Multiple opportunistic infections revealing Erdheim-Chester disease: an atypical presentation.

Multiple and atypical opportunistic infections in a HIV patient with Toxoplasma myocarditis.

Background: Erdheim- Chester Disease (ECD) is a rare hematopoietic neoplasm characterized by multi-organ infiltration with CD-68 -positive, CD1a-/S100-negative foamy histiocytes causing xantho-granulomatous inflammation. ECD most commonly involves the skeleton. CNS, pulmonary and CV involvement are also reported. Clinical Case: A 47-year-old male with a prior history of central Diabetes Insipidus (DI) presented with bone pain and ataxia. He was initially referred in 1993 for evaluation of DI. It was concluded that he had lymphocytic infundibulitis (LI), based on the finding of a thickened pituitary stalk on MRI while CSF revealed no evidence of infection or neoplasm. His DI was controlled with DDAVP. He had no other anterior pituitary hormone deficiencies. Although subsequent MRI showed resolution of the pituitary stalk thickening, his DI persisted. In 2012, he developed progressive gait instability, slurred speech and impaired motor coordination. On exam, he exhibited horizontal nystagmus, dysarthria, and truncal ataxia greater than limb ataxia. A brain MRI revealed absence of the posterior pituitary bright spot, enhancement along the proximal 7th and 8th nerve complex, disproportionate cerebellar atrophy and enhancement along the bilateral cerebellar folia. He complained of progressive, chronic leg pain since 2005. In 2018, he underwent tibial bone biopsy for an osteosclerotic lesion with diagnosis of Paget’s disease (PD). His Ca, Phos, 25OH- D, PTH, and Alk Phos were normal. Subsequent X-rays noted lesions of the pedicle of the left shoulder and pelvis, medullary sclerosis in the humeral diaphysis, and symmetrical lesions in the distal femur and tibia, bilaterally. Bone scan and FDG-Pet scan showed increased activity in the lesions. A repeat tibial biopsy revealed the marrow was infiltrated with histiocytes, fibrosis and sclerosis of trabecular bone. The histiocytes were highlighted by CD163, CD68, CD14, factor XIIIa and fascin A few scattered histiocytes were BRAF V600E immuno-stain positive, consistent with a diagnosis of ECD. His symptoms improved on Vemurafenib. Conclusion: We report a male with ECD who initially presented with isolated DI and a clinical course that mimicked LI. DI is a feature that occurs early in the disease process in 25% of patients. More than 10 years later, he developed ataxia and multifocal osteosclerotic bone lesions. His bone lesions were misdiagnosed as PD, but a repeat bone biopsy led to the correct diagnosis. In contrast to PD, the bone lesions in ECD are bilateral and symmetric and affect the diaphysis of long bones, specifically. As in our case, some patients with ECD can be asymptomatic for decades. For symptomatic patients who are BRAFV600E +, the B-Raf enzyme inhibitor, Vemurafenib, is recommended. His diagnosis was challenging, because ECD is rare (500 cases) and has features that overlap with other more common medical conditions.

A 45-year-old man was referred to the dermatology department for a 5–10-year history of enlarging periorbital xanthelasma-like lesions with a non-significant lipid profile. The periorbital lesions episodically and spontaneously became swollen and were associated with a throbbing sensation. After exercise and minimal motion, haemorrhage into the lesions occurred. Clinical examination revealed multiple coalescing, symmetrical, thick, yellow plaques and nodules with red–brown areas of discoloration associated with eyelid telangiectasia. His past medical history included hiatus hernia, lipoma and Osgood-Schlatter disease of the knee. The differential diagnosis included adult-onset xanthelasma, necrobiotic xanthogranuloma and amyloidosis. Punch biopsy of the lesions showed histological features consistent with a xanthogranuloma. Owing to the association of this entity with underlying haematological malignancy, computed tomography was performed, which revealed a subtle 33 × 70 mm low-attenuating mass within the posterolateral aspect of the right iliacus muscle. On further radiological investigation, including magnetic resonance imaging (MRI) and positron emission tomography, an avid, nonaggressive right iliac bone lesion and nonavid bilateral, symmetrical metaphyseal and diaphyseal sclerosis involving both distal femur and proximal tibia were seen. Previous MRI of his knee, performed 3 years earlier following a fall, was reviewed and found to show an incidental signal abnormality in his distal femur. Tissue from the periocular xanthogranuloma was positive for the BRAF V600E mutation and tissue from biopsy of the right iliac crest was consistent with focal osteosclerosis. Owing to the histopathological, clinical and radiological features, a diagnosis of Erdheim–Chester disease (ECD) was established. As a result, the haematology team initiated the patient on a reducing dose of oral prednisolone with long-term methotrexate (15 mg weekly). This led to an improvement in appearance of the periorbital lesions. The differential diagnosis for periocular xanthogranuloma includes adult-onset xanthogranulomas and adult-onset asthma with periocular xanthogranuloma, necrobiotic xanthogranuloma and ECD. ECD is a rare form of non-Langerhans cell histiocytosis that is highly associated with BRAF V600E and other mitogen-activated protein kinase pathway mutations (Diamond EL, Durham BH, Haroche J et al. Diverse and targetable kinase alterations drive histiocytic neoplasms. Cancer Discov 2016; 6:154–65). The clinical course of ECD is generally aggressive, but it can vary from indolent disease to fatal multiorgan failure. Although ECD can have multiorgan involvement, approximately 25% of these patients have cutaneous manifestations (Kobic A, Shah KK, Schmitt AR et al. Erdheim-Chester disease: expanding the spectrum of cutaneous manifestations. Br J Dermatol 2020; 182:405–9). This case highlights the importance of considering ECD when faced with atypical periorbital lesions as these lesions can mimic common benign xanthelasma.

