Acquired Immunodeficiency Disorders Research Articles

Gastrointestinal Manifestations of Immunodeficiency: Imaging Spectrum.

There is a wide spectrum of hereditary and acquired immunodeficiency disorders that are characterized by specific abnormalities involving a plethora of humoral, cellular, and phagocytic immunologic pathways. These include distinctive primary immunodeficiency syndromes due to characteristic genetic defects and secondary immunodeficiency syndromes, such as AIDS from HIV infection and therapy-related immunosuppression in patients with cancers or a solid organ or stem cell transplant. The gut mucosa and gut-associated lymphoid tissue (the largest lymphoid organ in the body), along with diverse commensal microbiota, play complex and critical roles in development and modulation of the immune system. Thus, myriad gastrointestinal (GI) symptoms are common in immunocompromised patients and may be due to inflammatory conditions (graft versus host disease, neutropenic enterocolitis, or HIV-related proctocolitis), opportunistic infections (viral, bacterial, fungal, or protozoal), or malignancies (Kaposi sarcoma, lymphoma, posttransplant lymphoproliferative disorder, or anal cancer). GI tract involvement in immunodeficient patients contributes to significant morbidity and mortality. Along with endoscopy and histopathologic evaluation, imaging plays an integral role in detection, localization, characterization, and distinction of GI tract manifestations of various immunodeficiency syndromes and their complications. Select disorders demonstrate characteristic findings at fluoroscopy, CT, US, and MRI that permit timely and accurate diagnosis. While neutropenic enterocolitis affects the terminal ileum and right colon and occurs in patients receiving chemotherapy for hematologic malignancies, Kaposi sarcoma commonly manifests as bull's-eye lesions in the stomach and duodenum. Imaging is invaluable in treatment follow-up and long-term surveillance as well. Online supplemental material is available for this article. ©RSNA, 2022.

STAT Immunodeficiency Disorders and Fungal Infection Susceptibility

Invasive fungal diseases (IFD) or complicated mucocutaneous fungal infections can occur secondary to both primary and acquired immunodeficiency disorders. The signal transducer and activator of transcription (STAT) proteins are critical transcription factors involved in a wide range of processes including the immune response. This review highlights the immune pathways, clinical phenotypes and current management options of fungal infections in patient with mutations in STAT1 and STAT3, the most relevant STAT molecules involved in the host response to fungal pathogens. STAT1 gain of function (GOF) and STAT3 loss of function (LOF) (cause of autosomal dominant Hyper IgE syndrome) mutations have been associated with both chronic mucocutaneous candidiasis (CMC) and invasive fungal infections, not only inhaled moulds, mostly Aspergillus spp., but also Pneumocystis, Cryptococcus and other endemic dimorphic fungi. Significant progress has been made in the insights into the immunopathogenesis of fungal infections in these patients; nevertheless, the concrete mechanisms involved are still not fully elucidated. Early initiation of antifungal therapy followed by long-term secondary prophylaxis is normally required. Some adjunctive therapies have also been employed, although their use has not been completely established. Besides a developing knowledge in STAT1 GOF and STAT3 LOF mutations, additional research is needed. It should aim for a better understanding of the pathogenesis, diagnosis, and management of fungal infections in these patients. The identification of new therapeutic targets should help to improve patient quality of life and outcomes.

Reference values of lymphocyte sub-populations in healthy human immunodeficiency virus-negative Iranian adults.

