Differing Performance of the Warning Signs for Immunodeficiency in the Diagnosis of Pediatric Versus Adult Patients in a Two-Center Tertiary Referral Population.

PURPOSE: Primary immunodeficiency (PID) represents disorders with a spectrum of clinical presentations. The medical community seeks clinical features to prompt evaluation for immunodeficiency given improved prognosis with early identification. We hoped to identify clinical characteristics that would improve the diagnostic accuracy of the widely disseminated Jeffrey Modell Foundation warning signs for immunodeficiency. METHODS: We performed a retrospective chart review in a two-center North American cohort of patients with PID. Charts of 137 pediatric and 400 adult patients with PID were evaluated for the presence of these warning signs and compared to controls with normal preliminary biochemical immune evaluation. RESULTS: Fewer than 45% of adults with PID presented with ≥ 2 warning signs, while diagnostic utility was improved in the pediatric population where the warning signs were found to be 64% sensitive. The warning signs found in a significantly increased proportion compared to controls differed for pediatric PID patients (recurrent pneumonia (OR 2.9, p < 0.001), failure to thrive (OR 2.1, p < 0.001), need for IV antibiotics (OR 2.1, p < 0.001), serious bacterial infection (OR 4.8, p < 0.001), recurrent otitis media (OR 1.5, p = 0.027)), versus adult PID patients (recurrent otitis media (OR 2.9, p < 0.001), recurrent sinusitis (OR 2.1, p < 0.001), diarrhea with weight loss (OR 2.2, p < 0.001), recurrent viral infection (OR 3.3 p < 0.001)). In evaluation for additional criteria to promote identification of immunodeficiency, linear regression models showed slightly improved diagnostic accuracy of the warning signs with the addition of autoimmunity in our pediatric PID cohort (8.7% v 2.8%, p < 0.001, ROC 0.58). Adult PID patients demonstrated atopy more frequently than controls (48.0% vs 40.3%, p = 0.011), while atopy was found to have a negative association with the presence of PID in the pediatric age group (OR 0.3, p < 0.01). No improvement in diagnostic accuracy of the warning signs was found with the addition of allergic disease, autoimmunity, or malignant and benign proliferative disease in the adult cohort. CONCLUSIONS: We demonstrate poor diagnostic performance of warning signs for immunodeficiency in patients with PID in a retrospective chart review. Divergent warning signs of statistically significant diagnostic utility were found in pediatric versus adult patients. We suggest education of physicians on differing presentations of possible immunodeficiency between age groups, and expansion of the warning signs to include non-infectious comorbidities such as autoimmunity in pediatric patients.

Orbital diffuse large B-cell lymphoma with combined variable immunodeficiency.

Common variable immunodeficiency (CVID) is a primary immunodeficiency manifesting as a reduction in the level of total immunoglobulin (Ig) G, a reduction in the level of either IgA or IgM, poor response to polysaccharide vaccine, and usually frequent infections. The association of CVID with an increased risk of malignancy, specifically lymphoma, is well known. A 63-year-old female with a past medical history significant for CVID presented with a 1-month history of dull, left eye pain with proptosis, hypoglobus, and left upper lid fullness without a discrete palpable mass. Magnetic resonance imaging (MRI) of the orbits revealed a diffuse infiltrating orbital mass superonasally with extension into the superior rectus muscle, medial rectus muscle, and optic nerve up to the orbital apex and ethmoid sinus. A superonasal orbital biopsy with a caruncular approach was performed and demonstrated a sparse lymphoid infiltrate that was suggestive for a large B-cell neoplasm. Positron emission tomography (PET) scan demonstrated a hypermetabolic right lymph node, anterior to the right submandibular gland, which was biopsied and histopathology confirmed diffuse large B-cell lymphoma (DLBCL). Our patient achieved a very good response to chemotherapy with minimal residual disease on PET scan at the end of treatment. She attained a complete remission after radiation therapy. In conclusion, patients with new orbital and adnexa masses in the setting of a primary immunodeficiency can have an aggressive malignancy such as DLBCL and early diagnosis and systemic treatment carries a good prognosis.

