Confirmed Cryoglobulinemia and Hyperviscosity Syndrome Secondary to Multiple Myeloma-IgA Kappa from Routine Blood Test: a Case Report.

BACKGROUND: Cryoglobulins and hyperviscosity syndrome (HS) sometimes occur in multiple myeloma (MM), which are considered clinical emergencies. In laboratory practice, aspiration failure in routine blood tests sometimes occurs when the sample is inadequate. Here, a case of cryoglobulinemia and HS associated with advanced multiple myeloma was reported, which unusually is initially confirmed by aspiration failure in a routine blood test with sufficient sample. METHODS: A case of a 48-year-old female whose diagnosis of cryoglobulinemia and hyperviscosity syndrome secondary to MM-IgA kappa was confirmed from routine blood test. RESULTS: The sufficient sample for routine blood test could not be analyzed in a hematology analyzer due to aspiration failure, which was found to be caused by high viscosity and poor liquidity. A peripheral blood smear showed numerous non-cellular clouds, erythrocyte rouleaux formation, and plasma cell infiltration. After a water bath, the non-cellular clouds evidently disappeared, and the routine blood test was successfully conducted. Centrifugation of the sample for biochemical test, which had previously failed, was also possible. The case was confirmed as complications of cryoglobulinemia and HS associated with advanced MM, and the non-cellular clouds were identified as cryoglobulins. CONCLUSIONS: This case report provides an effective way for clinicians to deal with this kind of abnormal sample and limited but important laboratory evidence to establish early diagnosis of cryoglobulinemia and HS secondary to MM.

Serum immunoglobulin G4 in Sjögren's syndrome: a pilot study.

Immunoglobulin IgG4 plays a role in the pathogenesis of the Mikulicz disease previously considered a form of primary Sjögren's syndrome (pSS). We investigated serum levels of IgG4, total IgG, C3, and C4 serum complementary components in patients suspected of Sjögren's syndrome. Basic laboratory and immunological tests, including IgG4 and IgG concentration, were performed on 20 healthy and 68 suspected of pSS individuals. We distinguished: group I: 48 pSS patients; group II (sicca): 20 patients with dryness without pSS. We revealed: statistical differences between groups I and II concerning hypergammaglobulinemia, ESR, RF, ANA, Ro, and La antibodies; lower IgG4 levels and IgG4/IgG ratio in group I compared to healthy individuals (p < 0.0435; 0.0035, respectively); no significant differences in the concentrations of IgG4 and IgG4/IgG ratio between sicca and control groups. significantly lower (p < 0.0002) C4 levels in group I compared to other groups; significant differences in C4 concentration and IgG4/IgG ratio between three groups (p = 0.0002 and p = 0.0090, respectively); a weak negative correlation between C4 and IgG (r =- 0.274) in the whole database; weak positive correlation between C4 and IgG4/IgG ratio (r = 0.237); a negative correlation of IgG4, IgG4/Ig ratio and C4 with focus score (r = - 0.281; r = - 0.327; r = - 0.406, respectively). IgG4 serum levels were significantly decreased compared to healthy subjects. IgG4 and C4 levels correlated with infiltrations in minor salivary glands. Hypergammaglobulinemia and decreased serum C4 component levels are typical for pSS.

An Extremely High IgA Value in a Young Child.

BACKGROUND: Hyper-IgA is not a rare finding in children although its causes are less reported than hypergamma-globulinemia in other classes of immunoglobulin. However, an isolated hyper-IgA might play a role as a diagnostic marker, in particular in children with an incomplete clinical picture at disease onset. RESULTS: We reported the case of a 3-year-old girl hospitalized for acute abdominal symptoms and suspicion of ruptured appendicitis. She presented severe inflammatory syndrome and her medical history related recurrent fever episodes. Serum immunoglobulin analysis was not in favor of an infection; indeed, IgA concentration alone increased and reached a surprising extremely high value in a young child (17-fold of the upper reference value). CONCLUSIONS: This case highlights the potential clinical significance of an isolated hyper-IgA that is known to be mostly found in serious diseases in children; it might contribute to reduce the delay in diagnosis and treatment of hyperimmunoglobulinemia D syndrome, an autoinflammatory disease.

[A case of hypertrophic pachymeningitis associated with probable sarcoidosis with increased serum IgG4].