7560 Background: Erdheim–Chester disease (ECD), an inflammatory myeloid neoplasm from the L group, is an histiocytosis associated with multisystem infiltration. Around 1500 cases have been reported worldwide since 1930. In 15% of cases, ECD is associated with another histiocytosis corresponding to mixed histiocytosis. Before 2004, 60% of patients died within 3 years after diagnosis. The targetable BRAFV600Emutation is present in as much as 70% of all ECD cases. Targeted therapies (BRAF inhibitors in April 2012, followed by MEK inhibitors after 2015) have revolutionized the therapeutic options and prognosis of refractory ECD and mixed histiocytosis. Methods: This retrospective study was conducted between April 2012 and December 2019 on 117 ECD patients who received targeted therapies in the French National Referral Center for Histiocytosis at Pitié-Salpêtrière Hospital in Paris, France. 28 patients (pts) (24%) had a mixed histiocytosis. Results: 43 (36.7%) pts were female and 95/116 exploitable pts (81.9%) had a BRAF V600E mutation. 12 (10.3%) pts had a co-ocurring hemopathy (myeloproliferative neoplasm or myelodysplastic syndrom). Age at diagnosis was 57.2 yr (+/- 13.8). The main sites of involvement were: vascular (“coated aorta”) in 85 pts (73%), heart in 83 pts (71%), xanthelasma in 30 pts (26%), central nervous system in 56 pts (48%) and peri-renal (“hairy kidney”) in 84 pts (72%). 34 pts (29%) had previously received corticosteroids, and 63 pts (54%) interferon alpha regimen (mainly PEG interferon). 86 (74%) pts received the BRAF inhibitor vemurafenib, and 42 (36%) pts the MEK inhibitor cobimetinib (some patients receiving both). 25 pts died during follow-up. The median survival of patients with targeted therapies in december 2019 was undefined, whereas the patients with no targeted therapies had a median survival of 133 months (HR 0.64 (0.42-0.99); p = 0.04). Among the 117 pts, only 2 had a progression of VAF of mutations within genes frequently mutated in myeloid neoplasms. The most serious adverse events were cutaneous (squamous cell carcinoma, basocellular carcinoma, DRESS) and acute pancreatitis with BRAF inhibitors, whereas chorioretinitis and left ventricular dysfunction were seen with MEK inhibitors. None of the patients receiving targeted therapies progressed. Conclusions: Targeted therapies (BRAF and/or MEK inhibitors) were found dramatically efficacious in 117 patients with severe and refractory ECD and mixed histiocytosis, improving survival of patients.

Ectopic adrenocorticotropic hormone secretion (EAS) is a rare cause of endogenous Cushing’s syndrome and is associated with immunosuppression and opportunistic infections. We report the case of a person who presented with rapid onset of hypertension, diabetes mellitus, and severe hypokalemia in the context of significantly elevated adrenocorticotropic hormone (ACTH) levels and marked hypercortisolism. Subsequent investigations led to a diagnosis of EAS without an identifiable source. Her clinical status continued to deteriorate despite medical management of her hypercortisolemia, thus an urgent bilateral adrenalectomy was performed. This patient’s course was complicated by multiple opportunistic infections with cytomegalovirus, Pneumocystis jirovecii (PJP), Mycobacterium tuberculosis and possibly BK virus. To the best of our knowledge, this is the first description of this specific constellation of opportunistic infections in the setting of EAS. Our case highlights the need to consider multiple and rare opportunistic infections while managing EAS and supports early bilateral adrenalectomy in critically ill patients with EAS of unknown origin.