Incisional and Parastomal Hernia following Radical Cystectomy and Urinary Diversion: The University of Southern California Experience.

PURPOSE: Hernia is a common complication following radical cystectomy and urinary diversion. We investigated the clinical and radiological evidence for parastomal and incisional hernias, and their risk factors in a large cohort. MATERIALS AND METHODS: Using an institutional review board approved prospective database we reviewed the records of 1,101 patients who underwent radical cystectomy from 2003 to 2013. Followup (median 57 months) was available for 670 patients. Of the 670 patients 92 underwent ileal conduit diversion using Turnbull stomas with a median followup 34 months. Patients were followed with computerized tomography cancer surveillance. Standardized criteria were used to define parastomal and incisional hernias by an expert radiologist. Multivariate logistic regression was done to identify independent predictors. RESULTS: Parastomal hernia was diagnosed in 21 of 92 patients (23%) with a mean age at diagnosis of 76.5 years. Incisional hernia was present in 125 of 670 patients (18.7%) with a mean age at diagnosis of 68.6 years. Five patients had both hernia types. Of patients with parastomal and incisional hernias 11 (53%) and 111 (88.8%), respectively, were male. Mean body mass index was 27.5 and 27.3 kg/m(2) in patients with parastomal and incisional hernias, respectively. Mean parastomal and incisional defect sizes were 3.8 and 2.4 cm, respectively. In 18 patients (85%) parastomal hernias were clinically and radiologically evident, 5 patients were symptomatic and 2 underwent repair. In 51 patients (40%) incisional hernias were clinically and radiologically evident, 34 were symptomatic and 48 underwent repair. Multivariate logistic regression showed significant associations of incisional hernia with age, gender, incision length, orthotopic diversion and body mass index. Parastomal hernia had no significant association. CONCLUSIONS: Hernia is common after cystectomy and diversion. Age, gender, body mass index, incision length and diversion type are risk factors for incisional hernia. Multi-institutional prospective studies may better identify patients at high risk.

Dectin-2 regulates the effector phase of house dust mite-elicited pulmonary inflammation independently from its role in sensitization.

The myeloid C-type lectin receptor Dectin-2 directs the generation of Th2 and Th17 immune responses to the house dust mite Dermatophagoides farinae through the generation of cysteinyl leukotrienes and proinflammatory cytokines, respectively, but a role for Dectin-2 in effector phase responses has not been described. In this study, we demonstrate that administration of the Dectin-2 mAb solely at the time of D. farinae challenge abrogated eosinophilic and neutrophilic inflammation in the bronchoalveolar lavage fluid and Th1, Th2, and Th17 inflammation in the lung of previously sensitized mice. Furthermore, Dectin-2 null mice (Clec4n(-/-)) sensitized with the adoptive transfer of D. farinae-pulsed wild-type (WT) bone marrow-derived dendritic cells (DCs) also had less D. farinae-elicited pulmonary inflammation, supporting an effector function for Dectin-2. The protection from pulmonary inflammation seen with the Dectin-2 mAb or in Clec4n(-/-) mice was associated with little or no reduction in lung-draining lymph node cells or their cytokine production and with no reduction in serum IgE. WT and Clec4n(-/-) mice recipients, sensitized with D. farinae-pulsed WT bone marrow-derived DCs, had comparable levels of D. farinae-elicited IL-6, IL-23, TNF-α, and cysteinyl leukotrienes in the lung. By contrast, D. farinae-elicited CCL4 and CCL8 production from pulmonary CD11c(+)CD11b(+)Ly6C(+) and CD11c(+)CD11b(+)Ly6C(-)CD64(+) monocyte-derived DCs was reduced in Clec4n(-/-) recipients. Addition of CCL8 at the time of D. farinae challenge abrogated the protection from eosinophilic, neutrophilic, and Th2 pulmonary inflammation seen in Clec4n(-/-) recipients. Taken together, these results reveal that Dectin-2 regulates monocyte-derived DC function in the pulmonary microenvironment at D. farinae challenge to promote the local inflammatory response.

Cysteinyl leukotriene 2 receptor on dendritic cells negatively regulates ligand-dependent allergic pulmonary inflammation.

