Immunologic Deficiencies

Immunologic Deficiencies
Joanna Kołodziejczyk Department of Allergology, Clinical Immunology and Internal Diseases

Evaluation of the immunodeficient patient
Immunodeficiency diseases can present with symptoms of susceptibility to infection but may also involve allergy, autoimmune disease or lymphoproliferation. There are over 120 primary immunodeficiency diseases (PIDs) and they can affect any aspect of the immune response. PIDS are generally hereditary and congenital deficiencies of the immune system. In contrast, secondary immunodeficiencies can present at any time, in that they are acquired disruptions in immune function that increase susceptibility to infection. Examples include severe combined immune deficiencies, DiGeorge syndrome, and chronic granulomatous disease, which are usually diagnosed in infants and young children. However, common variable immunodeficiency (CVID), an immunodeficiency of impaired antibody production that has an incidence between 1: and 1:50 000, typically does not cause symptoms until the third decade of life.

FREQUENCY AND DIFFERENTIAL DIAGNOSIS
Features of Congenital Antibody Deficiency >> Free of infections until 7–9 months of age, when antibodies that passed through the placenta from mother to infant are below protective levels. >> Severe infections with bacterial organisms, especially with encapsulated bacteria such as Streptococcus pneumoniae. >> Growth failure is generally not seen, except in the patient who has been chronically ill with severe infection. The incidence of congenital immunodeficiencies varies from the common selective IgA deficiency (1:300–1:700) to the rare X-linked severe combined immunodeficiency (1:50 000–1: ). Chronic granulomatous disease (CGD) occurs with an incidence of 1:

Primary immunodeficiency disorders: examples and typical presentation
Disorder group Examples of specific disorders Typical presentation T-cell and combined immunodeficiency X-linked SCID (γ-chain deficiency) CD8 Lymphocytopenia (ZAP-70 deficiency) SCID–T− B+ NK+ JAK3 deficiency Adenosine deaminase deficiency Purine nucleoside phosphorylase deficiency Failure to thrive, opportunistic infection, rash Wiskott–Aldrich syndrome Thrombocytopenia with bleeding and bruising, eczema, recurrent infection with encapsulated organisms Ataxia telangiectasia Chronic sinopulmonary disease, cerebellar ataxia, malignancy, oculocutaneous telangiectasia

Disorder group Examples of specific disorders Typical presentation DiGeorge anomaly Hypocalcemic seizures due to hypoparathyroidism, cardiac disease, abnormal facies, opportunistic infection Hyper-IgM syndrome Opportunistic infections, recurrent serious pyogenic infections, cytopenias, biliary tract and liver disease Complement disorder Terminal component deficiency Neisserial infection B-cell or antibody deficiencies X-linked agammaglobulinemia IgA deficiency Common variable immunodeficiency IgG subclass deficiencies Recurrent sinopulmonary infections

Disorder group Examples of specific disorders Typical presentation Neutrophil disorders Chronic granulomatous disease Deep-seated infection, abscess especially with catalase-positive organisms Leukocyte adhesion deficiency 1 Recurrent serious bacterial infections, especially on mucosal surfaces or wound sites; poor wound healing, lack of pus Interleukin (IL)-12 deficiency IL-12 receptor (R) deficiency Interferon-γ R deficiency Susceptibility to Mycobacteria and Salmonella

Disorder group Examples of specific disorders Typical presentation Disorders of innate immunity IL-1 receptor-associated kinase 4 (IRAK) deficiency Bacterial (pyogenic) infections Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID or NEMO defect) Anhidrotic ectodermal dysplasia with specific antibody production deficiency and various infections (mycobacterial and pyogenic)

Disorder group X-linked lymphoproliferative syndrome lymphoma Typical presentation Diseases of immune dysregulation EBV-infection triggered hepatitis, aplastic anemia Autoimmune lymphoproliferative syndrome (ALPS) Defective lymphocyte apoptosis, splenomegaly, adenopathy, autoimmune cytopenias Immune dysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) Autoimmune diarrhea, diabetes, thyroiditis, hemolytic anemia, thrombocytopenia, eczema