Lymphocyte subsets enumeration is considered prominent in the management of primary and acquired immunodeficiency disorders. Because of local variations due to race, age, gender, and environmental conditions on lymphocyte subsets, and to improve the accuracy of interpretation of laboratory findings, reference intervals must be determined in every population. To establish a normal reference range for CD3+, CD4+, CD8+, CD19+ and CD56+ lymphocytes in a healthy Iranian adult population using flowcytometry. Blood samples were collected from 221 HIV seronegative individuals, including 112 females and 109 males, with ages ranging from 20 to 40 years old. The percentage of lymphocytes expressing either of CD3, CD4, CD8, CD19 and CD56 surface markers were determined by flowcytometry assay. Total mean percentage and absolute count of lymphocyte subsets were as follows: CD3+: 70.90 ± 7.54%, 1800.87 ± 471.09 cells/µl; CD4+: 41.04 ± 7.86%, 1039.99 ± 338.02 cells/µl; CD8+: 31.11 ± 6.60%, 783.95 ± 234.87 cells/µl; CD19+: 12.77 ± 4.56%, 328.37 ± 153.17 cells/µl; CD56+: 15.53 ± 6.34%, 388.62 ± 176.17 cells/µl, respectively. The ratio of CD4+/CD8+ lymphocytes for the studied population was 1.39 ± 0.48. Significant differences were observed between male and female subjects indicating that the average percentage of CD3+ cells (p=0.017) and CD4+ T cells (p=0.003) were higher in the female population, whereas the average percentage of CD19+ cells (p=0.02) tended to be higher among males. However, investigations on the CD56+ NK cell and CD8+ T cell sub-populations did not show any statistical differences between the two genders. In comparison with reports of other populations, we were confronted with different results. Establishing reference values of lymphocyte subsets for each population is helpful in achieving standard criteria for the prognosis of HIV infection. Therefore, normal ranges established by this survey can be used as a reference for decisions made in clinical practice.

Use of intravenous immunoglobulin to treat chronic bilateral otomastoiditis in the setting of rituximab induced hypogammaglobulinemia

The temporal bone may be affected by a variety of systemic pathology because the disease nature, location, and extent determine the symptoms. Middle ear and mastoid infections may be the initial clinical manifestation of autoimmune and acquired immunodeficiency disorders. Rituximab, an anti-CD20 chimeric antibody, has become increasingly popular as a therapeutic agent for patients with a wide range of autoimmune disorders refractory to standard treatments. Normal levels of immunoglobulin levels are usually maintained during and after rituximab therapy, and clinical trials to date have shown no statistically significant increase of serious infections among patients with autoimmune diseases being treated with rituximab (Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, et al, for the REFLEX Trial Group. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at 24 weeks. Arthritis Rheum. 2006;54:2793-2806. Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, et al. Efficacy of B-cell–targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004;350:2572-2581). However, there have been several reports of opportunistic infections associated with rituximab (Kelesidis T, Daikos G, et al. Does rituximab increase the incidence of infectious complications? A narrative review. Int J Infect Dis 2011;15:e2-e16. Teichmann LL, Woenckhaus M, Vogel C, et al. Fatal Pneumocystis pneumonia following rituximab administration for rheumatoid arthritis. Rheumatology 2008;47:1256-1257), as well as cases of it accelerating the presentation of hypogammaglobulinemia (Diwakar L, Gorrie S, et al. Does rituximab aggravate pre-existing hypogammaglobulinaemia? J Clin Pathol 2010;63:275-277). Humoral immune defects can cause persistent acute and serous otitis media, with the development of chronic suppurative otitis media refractory to medical and surgical therapy (Sasaki CT, Askenase P, Dwyer J, et al. Chronic ear infection in the immunodeficient patient. Arch Otolaryngol 1981;107:82). Here, we describe the first presentation, diagnostic workup, and treatment with intravenous immunoglobulin of chronic bilateral otomastoiditis in the setting of rituximab-induced hypogammaglobulinemia.

Innate and adaptive immune responses against Staphylococcus aureus skin infections

Staphylococcus aureus is an important human pathogen that is responsible for the vast majority of bacterial skin and soft tissue infections in humans. S. aureus can also become more invasive and cause life-threatening infections such as bacteremia, pneumonia, abscesses of various organs, meningitis, osteomyelitis, endocarditis, and sepsis. These infections represent a major public health threat due to the enormous numbers of these infections and the widespread emergence of methicillin-resistant S. aureus (MRSA) strains. MSRA is endemic in hospitals worldwide and is rapidly spreading throughout the normal human population in the community. The increasing frequency of MRSA infections has complicated treatment as these strains are more virulent and are increasingly becoming resistant to multiple different classes of antibiotics. The important role of the immune response against S. aureus infections cannot be overemphasized as humans with certain genetic and acquired immunodeficiency disorders are at an increased risk for infection. Understanding the cutaneous immune responses against S. aureus is essential as most of these infections occur or originate from a site of infection or colonization of the skin and mucosa. This review will summarize the innate immune responses against S. aureus skin infections, including antimicrobial peptides that have direct antimicrobial activity against S. aureus as well as pattern recognition receptors and proinflammatory cytokines that promote neutrophil abscess formation in the skin, which is required for bacterial clearance. Finally, we will discuss the recent discoveries involving IL-17-mediated responses, which provide a key link between cutaneous innate and adaptive immune responses against S. aureus skin infections.

