Recurrent Opportunistic Infections Research Articles

A Novel Homozygous RHOH Variant Associated with T Cell Dysfunction and Recurrent Opportunistic Infections.

RHOH, an atypical small GTPase predominantly expressed in hematopoietic cells, plays a vital role in immune function. A deficiency in RHOH has been linked to epidermodysplasia verruciformis, lung disease, Burkitt lymphoma and T cell defects. Here, we report a novel germline homozygous RHOH c.245G > A (p.Cys82Tyr) variant in a 21-year-old male suffering from recurrent, invasive, opportunistic infections affecting the lungs, eyes, and brain. His sister also succumbed to a lung infection during early adulthood. The patient exhibited a persistent decrease in CD4+ T, B, and NK cell counts, and hypoimmunoglobulinemia. The patient's T cell showed impaired activation upon in vitro TCR stimulation. In Jurkat T cells transduced with RHOHC82Y, a similar reduction in activation marker CD69 up-regulation was observed. Furthermore, the C82Y variant showed reduced RHOH protein expression and impaired interaction with the TCR signaling molecule ZAP70. Together, these data suggest that the newly identified autosomal-recessive RHOH variant is associated with T cell dysfunction and recurrent opportunistic infections, functioning as a hypomorph by disrupting ZAP70-mediated TCR signaling.

Good's syndrome: brief overview of an enigmatic immune deficiency.

Good's syndrome, an infrequent adult-onset immunodeficiency is characterized by the triad of thymoma, hypogammaglobulinemia, and increased susceptibility to recurrent infections. The clinical presentation is highly variable, with a spectrum ranging from recurrent bacterial and opportunistic infections to concomitant autoimmune diseases and, sometimes malignant pathologies. Due to heterogeneous clinical phenotypes and the lack of adequate diagnostic criteria, its recognition is often challenging, even delaying it by years. It is one of the most unusual, less studied form of the immune deficiency syndromes with a still unknown pathophysiology. It was initially considered a thymoma-associated variant of primary antibody deficiencies with a reduced or absent number of mature B cells, but it later emerged that significant defects of T cell-mediated immune functions are the underlying cause of opportunistic infections. On the basis of current evidence, Good's syndrome is evaluated as a distinct acquired form of combined immunodeficiency states and classified as a phenocopy of primary immunodeficiency diseases. Epigenetic and acquired genetic factors can play an ultimate role in its evolution.

Cytomegalovirus colitis unmasking human immunodeficiency virus infection as a cause of IgA vasculitis

BackgroundHuman immunodeficiency virus (HIV) has a protean clinical picture, in rare instances manifesting as systemic autoimmune disorders such as vasculitides. HIV-induced autoimmune diseases often do not respond well to systemic immunosuppressive therapy. Opportunistic infections may occur in patients with either acquired immunodeficiency syndrome (AIDS) or heavy immunosuppressive treatment, and can further complicate the clinical presentation.Case presentationA patient presenting with immunoglobulin A (IgA) vasculitis (IgAV) with treatment-refractory purpuric skin rash and suspect intestinal vasculitis was discovered to have AIDS. HIV was the trigger of IgAV, and cytomegalovirus (CMV) colitis mimicked intestinal vasculitis. Antiretroviral treatment improved both CMV colitis and the control of the autoimmune disease.ConclusionsAn autoimmune disease relapsing despite adequate immunosuppressive treatment and/or the presence of recurrent severe opportunistic infections may be clues to an underlying HIV infection.

Exploring causal mechanisms and quantifying direct and indirect effects using a joint modeling approach for recurrent and terminal events.