Cysteinyl leukotrienes (cys-LTs) can mediate Th2 immunity to the house dust mite, Dermatophagoides farinae, via the type 1 receptor CysLT(1)R on dendritic cells (DCs). However, the role of the homologous type 2 receptor CysLT(2)R in Th2 immunity is unknown. D. farinae sensitization and challenge of CysLT(2)R-deficient mice showed a marked augmentation of eosinophilic pulmonary inflammation, serum IgE, and Th2 cytokines. Wild-type (WT) mice sensitized by adoptive transfer of D. farinae-pulsed CysLT(2)R-deficient bone marrow-derived DCs (BMDCs) also had a marked increase in D. farinae-elicited eosinophilic lung inflammation and Th2 cytokines in restimulated hilar nodes. This response was absent in mice sensitized with D. farinae-pulsed BMDCs lacking leukotriene C(4) synthase (LTC(4)S), CysLT(1)R, or both CysLT(2)R/LTC(4)S, suggesting that CysLT(2)R negatively regulates LTC(4)S- and CysLT(1)R-dependent DC-mediated sensitization. CysLT(2)R-deficient BMDCs had increased CysLT(1)R-dependent LTD(4)-induced ERK phosphorylation, whereas N-methyl LTC(4) activation of CysLT(2)R on WT BMDCs reduced such signaling. Activation of endogenously expressed CysLT(1)R and CysLT(2)R occurred over an equimolar range of LTD(4) and N-methyl LTC(4), respectively. Although the baseline expression of cell surface CysLT(1)R was not increased on CysLT(2)R-deficient BMDCs, it was upregulated at 24 h by a pulse of D. farinae, compared with WT or CysLT(2)R/LTC(4)S-deficient BMDCs. Importantly, treatment with N-methyl LTC(4) reduced D. farinae-induced CysLT(1)R expression on WT BMDCs. Thus, CysLT(2)R negatively regulates the development of cys-LT-dependent Th2 pulmonary inflammation by inhibiting both CysLT(1)R signaling and D. farinae-induced LTC(4)S-dependent cell surface expression of CysLT(1)R on DCs. Furthermore, these studies highlight how the biologic activity of cys-LTs can be tightly regulated by competition between these endogenously expressed receptors.

Preventing herpes zoster in immunocompromised patients: Current concepts.

Herpes zoster (HZ) incidence is much higher in immunocompromised individuals than in immunocompetent individuals. HZ also occurs at a younger age and is often more severe in immunocompromised persons. Preventive strategies center around the recombinant zoster vaccine (RZV), which is approved for immunocompromised adults age 19 and older. Identifying those at greatest risk is critical. For those considering vaccination, evidence gaps regarding vaccine efficacy, toxicity, length of protection, and potential effects on underlying conditions may complicate shared and informed decision-making. Recent data have filled some of these gaps, with several societies issuing recommendations regarding vaccination. Remaining gaps are currently addressed by expert opinion.

Tumor metabolism in pheochromocytomas: clinical and therapeutic implications.

Pheochromocytomas and paragangliomas (PPGLs) have emerged as one of the most common endocrine tumors. It epitomizes fascinating crossroads of genetic, metabolic, and endocrine oncology, providing a canvas to explore the molecular intricacies of tumor biology. Predominantly rooted in the aberration of metabolic pathways, particularly the Krebs cycle and related enzymatic functionalities, PPGLs manifest an intriguing metabolic profile, highlighting elevated levels of oncometabolites like succinate and fumarate, and furthering cellular malignancy and genomic instability. This comprehensive review aims to delineate the multifaceted aspects of tumor metabolism in PPGLs, encapsulating genetic factors, oncometabolites, and potential therapeutic avenues, thereby providing a cohesive understanding of metabolic disturbances and their ramifications in tumorigenesis and disease progression. Initial investigations into PPGLs metabolomics unveiled a stark correlation between specific genetic mutations, notably in the succinate dehydrogenase complex (SDHx) genes, and the accumulation of oncometabolites, establishing a pivotal role in epigenetic alterations and hypoxia-inducible pathways. By scrutinizing voluminous metabolic studies and exploiting technologies, novel insights into the metabolic and genetic aspects of PPGLs are perpetually being gathered elucidating complex interactions and molecular machinations. Additionally, the exploration of therapeutic strategies targeting metabolic abnormalities has burgeoned harboring potential for innovative and efficacious treatment modalities. This review encapsulates the profound metabolic complexities of PPGLs, aiming to foster an enriched understanding and pave the way for future investigations and therapeutic innovations in managing these metabolically unique tumors.