Ectopic adrenocorticotropic hormone secretion (EAS) is a rare cause of endogenous Cushing’s syndrome and is associated with immunosuppression and opportunistic infections. We report the case of a person who presented with rapid onset of hypertension, diabetes mellitus, and severe hypokalemia in the context of significantly elevated adrenocorticotropic hormone (ACTH) levels and marked hypercortisolism. Subsequent investigations led to a diagnosis of EAS without an identifiable source. Her clinical status continued to deteriorate despite medical management of her hypercortisolemia, thus an urgent bilateral adrenalectomy was performed. This patient’s course was complicated by multiple opportunistic infections with cytomegalovirus, Pneumocystis jirovecii (PJP), Mycobacterium tuberculosis and possibly BK virus. To the best of our knowledge, this is the first description of this specific constellation of opportunistic infections in the setting of EAS. Our case highlights the need to consider multiple and rare opportunistic infections while managing EAS and supports early bilateral adrenalectomy in critically ill patients with EAS of unknown origin.

Classical and non-classical phenotypes of Erdheim-Chester disease: Correlating clinical, radiographic and genotypic findings.

Crescentic glomerulonephritis (GN) is one of the common causes of rapidly progressive glomerulonephritis (RPGN). Pauci-immune crescentic GN is usually associated with anti-neutrophil cytoplasmic antibody (ANCA). However, patients with pauci-immune crescentic GN who lack ANCAs have recently been reported. Approximately 10-30% of patients with pauci-immune crescentic GN lack ANCAs. The clinical characteristics of patients with ANCA-negative pauci-immune crescentic GN are not entirely the same as patients with ANCA-positive GN, and this suggests that ANCA-negative and ANCA-positive pauci-immune crescentic GN might be different disease entities. We report a patient with ANCA-negative crescentic GN complicated with multiple opportunistic infections (Candida albicans, herpes simplex virus, and Cytomegalovirus) in the digestive tract during the course of immunosuppressive therapy. After antifungal and antiviral therapies including itraconazole, valaciclovir, and ganciclovir, she recovered from multiple opportunistic infections. The occurrence of comorbid opportunistic infections during the course of immunosuppressive therapy may not be rare in the elderly. However, a case of multiple opportunistic infections limited to the digestive tract is very rare.

OBJECTIVE. Radiology is essential for diagnosing and managing Erdheim-Chester disease (ECD), a rare multisystemic non-Langerhans cell histiocytic neoplasm. This study aimed to systemically investigate imaging characteristics of patients with ECD. MATERIALS AND METHODS. Radiographic, CT, and MR images of 28 Chinese patients (14 male, 14 female; 5-65 years old) diagnosed with ECD on histopathology at our medical center between January 2014 and January 2019 were retrospectively analyzed. Two radiologists analyzed the images in consensus and recorded the imaging manifestations qualitatively. RESULTS. Seventeen of the 23 patients (73.9%) who underwent CNS evaluation had findings positive for ECD including supratentorial and infratentorial regions; infiltration of the corpus callosum, choroid plexus, pineal body, and walls of cerebral arteries; and brain nodules mimicking metastases. In the facial and orbital regions, postorbital masses (34.8%) and masses in the nasal sinuses and mastoid processes were noted. Moreover, bone involvement was found in 27 (96.4%) patients, with lower extremities most commonly affected (85.7%); pathologic fracture caused by bone involvement was also observed. On chest CT, pulmonary parenchyma, mesenchyme, pleura, and mediastinum were seen to be infiltrated by ECD (57.1%). Half (50.0%) of the 28 patients had cardiovascular involvement with infiltration of the aorta and its branches, coronary arteries, or branches of the superior mesenteric artery resulting in stenosis and ischemic symptoms. In addition to retroperitoneal involvement in 13 (46.4%) patients, a presacral mass wrapping bilateral pelvic ureters and thickening of the mesentery, peritoneum, and omentum were also detected. CONCLUSION. Patients with ECD should be evaluated systemically, because involvement of vital organs could be lethal.