Recurrent events are commonly encountered in biomedical studies. In many situations, there exist terminal events, such as death, which are potentially related to the recurrent events. Joint models of recurrent and terminal events have been proposed to address the correlation between recurrent events and terminal events. However, there is a dearth of suitable methods to rigorously investigate the causal mechanisms between specific exposures, recurrent events, and terminal events. For example, it is of interest to know how much of the total effect of the primary exposure of interest on the terminal event is through the recurrent events, and whether preventing recurrent event occurrences could lead to better overall survival. In this work, we propose a formal causal mediation analysis method to compute the natural direct and indirect effects. A novel joint modeling approach is used to take the recurrent event process as the mediator and the survival endpoint as the outcome. This new joint modeling approach allows us to relax the commonly used "sequential ignorability" assumption. Simulation studies show that our new model has good finite sample performance in estimating both model parameters and mediation effects. We apply our method to an AIDS study to evaluate how much of the comparative effectiveness of the two treatments and the effect of CD4 counts on the overall survival are mediated by recurrent opportunistic infections.

Severe Combined Immunodeficiency-Classification, Microbiology Association and Treatment.

Severe combined immunodeficiency (SCID) is a primary inherited immunodeficiency disease that presents before the age of three months and can be fatal. It is usually due to opportunistic infections caused by bacteria, viruses, fungi, and protozoa resulting in a decrease in number and impairment in the function of T and B cells. Autosomal, X-linked, and sporadic forms exist. Evidence of recurrent opportunistic infections and lymphopenia very early in life should prompt immunological investigation and suspicion of this rare disorder. Adequate stem cell transplantation is the treatment of choice. This review aimed to provide a comprehensive approach to the microorganisms associated with severe combined immunodeficiency (SCID) and its management. We describe SCID as a syndrome and summarize the different microorganisms that affect children and how they can be investigated and treated.

Good-szindróma: egy ritka, szokatlan immunhiányos állapot

Good syndrome is an infrequent and unique clinical entity of associated thymoma and immunodeficiency, first described almost 70 years ago. It is characterized by increased susceptibility to recurrent invasive bacterial and opportunistic infections as well as autoimmune and malignant diseases with an omnious prognosis. The affected patients are mainly middle-aged persons. The most consistent immunological abnormalities are hypogammaglobulinemia and reduced/absent B cells. More recently it was classified as an acquired combined (T, B) immunodeficiency and labelled as a phenocopy. This complex immunocompromised condition can lead to heterogenous clinical phenotypes, making the diagnosis rather challenging. The thymoma is mainly benign, and an incidental finding. Since the thymus plays a critical role in the development of the immune system, the altered tissue structure and microenvironment in thymoma can both predispose to manifestation of immunodeficiency and autoimmunity. The etiopathogenesis of the disease is still unclear, but it is assumed that epigenetic and acquired genetic factors can be highly responsible for its evolvement. Currently there is no specific therapy for Good syndrome. In addition to thymectomy, control of infections, possibly secondary prevention, and regular immunoglobulin replacement are recommended. Orv Hetil. 2023; 164(22): 859-863.

CD40LG genotype does not correlate with clinical phenotype in X-linked hyper-IgM syndrome

IntroductionCD40 ligand is expressed on follicular helper T cells and binds to CD40 on B cells and antigen presenting cells (APC). The CD40L-CD40 interaction is integral to germinal center formation, immunoglobulin class switching and affinity maturation, as well as APC mediated cytokine secretion required for an effective T cell response. Patients with mutations in the CD40LG gene develop X-linked Hyper-IgM (XHIGM) syndrome characterized by recurrent sinopulmonary, opportunistic infections, liver disease and malignancy. Early studies identified no clear genotype/phenotype correlation; but a milder phenotype has been reported associated with certain variants such as T254M. PurposeTo understand if specific genetic mutations in CD40LG correlate with disease severity we developed a clinical severity scoring system and retrospectively analyzed the relationship between severity and genotype in 109 individuals with XHIGM. ResultsThe majority of reported mutations were missense (41%), splice site (27%), nonsense (13%) or deletion (13%) mutations. There was not a statistically significant difference in severity or survival among mutation type groups. We identified 10 unrelated individuals with amino acid substitution T254M and found a range of clinical phenotypes from mild disease with late onset to early manifestations, liver disease and death due to cholangiocarcinoma. ConclusionOur data confirms the lack of genotype/phenotype correlation in XHIGM and suggest the need to develop a clinical scoring system that would allow for better understanding of an individual prognostic outcome.

