LANGERHANS CELL HISTIOCYTOSIS IN A CHILD WITH MULTISYSTEMIC LESIONS ASSOCIATED WITH INFECTED POLIOMYELITIS AND SARS-COV-2, FEATURES OF DIAGNOSTICS. CLINICAL CASE.

Langerhans cell histiocytosis (LCH) is an abnormal clonal proliferation of Langerhans cells. The prognosis varies depending on the form of the disease and organ damage. Any organs and systems can be involved in the pathological process in various combinations. A poor response to standard therapy and an unfavorable prognosis are characteristic of patients with a multisystem form of LCH and involvement of organs at risk. Skin lesions are a classic sign of LCH. Purpose - to describe the complexity and duration of diagnosis of LCH with multisystem damage in a boy aged 2 years and 2 months, infected with poliomyelitis and coronavirus. Clinical case. The first clinical manifestations of LCH in the child debuted with an eczematous-seborrheic rash on the scalp with spread to the limbs and trunk. The child was treated for toxicoderma, hemorrhagic vasculitis at the place of residence for 6 months. The boy lost 1.5 kg of body weight in 1 month. At the time of hospitalization, seborrheic-eczematous rashes on the skin with a hemorrhagic component, trophic-inflammatory changes in the nails of the hands, signs of protein-energy deficiency, stomatitis, gingivitis, hepatosplenomegaly, polyserositis, diabetes insipidus, osteolytic foci of the frontal bones were found. Results of the tests: anemia, thrombocytopenia, hypoproteinemia and hypoalbuminemia, coagulation disorders. The patient had the onset of lower flaccid paraparesis, muscle hypotonia. The boy was diagnosed with a number of infectious complications, including poliomyelitis (a derivative of vaccine poliovirus type 2), COVID-19. The child received LCH-III cytostatic therapy with a positive effect. The research was carried out in accordance with the principles of the Helsinki Declaration. The informed consent of the patient was obtained for conducting the studies.Copyright © 2023 Institute of Physics of the Russian Academy of Sciences. All rights reserved.

Risk of failure in dental implant osseointegration among people with the post-covid syndrome

Dental implants are a standard of care in contemporary dental practice and are widely employed for the restoration of missing teeth. The long-term utility of an implant is largely dependent on the successful implant osseointegration and maintenance of the same over time. Bone metabolism and inflammatory mechanism are interrelated phenomena and are usually collectively termed osteoimmunology, which may affect the predictability and success of implant osseointegration. Many biochemical mediators of inflammation, especially Interleukin (IL)1, IL-6, and Tumour necrosis factor (TNF)alpha, have been documented to increase the activity of bone-resorbing cells through the Receptor Activator of Nuclear Factor Kappa-B (RANK) and Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL)systems. Some of the earlier studies with very limited data suggest that SARS-CoV2 infection may also directly affect bone resorption. Thus, it is imperative to understand the pathophysiology of osseointegration in COVID-19 patients, to enhance successful implant osseointegration and prevent peri-implant bone loss in these patients. Here, we present a summary of the connection between inflammatory pathways and bone metabolism on a molecular basis which may assume a significant bearing in situations of exaggerated host immune response as seen in COVID-19 infection.Copyright © 2022 Wolters Kluwer Medknow Publications. All rights reserved.

The therapeutic effect and mechanism of parthenolide in skeletal disease, cancers, and cytokine storm.

Parthenolide (PTL or PAR) was first isolated from Magnolia grandiflora and identified as a small molecule cancer inhibitor. PTL has the chemical structure of C15H20O3 with characteristics of sesquiterpene lactones and exhibits the biological property of inhibiting DNA biosynthesis of cancer cells. In this review, we summarise the recent research progress of medicinal PTL, including the therapeutic effects on skeletal diseases, cancers, and inflammation-induced cytokine storm. Mechanistic investigations reveal that PTL predominantly inhibits NF-κB activation and other signalling pathways, such as reactive oxygen species. As an inhibitor of NF-κB, PTL appears to inhibit several cytokines, including RANKL, TNF-α, IL-1ß, together with LPS induced activation of NF-κB and NF-κB -mediated specific gene expression such as IL-1ß, TNF-α, COX-2, iNOS, IL-8, MCP-1, RANTES, ICAM-1, VCAM-1. It is also proposed that PTL could inhibit cytokine storms or hypercytokinemia triggered by COVID-19 via blocking the activation of NF-κB signalling. Understanding the pharmacologic properties of PTL will assist us in developing its therapeutic application for medical conditions, including arthritis, osteolysis, periodontal disease, cancers, and COVID-19-related disease.