Vasculitis as a Major Morbidity Factor in Patients With Partial RAG Deficiency.

Vasculitis can be a life-threatening complication associated with high mortality and morbidity among patients with primary immunodeficiencies (PIDs), including variants of severe and combined immunodeficiencies ((S)CID). Our understanding of vasculitis in partial defects in recombination activating gene (RAG) deficiency, a prototype of (S)CIDs, is limited with no published systematic evaluation of diagnostic and therapeutic modalities. In this report, we sought to establish the clinical, laboratory features, and treatment outcome of patients with vasculitis due to partial RAG deficiency. Vasculitis was a major complication in eight (13%) of 62 patients in our cohort with partial RAG deficiency with features of infections and immune dysregulation. Vasculitis occurred early in life, often as first sign of disease (50%) and was complicated by significant end organ damage. Viral infections often preceded the onset of predominately non-granulomatous-small vessel vasculitis. Autoantibodies against cytokines (IFN-α, -ω, and IL-12) were detected in a large fraction of the cases tested (80%), whereas the majority of patients were anti-neutrophil cytoplasmic antibodies (ANCA) negative (>80%). Genetic diagnosis of RAG deficiency was delayed up to 2 years from the onset of vasculitis. Clinical cases with sole skin manifestation responded well to first-line steroid treatment, whereas systemic vasculitis with severe end-organ complications required second-line immunosuppression and/or hematopoietic stem cell transplantation (HSCT) for definitive management. In conclusion, our data suggest that vasculitis in partial RAG deficiency is prevalent among patients with partial RAG deficiency and is associated with high morbidity. Therefore, partial RAG deficiency should be included in the differential diagnosis of patients with early-onset systemic vasculitis. Diagnostic serology may be misleading with ANCA negative findings, and search for conventional autoantibodies should be extended to include those targeting cytokines.

Intra cranial granulomatous disease in common variable immunodeficiency: Case series and review of the literature.

BACKGROUND/PURPOSE: Common variable immunodeficiency (CVID) is typically characterized by hypogammaglobulinemia and often but not always recurrent infections. Paradoxically, 8-22% of patients with CVID develop granulomatous disease. Granulomata have been described in many organs including the lungs, skin, liver, spleen, kidneys, eyes, lymph nodes, and intestines. Data about central nervous system (CNS) involvement in CVID are extremely rare. We aim to describe a case series and include an extensive literature review of CNS involvement in CVID to understand the different features and patterns of the disease. METHODS: We searched the English Pubmed database for relevant articles between 1950 and 2014 using the Key Words "common variable immunodeficiency", "granulomatous disease", "brain", "sarcoidosis", and "sarcoid-like syndrome". Data from all case series, surveys, systematic reviews, and individual case reports, as well as retrospective studies were extracted. A total of 15 patients were reported in the literature. We combined our experience with four additional patients from The Cleveland Clinic between 2009 and 2014. Demographics, clinical features, laboratory and imaging findings, treatment and follow-up were extracted for the 19 patients and summarized descriptively. RESULTS: Female sex and Caucasian race represented 63.2% (12/19), and 80% of the patients, respectively. The mean age of CVID diagnosis was 24 years; mean age when the CNS disease was diagnosed was 21.5 years. 68.4% of the patients (13/19) had granulomas involving ≥2 organs including the central nervous system, 31.6% (6/19) had CNS granulomas only. Associated granulomatous diseases occurred in lungs (72.7%), lymph nodes (27.2%), spleen (27.2%), eyes (18.1%), liver (18.1%), parotid glands (9%), and skin (9%). Fifty-three percent (10/19) of the patients had documented recurrent infections, all of them being upper respiratory tract infections. CNS manifestations included seizures (31.6%), headaches (21%), vision loss (15.7%), decreased cognition (10.5%), focal weakness (5.2%), nystagmus (5.2%), ataxia (5.2%), coma (5.2%), polyuria, and polydipsia (5.2%). Brain mass was the most common radiologic finding (70%) followed by leptomeningeal enhancement (10%), non-specific white matter lesions (10%) and absence of normal signal of the neurohypophysis (10%). Brain pathology was available in 12 patients: findings included granulomatous disease in 83.3%, angiocentric granulomas in 50%, vasculitis without granulomas in 8.3%, and lymphocytic infiltrate of the meninges with diffuse non-caseating granulomas in 8.3%. Cerebrospinal fluid analysis revealed elevated total proteins with/or without lymphocytic pleocytosis in 80%. CONCLUSION: CNS disease is a rare challenging complication of CVID. Patients with brain involvement are generally female, Caucasian, and likely have lung involvement. Although immunoglobulin and steroids remain the first line of treatment, other immunosuppressive agents have shown some promise with regards to recurrent relapsing presentations.