Conversion to belatacept after lung transplantation: Report of 10 cases.

Calcineurin inhibitors (CNIs) remain the cornerstone of maintenance immunosuppression (IS) after lung transplantation (LTx), although CNI-related life-threatening toxic effects may occur. Belatacept, a novel immunosuppressant that blocks a T-cell co-stimulation pathway, is a non-nephrotoxic drug indicated as an alternative to CNIs in kidney Tx. In LTx, there are only a few reports of belatacept conversion as a CNI-free or CNI-sparing IS treatment. We reviewed a series of 10 LTx recipients with conversion to a CNI-free belatacept IS regimen within the first year post-LTx (n = 7) or a belatacept/low-dose CNI combination after the first year (n = 3). Use of belatacept was triggered by severe renal failure in 9 patients and under-IS with previous other IS-related toxicities in 1 patient. Mean estimated glomerular filtration rate after starting belatacept significantly improved at 6 months after initiation and at the last-follow-up (p = 0.006, and p = 0.002 respectively). The incidence of recurrent and/or severe acute cellular rejection (ACR) episodes was high in patients with CNI-free belatacept-based IS (n = 4/7). Chronic graft allograft dysfunction developed in 2 of 9 recipients under belatacept IS. Belatacept was stopped in 6 patients because of recurrent/severe ACR (n = 3), recurrent opportunistic infections (n = 1), center modified policy (n = 1), or other cause (n = 1). Early conversion to CNI-free belatacept-based IS improved renal function in this series but was counterbalanced by a high incidence of recurrent ACR, including life-threatening episodes. Other studies are needed to better determine the indications for its use after LTx, possibly with lower immunological risk IS regimens, such as CNI-sparing belatacept.

The STING/TBK1/IRF3/IFN type I pathway is defective in cystic fibrosis.

Cystic fibrosis (CF) is a rare autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most common mutation is F508del-CFTR (ΔF) which leads the encoded ion channel towards misfolding and premature degradation. The disease is characterized by chronic bronchopulmonary obstruction, inflammation and airways colonization by bacteria, which are the major cause of morbidity and mortality. The STING pathway is the main signaling route activated in the presence of both self and pathogen DNA, leading to Type I Interferon (IFN I) production and the innate immune response. In this study, we show for the first time the relationship existing in CF between resistant and recurrent opportunistic infections by Pseudomonas aeruginosa and the innate immunity impairment. We demonstrate through ex vivo and in vivo experiments that the pathway is inadequately activated in ΔF condition and the use of direct STING agonists, as 2',3'-cyclic GMP-AMP (2', 3' cGAMP), is able to restore the immune response against bacterial colonization. Indeed, upon treatment with the STING pathway agonists, we found a reduction of colony forming units (CFUs) consequent to IFN-β enhanced production in Pseudomonas aeruginosa infected bone marrow derived macrophages and lung tissues from mice affected by Cystic Fibrosis. Importantly, we also verified that the impairment detected in the primary PBMCs obtained from ΔF patients can be corrected by 2', 3' cGAMP. Our work indicates that the cGAS/STING pathway integrity is crucial in the Cystic Fibrosis response against pathogens and that the restoration of the pathway by 2', 3' cGAMP could be exploited as a possible new target for the symptomatic treatment of the disease.

