-organ involvement. We have recently encountered three cases of fibrosing disease of uncertain etiology with shared microscopic appearances. Case 1 (56-year-old man) had an irregular mass at the base of mesentery. Case 2 (29-year-old woman) presented with obstructive jaundice due to an ill-defined mass at the hepatic hilum and two lung nodules. Case 3 (53-year-old man) had multiple solid nodules in the mediastinum, peritoneum, retroperitoneum, and mesentery; he also had diffuse irregular narrowing of the intra- and extra-hepatic bile ducts in keeping with sclerosing cholangitis. Serum IgG4 concentrations were not elevated. Biopsies from the nodular lesions showed extensive hyalinizing fibrosis with an only focal lymphoplasmacytic infiltrate. Thick collagenous bundles are arranged in an irregular or partly whorl pattern. Typical storiform fibrosis or obliterative phlebitis was not observed. The number of IgG4-positive plasma cells was <10 cells/high-power field; the ratio of IgG4/IgG-positive plasma cells was <30%. After the histological diagnosis of sclerosing mesenteritis, pulmonary hyalinizing granuloma, and mediastinal fibrosis was made, they were treated with a trial of steroids, but none showed a significant response. In conclusion, a hyalinizing fibrotic condition can occur at various anatomical sites. They have shared microscopic findings, and are steroid-resistant. Although the clinical presentation may mimic IgG4-RD, the two conditions are likely distinct. We would propose a diagnostic term of 'idiopathic hyalinizing fibrosclerosis' for this under-recognized, rare, systemic condition.