Indeterminate Results of QuantiFERON-TB Gold In-Tube Assay in Nonimmunosuppressed Children

QuantiFERON-TB Gold In-Tube (QFT-IT) assay is a highly sensitive and specific test for the diagnosis of latent tuberculosis infection. Data on the use of QFT-IT assay in children are scarce and contradictory. The aim of the study was to assess the rate of indeterminate test results and to identify factors contributing to indeterminate results on routine use of QFT-IT assay in nonimmunosuppressed children. This retrospective study included 2173 children with ages ranging from 1 month to 18 years. Determination of interferon-gamma (IFN-γ) in peripheral blood was performed by commercial QFT-IT assay. Indeterminate test results were recorded in ten (0.46%) subjects with ages ranging from 15 months to 15 years. The value of negative control was >8.0 kIU/L in one subject, whereas in the remaining nine subjects indeterminate results were consequential to positive control (<0.50 kIU/L). None of these subjects had any history data on congenital or acquired immunodeficiency disorders. Bacterial infection (with elevated body temperature and therapy with β-lactam antibiotics) was present in eight subjects with indeterminate results, one subject had exacerbation of asthma (therapy with inhalation corticosteroids), and one subject was clinically healthy. Repeat IFN-γ determination performed in seven subjects did not yield indeterminate results. Study results showed the rate of indeterminate QFT-IT results in nonimmunosuppressed children of all age groups to be very low. QFT-IT should preferably be performed upon resolution of acute inflammation in order to avoid repeat testing of indeterminate results in a new blood sample and to reduce the cost of testing.

You Can Make a Difference in the Administration of Intravenous Immunoglobulin Therapy

Intravenous immunoglobulin is a preparation of immune globulins containing antibodies given intravenously to patients with both inherited and acquired immunodeficiency disorders, such as primary immune deficiency diseases, idiopathic thrombocytopenia purpura, chronic lymphocytic leukemia, and bone marrow transplantation. This article discusses immune globulin products, routes of administration, and the role of the infusion nurse in the administration of intravenous immunoglobulin to the patient.

The use of archived tissue — an analysis of juridical and ethical pitfalls

The temporal bone may be affected by a variety of systemic pathology because the disease nature, location, and extent determine the symptoms. Middle ear and mastoid infections may be the initial clinical manifestation of autoimmune and acquired immunodeficiency disorders. Rituximab, an anti-CD20 chimeric antibody, has become increasingly popular as a therapeutic agent for patients with a wide range of autoimmune disorders refractory to standard treatments. Normal levels of immunoglobulin levels are usually maintained during and after rituximab therapy, and clinical trials to date have shown no statistically significant increase of serious infections among patients with autoimmune diseases being treated with rituximab (Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, et al, for the REFLEX Trial Group. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at 24 weeks. Arthritis Rheum. 2006;54:2793-2806. Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, et al. Efficacy of B-cell–targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004;350:2572-2581). However, there have been several reports of opportunistic infections associated with rituximab (Kelesidis T, Daikos G, et al. Does rituximab increase the incidence of infectious complications? A narrative review. Int J Infect Dis 2011;15:e2-e16. Teichmann LL, Woenckhaus M, Vogel C, et al. Fatal Pneumocystis pneumonia following rituximab administration for rheumatoid arthritis. Rheumatology 2008;47:1256-1257), as well as cases of it accelerating the presentation of hypogammaglobulinemia (Diwakar L, Gorrie S, et al. Does rituximab aggravate pre-existing hypogammaglobulinaemia? J Clin Pathol 2010;63:275-277). Humoral immune defects can cause persistent acute and serous otitis media, with the development of chronic suppurative otitis media refractory to medical and surgical therapy (Sasaki CT, Askenase P, Dwyer J, et al. Chronic ear infection in the immunodeficient patient. Arch Otolaryngol 1981;107:82). Here, we describe the first presentation, diagnostic workup, and treatment with intravenous immunoglobulin of chronic bilateral otomastoiditis in the setting of rituximab-induced hypogammaglobulinemia.

Ophthalmic manifestations of immunodeficiency states.