Melatonin as an immunomodulator in combined therapy of herpesvirus skin diseases associated with HIV

Introduction. Highly active antiretroviral therapy is the current standard of care for patients with HIV/AIDS. Although antiretroviral therapy is etiotropic, quite effective in reducing viral load, recurrent opportunistic infections can lead to adverse effects in the management of such patients, and side effects may limit its effectiveness. Among opportunistic infections, a large group are herpesvirus infections, they are frequent manifestations of dermatological manifestations of HIV, which can sometimes lead to death. Melatonin (N-acetyl-5-methoxytryptamine) was thought to be of purely epiphyseal origin, but recent studies have shown that melatonin synthesis can occur in some other cells and organs of the human body. In addition, it was found that melatonin regulates circadian rhythms, has a number of important functions and areas of influence. Studying its structure and action, researches over the past decade have shown that melatonin enhances the immune response of T-helpers, stimulates the production of cytokines, has antioxidant properties. Due to these effects, and possibly other mechanisms yet to be determined, melatonin has been shown to reduce drug toxicity and have immunomodulatory effects. Objective: to study the effectiveness of melatonin as an immunomodulatory agent in herpesvirus skin diseases associated with HIV as part of combined therapy. Objectives of the study: to determine serum levels of CD4 + cells and to investigate changes in immunogram parameters in patients with herpesvirus infection associated with HIV before and after melatonin therapy and to compare them with the levels of the control group. Materials and methods. In the current study, HIV patients who had an acute herpesvirus infection caused by HSV-1, HSV-2, VZV, EBV, and HHV-8 were selected. Patients were divided into two groups: group I consisted of patients receiving antiretroviral therapy, valaciclovir in standard therapeutic doses and melatonin as immunomodulatory therapy, once daily, in the evening at a dose of 3 mg. Group II included patients who received antiretroviral therapy alone in combination with valaciclovir. Clinical and laboratory evaluation was performed before and after 30 days of therapeutic intervention. Patients were asked to report any complications. Results. The study involved forty HIV patients who had an exacerbation of herpesvirus infection; the levels of CD4 + cells averaged 311 ± 128. All patients received antiretroviral therapy for at least five years with a mean infection period of 10 years. The age of patients ranged from 32 to 60 years with a mean of 41.4 ± 17.2 years. After treatment, CD4 + cells were significantly higher in group I subjects receiving antiretroviral therapy in combination with valaciclovir and melatonin than in control subjects wo not receiving melatonin after one month of treatment. The level of CD4 + cells was 37 % higher in patients taking melatonin compared with the control group (p < 0.05). The current study showed that 60% of patients (12/20) had positive changes in the parameters of the immunogram (p < 0.05). Significant differences between groups, which were statistically validity in levels of CD4 + cells and immunogram parameters, indicate that melatonin had a positive effect on the state of the immune system. Conclusion. Our study has proven the beneficial effect of melatonin on the state of the immune system in patients herpesvirus skin diseases associated with HIV. Given the low toxicity of melatonin and its ability to reduce side effects and increase the effectiveness of therapeutic agents, its use may be important and significant in combination therapy in combination with highly active antiretroviral therapy.

Variable clinical characteristics and laboratory results in five patients with Chinese Good's syndrome (thymoma and hypogammaglobulinemia): an 8-year retrospective analysis in a university hospital in China

BackgroundGood's syndrome (GS) is a rare secondary immunodeficiency disease presenting as thymoma and hypogammaglobulinemia. Due to its rarity, the diagnosis of GS is often missed.MethodsWe used the hospital information system to retrospectively screen thymoma and hypogammaglobulinemia patients at the First Affiliated Hospital of Wenzhou Medical University from Apr 2012 to Apr 2020. The clinical, laboratory, treatment, and outcome data for these patients were collected and analyzed.ResultsAmong the 181 screened thymoma patients, 5 thymoma patients with hypogammaglobulinemia were identified; 3 patients had confirmed diagnoses of GS, and the other 2 did not have a diagnosis of GS recorded in the hospital information system. A retrospective review of the clinical characteristics, laboratory results, and follow-up data for these 2 undiagnosed patients confirmed the diagnosis of GS. All 5 GS patients presented with pneumonia, 2 patients presented with recurrent skin abscesses, 2 patients presented with recurrent cough and expectoration, 1 patient presented with recurrent oral lichen planus and diarrhea, and 1 patient presented with tuberculosis and granulomatous epididymitis. In the years after the diagnosis of hypogammaglobulinemia with mild symptoms, all 5 patients had received irregular intravenous immunoglobulin (IVIG) treatment. As the course of the disease progressed, the clinical symptoms of all patients worsened, but the symptoms were partly resolved with IVIG in these patients. However, 4 patients died due to comorbidities.ConclusionGS should be investigated as a possible diagnosis in thymoma patients who present with hypogammaglobulinemia, especially those with recurrent opportunistic infections, recurrent skin abscesses, chronic diarrhea, or recurrent lichen planus.

