This is a 14 month old male infant who presents to the emergency department with a chief complaint of high fever and no response to antipyretic therapy. This illness started suddenly with the abrupt onset of fever early yesterday morning. He then developed a severe cough and increased work of breathing. No other symptoms are noted. The patient was born in a refugee camp and has lived in Florida and Texas before moving to Hawaii 3 months ago. The mother reports that he is frequently ill. No reports from Florida or Texas are available, but his mother reports he was also seen as an outpatient frequently and he was hospitalized at least once in Florida. He was hospitalized 2 months ago for pneumococcal pneumonia (right upper lobe consolidation and pneumococcal bacteremia).
Exam: VS T 40.3, P 145, R 55, BP 100/60, oxygen saturation 98%, weight 7 kg (<5th percentile). He is a listless, tired, and small for age. He is lying on the gurney, moving little and whimpering slightly to stimulation with tachypnea and chest retractions. His head is normocephalic, without signs of trauma. Both ear canals contain purulent drainage. Mouth exam is unremarkable. His heart is tachycardic with no murmurs heard. His chest shows mild retractions, tachypnea, dullness to percussion over the posterior upper chest, decreased breath sounds in the area of dullness with occasional fine crackles. His abdomen is scaphoid and soft, with active bowel sounds, no masses, and no hepatosplenomegaly. His extremities are slender and wasted with decreased muscle mass and strength. Neurological exam is normal.
Because of his poor general appearance, he is hospitalized for possible sepsis. He is treated with intravenous antibiotics and he improves slowly over one week. A blood culture is positive for pneumococcus. Because of his recurrent infections and the failure to meet normal growth expectations, an immunologic work up is done. He is found to have markedly elevated IgM, undetectable IgG and IgA with diminished total B lymphocytes (CD19). His clinical picture is consistent with hypogammaglobulinemia with high IgM or Hyper-IgM syndrome. A confirmed diagnosis shows a deficiency of CD40 ligands on T cells. He is placed on monthly IVIG replacement therapy with trimethoprim-sulfamethoxazole prophylaxis for Pneumocystis carinii pneumonia (PCP) and he begins to gain weight and he clears his ear infections.
Recurrent infections in children are one of the common problems encountered by physicians. The majority of these children have normal immune function. However, some patients have immune deficiencies and these patients are frequently not diagnosed. Therefore, physicians should be aware of recurrent infections caused by non-immunologic conditions (Table 1) and clinical clues suggestive of immunologic disorders (Table 2). Immune defects may be either primary (congenital) or secondary to certain diseases or agents (Table 3).
Table 1: Nonimmunologic Causes of Recurrent Infections
. . . . . Abnormal mucous membranes and integuments: Burns, severe eczema, bullous diseases, ectodermal dysplasia, percutaneous catheters.
. . . . . Obstruction of hollow viscus: Cystic fibrosis, inhaled foreign body, posterior urethral valves, ureteropelvic junction obstruction.
. . . . . Foreign body: Ventriculoperitoneal shunt, prosthetic cardiac valves, orthopedic devices, catheters.
. . . . . Vascular abnormalities: Large left to right intracardiac shunt, diabetes mellitus.
. . . . . Congenital: Cysts and sinus tracts, tracheoesophageal fistula, abnormal ciliary function.
. . . . . Neurologic: Incoordinate swallowing, recurrent aspiration, poor respiratory effort.
. . . . . Metabolic disorders: Galactosemia, certain amino acid and organic acid disorders.
. . . . . Secondary immunodeficiency: Malignancy, chemotherapy, chronic renal failure, protein losing enteropathy.
Table 2: Conditions suggestive of immune deficiency
. . . . . >10 episodes acute otitis media per year (infants and children).
. . . . . >2 episodes consolidated pneumonia per year.
. . . . . >2 life-threatening infections per lifetime.
. . . . . Two or more serious sinus infections within 1 year.
. . . . . Unusual organisms.
. . . . . Unusual response to organism.
. . . . . Recurrent deep skin or organ abscesses.
. . . . . Two or more deep-seated infections such as meningitis, osteomyelitis, cellulites or sepsis.
. . . . . Persistent oral thrush or candida infection elsewhere on the skin, after age 1 year.
. . . . . Recurrent autoimmune phenomena.
. . . . . Dysmorphic features associated with recurrent infection.
. . . . . Infections worsening chronic disorders (asthma or seizure).
. . . . . Development of vaccine pathogen after vaccination (e.g., HiB infection despite previous HiB vaccine).
. . . . . Family history of immunodeficiency or recurrent infection.
Table 3: Classification of Primary and Secondary Immunodeficiency Disorders
Primary Antibody Deficiency Diseases (50%):
. . . . . X-linked agammaglobulinemia.
. . . . . Hyper-IgM syndrome, autosomal recessive.
. . . . . Common variable immunodeficiency (CVID).
. . . . . IgA deficiency.
. . . . . Selective IgG subclass deficiencies.
. . . . . Specific antibody deficiency with normal immunoglobulins (SADNI).