Biologic Therapy in the Treatment of Chronic Skin Disorders.

Understanding of the immunologic pathways involved in the pathogenesis of skin-related diseases is constantly advancing. Several biologic agents play important therapeutic roles for management of patients with chronic urticaria, atopic dermatitis, and psoriasis, particularly omalizumab for antihistamine-resistant chronic urticaria, interleukin (IL)-1 inhibitors for cryopyrin-associated periodic syndrome and Schnitzler syndrome, dupilumab for recalcitrant atopic dermatitis, and IL-17 inhibitors for psoriasis. The therapeutic utility of biologic agents for patients with immune-related dermatologic disorders is likely to expand in the future. This article reviews the data regarding biologic agents and their utility in the management of specific skin-related disorders.

Safety, Costs, and Efficacy of Rapid Drug Desensitizations to Chemotherapy and Monoclonal Antibodies.

BACKGROUND: Rapid drug desensitization (RDD) is used to address hypersensitivity reactions to chemotherapeutics and monoclonal antibodies, allowing patients to be treated with optimal pharmacological agents. RDD protocols are tailored to each individual patient's reaction and needs, and protect against anaphylaxis, but overall risks, costs, and benefits have not been determined. OBJECTIVE: We investigated the safety, efficacy, costs, and life expectancy of patients in a large population undergoing RDD. METHODS: We analyzed 2177 RDD procedures performed in 370 patients with cancer, vasculitis, and hematological and connective tissue diseases who presented 402 reactions. A subgroup of carboplatin allergic patients with ovarian cancer treated with RDD was analyzed for costs and life expectancy and compared with a nonallergic control group. RESULTS: RDD allowed all patients to receive safely the full dose of the medication to which they were reactive. A gradual increase in the fraction of outpatient desensitizations from 81% to 98% was achieved through risk stratification. Of the 2177 desensitizations, 93% had no or mild reactions whereas 7% had moderate to severe reactions, which did not preclude the completion of the treatment, and there were no deaths. Overall health costs in the carboplatin allergic group were not higher than those in the nonallergic group treated with standard of care. Administration of carboplatin through RDD was as effective as standard administration with a nonsignificant increase in life expectancy in desensitized patients as compared with nonallergic, nondesensitized controls. CONCLUSIONS: RDD is cost effective and safe for allergic patients with cancer and chronic disease to remain on first line therapy.

Design and development of an ethnically-diverse imaging informatics-based eFolder system for multiple sclerosis patients.