FUNGAL NEUROLOGICAL SEQUELAE IN A HYPER IMMUNOGLOBULIN E SYNDROME FROM PESHAWAR, PAKISTAN: AN UNUSUAL PRESENTATION

Hyper IGE syndrome is one of the primary immunodeficiency syndromes characterized by the presence of abnormally raised serum IGE levels (2000 IU/ml) with defective humoral and cell mediated immunity presenting in infancy or early childhood. It is a rare disease with only about 200 cases reported in literature. Usually, it is diagnosed clinically and by raised serum IGE levels. Mostly, it presents with recurrent staphylococcal skin abscesses, sinopulmonary infections, and opportunistic mycotic infections due to the immunodeficient state. Rarely, the central nervous system is involved by this condition.This case study deals with an 11-year-old girl who was diagnosed as a case of hyper IGE syndrome. She presented with low GCS and focal neurological deficits which were attributed to aspergillus fumigatus infection spreading to the brain resulting in multiple abscesses and eventually to death of the patient despite treatment interventions. This case emphasizes the likelihood of dissemination of fungal infections to multiple organs including the brain and the potential role of early neuroimaging to detect such lesions. Moreover, it shows significance of serial imaging in admitted patients particularly with the onset of new and unusual neurological symptoms. With more extensive studies, we may be able to diagnose and treat such infections and their complications on time with better outcomes.

HLA-mismatched allogeneic adoptive immune therapy in severely immunosuppressed AIDS patients

Severely immunosuppressed AIDS patients with recurrent opportunistic infections (OIs) represent an unmet medical need even in the era of antiretroviral therapy (ART). Here we report the development of a human leukocyte antigen (HLA)-mismatched allogeneic adaptive immune therapy (AAIT) for severely immunosuppressed AIDS patients. Twelve severely immunosuppressed AIDS patients with severe OIs were enrolled in this single-arm study. Qualified donors received subcutaneous recombinant granulocyte-colony-stimulating factor twice daily for 4–5 days to stimulate hematopoiesis. Peripheral blood mononuclear cells were collected from these donors via leukapheresis and transfused into the coupled patients. Clinical, immunological, and virological parameters were monitored during a 12-month follow-up period. We found AAIT combined with ART was safe and well-tolerated at the examined doses and transfusion regimen in all 12 patients. Improvements in clinical symptoms were evident throughout the study period. All patients exhibited a steady increase of peripheral CD4+ T cells from a median 10.5 to 207.5 cells/μl. Rapid increase in peripheral CD8+ T-cell count from a median 416.5 to 1206.5 cells/μl was found in the first 90 days since initiation of AAIT. In addition, their inflammatory cytokine levels and HIV RNA viral load decreased. A short-term microchimerism with donor cells was found. There were no adverse events associated with graft-versus-host disease throughout the study period. Overall, AAIT treatment was safe, and might help severely immunosuppressed AIDS patients to achieve a better immune restoration. A further clinical trial with control is necessary to confirm the efficacy of AAIT medication.

M265 NOVEL RAG1 MUTATION IN A CASE OF SCID WITH A NORMAL TREC NEWBORN SCREEN

Severe Combined Immunodeficiency (SCID) is a rare group of disorders characterized by severe defects in T-cell and B-cell development and function. Clinical features of SCID include recurrent and severe opportunistic infections within the first year of life. SCID is fatal without treatment, such as hematopoietic stem cell transplantation, and early diagnosis improves survival outcomes. Newborn screening (NBS) using the T-cell receptor excision circle (TREC) assay has dramatically improved early identification of SCID. We describe the case of an infant with a normal NBS found to have T-B-NK+ SCID due to a novel RAG1 mutation.