We report a 54-year-old man, who presented with an acute onset of diplopia and ptosis on the left side. On admission, neurological examination showed left oculomotor and abducens nerve palsy. Brain MRI showed thickening of the left parieto-temporal dura mater with gadolinium enhancement. Whole-body CT revealed a mass lesion in the right submandibular gland, diffuse goiter, and bilateral hilar lymph node enlargement. Initially, IgG4-related disease was considered because of an elevated serum IgG4 level (240 mg/dl); however, biopsy of the submandibular gland showed non-caseating epithelioid cell granulomas that suggested sarcoidosis, which could be associated with the intracranial lesions causing his neurological manifestation. In cases of hypertrophic pachymeningitis, especially with increased serum IgG4 including our case, a careful assessment with pathological examination is critical for identifying various underlying conditions.

Perturbation of Thymocyte Development Underlies the PRRS Pandemic: A Testable Hypothesis.

Porcine reproductive and respiratory syndrome virus (PRRSV) causes immune dysregulation during the Critical Window of Immunological Development. We hypothesize that thymocyte development is altered by infected thymic antigen presenting cells (TAPCs) in the fetal/neonatal thymus that interact with double-positive thymocytes causing an acute deficiency of T cells that produces "holes" in the T cell repertoire allowing for poor recognition of PRRSV and other neonatal pathogens. The deficiency may be the result of random elimination of PRRSV-specific T cells or the generation of T cells that accept PRRSV epitopes as self-antigens. Loss of helper T cells for virus neutralizing (VN) epitopes can result in the failure of selection for B cells in lymph node germinal centers capable of producing high affinity VN antibodies. Generation of cytotoxic and regulatory T cells may also be impaired. Similar to infections with LDV, LCMV, MCMV, HIV-1 and trypanosomes, the host responds to the deficiency of pathogen-specific T cells and perhaps regulatory T cells, by "last ditch" polyclonal B cell activation. In colostrum-deprived PRRSV-infected isolator piglets, this results in hypergammaglobulinemia, which we believe to be a "red herring" that detracts attention from the thymic atrophy story, but leads to our second independent hypothesis. Since hypergammaglobulinemia has not been reported in PRRSV-infected conventionally-reared piglets, we hypothesize that this is due to the down-regulatory effect of passive maternal IgG and cytokines in porcine colostrum, especially TGFß which stimulates development of regulatory T cells (Tregs).

HYPERGAMMAGLOBULINEMIA AND MYELOMA IN FIVE TIGERS (PANTHERA TIGRIS): CLINICOPATHOLOGICAL FINDINGS.

Five adult tigers (Panthera tigris) presented with a range of clinical signs, including paresis (2/5), lameness (2/5), ataxia (3/5), anorexia (5/5), and lethargy (5/5). Each tiger demonstrated elevated plasma globulin levels (7.8-14.8 g/dl; [reference interval 2-5.1 g/dl]) on routine biochemistry, confirmed as a monoclonal gammopathy using protein electrophoresis. Serum gammaglobulin concentration ranged from 5 to 7.5 g/dl, or 45.1-63.4% of total protein concentration. Azotemia was present in three tigers. Diagnostics and management varied with the presenting signs but included magnetic resonance imaging, radiography, chemotherapy, supportive care, and euthanasia. In each case, necropsy revealed a neoplastic plasma cell proliferation in the bone marrow and one or more extramedullary sites. Lytic lesions in the thoraco-lumbar spine were found in three animals, and one lesion was associated with spinal cord compression. Splenomegaly was present in 4/5 cases. Histopathology confirmed a plasma cell neoplasm in each case, and immunohistochemistry staining with multiple myeloma oncogene 1 (MUM1) was positive in each case. CD20 staining was performed in two cases and was positive in one. CD3 staining was performed in the same two cases, and was negative in each. Based on the clinical, gross, microscopic, and immunohistochemical findings, myeloma was diagnosed in all five tigers.

Development and validation of a new simplified diagnostic scoring system for pediatric autoimmune hepatitis.

BACKGROUND: Children with autoimmune hepatitis (AIH) often exhibit particular features. Accordingly, seven pediatric-specific criteria have been proposed. AIM: To develop a prediction model based on them, transform it into a scoring system and study its accuracy. METHODS: A cohort of children under study for liver disease was consecutively selected. AIH diagnosis was based on classical criteria. Already proposed pediatric criteria were recorded. The best possible regression model was selected, and the beta coefficient of each criterion was translated into a whole number (points). Total scores were obtained following the points system and the best cut-off was calculated. Subsequently, accuracy of the diagnostic score was studied in the validation set. RESULTS: Among 212 included patients, 100 had AIH. The score included 5 criteria: autoantibodies (0-2 points), hypergammaglobulinemia, exclusion of viral hepatitis, exclusion of Wilson's disease (1 point each) and liver histology (3 points). In addition, a normal cholangiogram is mandatory. The validation set was formed of 70 patients (24 with AIH). In this subsample, a score of ≥6 renders a sensitivity/specificity of 95.8%/100%. The area under the receiver operating characteristic curve was 97.1%. CONCLUSION: Pediatric-specific criteria for the diagnosis of AIH can be reliably used as a scoring system.