Evaluation of immunity in a patient with recurrent infections involves a careful history and physical examination. Red flags in the history include the following: - more than eight upper respiratory tract infections per year for a child; - more than four upper respiratory tract infections per year for an adult; - more than one episode of pneumonia in the past; - one or more life-threatening infections; - infections with unusual organisms; unusual course of illness; - a family history of early infant deaths or immunodeficiency. The number of upper respiratory tract infections will depend upon exposure. The members of a family with a child in daycare would be expected to have more upper respiratory infections than members of a family with children kept at home. The outlined laboratory tests provide an adequate screen of immunity in a patient with no suspicious findings or red flags in the history or on physical examination.

Evaluation of immunity in a patient with recurrent infections

PHYSICAL EXAMINATION The physical examination supplies important clues about the etiology. Patients who are small for their age may have growth delay secondary to recurrent infections, or may have short stature associated with specific T- and B-cell immunodeficiencies. A paucity of lymphoid tissue such as tonsils and lymph nodes suggests immune deficiency and is especially seen in X-linked agammaglobulinemia. Hepatosplenomegaly and diffuse lymphadenopathy might suggest HIV infection or a disorder of immune dysregulation. Certain physical findings are suggestive of specific disorders, such as with telangiectasias over the bulbar conjunctivae, the bridge of the nose, and the ears and antecubital fossa with or without ataxia in ataxia telangiectasia; chronic eczema in hyper-IgE syndrome, IPEX, and in Wiskott–Aldrich syndrome; chronic periodontitis in chemotactic defects of the neutrophils; and silvery hair, pale skin, and photophobia in Chediak–Higashi syndrome. Children with LAD can present with severe gingivostomatitis and dental erosion as a consequence of abnormal leukocyte function

Screening Tests for Suspected Immunodeficiency
Evaluate for neutropenia, lymphopenia, thrombocytopenia, and/or small platelets with a complete blood count with differential and platelet count. >> IgG, IgA, IgM, and IgE levels. Measure of isohemagglutinin titers and of antibodies produced to vaccine antigens, such as specific antibodies to tetanus toxoid and pneumococcal polysaccharide antigens to test B-cell immune function. >> Lateral chest radiograph in infants, and delayed hypersensitivity skin tests (≥6 months of age). Consider flow cytometry to quantify T cells, T- cell subsets, B cells, and NK cells (especially in infants). >> Measurement of CH50 level. >> Flow cytometry of phagocytic oxidative burst using dihydrorhodamine.

Predominant pathogens associated with selected immunological defects
Abnormality Bacterial Fungal Viral Protozoal Neutropenia or qualitative defects of phagocytes Gram-positive Staphylocci (coagulase-positive and negative) Streptococci (enterococcus, α-hemolytic) Nocardia spp. Gram-negative Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, other Enterobacteriaceae Candida spp. Aspergillus spp Defective cell-mediated immunity Legionella spp. Salmonella spp. Mycobacteria Listeria spp Histoplasma capsulatum Coccidioides immitis Cryptococcus neoformans Candida species Pneumocystis jiroveci Cytomegalovirus Varicella-zoster virus Herpes simplex virus Epstein–Barr virus Live viral vaccines (measles, mumps, rubella, polio) Toxoplasma gondii Strongyloides stercoralis Cryptosporidia Microsporidia Isopora spp. Immunoglobulin deficiency Streptococcus pneumoniae Haemophilus influenzae Enteroviruses Giardia Complement deficiency H. influenzae Neisseria spp. Splenectomy S. pneumoniae Babesia spp.

SEVERE COMBINED IMMUNODEFICIENCY DISORDERS (SCID)
The syndromes of SCID are characterized by great diversity at the cellular, molecular, and genetic level. Regardless of the molecular defect, patients with SCID exhibit an absence of all adaptive immunity from birth. There is profound lymphopenia, hypogammaglobulinemia, and absent in vitro B- and T-lymphocyte responses to antigens and mitogens. Most patients exhibit failure to thrive and develop abnormal infections during the first months of life. These patients develop infections characteristic of defects in both humoral and cell-mediated immunity. Infections frequently seen include: bacterial pneumonia and septicemia due to Staphylococcus aureus, Streptococcus pneumoniae, and H. influenzae; P. jiroveci pneumonia, cutaneous and systemic infections with Candida; and disseminated infection with herpes group viruses.