Hematopoietic stem cell transplantation in CD40 ligand deficiency: A single-center experience.

Deficiency of the CD40L, expressed on the surface of T lymphocytes, is caused by mutations in the glycoprotein CD40L (CD154) gene. Resulting defective humoral and cellular responses cause a clinical presentation that includes recurrent sinopulmonary bacterial infections, opportunistic infections, sclerosing cholangitis, neutropenia, and autoimmune manifestations. HSCT represents the only curative treatment modality. However, the therapeutic decision to use HSCT proves challenging in many cases, mainly due to the lack of a phenotype-genotype correlation. We retrospectively reviewedpatients with CD40L deficiency who were transplanted in Antalya and Göztepe MedicalPark Pediatric HSCT units from 2014 to 2019 and followed by Akdeniz University School of Medicine Department of Pediatric Immunology. The records of eight male cases, including one set of twins, were evaluated retrospectively. As two transplants each were performed on the twins, a total of ten transplants were evaluated. Conditioning regimens were predominantly based on myeloablative protocols, except for the twins, who received a non-myeloablative regimen for their first transplantation. Median neutrophil and platelet engraftment days were 13 (range 10-19) and 14 (range 10-42) days, respectively. In seven of ten transplants, a CMV reactivation was developed without morbidity. None of the patients developed GVHD, except for one mild case of acute GVHD. All patients survived, and the median follow-up was 852days. Our data show that HSCT for patients with CD40 ligand deficiency is a potentially effective treatment for long-term disease control.

Novel CD40LG Mutation in Two Cousins With Immunoglobulin Class Switch Recombinant Deficiency

The hyper-immunoglobulin M (HIGM) syndrome comprises a group of rare inherited immunodeficiency disorders characterized by normal or elevated levels of serum IgM with low or absent levels of serum IgG, IgA, and IgE. Patients with this syndrome usually present with a history of recurrent infections or opportunistic infections. Here, we report two male cousins from homozygote twin mothers. The first cousin presented with no signs or symptoms other than neutropenia, which was accidentally found in a routine blood test. Immunological workup in this patient showed undetectable IgG and IgA levels and normal IgM levels. The second cousin had a history of recurrent infections, and at the time of admission, he was diagnosed with Pneumocystis jirovecii infection. The immunologic workup of this patient showed undetectable IgG, decreased IgA, and increased IgM level. Due to their interesting family relationship, genetic analysis was performed, which detected a novel mutation in exon 2 (c.266 del G) of the CD40 ligand gene (CD40LG).

Dietary Micronutrients and Gender, Body Mass Index and Viral Suppression Among HIV-Infected Patients in Kampala, Uganda.

Background:HIV/AIDS is a hallmark of immune suppression. Micronutrient deficiencies in diet and recurrent opportunistic infections play major roles in the lives of people living with HIV. Although benefits of providing adequate diet to HIV positive persons are well documented, the demand for key elements still remain unclear in particular settings, especially in low and middle-income countries.Methods:This was a cross sectional analysis of baseline data collected from HIV-infected adults initiating antiretroviral therapy, and who were enrolled in a multivitamin supplementation trial. A food frequency questionnaire was used and intake were obtained as a product of quantities consumed. Adequacy was calculated as the proportion of Recommended Dietary Allowances (RDA). A chi square test and logistic regression analysis were used at p-value 0.05 to show significant associations.Results:Mean intakes were above minimum requirements for analyzed micronutrients with the exception of Calcium and Iron. Participants who met RDA intakes were as follows: highest (≥ 80%) for Magnesium, Selenium, Zinc and Vitamins B2, B6, B9, C and E; moderate (50% to <80%) for Vitamins B3, and A; and lowest (≤50%) for Iron (30%), Calcium (14.9%), Vitamins B12 and B1. Gender differences in met RDA were observed for Iron, Selenium, Zinc, Vitamins A, B1, B3 and E. In multivariable analyses, nutritional status and CD4 count had no influence on meeting RDA for majority of micronutrients such as magnesium, Selenium, B class vitamins (B1, B2, B3, B6, B9, B12), vitamin (A, C, and E), Zinc and Calcium, but not including iron.Conclusion and Global Health Implications:Diets consumed by the study participants were low in most protective nutrients (Iron, Calcium, Zinc, Vitamin A, B1, B3, and B12). This deficiency was more common among females than males, and irrespective of BMI or CD 4 count. Findings warrant further investigation on the impact and cost implications for suplementation interventions that target the elements lacking in the diets of people living with HIV in similar low-resourced settings.