PURPOSE: MRI has been used to identify multiple sclerosis (MS) lesions in brain and spinal cord visually. Integrating patient information into an electronic patient record system has become key for modern patient care in medicine in recent years. Clinically, it is also necessary to track patients' progress in longitudinal studies, in order to provide comprehensive understanding of disease progression and response to treatment. As the amount of required data increases, there exists a need for an efficient systematic solution to store and analyze MS patient data, disease profiles, and disease tracking for both clinical and research purposes. METHOD: An imaging informatics based system, called MS eFolder, has been developed as an integrated patient record system for data storage and analysis of MS patients. The eFolder system, with a DICOM-based database, includes a module for lesion contouring by radiologists, a MS lesion quantification tool to quantify MS lesion volume in 3D, brain parenchyma fraction analysis, and provide quantitative analysis and tracking of volume changes in longitudinal studies. Patient data, including MR images, have been collected retrospectively at University of Southern California Medical Center (USC) and Los Angeles County Hospital (LAC). The MS eFolder utilizes web-based components, such as browser-based graphical user interface (GUI) and web-based database. The eFolder database stores patient clinical data (demographics, MS disease history, family history, etc.), MR imaging-related data found in DICOM headers, and lesion quantification results. Lesion quantification results are derived from radiologists' contours on brain MRI studies and quantified into 3-dimensional volumes and locations. Quantified results of white matter lesions are integrated into a structured report based on DICOM-SR protocol and templates. The user interface displays patient clinical information, original MR images, and viewing structured reports of quantified results. The GUI also includes a data mining tool to handle unique search queries for MS. System workflow and dataflow steps has been designed based on the IHE post-processing workflow profile, including workflow process tracking, MS lesion contouring and quantification of MR images at a post-processing workstation, and storage of quantitative results as DICOM-SR in DICOM-based storage system. The web-based GUI is designed to display zero-footprint DICOM web-accessible data objects (WADO) and the SR objects. SUMMARY: The MS eFolder system has been designed and developed as an integrated data storage and mining solution in both clinical and research environments, while providing unique features, such as quantitative lesion analysis and disease tracking over a longitudinal study. A comprehensive image and clinical data integrated database provided by MS eFolder provides a platform for treatment assessment, outcomes analysis and decision-support. The proposed system serves as a platform for future quantitative analysis derived automatically from CAD algorithms that can also be integrated within the system for individual disease tracking and future MS-related research. Ultimately the eFolder provides a decision-support infrastructure that can eventually be used as add-on value to the overall electronic medical record.

PCP: thinking beyond HIV.

A 40-year-old man with a previous AIDS-defining opportunistic infection and five negative HIV tests presented to our outpatient clinic. The laboratory test was relevant for less than 300 total lymphocytes on two separate occasions. He was diagnosed with idiopathic CD4 lymphocytopenia and was started on antibiotic prophylaxis for Pneumocystis carinii pneumonia and Micobacterium avium-intracellulare infection (MAI). This case report summarises the importance of further immunological characterisation in patients presenting with opportunistic infections and decreased cellular immunity.

Dectin-2 mediates Th2 immunity through the generation of cysteinyl leukotrienes.

The innate signaling pathways for Th2 immunity activated by inhaled antigens are not well defined. We previously identified Dectin-2 as a receptor for glycans in allergen extracts from the house dust mite Dermatophagoides farinae (Df) that mediates cysteinyl leukotriene (cys-LT) generation from pulmonary CD11c+ cells and from GM-CSF-cultured bone marrow cells (BMCs(GM-CSF)). Using lentiviral knockdown of Dectin-2 in BMCs(GM-CSF) and adoptive transfer of Df-pulsed BMCs(GM-CSF) to sensitize naive mice, we now report that Dectin-2 is critical for the development of Df-elicited eosinophilic and neutrophilic pulmonary inflammation and Th2 cytokine generation in the lungs and restimulated lymph nodes. Sensitization with Df-pulsed BMCs(GM-CSF) from LTC(4) synthase (LTC(4)S)-deficient mice or type 1 cys-LT receptor (CysLT1R)-deficient mice demonstrated that both proteins were required for Df-elicited eosinophilic pulmonary inflammation and Th2 cytokine generation in the lungs and restimulated lymph nodes. Direct sensitization and challenge of Ltc4s-/- and Cysltr1-/- mice confirmed that cys-LTs mediate these parameters of Df-elicited Th2 pulmonary inflammation. Thus, the Dectin-2-cys-LT pathway is critical for the induction of Th2 immunity to a major allergen, in part through CysLT1R. These findings identify a previously unrecognized link between a myeloid C-type lectin receptor and Th2 immunity.