Multisystemic Diseases

My Approach to the Treatment of Scleroderma

Children treated for Langerhans cell histiocytosis (LCH) are at risk for short and long term endocrine sequelae, but biological predictors of specific deficits are not well defined. We evaluated the frequency and progression of LCH-related endocrine deficits during long term follow-up and assessed the ability of dynamic endocrine testing to identify patients at risk for late anterior or posterior pituitary hormone dysfunction. The 17 patients (5 males and 12 females) were followed a median of 10 yr after diagnosis of single system (n = 6) or multisystem (n = 11) disease. Study evaluations, performed a median of 4.1 yr after the diagnosis, comprised pituitary hormone responses to the appropriate challenge, 7-h water deprivation test, 3% hypertonic saline infusion, and magnetic resonance imaging (MRI). The six patients with GH deficiency at the time of evaluation had a significantly lower GH response to GHRH than the other patients [median peak, 7.3 vs. 21.5 micrograms/L (P = 0.03); median area under the curve, 4.7 vs. 13.5 micrograms/L (P = 0.03)]; levels in the latter group did not differ significantly from those in 20 age- and sex-matched controls with constitutional or familial short stature. Two patients who had GH responses to GHRH of 20.6 and 23 ng/mL at 2.8 and 9.5 yr of age developed GH deficiency at 6.5 and 11.2 yr of age, respectively. The TSH response to TRH was less than 10 mU/L in three patients, two of whom later developed central hypothyroidism. ACTH and cortisol responses to CRF, and PRL responses to TRH were normal in all cases, and LH and FSH responses to GnRH were compatible with pubertal stage. Abnormalities in arginine vasopressin responses to water deprivation or hypertonic saline infusion were seen only in four patients who had preexisting diabetes insipidus (DI); one patient who later developed DI had normal findings. On standard MRI, posterior pituitary hyperintensity was absent only in the patients with DI. Pituitary stalk thickening was seen in seven patients, including three who did not have DI and had normal arginine vasopressin responses. Delayed posterior and anterior enhancement on dynamic MRI was present in two patients, both of whom later developed central hypothyroidism. Patients with single system disease had a lower 5-yr probability of LCH reactivation (41% vs. 83% for those with multisystem disease; P = 0.21) and a significantly lower risk of endocrine dysfunction (P = 0.007). In this series, dynamic evaluation of pituitary function was not a useful predictor of late endocrine sequelae, with the possible exception of the progressively decreasing TSH response to TRH. Similarly, a standard MRI was not predictive, although dynamic imaging may be informative regarding evolving pituitary hormone deficiency.

Objective: Langerhans cell histiocytosis (LCH) is a rare disorder of clonal proliferation of dendritic cells usually affecting children. However, it may also appear later in life at any age. The severity of the disease varies widely, and multi-system involvement of the lungs, liver and hematopoietic system may be life threatening. This study evaluated the role of 18F-fluorodeoxyglucose positron emission tomography / computed tomography (FDG PET/CT) in patients with single system and multisystem LCHfor disease extent, restaging and response to therapy. Methods:We retrospectively evaluated the data of 37 patients (27 male, 10 female) aged 21.3 ± 18.9 years, comprising 20 children (aged 1-16 years) and 17 adults (aged 20-69 years) with pathologically confirmed LCH. All patients had undergone whole body FDG PET/CT to assess the extent of disease involvement between January 2011 and May 2019. A total of 52 scans were evaluated by two experienced nuclear medicine physicians. Increased FDG uptake with morphological changes on the corresponding CT images were interpreted as PET/CT positive and absence of FDG uptake or any structural lesion were considered PET/CT negative. The metabolic and morphological tumor status and response after chemotherapy were assessed. Out of 52 PET/CT scans, 25 scans were performed for initial work-up and the rest for restaging, follow-up or response evaluation. The results of PET/CT imaging were compared with CT or magnetic resonance imaging (MRI) reports (if available). Results: Of the 37 patients, 20 had multisystem disease (8 high risk, 12 low risk), while single system involvement was noted in 17 patients (9 unifocal, 8 multifocal). FDG PET/CT was positive in 32/37 and detected skeletal (n=28), lymph nodal (n=13), lung (n=5), liver (n=4), pituitary (n=3), ano-cutaneous (n=2) and thyroid (n=2) lesions. In the two groups, FDG PET/CT identified more lesions compared to CT or MRI in 22 patients, including bone, lymph nodal and ano-cutaneous lesions. Six patients with lung lesions had very low FDG avidity. FDG PET/CT upstaged the disease in 8 patients from single system disease to multisystem involvement (2 primary pituitary, 2 primary thyroid and 4 primary skeletal). PET positive lesions had SUVmax of 8.9 ± 3.7 (range 3.8 - 18.8). In patients with follow-up or response evaluation imaging, a complete metabolic response was noticed in the low risk group (n=7), while disease progression was noted in patients with high risk and multisystem involvement group (n=3). Conclusion:Except for lung lesions, FDG PET/CT is a better imaging modality than conventional imaging (CT/MRI) for initial staging as well as restaging and response evaluation in both single system and multisystem LCH. It also helps in management planning by upstaging the disease from single system to multisystem involvement. Citation Format: ANISH BHATTACHARYA, RAJENDER KUMAR, BHAGWANT RAI MITTAL. Is there a role for 18F-FDG PET/CT imaging in Langerhans cell histiocytosis? [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B040. doi:10.1158/1535-7163.TARG-19-B040