Abdominal aortic aneurysm as an IgG4-related disease.

The objectives of this study were to evaluate patients with aortic abdominal aneurysm (AAA) with regard to immunoglobulin (Ig)G4-related disease (IgG4-RD). IgG4-RD represents a recently defined condition comprised of a collection of disorders characterized by IgG4 hypergammaglobulinemia, the presence of IgG4-positive plasma cells in organs affected with fibrotic or sclerotizing changes and typical histopathological features. It was identified as a possible cause of vasculitis in large vessels. Studies have been published on a possible association between inflammatory aortic or cardiovascular disease and IgG4-RD. We examined 114 patients with AAA requiring surgery in order to identify findings which are characteristic of IgG4-RD. Aneurysm samples from seven patients showed histopathological features consistent with IgG4-RD and the presence of IgG4+ plasma cells. Only two of these seven patients showed elevated IgG4 serum levels higher 1·35 g/l. In five of the patients, the concentration of serum IgG4 was lower than 1·20 g/l, with the number of IgG4+ plasma cells being higher than 50/high-power field. These findings were consistent with AAA being a heterogeneous group of inflammatory diseases with different pathogenesis.

A 45-year-old man with elevated levels of immunoglobulin A.

Quantitative immunoglobulin tests are often ordered as part of the initial evaluation for suspected immune deficiency. Although alterations in immunoglobulin levels can explain recurrent infections, in a patient without symptoms, there are a variety of other factors that can alter immunoglobulin levels. Common causes for elevated immunoglobulin A levels include malignancy and hepatic impairment in addition to a variety of infiltrative, infectious, and inflammatory diseases. We present a case of a 45-year-old man with a history of recurrent sinopulmonary symptoms without bacterial infection found to have an isolated elevated level of immunoglobulin A.

Acute hyperviscosity: syndromes and management.

Plasma hyperviscosity is a rare complication of both monoclonal and polyclonal disorders associated with elevation of immunoglobulins. Asymptomatic patients with an elevation in the serum viscosity do not require plasma exchange, and the majority will have other indications for therapeutic intervention. For patients with hemorrhagic or central nervous system manifestations, plasma exchange is the therapy of choice and is relatively safe. Viscosity measurements are not required to initiate therapy if the index of suspicion is high and the clinical presentation is typical. However, patients should have a sample sent for confirmation of the diagnosis. Whole-blood hyperviscosity is seen in patients with extreme elevation of the red cell and white cell count. Phlebotomy of patients with primary and secondary elevation of the red cell count is a well-established therapy.

Efficacy and safety of omalizumab in pediatric patients with high immunoglobulin E levels: A case series.

BACKGROUND: The efficacy and safety of omalizumab has been demonstrated in children as young as 6 years of age. Omalizumab is currently approved for a range of immunoglobulin E (IgE) levels that differ by age. In patients with IgE levels higher than the indicated therapeutic window, only a few studies have demonstrated the efficacy and safety of its use. Specifically, no reported studies exist to describe the use of omalizumab in pediatric patients with asthma ages <12 years and with high IgE levels. OBJECTIVE: We reported a series of pediatric patients who were initiated on omalizumab despite an IgE level higher than the age-indicated therapeutic windows and aimed to describe whether omalizumab was safe and improved asthma outcomes. METHODS: Patients who initiated omalizumab in our pediatric allergy clinic between January 2008 and December 2015, with serum IgE levels higher than the age-indicated therapeutic ranges were included. Patient charts were reviewed to determine the number of asthma-related events in the 12 months before and after initiation of omalizumab and the Asthma Control Test™ scores at the time of initiation and at 12 months of therapy. RESULTS: Eleven patients were identified with pretreatment IgE levels higher than the age-approved thresholds. Five patients were ages <12 years, and six patients were ages >12 years. For all but one patient, the maximum recommended dose of 375 mg every 2 weeks was effective in reducing the need for corticosteroids, emergency department visits, or hospitalizations in the year after initiation of therapy. During the period of therapy, there were no reports of severe reactions. CONCLUSION: Despite a small study group, our results indicated that omalizumab may be safely used in pediatric patients with IgE levels higher than the indicated therapeutic windows.