Post-COVID-19 Lymphocytopenia and Opportunistic Pathogens Infection in a Thalassemia Major Patient

Transfusion-dependent thalassemia patients undergo transfusion immunomodulating effects, which result in a general immune response depression and, consequently, an increase in the frequency of infectious episodes and neoplastic events due to a reduction in phagocytic function. Altered natural killer functions and IL-2-mediated lymphocytic response, defects in antigen presentation due to monocyte–macrophage cells, and decreases in bone marrow precursors and HLA II+ cells all play key roles in immunodepression in thalassemia major. SARS-CoV-2 infection presents marked lymphopenia, occurring in 96.1% of severe cases. COVID-19-related lymphopenia is due to various mechanisms, which lead to an increase in lymphocytic apoptosis. Post-COVID-19 lymphocytic quantitative and functional disorders may compromise immune response and promote the onset of infections via opportunistic pathogens. Herein, we report a case of a thalassemia major patient who developed severe post-COVID-19 lymphocytopenia, which may have facilitated the onset of a severe Klebsiella Pneumoniae infection.

CT-scan model of ageing: muscle mass, bone density and vascular calcification in elderly people with COVID-19 pneumonia

Background and Aim: Several studies described the association of COVID-19 with frailty and mortality in patients over 65 years old. These considerations have inspired the researchers to recognize changes in organ and tissue as a marker of frailty in older people. The aim of this study was to investigate the relation between muscle mass, bone loss and arterial calcifications in patients over 75 years old affected by COVID-19 pneumonia. Results: In this retrospective observational study, we analyzed on a thoracic CT paravertebral skeletal muscle area (cm2) and density (HU) at the Th12 level, descending thoracic aortic calcification (DTAC) - Agatston Score and L1 bone mineral density (HU) in 25 patients admitted to our Unit. 25 patients (13 males, 12 females), with a mean age of 83±2.83 years, were included. Agatstone score was inversely associated with L1 density (rho=- 0.452, p=0.024) and with muscle density (rho=- 0.43, p=0.03), also after adjustment for age and gender. L1 density was directly associated with muscle mass density (rho=0.42, p=0.03). The area under the curve of the ROC curve constructed to evaluate the discriminating power of the total DTAC in order to predict the death of patient was 0.81. The cut-off value of DTAC=2930,98 had a sensitivity of 89% and a specificity of 69%. Conclusions: The results of this study demonstrated that vascular calcification is inversely related to bone mineral density and muscle mass density, while bone and muscle density are directly correlated. Finally, DTAC in elderly people with COVID-19 pneumonia has a good power to discriminate the surviving patients from those who dead.

