Case report: Cellular therapy for hydroa vacciniforme-like lymphoproliferative disorder in pediatric common variable immunodeficiency with chronic active Epstein-Barr virus infection.

Hydroa vacciniforme-like lymphoproliferative disorder (HV-LPD) is a cutaneous form of chronic active Epstein-Barrvirus (EBV) infection, which can develop into the extremely rare systemic lymphoma. Patients with Inborn errors of immunity (IEI), such as common variable immunodeficiency (CVID), are at higher risk of developing a severe course of infections especially viral and malignancies than the general population. The aim of the study was to present complex diagnostic and therapeutic management of HV-LPD. The clinical diagnosis was confirmed at the histological and molecular level with next generation sequencing. HV-LPD was diagnosed in a patient with CVID and chronic active Epstein-Barr virus (CAEBV) infection. The patient was refractory to CHOP chemotherapy and immunosuppressive treatment in combination with antiviral drugs (prednisone, bortezomib, gancyclovir). The third-party donor EBV-specific cytotoxic T cells (EBV-CTL, tabelecleucel) were used, which stabilised the disease course. Finally, matched unrelated donor hematopoietic cell transplantation (MUD-HCT) was performed followed by another cycle of EBV-CTL.

A Novel Hypothesis on Excessive Activation of Residual B Lymphocytes in Common Variable Immunodeficiency Concurrent with Aseptic, Erosive Polyarthritis.

The aim of this study was to report aseptic, erosive polyarthritis in a patient with common variable immunodeficiency (CVID), which is quite different from the vastly more common nonerosive form. Peripheral blood mononuclear cells of the patient were isolated. Flow cytometry was used to analyze the proportion and function of lymphocytes. A Parker-Pearson needle biopsy was performed on the right knee. Four of her unaffected family members were enrolled as controls. A 21-year-old woman was admitted for recurrent polyarthritis of 3-year duration. The right knee, hip, wrist, proximal interphalangeal joints, and left elbow were involved, with progressive joint destruction. She was diagnosed as having CVID based on her recurrent infections, poor response to vaccines, and marked hypogammaglobulinemia. No bacterium or mycobacterium was detected in synovium or synovial fluid. The synovium was infiltrated by lymphocytes rather than neutrophils. Polyarthritis did not resolve by adequate intravenous immunoglobulin substitution and empirical antibiotic treatment, but resolved gradually after treatment with methylprednisolone and tacrolimus, supporting the diagnosis of aseptic polyarthritis. Further analyses showed that although only 0.5% of residual B lymphocytes were existent in peripheral blood of the patient, expressions of activation marker CD69 and production of IL-1ß, IL-6, and TNF-α were high. Marked infiltration with CD19+B lymphocytes (as well as CD4+ or CD8+ T lymphocytes) was detected in the synovium. The proportion of IL21+CD4+Th cells from peripheral blood of the patient was high. CD4+ Th cells from the patient secreted nearly 3 times more IL-21 than the same cell type analyzed from unaffected family members, perhaps due to excessive compensation to assist the function of residual B lymphocytes. A novel hypothesis in CVID concurrent with aseptic, erosive polyarthritis is that excessive activation of residual B lymphocytes infiltrate into the synovium of the involved joints and lead to polyarthritis and joint destruction.

Novel variant of common variable immunodeficiency.

A 57-year-old woman with frequent respiratory infections was initially diagnosed with IgG subclass deficiency based on low levels of IgG subclasses 2 and 3. Three years later, she progressed to having IgA deficiency as well. With a normal total IgG level, she does not meet criteria for common variable immunodeficiency (CVID). This may represent a variant of CVID. This also highlights the importance of immunoglobulin subclass estimation in patients where immunodeficiency is suspected clinically. She is being treated with rotational antibiotics the first 10 days of every month, monthly intravenous immunoglobulin (IVIG) infusion and osteopathic manipulation one to two times per month. On this regimen, although she has had several viral respiratory infections, she has avoided further hospitalisation for more than 1 year.

Immunodeficiency, AIDS-related pneumonia, and risk of lung cancer among HIV-infected individuals.

OBJECTIVE: The objective is to clarify the role of immunodeficiency and pneumonia in elevated lung cancer risk among HIV-infected individuals. DESIGN: Cohort study of HIV-infected and HIV-uninfected adults in a large integrated healthcare system in California during 1996-2011. METHODS: We used Poisson models to obtain rate ratios for lung cancer associated with HIV infection, overall and stratified by recent CD4 cells/µl (HIV-uninfected as reference group), with χ tests for trends across CD4 strata. Fully adjusted models included demographics, cancer risk factors (smoking, drug/alcohol abuse, overweight/obesity), and prior pneumonia. RESULTS: Among 24 768 HIV-infected and 257 600 HIV-uninfected individuals, the lung cancer rate per 100 000 person-years was 66 (n = 80 events) for HIV-infected and 33 (n = 506 events) for HIV-uninfected individuals [rate ratio 2.0, 95% confidence interval (CI): 1.7-2.2]. Overall, HIV-infected individuals were at increased risk of lung cancer after adjustment for demographics and cancer risk factors (rate ratio 1.4, 95% CI: 1.1-1.7), but not after additional adjustment for pneumonia (rate ratio 1.2, 95% CI: 0.9-1.6). Lower CD4 cell counts were associated with higher risk of lung cancer in unadjusted and demographics-adjusted models (P < 0.001 for all), but this trend did not remain after adjustment for cancer risk factors and pneumonia. Compared with HIV-uninfected individuals, HIV-infected individuals with CD4 less than 200 cells/µl were not at increased risk of lung cancer in fully adjusted models. CONCLUSION: The increased lung cancer risk among HIV patients is attributable to differences in demographics, risk factors such as smoking, and history of pneumonia. Immunodeficiency does not appear to have an independent effect on lung cancer risk.