. . . . . Transient hypogammaglobulinemia of infancy.
T-cell and Combined Immunodeficiency Diseases (30%):
. . . . . Severe combined immunodeficiency (SCID).
. . . . . X-linked Hyper-IgM syndrome.
. . . . . DiGeorge anomaly.
. . . . . Wiskott-Aldrich syndrome (WAS).
. . . . . Ataxia-telangiectasia (AT).
. . . . . Cartilage-hair hypoplasia.
. . . . . Chronic mucocutaneous candidiasis.
. . . . . X-linked Lymphoproliferative syndrome.
Phagocytic Disorders (18%) (described further in the chapter on neutrophil disorders):
. . . . . Chronic granulomatous disease (CGD).
. . . . . Leukocyte adhesion defect (LAD).
. . . . . Cyclic neutropenia.
. . . . . Chediak-Higashi syndrome.
. . . . . Myeloperoxidase deficiency.
. . . . . Shwachman syndrome.
. . . . . Kostmann's syndrome.
Complement Deficiency (2%):
. . . . . C1q, C1r, C2-C7, C8a, C8b, C9, C1 inhibitor.
. . . . . Factor I, H, D, Properdin.
Other well defined immunodeficiency:
. . . . . Hyper-IgE syndrome.
. . . . . Lymphoproliferative syndrome.
Immunodeficiency associated with other congenital conditions:
. . . . . Down syndrome
. . . . . Shwachman syndrome
. . . . . Malnutrition.
. . . . . Infection (congenital rubella, HIV infection, infectious mononucleosis and other such infections).
. . . . . Protein-losing enteropathy.
. . . . . Nephrosis.
. . . . . Sickle cell disease.
. . . . . Infiltrative diseases such as histiocytosis, leukemia.
. . . . . Metabolic problems such as diabetes mellitus, uremia, vitamin and mineral deficiency.
. . . . . Immunosuppressive medications.
. . . . . Splenectomy.
. . . . . Disruption of barrier protection (burns, severe eczema, catheters).
Over 70 primary immune deficiency diseases have been recognized. The antibody deficiencies constitute about 50% of all cases of primary immunodeficiencies. T cell deficiencies and combined immunodeficiencies are the second largest group, making up about 30%. Phagocytic defects and complement disorders make up about 18% and 2% of immunodeficiencies. Only the more common primary immune deficiency syndromes will be emphasized in this chapter. HIV infection is covered in a separate chapter.
1. Transient hypogammaglobulinemia in infancy (THI). THI is due to a normal variability of the developing immune system in infants with prolonged periods of physiologic hypogammaglobulinemia. All infants develops physiologic hypogammaglobulinemia at approximately 5-6 months of age. In these age groups, the serum Ig level reaches its lowest point (approximately 350mg/dl), and many normal infants begin to experience recurrent respiratory tract infections. The diagnosis of THI is based on low levels of IgG and normal levels of IgA with variable levels of IgM. The normal levels of IgA exclude other congenital hypogammaglobulinemia. Most children with THI are typically able to synthesize specific antibodies in response to immunizations. However, inadequate specific antibody responses do not exclude the diagnosis of THI, but should prompt further investigation for other forms of immunodeficiency. Most cases of THI will spontaneously resolve by 4 years of age.
2. X-linked agammaglobulinemia (XLA) is characterized by four findings: 1) Onset of recurrent bacterial infections in the first 5 years of life; 2) Serum IgG, IgM and IgA values that are at least 2SD below the normal for age; 3) Absent isohemagglutinins or poor response to vaccines; and 4) Less than 2% CD19+ B cells in the peripheral circulation. It should be noted that the variability of clinical and laboratory findings for XLA is exist. Some XLA cases have been undiagnosed and untreated for more than five decades. 10-20% of XLA have serum IgG values greater than 200mg/dl at the time of diagnosis. The most consistent findings in XLA are the marked reduction in the number of B cells in the peripheral circulation.
The primary defect in XLA is the failure of pre-B cells to differentiate into mature B lymphocytes due to a gene mutation of Bruton's tyrosine kinase (Btk) which plays a multifaceted role in signal transduction for normal B cell development. However, approximately 10% of boys with presumed XLA do not have the mutation in Btk and 10% of patients with the early onset of recurrent infections, profound hypogammaglobulinemia and absent B cells, are girls. These observations suggest that there are autosomal recessive disorders clinically indistinguishable from XLA.
Intravenous immunoglobulin (IVIG) has been used as a mainstay therapy for XLA and other antibody deficiency disorders or combined immunodeficiency including autosomal recessive agammaglobulinemia, CVID, Hyper-IgM syndrome, SCID, WAS and AT. IVIG therapy may be beneficial for a selective antibody deficiency with IgG1 or IgG2 deficiency and significant recurrent infections. The usual dose of IVIG is 400 mg/kg every 4 weeks and then the dose should be adjusted based on the IgG level after 3-4 infusions (to keep IgG levels above 500mg/dl). Headache, fever, myalgia, chills, rigors, nausea and vomiting are common adverse reactions of IVIG infusion; however, aseptic meningitis has been reported.