The eye is a common site for the manifestation of systemic disease. Although the eye may only be a small component of the disease process, it frequently manifests important signs and clues that help in making an accurate diagnosis. Over the past several years, primary and acquired immunodeficiency disorders have gained increasing importance and public awareness, especially with the prominence of the HIV epidemic. Although these conditions as a group are not uncommonly seen, many of them manifest specific ophthalmic pathology. In this chapter, selected primary immunodeficiency conditions are reviewed, with emphasis on their associated ophthalmic findings. Specific disorders to be discussed include ataxia-telangiectasia (A-T), Wiskott-Aldrich syndrome (WAS), chronic mucocutaneous candidiasis (CMC), chronic granulomatous disease (CGD), Chediak-Higashi syndrome (CHS), complement disorders, and acquired immunodeficiency disorders (AIDS).

Hodgkin's disease in the setting of human immunodeficiency virus infection.

Although Hodgkin's disease (HD) is not usually associated with congenital or acquired immunodeficiency disorders, recent evidence would suggest a statistically significant increase in HD among individuals infected with human immunodeficiency virus (HIV). In the setting of underlying HIV infection, clinical and pathologic characteristics of HD may differ from usual expectations. Thus, 70%-100% of HIV-infected patients with HD present with systemic "B" symptoms. Likewise, disseminated, stage III or IV disease is reported in approximately 75%-90%. Bone marrow is a common site of extranodal HD, occurring in 40%-50%. Complete response rates after multiagent chemotherapy range from approximately 45% to 70%, although median survival has been only in the range of approximately 18 months. Hematologic toxicity from multiagent chemotherapy may be substantial, even with the use of hematopoietic growth factor support. It is apparent that new strategies of therapeutic intervention must be explored.

What's New in Malignant Tumors in Acquired Immunodeficiency Disorders?

An increased incidence of malignant tumors has long been recognized in patients with primary immune defects such as the X-linked lympho-proliferative syndrome or the Wiskott Aldrich syndrome and has recently become a major concern also in cases with acquired immunodeficiency. The latter may be induced by cytostatic therapy for cancer, extended immunosuppression following organ transplantation or HIV infection. The spectrum of secondary cancers is, however, different within these three groups of secondary immune defects with acute myeloid leukemia being the most common malignant disease after cytostatic therapy, with skin or lip cancer followed by non-Hodgkin's lymphoma as the prevalent malignancies after organ transplantations and Kaposi sarcoma and non-Hodgkin's lymphoma as the predominant cancers associated with HIV infection. The pathogenesis of Kaposi sarcoma and non-Hodgkin's lymphoma is possibly related to viral infections by cytomegalovirus and Epstein-Barr virus inducing an increased proliferation and possibly the coactivation of transforming genes of oncogenic potential. In AIDS patients Kaposi sarcoma is diagnosed in up to 40% of homosexual men while the other risk groups are less frequently involved. 4-10% of HIV infected patients experience non Hodgkin's lymphoma predominantly of B-cell type and intermediate or high grade malignancy with frequent extranodal manifestations. Other types of tumors occur at a substantially lower frequency and are not clearly related to the HIV infection. The overall survival of patients suffering from malignant tumors in the state of immunodeficiency is poor and the possibilities for therapeutic intervention are limited by the risk of accelerating the pre-existing suppression of defense mechanisms.

Serologic and molecular diagnosis of epstein-barr virus infections

Epstein-Barr virus (EBV), a member of the herpesvirus group, was isolated from cultured Burkitt's lymphoma (BL) cell lines in 1964 (2). EBV is a ubiquitous virus that may be the most widely disseminated human virus, affecting more than 95% of the world population. Additionally, EBV is the causative agent of infectious mononucleosis (IM) and is associated with certain human malignancies, such as BL and nasopharyngeal carcinoma (NPC) (1, 2, 6-8). EBV-associated lymphoproliferative lesions also occur in both primary and acquired immunodeficiency disorders (6-8). Chronic active EBV infection is another category of EBV-related disorders, which recently has been described in persons without clearly defined underlying disease (6, 7). Significant differences prevail in the prevalence and age-specific incidence of primary infection in persons among geographic areas and socioeconomic groups in any given country (1). Most primary EBV infections, transmitted through saliva, occur during childhood in Africa, Asia, and developing countries, and result in a subclinical infection (1, 6, 8). In contrast, persons residing in North America, Europe, and most other developed countries are frequently seronegative for EBV antibodies until adolescence, and two-thirds of newly seroconverted persons of this age group manifest with IM (1, 6, 8). In vitro, EBV infects B lymphocytes of humans and some primates, and lifelong latency develops (2, 6, 8). Defenses against EBV infection include mucus, epithelial barriers, interferon, neutralizing antibodies, EBV-specific and non-EBV-specific activation of cytotoxic T cells, and antibody-dependent cell-mediated cytotoxicity (6, 8). The clinical and pathophysiological manifestations of the infection are chiefly due to the enlargement of lymphoid tissues caused by the proliferation of infected B cells and reactive T cells (6, 8). Also cellular infiltration of liver, brain, bone marrow, and other organs can induce lesions and dysfunction. Herein, we describe our approach to serologic and molecular studies to document EBV infection.