X-LINKED AGAMMAGLOBULINEMIA
XLA, also known as Bruton agammaglobulinemia, is the prototypic humoral immunodeficiency. Function-loss mutations in BTK lead to a block in B-cell maturation, a near- total absence of B cells in the periphery, and panhypogammaglobulinemia. Due to the transplacental transfer of maternal immunoglobulin, affected boys typically do not begin to suffer recurrent pyogenic infections until after age 6 months. The normal delay in endogenous immunoglobulin production and the presence of maternal IgG require that testing of infants known or suspected to have XLA should begin with examination of the number of B cells in the blood. Deficient expression of BTK protein can be detected by flow cytometry, a technique that can also be used for carrier detection. For those cases where protein is present but the phenotype suggests XLA, analysis of the BTK gene at the nucleotide level remains the definitive diagnostic procedure.

Although patients begin to suffer recurrent infections by age 1 year, with antibiotics and good hygiene it is not uncommon to delay suspicion of the diagnosis well into mid-childhood. Indeed, diagnoses have been made in older adults, including aged male relatives of affected probands. Recurrent upper and lower respiratory tract infections are common, including otitis media, sinusitis, bronchitis, and pneumonia. Untreated, these infections may lead to bronchiectasis, pulmonary failure, and death at an early age. The infections are typically due to pyogenic encapsulated bacteria, including Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Pseudomonas species. Diarrhea due to Giardia lamblia is also common. Systemic infections include bacterial sepsis, meningitis, osteomyelitis, and septic arthritis. Mycoplasma and Chlamydia infections of the urogenital tract may lead to epididymitis, prostatitis, and urethral strictures. Skin infections include cellulitis, boils, and impetigo.

Although patients with XLA can resolve most viral infections, they are unusually sensitive to infections with enteroviruses, including echovirus, coxsackievirus, and poliovirus. Patients with XLA can develop paralytic poliomyelitis after vaccination with live virus. Echovirus and coxsackievirus infections may involve multiple organs, with the patients going on to develop chronic meningoencephalitis, dermatomyositis, and/or hepatitis. Untreated patients often complain of arthritis affecting the large joints. This appears to have an infectious etiology, because the arthritis typically resolves with immunoglobulin replacement therapy. Enterovirus and Mycoplasma have been identified in the affected joints of these patients. Infections with opportunistic organisms, such as tuberculosis, histoplasmosis and Pneumocystis jiroveci, and malignancies are rare, likely reflecting intact cell-mediated immunity. The primary goal of therapy is to prevent damage to the lungs. Human immunoglobulin replacement therapy should be started as soon as the diagnosis is made. Patients treated with quantities (0.4–0.6 g/kg every 3–4 weeks) of intravenous immunoglobulin sufficient to achieve trough levels of>500 mg/dl suffer few lower respiratory tract infections.

IGA DEFICIENCY Approximately 1 in 600 individuals of European ancestry are unable to produce detectable quantities of IgA1 and IgA2, making selective IgAD the most frequently recognized primary immunodeficiency in the Americas, Australia, and Europe. The diagnosis is dependent on the sensitivity of the laboratory measurement. The clinical laboratory typically reports serum IgA levels of less than 7 mg/dl. Patients can also suffer from recurrent infections. IgA-deficient patients rarely produce IgG or IgE anti-IgA antibodies. These uncommon patients are at risk for adverse reactions following transfusion with blood products, as mentioned previously, plasma from normal donors, or from some preparations for immunoglobulin replacement therapy which, of course, contain IgA. These patients are at risk for severe anaphylaxis