Serum Levels of IL-33 and Correlation with IL-4, IL-17A, and Hypergammaglobulinemia in Patients with Autoimmune Hepatitis.

This study investigated the role of IL-33 in the pathogenesis of autoimmune hepatitis (AIH). The levels of IL-33/sST2 and Th1/Th2/Th17-type cytokines were determined by enzyme-linked immunosorbent assay in serum samples obtained from 30 AIH patients and 20 healthy controls (HCs). In addition, a murine model of experimental AIH (EAIH) was established to investigate the role of IL-33 in disease progression. The serum levels of IL-33, sST2, Th17 cytokines (IL-17A), Th1 cytokines (IFN-γ, TNF-α), and Th2 cytokines (IL-4) were significantly elevated in AIH patients compared to HCs. Following immunosuppression therapy, serum levels of IL-33 and sST2 were significantly decreased. Additionally, the serum levels of IL-33 in AIH patients were correlated positively with markers of hypergammaglobulinemia (IgG, IgM, and IgA) and liver injury (γ-GT/ALP). Also, the serum levels of IL-33 in AIH patients were correlated positively with proinflammatory cytokine levels (IL-17A and IL-4). Interestingly, treatment of EAIH mice with a specific IL-33 neutralizing antibody significantly reversed the increasing trend in serum ALT/AST and inhibited the production of the type 2 (IL-4) and type 17 cytokines (IL-17) but not the type 1 cytokine (IFN-γ). Our findings highlight the possible role of the IL-33/sST2 axis in the progression of AIH, opening a new door for developing a novel therapeutic strategy for AIH.

Immunoglobulinopathies in patients with angioimmunoblastic T-cell lymphoma.

AIM: The aim of the study was to characterize quantitative and qualitative immunoglobulinopathies in patients with AITL at the onset of the disease. MATERIALS AND METHODS: 55 patients with newly diagnosed AITL were enrolled in the study, the male/female ratio was 30/25; median age was 61 (29-81) years. Diagnosis was based on standard WHO criteria. Immunochemical studies of blood serum included serum protein electrophoresis/immunofixation, nephelometric quantification of total immunoglobulins, serum free light chain assay. RESULTS: Quantitative and qualitative immunoglobulinopathies were determined in 49 (89,1%) of 55 pts. Quantitative immunoglobulinopathies were revealed in 47 (85.5%) of 55 cases, qualitative - in 14 (25,5%). Combination quantitative and qualitative immunoglobulinopathies was observed in 12 (21,8%) of 55 pts. The detected immunoglobulinopathies were divided into 4 groups: polyclonal hypergammaglobulinaemia, hypogammaglobulinaemia, oligoclonal gammapathy, and monoclonal gammapathy. Polyclonal hypergammaglobulinaemia was marked in 41 (74.5%) of 55 pts, elevated level of IgG was determined in 27 (49,15%) of 55 cases, IgM - in 18 (32,7%) and IgA - in 21 (38.2%). Interestingly, polyclonal IgE hypergammaglobulinaemia was detected in 12 (48,0%) of 25 cases of performed studies. Hypogammaglobulinaemia was detected in 8 (14,5%) of 55 cases. Oligoclonal gammapathy was determined in 4 (7.3%) of 55 pts. Monoclonal gammapathy was revealed in 11 (20,0%) of 55 cases. The amount of monoclonal immunoglobulin varied from 2.6 to 14.1 g/l. Monoclonal immunoglobulin Gk was detected in 5 of 11 pts, Gλ - in 2, Mλ - in 2, Mk - in 2. Monoclonal gammapathy was accompanied by polyclonal hypergammaglobulinaemia in 9 of 11 cases, hypogammaglobulinaemia - in 2. CONCLUSION: Quantitative and qualitative immunoglobulinopathies are observed in most patients at the onset of AITL. Quantitative abnormalities were determined more often than qualitative. Monoclonal gammapathy can be a manifestation of lymphoproliferation and other concomitant disorders. The prognostic value of immunochemical parameters is still unclear and requires dynamic observation and study.

Hyperferritinemia and hypergammaglobulinemia predict the treatment response to standard therapy in autoimmune hepatitis.