It is still not known whether patients survive longer on one modality of dialysis compared to the other. We have tried to answer this question using data from the Scottish Renal Registry. To avoid the confounding effects of co-morbidity, we limited our survival analysis to those patients listed for a renal transplant and excluded patients with a primary renal diagnosis (PRD) of diabetic nephropathy. We studied patients starting dialysis between 01 January 1982 and 31 December 2006. Three thousand one hundred and ninety-seven patients fulfilled our criteria. A Kaplan-Meier plot showed no difference in survival between initial dialysis modality (log-rank P = 0.996). In the Cox regression model, initial dialysis modality was not a significant predictor of survival; hazard ratio = 0.97 (95% CI 0.80 to 1.18) after adjusting for age, sex and PRD. Age at the start of dialysis, hazard ratio = 1.05 (95% CI 1.04 to 1.06) and a PRD group of 'multi-system disease' or 'unknown' were found to significantly influence survival. When survival was also censored for change in modality, there was no difference in survival over the whole study period with the hazard of death for patients on haemodialysis compared to those on peritoneal dialysis being 1.04 (95% CI 0.78 to 1.38; P = 0.803). Age at the start of dialysis remained a significant predictor of death. This study shows that there was no survival advantage between initial dialysis modalities in non-diabetic patients who are deemed healthy enough for listing for a renal transplant.

Objective: To evaluate the clinical outcome of Langerhans cell histiocytosis (LCH) in countries with limited resources.Material and Methods: A retrospective chart review of patients <15 years old, diagnosed with LCH and treated at Siriraj Hospital; from January 1, 2002 until December 31, 2016, was performed. The patients’ demographic data, treatment protocol, and efficacy of treatment were collected and analyzed.Results: LCH was diagnosed in 38 patients, with a median age of 1.9 years old; of whom, 24 had multisystem disease (MS) and 14 had single system disease (SS). In the MS group, 16 patients had risk of organ (RO) involvement, with hepatic involvement being most common. The prevalence of central diabetes insipidus was 21.0%. Reactivation was observed in 11 patients (28.9%). RO involvement of the hematopoietic system (p-value=0.016), spleen (p-value=0.031), and MS (p-value=0.001) were significantly associated with a poor response to induction therapy. RO involvement of the hematopoietic system (p-value=0.016), liver (p-value=0.0), and spleen (p-value=0.005), as well as MS (p-value=0.013) were significantly associated with reactivation risk. The 5-year event-free survival rate of patients with and without RO involvement were 9.2% and 88.3%, respectively. The 5-year overall survival rate of patients with and without RO involvement were 82.5% and 96.4%, respectively.Conclusion: The prevalence of MS and RO involvement seemed high in this cohort; however, the outcomes were comparable to other Asian studies. Novel treatment for RO involvement may improve clinical outcomes.