The patient was a 57-year-old man who developed bilateral thigh pain and chest tightness 1 year ago. Chest computed tomography (CT) scan showed reticular shadows, thickened interlobular septa in both lung fields, and pericardial effusion. Three months ago, his symptoms worsened. A contrast CT scan revealed increased pericardial effusion, multiple masses in the right atrium, soft tissue shadows suggestive of retroperitoneal fibrosis, and soft tissue shadows around the thoracic and abdominal aorta. He visited University Hospital of University of Occupational and Environmental Health, Japan suspecting IgG4-related disease (IgG4-RD) or large vessel vasculitis (LVV). Based on the involvement of various organs and bilateral thigh pain, Erdheim-Chester disease (ECD) was suspected, and an 18F-fluorodeoxyglucose Positron Emission Tomography (FDG-PET) scan was performed. In addition to increased accumulation around the right ventricle, right coronary artery, and aorta, increased accumulation was confirmed in the distal femurs and proximal tibias on both sides, strongly suggesting ECD. A bone biopsy confirmed the diagnosis of ECD, showing bone fibrosis with CD68-positive and CD1a-negative foam cell infiltration, which is a characteristic of ECD. ECD is an extremely rare form of non-Langerhans cell histiocytosis. ECD affects a wide variety of organs, and its imaging findings can sometimes resemble those of IgG4-related disease or LVV. However, bone lesions are characteristic of ECD and are a key finding for its diagnosis. When systemic organ lesions, including bone lesions, are present, ECD should be included in the differential diagnosis, and PET-CT should be considered.

We report the case of a 55-year-old male diagnosed with Erdheim–Chester disease, who underwent 18 F-fluorodeoxyglucose positron emission tomography–computed tomography ( 18 F-FDG PET/CT) for baseline evaluation as well as posttreatment. The patient was treated with interferon-alpha but was lost to follow-up due to COVID pandemic, 2 years later the disease status, and the response to therapy was documented using FDG-PET/CT. We would also like to highlight the varied presentations of lesions in kidneys, retroperitoneum, lungs, and paranasal sinuses with special focus on atypical finding of the kidney. Thus, FDG-PET/CT is a useful modality for demonstrating response to therapy and mapping the disease status in Erdheim–Chester disease and therefore helps in further planning of management.

ERDHEIM-CHESTER DISEASE: A RARE ENTITY

The main issue of our case report is that Erdheim-Chester disease (ECD) clinically presents most commonly with bone and joint pain. We would again like to stress that technetium-99 bone scintigraphy has an important role to identify ECD in an early phase of the disease. Most diagnoses of ECD are made serendipitously. In their reply, Aouba et al compare stand-alone [F] fluorodeoxyglucose ([F]FDG) positron emission tomography (PET) results with computed tomography (CT) scan results. This may be a somewhat obsolete discussion; a hybrid PET/CT delivers the advantage of the synergy of the anatomic and metabolic information. As in any disease, in ECD metabolic changes precede the anatomic changes, creating a higher sensitivity in early stages of the disease. The PET component of a hybrid PET/CT camera is very useful in identifying subtle lesions on CT images that would otherwise be missed. In the wide clinical range that a patient with ECD may present, our patient has the indolent and isolated bone involvement, and not a more systemic and potentially life-threatening form. The irregular mildly increased uptake in the basal field of the right lung and in the lingual of the left lung was, together with the CT findings, indicative of transient infiltrative changes caused by a banal lung infection (Fig 1A). A control CT of the thorax 1 month later showed normalized images. A repeated [F]FDG PET/CT 1 year after diagnosis revealed no lung abnormalities or any other pathology suggestive of extraskeletal involvement of ECD (Fig 1B). The characteristic symmetric pathologic uptake in both distal femurs and both proximal tibiae did not show progression. We would like to thank Aouba et al for their suggestion to use anakinra for the treatment of extra-skeletal involvement of ECD. Because our patient has no extraskeletal involvement, neither anakinra, imatinib mesylate, nor any other systemic therapy is indicated.

Erdheim-Chester disease (ECD) is a rare type of non-Langerhans cell histiocytosis, with only 550 cases reported worldwide. ECD is characterized by diffuse histiocytic infiltration of multiorgans. The age of presentation of this disease is typically between 40 and 70 years. Bone disease is the most common symptom, as unique radiological findings of long bone sclerosis occur in 96% of cases. Furthermore, BRAF V600E mutation is detected in 60% of ECD cases. In this manuscript, we are describing a unique case of ECD; the patient is younger than most reported cases and has no bone pain or any skeletal involvement. This patient has unintentionally lost about 50% of his body mass and is suffering from progressive cerebellar manifestations with radiological evidence of cerebellar atrophy, in contrast to the usual ECD manifestation of cerebellar infiltration. In addition, the patient has cardiac, retroperitoneal, and perinephric involvement, but he retains his sexual drive and fertility. A tissue biopsy from the retroperitoneal mass displayed typical morphological and immunohistochemical features of ECD, and BRAF V600E mutation was detected. He was treated with pegylated interferon alpha, but his disease progressed and the treatment was changed to vemurafenib to which he had an excellent response at 6 weeks.

Classical and Non-Classical Phenotypes of Erdheim-Chester Disease: Correlating Clinical, Radiographic, and Genotypic Findings