IGA DEFICIENCY IgAD patients often develop autoimmune diseases. These include juvenile rheumatoid arthritis, systemic lupus erythematosus, Addison's disease, chronic nephritis, dermatomyositis, Evans syndrome, isolated hemolytic anemia, isolated idiopathic thrombocytopenic purpura, insulin-dependent diabetes mellitus, pulmonary hemosiderosis, sarcoidosis, Sjögren's syndrome, Henoch–Schönlein syndrome or hemorrhagic purpura, and thyroiditis. Gastrointestinal disorders include celiac disease, inflammatory bowel disease, intestinal disaccharidase deficiency, lactase deficiency, pancreatic insufficiency, and pernicious anemia. Hepatobiliary disorders include chronic active hepatitis, cholelithiasis, lupoid hepatitis, and primary biliary cirrhosis. Skin disorders include pyoderma gangrenosum, perinychia, and vitiligo.

IGA DEFICIENCY IgAD is associated with an increased risk for the development of malignancies, including gastric and colonic adenocarcinoma and acute lymphoblastic leukemia. Hepatoma, lymphosarcoma, melanoma, multiple myeloma, ovarian carcinoma, squamous cell carcinoma, and malignant thymoma have also been reported. Most individuals with IgAD suffer respiratory infections no more frequently than the average individual and thus require no special treatment. All individuals with IgA deficiency should be warned of the risk of serious transfusion reactions caused by antibodies to IgA. Wearing a medical alert bracelet is recommended. Should transfusion be necessary, the ideal donors are other individuals with IgAD. Washed erythrocytes are safer than whole blood. Patients with selective IgA deficiency who suffer from clinically significant, recurrent upper respiratory infections often respond to prophylactic antibiotics. Treatment of allergy in those patients with a compensatory increase in IgE is helpful. Patients who present with combined IgA and IgG subclass deficiencies may require immunoglobulin replacement.

COMMON VARIABLE IMMUNODEFICIENCY
The diagnostic category of CVID includes a heterogeneous group of patients, mostly adults, who exhibit deficient production of all the different classes of antibodies. These patients typically have normal numbers of B lymphocytes in their blood that are clonally diverse, but phenotypically immature. B lymphocytes in CVID patients are able to recognize antigens and respond with proliferation, but they are impaired in their ability to become memory B cells and mature plasma cells. In infected patients, abortive differentiation can lead to massive B- lymphocyte hyperplasia, splenomegaly and intestinal lymphoid hyperplasia. With an estimated prevalence of 1 in , CVID is the most prevalent human primary immunodeficiency requiring medical attention. Men and women are equally affected.

Some patients present during childhood, but most are diagnosed in the third decade of life. The typical patient reports a normal pattern of recurrent otitis media as an infant and toddler that resolved in childhood. During adolescence, respiratory infections recur and steadily increase in frequency. Recurrent pneumonia as a young or middle-aged adult is often the precipitating complaint that brings the patient to the attention of the clinical immunologist. Common variable immunodeficiency is a diagnostic category of primary immunodeficiencies that includes a number of immune disorders. Most CVID patients of northern European descent exhibit a distinctive phenotype characterized by a broad deficiency of immunoglobulin isotypes in spite of the presence of normal numbers of surface immunoglobulin-bearing B-cell precursors in the peripheral blood. Almost all of these patients are IgA-deficient and by definition demonstrate total serum IgG levels of less than 500 mg/dl. Some IgG subclasses are more affected than others, with the sequential order of involvement being IgG4>IgG2>IgG1>IgG3. Most patients are also deficient in IgM and IgE.