PETRAM RESULTS: BONE TURNOVER CHANGES on 18F-PET/CT after A RANDOMIZED SWITCH to TAF

Background: The mechanism of bone loss in antiretroviral-treated HIV-positive patients is poorly understood. Plasma bone turnover markers(BTMs) suggest uncoupling of bone resorption and formation by a treatment effect on bone cells. Switching away from TDF to TAF-containing regimens has been associated with bone mineral density(BMD) gains measured by dual-energy X-ray absorptiometry (DXA). One explanation is reversal of ongoing subclinical bone loss in the TDF to TAF switchers. Quantitative imaging with 18F-PET/CT allows assessment of regional bone formation at specific skeletal sites and can help differentiate if BMD changes are associated with increased bone formation or reduced bone loss. Methods: PETRAM, an open-label, randomised study conducted at a single UK site, enrolled non-osteoporotic virologically suppressed HIV-positive males, on >24 weeks rilpivirine/emtricitabine/TDF (RPV/FTC/TDF). They were randomised 1:1 to remain on RPV/FTC/TDF or switch to RPV/FTC/TAF. The protocol specified scanning by DXA (to measure BMD) and 18F-PET/CT at several regions of interest-with primary focus on the lumbar spine (LS) and total hip (TH)-at baseline, 24 weeks, and 48 weeks. However, the timing of scans was disrupted, and in some cases considerably delayed, by COVID-19. The primary analysis was therefore based on change between the baseline and final scans, adjusting for the interval between them. Regions of interest were drawn on the PET/CT images and the standardised uptake value (SUV) measured. A sample of 30 (15 per arm) was estimated to provide 90% power to detect a difference in change of 25% in SUV between the randomised groups. Results: 32 males, median age 51 years, 76% White ethnicity, median duration RPV/FTC/TDF of 49 months, BMI 25.5 kg/m2 were enrolled;27(16 TAF:11 TDF) were included in the final analysis. The interval between baseline and final scans ranged between 23-103 weeks (median 55 weeks). There was no significant difference in change in SUV(18F-PET/CT) at the LS or TH between the TAF and TDF arms (Table);there was a trend towards improved LS BMD, but not TH BMD, in the TAF arm. Conclusion: As measured by 18F-PET/CT, regional bone formation at the hip or LS in patients replacing TDF with TAF in their ART combination did not differ, and contrary to our hypothesis, switching to TAF vs. remaining on TDF over 23-103 weeks did not change BMD or SUV at these key skeletal sites. The improved LS BMD in those switching to TAF is consistent with findings from other TAF-switch studies.

COVID-19 Associated Hypercalcemia, A Rare Yet Interesting Case

Introduction: Hypercalcemia is a common clinical diagnosis. Hyperparathyroidism is one of the most common etiologies. Rarely hypercalcemia is associated with intense inflammation secondary to IL-6 production. Herein we present an interesting case of hypercalcemia associated with COVID-19. Case Description: 36-year-old woman with history of Cirrhosis secondary to hepatitis C and alcohol abuse initially admitted for COVID/ARDS and cryptococcemia without CNS involvement. She was initially treated with amphotericin B and continued on fluconazole. Patient was re-admitted after 2 weeks with abdominal pain, constipation and hypercalcemia (Ca 14.2 mg/dl (normal range 8.7-10.1mg/dl). Her ionized calcium was 1.78 mmol/L (normal range 1.12-1.32 mmol/L). Serum phosphorus was 2.5 mg/dl (normal range 2.5-4.5mg/dl). Intact PTH level was 6.7 pg/ml (normal range 6-48pg/ml). Vitamin D 25-OH level was 26.8 ng/ml (sufficient range 32-100 ng/ml);Vitamin D 1,25-OH level was 7.4 pg/ml (normal 19.9-79.3pg/ml). PTH-rp was unmeasurable (< 2pmol/l). CRP was elevated at 31.7mg/L (normal range 0.2-8 mg/L). She was not on calcium, Vitamin D supplementation or thiazide diuretics. Her renal functions were normal. She was given Intravenous fluids & Intravenous pamidronate. Steroids were not used due to an ongoing fungal infection. It was proposed that the patient had Interleukin-induced hypercalcemia secondary to COVID-19 infection. Her serum calcium normalized with improvement in clinical status Discussion: Recent literature suggests COVID-19 is associated with inflammatory response with cytokines & interleukins production. IL-6 production is significantly upregulated especially in severe cases of COVID-19 known as “Cytokine storm”. IL-6 is produced by bronchial epithelial cells. High levels of IL-6 are associated with worse outcomes and much more severe disease. IL-6 in turn causes osteoclast activation, bone resorption & hypercalcemia. In our patient other potential causes of hypercalcemia were ruled out. The proposed mechanism of her hypercalcemia is an intense inflammatory response associated with COVID-19 infection. Conclusion: We present a rare sequelae of COVID-19 infection which presents a teaching point for clinicians to consider while managing such novel disease