Non-sarcoidal, non-tuberculoid granuloma in common variable immunodeficiency.

Sarcoidal (non-caseating) or tuberculoid granulomas are cutaneous manifestations of common variable immunodeficiency (CVID). In this case report, we describe a patient with CVID but with non-sarcoidal, non-tuberculoid granuloma. The 29-year-old Egyptian male patient presented with a vitiliginous patch on the chin of 1 year duration and multiple recurrent warts on the hands and feet of 8 years duration. He is a known case of CVID with chronic diarrhea, recurrent otitis media, pneumonia, purulent conjunctivitis, septic arthritis, hepato-splenomegaly, and generalized lymphadenopathy. In addition, he had evidence of multiple non-tender subcutaneous nodules predominantly juxta-articular and recurrent rheumatoid-like arthritis. The skin overlying the nodules was either normal or slightly erythematous. Laboratory findings revealed markedly reduced serum immunoglobulins (IgG 3.4, n = 7.2-16.9 g/l; IgA 0.1, n = 0.69-3.82 g/l and IgM 0.1, n = 0.63-2.77 g/l) and deficient T cell function. Histopathologic examination of a skin nodule showed well demarcated areas of fibrinoid degeneration of collagen that stain homogeneously and are surrounded by histiocytes in a palisading arrangement, suggestive of granuloma annulare. No microorganisms could be detected. Serology for rheumatoid factor and HIV infection has been persistently negative. Although most infections, including common warts responded well to intravenous immunoglobulin replacement therapy (12 g/i.v., every 2 weeks) and oral broad spectrum antibiotic therapy, the subcutaneous nodules persisted. The vitiliginous patch responded favorably and disappeared within 24 local PUVA sessions. Since skin nodules are asymptomatic, no further treatment was given.

Vitamin a deficiency in patients with common variable immunodeficiency.

Vitamin A, a naturally occuring antioxidant micronutrient, has immunomodulating effect in patients with immunodeficiency, including an influence on cytokine production and lymphocyte growth and functions. Vitamin A deficiency is associated with a shift from type 2 cytokines to predominantly type 1 cytokines. The aims of this study were to determine Vitamin A status in Common variable immunodeficiency (CVID) patients and the relationship between Vitamin A status and cytokines production. Serum Vitamin A, neopterin, TNF-alpha, IL-2, IL-4, and IL-10 levels were determined in 19 CVID patients and 15 healthy children. Effects of 9-cis retinal, Vitamin A derivative, on cytokines (TNF-alpha, IL-2, IL-4 and IL-10) production in lymphocytes were tested in vitro condition using lymphocyte cultures obtained from CVID patients and healthy children.Serum Vitamin A level in CVDI patients was, 21.1+/- 1.5 microg/dL, significantly (p < 0.001) lower than the value, 35.7+/- 1.8 microg/dL, observed in healthy children. Serum neopterin level in the patients was, 9.8+/- 2.9 nmol/L, higher (p < 0.05) than the value, 3.9+/- 0.7 nmol/L, observed in control group. Common variable immunodeficiency patients, serum IL-4 level was significantly (p < 0.05) lower than the value observed for healthy children. Serum TNF-alpha, IL-2 and IL-10 levels were similar in the patients and healthy children. Vitamin A derivative, 9-cis retinal, increased TNF-alpha and IL-4 production in cultured mononuclear cells obtained from control and CVID patients. Vitamin A derivative, also, increased IL-2 and Il-4 production in cultured mononuclear cells obtained from CVID patients. These results show that CVID patients have low serum Vitamin A levels and high serum neopterin levels. A supplementation with Vitamin A may have role in downregulation of inflammatory responses in CVID patients.

A new strategy for the prevention of IgA anaphylactic transfusion reactions.