Uncomplicated patients demonstrate normal cell-mediated immunity, but a minority of patients may have evidence of T-cell dysfunction as well as other hematopoietic cell types. Respiratory symptoms often begin with recurrent sinusitis, otitis media, and mild bronchitis, which are typically due to encapsulated bacteria such as Haemophilus influenzae and Streptococcus pneumoniae. The frequency and severity of the upper respiratory infections worsen in the young adult and lower respiratory infections such as pneumonia become common. Intermittent or chronic diarrhea due to Giardia lamblia is a common complaint. Some unfortunate patients develop a malabsorption syndrome that resembles celiac sprue but is unresponsive to the avoidance of gluten CVID patients are often anergic, but only a minority suffer infections characteristic of cell-mediated immune dysfunction, such as mycobacteria, Pneumocystis jiroveci, and fungi. CD8 T-cell numbers may be depressed in such patients. Most viral infections are cleared normally. Exceptions include enteroviral infections, including meningoencephalitis, as well as hepatitis B and C, which can progress to a fatal chronic active hepatitis. Lack of humoral immunity enhances susceptibility to viral reactivation. Untreated patients often complain of recurrent herpes zoster infections (shingles).

Autoimmune diseases are common in CVID and include pernicious anemia, autoimmune neutropenia, Graves disease, hypothyroidism, rheumatoid arthritis, systemic lupus erythematosus, and Sjögren syndrome. Coombs- positive hemolytic anemia with idiopathic thrombocytopenic purpura, a combination known as Evans syndrome, may predate the diagnosis of CVID. There is an increased risk for the development of gastrointestinal and lymphoid malignancies, especially non-Hodgkin's lymphomas. Therapy in CVID begins with the aggressive treatment of ongoing infections and the institution of prophylactic measures to prevent or ameliorate future infection. Some patients with CVID can sustain severe anaphylaxis when given intravenous immunoglobulin or other blood products that contain serum or plasma. Serum immunoglobulin concentrations in patients with CVID may change over time,[2] with rare patients regaining normal serum IgG levels and no longer requiring immunoglobulin therapy.

Immunoglobulin therapy
The goal of immunoglobulin replacement in patients with primary immunodeficiency was to provide adequate antibodies to prevent infections and long-term complications, especially pulmonary disease. Practically, all commercial IgIV preparations are derived from ~ (range –60 000) donors. Although there is no standardization for the titer of antibodies against common organisms such as Streptococcus pneumoniae and Haemophilus influenzae, each lot must contain adequate levels of antibody to potential pathogens. Typical rate-related adverse reactions with IgIV include tachycardia, dyspnea, chest tightness, back pain, arthralgia, myalgia, hypertension or hypotension, headache, pruritus, rash, and low-grade fever. Aseptic meningitis has been reported as one of the complications of IgIV, especially with large doses, rapid infusions, and in the treatment of patients with autoimmune disease. Although we don't understand all the mechanisms by which IgIV has immunomodulatory effects, knowledge of how IgIV exerts its actions in these diseases will allow us to define appropriate indications and schedules of administration of IgIV and to design a new-generation of IgIV products that are better able to target the immune perturbations in these autoimmune and inflammatory processes.

Common conditions associated with secondary immunodeficiencies
Congenital Cellular immunity Humoral immunity Down's syndrome T cell cytopenia, decreased LPR to mitogens, thymus hypotrophy, decreased naïve T cells, defective NK-cell activity, decreased phagocytosis and chemotaxis Decreased antibody response to vaccines, increased autoimmune antibodies Turner's syndrome T-cell cytopenia, anergy, poor LPR to mitogens Decreased serum IgG and IgM levels

Metabolic Cellular immunity Humoral immunity Protein–calorie malnutrition T-cell cytopenia, thymus hypotrophy, impaired cytokine secretion, decreased chemotaxis and phagocytosis Poor antibody response to vaccines, elevated serum IgA levels, decreased serum IgG levels Diabetes mellitus T-cell cytopenia, decreased LPR to mitogens, decreased chemotaxis and phagocytosis. Decreased antibody response to vaccines Nephrotic syndrome T-cell cytopenia, anergy, poor LPR to mitogens Decreased serum IgG levels and response to vaccines Uremia Increased T-cell apoptosis, lymphopenia decreased LPR to mitogens, decreased chemotaxis and phagocytosis, decreased oxidative response.