MACHINE LEARNING AND RADIOMICS IDENTIFY NOVEL BIOMARKERS OF BONE LOSS

Purpose: Altered bone turnover is a factor in many diseases including osteoarthritis (OA), osteoporosis, inflammation, and viral infection. The absence of obvious symptoms and insufficiently sensitive biomarkers in the early stages of bone loss limits early diagnosis and treatment. Therefore, it is urgent to identify novel, more sensitive, and easy-to-detect biomarkers which can be used in the diagnosis and prognosis of bone health. Our previous data using standard micro-computed tomography (μCT) measurements showed that SARS-CoV-2 infection in mice significantly decreased trabecular bone volume at the lumbar spine, suggesting that decreased bone mass, increased fracture risk, and OA may be underappreciated long-haul comorbidities for COVID patients. In this study, we applied integrated state-of-the-art radiomics and machine learning models to identify more sensitive image-based biomarkers of SARS-CoV-2-induced bone loss from μCT images. These radiomic biomarkers can potentially provide a non-invasive way of quantifying and monitoring systemic bone loss and evaluating treatment efficacy in both research and clinical practices. Methods: All animal use was performed with approval of the Institutional Animal Care and Use Committee. To quantify SARS-CoV-2-induced bone loss, 6-week-old transgenic mice (16 male, 16 female) expressing humanized ACE2 receptors were inoculated with a 2020 strain of SARS-CoV-2 or phosphate-buffered saline (Control) [Fig. A]. Viral infection was confirmed by detection of infectious SARS-CoV-2 in throat swabs and histological identification of SARS-CoV-2 labeled cells. At 6-14 days post-infection, lumbar vertebral bodies (L5) were scanned with μCT (μCT 35, SCANCO Medical AG;6 μm nominal voxel size). The open-source research platform 3D Slicer v2020 with a built-in Python console v3.8 was used for medical image computing and fully automated segmentation of cortical and trabecular bone. Standard μCT assessment of bone microstructure was performed. Radiomic feature extraction and data processing were performed using python based PyRadiomics v3.0.1. A total of 120 radiographic features were extracted from the segmented images [Fig. B]. Principle component analysis (PCA) for feature selection, a support vector machine learning (SVML) predictive model for classification, holdback method for model validation, and all statistical analyses (significance at p<0.05) were performed using JMP Pro v15 (SAS). Results: Using standard μCT methods, SARS-CoV-2 infection significantly reduced the bone volume fraction (BV/TV) by 10 and 10.5% (p= 0.04) and trabecular thickness (Tb.Th) by 8 and 9% (p= 0.02) in male and female mice, respectively, compared to PBS control mice [Fig. C]. Radiomics detected a 20-fold greater magnitude in change over standard methods. SARS-CoV-2 infection significantly changed radiographic parameters with the largest change being a 300% increase in the second-order parameter: cluster shade [Fig. D]. The 45 radiomic features comprising the first 3 principal components were selected for inclusion in the SVML model. The SVML Model (radial basis function kernel;cost = 4.8;gamma = 0.46) produced an area under the receiver operating characteristic curve (AUC) of 1.0 which reflects a perfectly accurate test [Fig. E]. Conclusions: SARS-CoV-2 infection of humanized ACE2 expressing mice caused significant bone changes, suggesting that decreased bone mass, increased fracture risk, OA, and other musculoskeletal complications could be long-term comorbidities for people infected with COVID-19. We developed an open-source, fully automated segmentation and radiomics system to assess systemic bone loss using μCT images. When coupled with machine learning, this system was able to identify novel radiographic biomarkers of bone loss that better discriminate differences in bone microstructure between SARS-CoV-2 infected and control mice than standard bone morphometric indices. The high accuracy of the SVML model in classifying SARS-CoV-2 infected mice opens the possibility of translating these biom rkers to the clinical setting for early detection of skeletal changes associated with long-haul COVID. The methods presented here were demonstrated using SARS-CoV-2 as a model system and can also be adapted to other diseases associated with altered bone turnover. Development of machine-learning methods for radiomic applications is a crucial step toward clinically relevant radiomic biomarkers of bone health and provides a non-invasive way of quantifying and monitoring systemic bone loss and evaluating treatment efficacy. [Formula presented]