Autoimmune hepatitis (AIH) is a chronic hepatitis with an increasing incidence. The majority of patients require life-long immunosuppression and incomplete treatment response is associated with a disease progression. An abnormal iron homeostasis or hyperferritinemia is associated with worse outcome in other chronic liver diseases and after liver transplantation. We assessed the capacity of baseline parameters including the iron status to predict the treatment response upon standard therapy in 109 patients with untreated AIH type 1 (AIH-1) in a retrospective single center study. Thereby, a hyperferritinemia (> 2.09 times upper limit of normal; Odds ratio (OR) = 8.82; 95% confidence interval (CI): 2.25-34.52) and lower immunoglobulins (<1.89 times upper limit of normal; OR = 6.78; CI: 1.87-24.59) at baseline were independently associated with the achievement of complete biochemical remission upon standard therapy. The predictive value increased when both variables were combined to a single treatment response score, when the cohort was randomly split into a training (area under the curve (AUC) = 0.749; CI 0.635-0.863) and internal validation cohort (AUC = 0.741; CI 0.558-0.924). Patients with a low treatment response score (<1) had significantly higher cumulative remission rates in the training (p<0.001) and the validation cohort (p = 0.024). The baseline hyperferritinemia was accompanied by a high serum iron, elevated transferrin saturations and mild hepatic iron depositions in the majority of patients. However, the abnormal iron status was quickly reversible under therapy. Mechanistically, the iron parameters were not stringently related to a hepatocellular damage. Ferritin rather seems deregulated from the master regulator hepcidin, which was down regulated, potentially mediated by the elevated hepatocyte growth factor. In conclusion, baseline levels of serum ferritin and immunoglobulins, which are part of the diagnostic work-up of AIH, can be used to predict the treatment response upon standard therapy in AIH-1, although confirmation from larger multicenter studies is pending.

Is extra-glandular organ damage in primary Sjögren's syndrome related to the presence of systemic auto-antibodies and/or hypergammaglobulinemia? A long-term cohort study with 110 patients from the Netherlands.

AIM: To test the hypothesis that systemic auto-antibodies or hypergammaglobulinemia are related to the prevalence of extra-glandular tissue organ damage (EGOD) in primary Sjögren's syndrome (SS). METHODS: A real practice-based investigation of a relatively large (n = 110) Dutch cohort of primary SS patients systematically followed up in a large non-academic hospital. RESULTS: After a follow up of mean 8.2 years a significant correlation was found between disease duration and the prevalence of EGOD. We did not observe a relationship between the total number or type of systemic auto-antibodies or hypergammaglobulinemia and the total number of EGOD. However, there was a correlation between the prevalence of polyneuropathy (PNP) and antinuclear antibodies (ANA) as well as anti-Ro/SS-A positivity and there was an inverse relationship between the presence of anti-Ro/SS-A antibodies and primary biliary cirrhosis (PBC). All PBC cases were anti-Ro/SS-A and anti-La/SS-B negative but ANA positive. There was a trend for a higher occurrence of pleuro-pulmonary disease in the ANA negative cases. CONCLUSIONS: Although we did not find a relationship between the total number or type of systemic auto-antibodies and the total number of EGOD, there were correlations between specific systemic auto-antibodies and specific types of EGOD. The presence of ANA and anti-Ro/SS-A was associated with the occurrence of PNP, as well as was the absence of anti-Ro/SS-A with PBC.

Crystal-Storing Histiocytosis: Report of a Rare Case Presenting With Pathological Fracture of Femur. Is There More to the Entity?

Crystal-storing histiocytosis (CSH) is a rare histiocytic lesion, most often described in association with lymphoid malignancies, especially plasma cell myeloma or lymphomas associated with monoclonal gammopathy. A few cases have also been described in patients without an underlying lymphoid/plasmacytic neoplasm. The histiocytes are characterized by intralysosomal accumulation of crystals composed of whole or part of the immunoglobulin molecule. The pathobiology is largely unclear. It is a rare phenomenon and the available literature is restricted to case reports and a few case series. We present a case of a 70-year-old gentleman who presented with pathological fracture of left neck of femur secondary to CSH, a presentation so far unreported in the literature. Because of associated clinical features, a plasma cell dyscrasia was suspected and the workup, including bone marrow biopsy, yielded a diagnosis of plasma cell myeloma. Histological examination of the excised femoral head showed near complete replacement of the marrow spaces with sheets of histocytes rich in intracytoplasmic crystals and only occasional plasma cells. The peculiar presentation with pathological fracture of femur in the index case and predominant tumefactive lesions in the cases in the literature might suggest a possible neoplastic origin of this lesion.