Primary and acquired immunodeficiency disorders

Primary and acquired immunodeficiency disorders

Immunodeficiency: Immunoregulation and immunogenetics

During the past decade, our knowledge of normal immunologic development and function as well as disorders that lead to immunodeficiency has expanded rapidly as a result of the interplay between studies of the immune system in animals and studies of patients with immunodeficiency diseases or with malignancies of the cells of the lymphoid system. The study of immunodeficiency diseases has been particularly valuable in defining the critical stages in the differentiation of stem cells into mature lymphoid effector cells and the roles played by different subpopulations of cells in regulating the immune response. Our understanding of the immunodeficiency diseases has been facilitated by a number of important advances: (a) The identification of distinct surface determinants on lymphoid cells has led to improved procedures for the isolation of defined lymphoid cell subpopulations; (b) the demonstration that both T- and B-cell populations encompass subpopulations of lymphocytes with different and at times opposing functions; (c) the development of in vitro techniques to assess the functional behavior of isolated lymphoid subpopulations; and (d) the isolation and characterization of genes encoding immunoglobulin molecules and the antigen-specific T-cell receptor, thus defining at a molecular level the mechanisms leading to antibody diversity and to the organization of a recognition unit on T lymphocytes. These advances have not only been important for our understanding of the pathogenesis of immunodeficiency in patients with congenital and acquired immunodeficiency disorders, but have also provided the scientific basis for more rational approaches to the diagnosis and therapy of these disorders. This report will review (a) the defects in cellular maturation, cellular interaction, and cellular biosynthesis that have been observed in patients with immunodeficiency diseases; (b) the immunoglobulin gene rearrangements that are involved in the generation of antibody diversity; (c) the structure and genetic basis for the generation of antigen-specific T-cell receptors; and (d) potential future applications of molecular genetic approaches to the definition of the pathogenesis and to the treatment of immunodeficiency diseases.

Resistance to herpes simplex virus - type 1 (HSV-1).

In man herpes simplex virus-type 1 (HSV-1) has been shown to be the cause of several clinically important infections, including primary gingivostomatitis, herpes keratitis, and encephalitis (Nahmias and Roizman 1973; Rawls 1973). Clinically apparent as well as inapparent infections with HSV-1 have the capacity to become latent, i.e., the virus remains dormant in neurons but can become reactivated and cause an infection at a later date (Stevens 1975). Although the mechanism(s) involved in the establishment and maintenance of latency or in the subsequent reactivation of HSV-1 are not well understood, immunosuppression does not appear to be the trigger responsible for inducing the virus to reappear (Spencer and Andersen 1970; Price and Schmitz 1978). However, HSV-1 infections have been found to be especially problematic for those afflicted with congenital or acquired immunodeficiency disorders (St. Geme et al. 1965; Aston et al. 1972; Lopez and Simmons 1977). Thus, although the incidence of reactivated HSV-1 infections is not increased with immunosuppression, clearly the severity of reactivated infections is markedly exaggerated. These observations in man as well as a number of earlier animal studies (for example, Nahmias et al. 1969) have been taken as evidence that the immune response and especially the cell-mediated immune (CMI) system plays a primary role in resistance to these infections. Because of the complex nature of the pathogenesis of HSV-1 infections, resistance probably depends on several interacting subpopulations of cells (Allison 1914). The definition of these cells, their interactions, and their relative contributions will be important to future studies aimed at augmenting resistance to HSV-1.