Good's syndrome, a rare form of acquired immunodeficiency associated with thymomas.

Good’s syndrome (GS) or thymomaassociated immunodeficiency is a rare clinical entity that should be ruled out in patients with thymoma who develop severe, recurrent bacterial infections and opportunistic viral and fungal infections. There are no treatment protocols established, hence, early recognition is imperative to avoid complications. We report the case of a 42-year-old female, known for a previous thymectomy for giant thymoma who has suffered for a long time from recurrent pulmonary and urinary tract infections and cold sores. In March 2016 she referred to our unit complaining of fever, cough, chest pain, and cold sores due to Herpes simplex virus (HSV), confirmed serologically as HSV-1. Chest X-ray showed left pneumonia due to Streptococcus pneumoniae. She started antibiotics (amoxicillin/clavulanic acid associated with azithromycin) with gradual improvement. Given her history she was studied for an underlying immunodeficiency: IgG, IgA, and IgM were significantly low or absent, as well as all IgG subclasses; blood and bone marrow aspirate leucocyte immunophenotyping showed complete absence of B lymphocytes and reduced CD4+ T cells. In light of: i) thymoma; ii) B lymphocyte deficit; iii) hypogammaglobulinemia; iv) recurrent infections, GS was diagnosed and pre-emptive immunoglobulin treatment, associated with HSV and Pneumocystis jiroveci prophylaxis (Acyclovir for HSV and Sulfamethoxazole- Trimethoprim for P. jiroveci) were started. Since then the patient has no longer presented any infectious episodes.

Primary immunodeficiencies and hematological malignancies

Primary immunodeficiency disease (PID) is characterized by an impaired immune system along with recurrent and severe and/or opportunistic infections; these infections are frequently associated with malignancies and autoimmune disorders. Dysregulation of the adaptive immune system leads to an increased risk of malignancies. Various mechanisms contribute to increased tumor susceptibility in patients with PIDs, which are as follows: defective cell-mediated tumor surveillance, defective apoptosis, specific susceptibility to carcinogens, decreased pathogen clearance and over-active inflammatory responses, defects in cytokinesis, impaired control of virus-infected cells, defects in cell cycle control, and impaired cellular response to genotoxic agents. Moreover, some malignancies might arise owing to germline mutations in PID-causative genes. Here, we describe the close association between PIDs and malignancies, particularly hematopoietic malignancies.

Hairy Cell Leukemia, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology.

Hairy cell leukemia (HCL) is a rare type of indolent B-cell leukemia, characterized by symptoms of fatigue and weakness, organomegaly, pancytopenia, and recurrent opportunistic infections. Classic HCL should be considered a distinct clinical entity separate from HCLvariant (HCLv), which is associated with a more aggressive disease course and may not respond to standard HCL therapies. Somatic hypermutation in the IGHV gene is present in most patients with HCL. The BRAF V600E mutation has been reported in most patients with classic HCL but not in those with other B-cell leukemias or lymphomas. Therefore, it is necessary to distinguish HCLv from classic HCL. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of classic HCL.