Differential diagnosis of malformations of lymphatic vessels in dermatological practice

Lymphangiomas (LG) are uncommon, rare congenital anomalies or acquired lymphatic dilations of a benign flow that can involve the skin [1, 2]. There are main groups of lymphangiomas: 1) a superficial variant, characterized by grouped vesicles (circumscriptum lymphangioma), 2) a deeper variant in the form of a cavernous lymphangioma. The prevalence of LG may be focal or diffuse. Secondary acquired LG with a rarer frequency are known [3, 4]. LG can be one of the manifestations of a symptom complex, for example, Gorham-Stout syndrome, which is characterized by progressive osteolysis [5]. The rare occurrence of LG, clinical diversity, undulating course of congenital forms, the possibility of an acquired nature of the disease causes a high risk of diagnostic errors in establishing the final diagnosis. At the Department of Dermatovenereology, Cosmetology and Additional Professional Education of Smolensk State Medical University for the period from 2018 to 2021, 5 patients (age from 5 to 17 years) with LG were observed. Of these: in four children, the disease existed from birth, in one girl it had an acquired character and developed after covid infection [4]. Gender characteristics: 4 girls (5, 6, 12 and 17 years old) and 1 boy (9 years old). All patients are urban residents. The time to establish the final diagnosis from the moment of seeking medical help ranged from 15 months to 12 (!) years, the average value being 6.5 years. The range of diagnoses of LG 'masks': herpetic infection, molluscum contagiosum, atopic dermatitis, contact dermatitis, epidermolysis bullosa. A frequent change in diagnoses was established in the same patient. Clinical case 1. The boy is 12 years old. The debut of skin lesions from birth and progression to 3 years of age, then spontaneous regression within 4 years (without signs of dermatosis). From 7 years to the present, there has been an increase in the number of rashes. Localization: the skin of the lateral surface of the trunk. Features of the rash: flesh-colored and/or reddish- purple bubbles. A pathognomonic symptom of 'frog calves' is found. The frequent autodestructive effect on the rash provokes its subsequent progression. Family history: his father is a liquidator of the atomic catastrophe in Chernobyl. Previous diagnoses: molluscum contagiosum, herpes zoster. Clinical case 2. The girl is 17 years old. The debut of the disease from birth. Lack of progression up to 5 years of age (up to 5 years of age did not apply to dermatologists). At the age of 5, she began to engage in rhythmic gymnastics (she continues to practice professionally at the present time) and noted an active increase in the number and size of the elements of the rash. She repeatedly consulted dermatologists: diagnoses of molluscum contagiosum (laser removal), herpetic infection (courses of antiherpetic therapy without effect) were assumed. The diagnosis was established 12 years after the moment of seeking medical help. Unilateral location of the rash along the inner surface of the right upper limb with transition to the axillary region;on the right lateral surface of the body, the right inguinal-femoral fold and the inner surface of the right thigh. Focuses of a rash in the form of different sizes of vesicular elements with a tendency to lymphorrhea and oozing, areas of maceration around. Single elements with a hemorrhagic component. The patient notes an increase in the inflammatory response and vesicle lymphorrhea after each workout. Dermatoscopy: yellow-pink lacunae alternating with single dark red lacunae. Histological examination: multiple dilated lymphatic vessels in the papillary and reticular dermis. Clinical case 3. Girl 6 years old. Sick from birth. The diagnosis of LG of the genitals was established at the age of 1, 5 years. Due to the localization of the rash in the external genital area, the girl's parents (at the age of 1 month) consulted an obstetrician-gynecologist, who suggested a hemangioma and referred to a dermatologist. The disease is of a family nature her grandmother (on the maternal side) and her lder brother have similar rashes on the skin of the trunk and in the mouth. The diagnosis was verified by histological examination. The pathological process is localized in the area of the labia majora and labia minora: multiple vesicular rashes with translucent contents, easily traumatized and accompanied by itching, were found. Conclusions: LG is a multidisciplinary problem, which is caused by mimicry of manifestations, varied localization and prevalence of the rash. To verify the diagnosis, the following algorithm should be followed: 1) the debut more often at birth or in the first months of life (with the exception of acquired forms of LG);2) the nature of evolution: a stable state or slow progression in the absence of traumatic factors;3) clinical features: the formation of grouped deep vesicles that resemble 'frog eggs'. The color of the bubbles is transparent or red-purple due to the hemorrhagic component. LG lesions may have hemangioma components. It should be remembered about the frequent localization of LG on the mucous membrane of the cheeks, tongue and floor of the oral cavity, which can manifest itself as bleeding from the elements of the rash when chewing or when providing dental care;4) biopsy reveals dilated lymphatic vessels in the upper layers of the dermis.