BACKGROUND: Management of patients with clinically significant anti-IgA is difficult and unsatisfactory in many aspects. PATIENTS AND METHOD: A 40-year-old man with common variable immunodeficiency had a previous history of anaphylaxis after an intramuscular immunoglobulin administration. His serum contained anti-IgA, and he required immunoglobulins for recurrent infections. RESULTS: The administration of intravenous immunoglobulins (IVIgG) containing less than 0.1 mg per mL IgA led to an anaphylactic reaction after the transfusion of only 2 to 3 mL. The same IVIgG charge was subsequently pretreated with freshly separated autologous plasma and given to the patient on three consecutive days without any reaction (1.25, 10, and 10 g each in 400 mL plasma). Anti-IgA activity did not increase, and the patient was treated again without complications. DISCUSSION: Ex vivo pretreatment of IVIgG preparations with autologous plasma appears to be safe and useful in the management of patients with clinically significant anti-IgA. To achieve a significant IgA blockage, the preparation to be used should not contain large amounts of IgA. CONCLUSION: The strategy described here appears to be safe and may help prevent anaphylaxis in many instances.

[Therapy with cytokines and thymic factors in a complicated case of common variable immunodeficiency]. / Terapia con citocinas y factores tímicos en un caso complicado de inmunodeficiencia común variable.

A case with common variable immunodeficiency associated to hyperprolactinaemia and severe damage of mucosal defenses is reported, in which humoral and cellular response was widely explored. The impact of the cytokines therapy was analyzed as complementary schedule to the conventional therapy with gammaglobuline. Immune response to the treatment was long-time evaluated in relation with therapeutic interventions. Combination of alpha 2 b-IFN, thymic factors, gammaglobuline and GM-CSF was a good alternative to treat complicated common variable immunodeficiency.

Decreased vitamin A levels in common variable immunodeficiency: vitamin A supplementation in vivo enhances immunoglobulin production and downregulates inflammatory responses.

BACKGROUND: Vitamin A has a broad range of immunological effects, and vitamin A deficiency is associated with recurrent infections. Common variable immunodeficiency (CVI) is a group of B-cell deficiency syndromes with impaired antibody production and recurrent bacterial infections as the major manifestations, but the immunological dysfunctions may also include T cells and macrophages. In the present study we examined the possible role of vitamin A deficiency in CVI. PATIENTS AND METHODS: We analysed plasma vitamin A levels in 20 CVI patients and 16 controls, and examined the relationships between vitamin A and clinical, immunological and metabolic parameters in CVI. In the six CVI patients with the lowest vitamin A levels we also studied the effect of vitamin A supplementation in vivo on several immunological functions in these patients. RESULTS: (i) The majority of CVI patients had decreased vitamin A levels compared with healthy controls, as found in both cross-sectional and longitudinal testing. (ii) Low vitamin A levels were associated with the occurrence of chronic bacterial infections and splenomegaly as well as high neopterin levels. Decreased levels of carrier protein and malabsorption were not observed. (iii) Vitamin A supplementation in patients with low vitamin A levels resulted in increased interleukin-10 (IL-10) and decreased tumour necrosis factor-alpha (TNFalpha) levels, as found in both plasma and monocyte supernatants, possibly favouring anti-inflammatory net effects. (iv) Vitamin A supplementation in vivo also enhanced anti-CD40-stimulated IgG production, serum IgA levels and phytohaemagglutinin (PHA)-stimulated peripheral blood mononuclear cell (PBMC) proliferation. CONCLUSION: A considerable subgroup of CVI patients appears to be characterized by low vitamin A levels. Our findings support a possible role for vitamin A supplementation in CVI, perhaps resulting in enhanced immunoglobulin synthesis and downregulated inflammatory responses.

Manifestaciones articulares en inmunodeficiencias primarias / Articular manifestations in primary immunodeficiencies

Las inmunodeficiencias primarias constituyen entidades clínicas que, aun cuando se presentan esporádicamente en la práctica diaria, suelen acompañarse de gran morbilidad y mortalidad si no se efectúan un diagnóstico y un tratamiento oportunos. Algunas de estas inmunodeficiencias pueden iniciar su sintomatología con manifestaciones articulares que semejan un proceso reumatológico. De las numerosas inmunodeficiencias primarias descritas hasta la fecha, la hipogamaglobulinemia común variable es la entidad que con más frecuencia se asocia con estas manifestaciones. La enfermedad se caracteriza por una deficiencia severa en la producción de anticuerpos, lo que conduce a infecciones bacterianas recurrentes. En tanto, ciertas condiciones predisponentes para algunas enfermedades reumatológicas, tales como Lupus eritematoso Diseminado, Vasculitis, Nefropatía y otras. El conocimiento de estas condiciones inmunológicas reviste una gran importancia en la patogenia y manejo de las enfermedades reumatológicas

Oral conditions in individuals with selective immunoglobulin A deficiency and common variable immunodeficiency.

Saliva and serum samples were collected from 36 individuals with selective immunoglobulin A deficiency (IgAd) and 23 patients with common variable immunodeficiency (CVI). The oral examination included registration of the teeth, Russell's periodontal index (PI), pocket formation, and salivary flow rate in both unstimulated and stimulated saliva. No differences were found in salivary flow rate, number of teeth, or pocket depth when donors with IgAd or CVI were compared to age and sex matched controls. However, mucosal manifestations of lichenoid type were more frequent in both types of immunoglobulin deficient individuals. An increased PI was also seen in CVI patients. Increased serum IgG and salivary IgM levels were found in the IgAd population.