Infectious diseases Cellular immunity Humoral immunity HIV infection CD4 T-cell cytopenia, decreased LPR to mitogens and antigens, decreased DTH, decreased naïve T cells, thymus hypotrophy. Poor NK cell and phagocytic activity Poor antibody responses, increased serum IgG levels. Viral infections – measles Impaired antigen presentation, cell-mediated killing Decreased serum IgG levels, decreased antibody responses Stress Trauma T-cell cytopenia, depressed DTH, decreased chemotaxis. Decreased complement activity Splenectomy Not reported Poor antibody responses, negligible to polysaccharides

Environmental conditions Cellular immunity Humoral immunity Radiation and UV ligh T-cell anergy, poor antigen presentation, severe immunosuppression at high doses Defective response secondary to impaired cellular immunity High altitude T- and NK cell cytopenia Decreased serum IgG level Space flight Lymphopenia, decreased LPR to mitogens, decreased NK cell activity and cytokine secretion (IL-10, IL-1a). Norrmal in a space flight model

MALNUTRITION Malnutrition is one of the most frequent causes of secondary immunodeficiency, affecting individuals of all ages. Protein–calorie malnutrition may result from poor intake, malabsorption or excessive loss of nutrients. Individuals with protein–calorie malnutrition progressively lose T-cell production and function, resulting in immunodeficiency with an increased incidence of diarrhea and respiratory infections. These conditions are complicated by a concomitant deficit of micronutrients (e.g., zinc) that augment the susceptibility of infections by inducing defects in the barrier mucosae. Serum immunoglobulin levels appear to remain normal for a relative prolonged period, as does the effectiveness of vaccination to elicit antibodies. Nutritional replenishment in malnourished children results in reversal of deficiencies of lymphocyte proliferation and phagocytosis, and significant recovery of thymus size by ultrasonography.

Immune defects in micronutrient deficiencies
Cellular immunity Humoral immunity Vitamin A deficiency T cell cytopenia, decreased phagocytic and NK-cell function Lower antibody response to immunization Vitamin E deficiency Decreased oxidative activity of phagocytes, increased PGE2 secretion (inhibitory) Increased IgE Vitamin C deficiency Decreased phagocytic activity and oxidative response to ingested organisms Not reported Zinc deficiency Lymphopenia, thymus hypotrophy, Decreased T cell-dependent antibody responses Iron deficiency T-cell cytopenia, thymus hypotrophy, decreased phagocytosis Decreased serum IgG levels Copper deficiency Lymphopenia and neutropenia Selenium deficiency Decreased oxidative response in phagocytes and NK cells

IMMUNOLOGICAL DEFECTS INDUCED BY SURGERY OR TRAUMA
After trauma or injury, inflammation develops to promote healing. However, massive inflammation may result in tissue damage (e.g. systemic inflammatory response syndrome – SIRS – or adult respiratory distress syndrome, ARDS). Immune regulatory mechanisms in response to inflammation may in turn induce a transient immunosuppressive state, mediated by IL-10, TGF-β and other soluble mediators.

ULTRAVIOLET (UV) LIGHT
UV light causes immunosuppression by two mechanisms: it induces apoptosis of skin lymphocytes and other immune cells by directly altering their DNA; it also activates kinases that lead to the activation of NF-κB and ultimately to cell apoptosis when other immune activation signals are missing.

IONIZING RADIATION The immunosuppressive effect of ionizing radiation has been clinically evidenced by the increased susceptibility to infections and tumors in survivors of exposure to nuclear power plant accidents and atomic bomb explosions. Irradiation significantly impairs cell-mediated and humoral immunity, depending on the radiation dose, the frequency of administration, rate, and temporal relationship to antigen administration. The production of lymphocytes and neutrophils, as well as other blood cell lineages, is affected according to the radiation dose causing apoptosis of hematopoietic cells in the bone marrow. All immunological components, including total, CD4 and CD8 T cells, serum immunoglobulin levels and the proliferative response to mitogens, decrease after radiotherapy. Specific immune responses are compromised primarily because of the lymphopenia. The number of macrophages can also be decreased. Phagocytosis is relatively radioresistant, whereas antigen processing by macrophages is easily impaired by low-dose radiation.

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