Zolendronic acid after teriparatide: Pandemic observations

Objective: Teriparatide for sever osteoporosis is followed by antiresorptive drugs, and one option in patients with gastric intolerance is zolendronic acid or denosumab (1-5). During pandemic lockdown, the access to bone assessment was limited (1-5). Type 1 diabetic patients are particularly at risk for bone loss, but also for COVID-19 infection, thus the importance of respecting the pandemic rules (1-5). We aim to introduce a female case diagnosed with severe menopausal osteoporosis that was followed during post-teriparatide sequence of medication, including during pandemic days. Case report: This is a type 1 diabetic female of 77 y who was first diagnosed with menopausal osteoporosis 8 y ago (lumbar T-score of-3.1 SD) and started medication with weekly alendronate in addition to vitamin D supplements. After 3 y, she suffered a single spontaneous vertebral fracture thus teriparatide was initiated for 2 y (with good tolerance): lumbar T-score went from -3.1 to -1.9 SD. In the meantime, due to bilateral coxarthrosis she needed bilateral hip replacement. Further on, she continued with biannually denosumab for 8 injections, reaching a lumbar BMD-DXA 0.942 g/cm2, T-score of -2 SD, Z-score of -0.8 SD so an intravenous perfusion with zolendronic acid 5 mg was administered plus vitamin D supplements. While she had no additional fracture and glycated haemoglobin A1c remained around 6.2-6.4%, one year later, the pandemic started, so only bone turnover markers (BTM) were assessed, not DXA: suppressed CrossLaps=0.22 ng/mL (normal: 0.33-0.782 ng/ mL), osteocalcin=11 ng/mL (normal: 15-46 ng/mL), P1NP=27 pg/mL (normal: 15-45 pg/mL). She continued with vitamin D, and 20 months after injection CrossLaps remained low (=22 ng/mL) with normal osteocalcin (=15 ng/mL), P1NP (=28 pg/mL) and stationary BMD. Conclusion: Zolendronic acid effect in osteoporotic patients is easy to access by blood assays if DXA is not available, while lack of BTM increase is suggestive for a good outcome.

Controversies in the use of new bone-modifying therapies in multiple myeloma.

Bone-modifying therapies are essential in the treatment of patients with multiple myeloma. Zoledronic acid is preferred over other bisphosphonates due to its superiority in reducing the incidence of skeletal-related events and improving survival. The anti-receptor activator of nuclear factor-κΒ ligand (RANKL)-targeted agent denosumab has shown its non-inferiority compared to bisphosphonates in preventing skeletal-related events among newly diagnosed patients with myeloma bone disease. Denosumab may confer a survival benefit in patients eligible for autologous transplantation. Denosumab may present a safer profile for patients with renal impairment. Discontinuation of bone-directed therapies can be considered for patients with deep responses and after an adequate time period on treatment; however, a rebound effect may become evident especially in the case of denosumab. Three-monthly infusions of zoledronic acid or at-home denosumab administration should be considered during the coronavirus disease 2019 (COVID-19) pandemic. Measures to prevent hypocalcaemia, renal toxicity and osteonecrosis of the jaw are important for all bone-modifying agents.