Skin-limited versus multisystem Langerhans cell histiocytosis

Histiocytoses are rare and heterogeneous group of disorders in childhood. The clinical presentation of Langerhans cell histiocytosis (LCH) is highly variable, from asymptomatic to clinically significant symptoms and consequences. As it can involve nearly every organ of the body, the clinical manifestations depend on the site of the lesions, on the organs and systems involved and whether their function is affected. The most common sites of involvement in LCH are bone, skin, lymph nodes, lung, bone marrow and hypothalamic-pituitary region. The classical presentation of LCH is a unifocal bone disease, previously known as eosinophilic granuloma. LCH can be divided according to disease extent: single- or multi-system disease. There is very high chance of spontaneous resolution and favourable outcome for single-system disease involving the skin or bone. In many cases, no therapy or only local therapy is enough. For patients with multi-system disease currently systemic therapy is the treatment of choice. The goal of treatment is to relieve clinical symptoms, to increase survival and prevent complications. Currently cooperative international trials of the Histiocyte Society are used for treatment of LCH based on a€Eœrisk group stratification' with therapeutic agents have generally paralleled those used for the treatment of malignancies. There is no standardized therapy for chronic relapsing, acute refractory and progressive disease, some alternative approaches have been tested. Childhood LCH is a well treatable disease and the survival rate is high. This article summarizes the classification, pathophysiology, diagnostic criteria, different clinical manifestations, treatment possibilities, prognosis and long-term sequelaes of LCH in children.

Background: Eosinophilia has not been reported as a manifestation of a mitochondrial disorder (MID). Here, we report a patient with clinical features suggesting a MID and permanent eosinophilia, multisystem disease, and progressive hyper-creatine-kinase (CK)-emia for at least 10 years. Materials and Methods: Methods applied included a clinical exam, blood chemical investigations, electrophysiological investigations, imaging, and invasive cardiological investigations. The patient was repeatedly followed up over several years. He required replacement cardiac surgery. Results: In a 57-year-old male, eosinophilia was first detected at the age of 44 years and has remained almost constantly present until today. In addition to eosinophilia, he developed progressive hyper-CK-emia at the age of 47 years. His history was further positive for hepatopathy, hyperlipidemia, hypothyroidism, renal insufficiency, spontaneous Achilles tendon rupture, double vision, exercise intolerance, muscle aching, mild hypoacusis, sensory neuropathy, seizures, and mitral insufficiency/stenosis requiring valve replacement therapy, oral anticoagulation, and pacemaker implantation. Based on the multisystem nature of his abnormalities and permanent hyper-CK-emia, a MID was suspected. Conclusion: Eosinophilia can be associated with a MID with myopathy, possibly as a reaction to myofiber necrosis. If eosinophilia is associated with progressive hyper-CK-emia and multisystem disease, a MID should be suspected.

The aim of the present study was to further evaluate the concentrations of major acute phase proteins in calves with respiratory diseases and to determine the influence of other commonly occuring diseases on the concentrations of these inflammatory proteins in calves. Into the evaluation we included 69 sick calves with clinical signs of various inflammatory diseases such as respiratory diseases (n = 46), diarrhoea (n = 10), omphalophlebitis (n = 5) and multisystemic diseases (n = 8). The calves were of a Slovak spotted breed, lowland black spotted breed or their crossbreeds at the age from 2 weeks to 6 months. Blood for the investigations was taken once, when the clinical signs of the diseases were obvious. Blood samples were analysed for haptoglobin, serum amyloid A and fibrinogen. The results obtained in sick animals were compared with those in 28 clinically healthy calves. In calves suffering from respiratory diseases, we found significantly higher concentrations of haptoglobin (P < 0.001), serum amyloid A (P < 0.001) as well as fibrinogen (P < 0.001) than in clinically healthy calves. Insignificantly higher concentrations of serum amyloid A were obtained also in calves with signs of diarrhoea and omphalophlebitis, while the values of haptoglobin and fibrinogen were not markedly different from those measured in healthy animals. An opposite trend was observed in calves affected by multisystemic diseases with non-significantly higher concentrations of haptoglobin and fibrinogen. Thus, the presented data showed increased production of evaluated acute phase proteins in calves with respiratory diseases, and indicated that other diseases in calves, e.g. diarrhoea and omphalophlebitis, as well as multisystemic diseases, although in a less extent, may also induce an acute phase response.

Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation. We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare. All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events. Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations. (ClinicalTrials.gov number, NCT00069329 [ClinicalTrials.gov].).

Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides are multisystem diseases with significant potential for morbidity and mortality. This group includes Wegener granulomatosis, microscopic polyarteritis, and Churg-Strauss granulomatosis. Traditional therapy includes corticosteroids and immunosuppressive agents. The search for safer yet effective treatments continues, particularly in this era of biologic therapies. Etanercept was not effective in earlier studies, and patients developed significant adverse reactions (see JW Dermatol …

Introduction: The coronavirus disease-2019 (COVID-19) pandemic has been the most significant event in 2020, with ~86.8 million cases and 1.88 million deaths worldwide. It is a highly infectious disease, wherein the virus (severe acute respiratory syndrome coronavirus 2) rapidly multiplies and spreads to all parts of the body. Therefore, COVID-19 is not only respiratory disease but also a multisystem disease. Many people, including physicians, incorrectly believe that the disease affects only the respiratory tract. In this study, we aimed to describe COVID-19 manifestations and the underlying pathophysiology to provide the readers with a better understanding of this disease to achieve good management and to control the spread of this disease.Methods: Secondary data were obtained from PubMed, Google Scholar, and Scopus databases. The keywords used for the search were as follows: COVID-19, COVID-19 pulmonary manifestations, COVID-19 extra pulmonary manifestations, and pathophysiology of COVID-19. We collected secondary data from systemic reviews, metaanalyses, case series, and case reports in the form of public data that was published on websites of the government, medical corporations, medical peer-reviewed journals, and medical academies, all of which were indexed in PubMed, Google Scholar, or Scopus. Our questions were as follows: Is COVID-19 a respiratory disease only? and What are the extrapulmonary manifestations of COVID-19?Results: From our data, we found that a patient with COVID-19 may be either asymptomatic or symptomatic. Symptomatic cases may have either pulmonary or extrapulmonary manifestations. Pulmonary manifestations occur as mild, moderate, or severe cases. In mild and moderate cases, extrapulmonary manifestations such as gastroenteritis, fever, or vomiting may present alone. Some of these cases may be missed for diagnosis, and the patient may receive symptomatic treatment without a COVID-19 diagnosis, leading to increased spread of the infection. Extrapulmonary manifestations may occur in severe and critical cases as complications of severe infections (high viral overload) or the cytokine storm, such as in acute kidney injury (AKI), heart failure (HF), and venous thromboembolic (VTE) manifestation.Conclusion: COVID-19 is not a respiratory disease alone; rather, it is a multisystem disease. Pulmonary and extrapulmonary manifestations should be considered for early diagnosis and to control the spread of the infection.

To observe the clinicopathologic features of Langerhans cell histiocytosis (LCH), and to evaluate the values of langerin, CD1a and S-100 protein expression in diagnosis of the tumor. Total 258 cases of Langerhans cell histiocytosis in the past 18 years (from 1992 to 2008) were collected, morphologic review and immunohistochemical staining were performed. In all 258 cases, the ages of patients older than 16 years or younger than 2 years were 126 (48.8%) and 37 (14.3%), respectively, in the remaining 95 (36.8%) of the cases, the age of the patients ranged from 2 to 16 years. For all of 258 cases, there were 364 diseased sites. Bony lesions accounted for 77.2% (281 cases), especially the skull (112 cases, 39.9%), followed by lymph node (25 cases, 6.9%) and skin (14 cases, 3.8%). Clinically, unisystem or unifocal disease was predominant (201 cases, 77.9%), followed by unisystem and multifocal disease (21 cases, 8.1%), multi-system disease (26 cases, 10.1%), isolated pulmonary LCH (2 cases, 0.8%), and unclassified (8 cases, 3.1%). Histologically, variable number of Langerhans cells was present in 265 samples of 258 cases. Multinucleated giant cells were found in 166 (62.6%) of the samples. Eosinophils were the major infiltrating non-neoplastic cells, and eosinophilic abscess was seen in 57 cases (21.5%). Coagulative necrosis and dead bone were detected in 29 (10.9%) and 124 (46.8%) of the cases, respectively. Immunohistochemically, the expression of S-100 protein, CD1a and langerin was 99.1% (209/211), 100% (206/206) and 98.5% (193/196), respectively, and the sensitivity of them had no statistical difference. In this group of LCH cases, the ratio of adult patients is high, but the proportion of multi-organ lesion is low. No significant difference of the sensitivity is found among langerin, CD1a and S-100 expression in diagnosis of LCH.

Chapter 1 - Introduction

Clinical experience in anesthetic management for children with mucopolysaccharidoses: Report of ten cases.