3. Common variable immunodeficiency (CVID) is a heterogeneous syndrome, presenting with low IgG levels and no association with drugs or diseases known to cause secondary antibody deficiency. More than 95% of CVID clinically presents with recurrent sinopulmonary infections just like XLA or other hypogammaglobulinemia syndromes. The cause of CVID has not been identified yet. However the intrinsic defects of B cells, diminished T helper cells and dysregulation of cytokines have been described. Most of the patients usually do not become symptomatic until 15-35 years of age. CVID patients have an increased risk of developing autoimmune diseases, lymphatic and gastrointestinal malignancies, malabsorption and granulomatous inflammation.
The diagnosis of CVID is based on low IgG levels and poor specific antibody responses to immunizations without an identified cause of the hypogammaglobulinemia. IgM and IgA levels may present in significant amounts or absent. A patient with borderline immunoglobulin levels needs an evaluation of specific antibody responses with immunizations. T cell and B cell enumeration are usually normal; however, decreasing numbers of the cells have been occasionally seen. Some patients may have abnormal T cell function studies such as absent delayed hypersensitivity or depressed responses of mitogen stimulation. Treatment of CVID is identical to XLA. Frequent use of broad-spectrum antibiotics is required. The delayed diagnosis and treatment leads to chronic lung diseases such as bronchiectasis so periodic screening with chest x-rays, high resolution chest CT and pulmonary function tests are needed.
4. Hyper-IgM syndrome (HIM) is characterized by high levels of IgM with deficiency of IgG, IgA and poor specific antibody responses to immunizations. X-linked hyper-IgM syndrome is the commonest type which has a defect of the CD40 ligand (CD40L or CD154) gene of T cells. The interaction between CD40 on the B cells and CD40L on T cells is essential for the immunoglobulin class switching from IgM to IgG production, which explains why a deficiency in CD40L leads to hyper-IgM production with deficiency of IgG and IgA. HIM presents with recurrent sinopulmonary infections and Pneumocystis carinii pneumonia (PCP). There are associated abnormalities including neutropenia, hemolytic anemia and aplastic anemia. The unique susceptibility to opportunistic infections and neutropenia with high IgM levels distinguishes HIM from XLA or other hypogammaglobulinemias. Treatment of HIM is based on regular administration of IVIG and use of trimethoprim-sulfamethoxazole to prevent PCP. IVIG not only reduces the severity and frequency of infections, but also diminishes IgM levels and neutropenia. G-CSF (granulocyte colony stimulating factor) may be given for severe neutropenia. Recently stem cell transplantation has been performed successfully. The long term prognosis of HIM appears to be worse than in other forms of congenital hypogammaglobulinemia. Pneumocystis carinii infection has an important impact on morbidity and mortality during the first years of life, whereas liver disease mainly contributes to late mortality.
5. Selective IgA deficiency is the most common primary immunodeficiency disorder with the prevalence between 1 in 400 to 1 in 800. Although many patients are asymptomatic, IgA deficiency predisposes to respiratory, GI and urogenital tract infections, autoimmune diseases, sprue-like syndrome, malignancy, allergy and anaphylaxis reactions to blood products. Moreover, the progression of selective IgA deficiency to CVID or IgG2 subclass deficiency has been reported. The cause of the disease has not been known. Some infectious agents and drugs such as congenital rubella, EBV infection or phenytoin, may cause low IgA levels. The physiologic lag in serum IgA may delay the diagnosis until after the age of 2. The diagnosis can be made if a patient presents with IgA levels less than 7 mg/dL with no other evidence of any immune defects. Unlike XLA, HIM or CVID, selective IgA deficiency has a normal IgM and IgG response to pathogens and vaccines, therefore the routine schedule of immunization is suggested. IVIG replacement is not indicated. Aggressive treatment with broad spectrum antibiotics is recommended for recurrent sinopulmonary infections to avoid permanent pulmonary complications. Some selective IgA deficiency patients may develop antibody to IgA, in which case, there is a risk of anaphylaxis with blood product transfusions.
6. Selective IgG subclass deficiencies are generally defined as a serum IgG subclass concentration that is at least 2 standard deviations below the normal for age. There are four subclasses of human IgG, designated IgG1, IgG2, IgG3 and IgG4. Approximately 67% of serum IgG is IgG1, 20-25% is IgG2, 5-10% is IgG3 and 5% is IgG4. The concentrations of IgG subclasses are physiologically varied with age; IgG1 reaches adult levels by 1 to 4 years of age, whereas IgG2 level normally begins to rise later in childhood compared to other subclasses. The subclass deficiency has been reported in patients with recurrent infections, despite normal total IgG serum or with an associated deficiency of IgA and IgM deficiency.
The diagnosis and its implication have long been problematic since there are insufficient normative data for very young children and major technical problems of measurement of IgG subclass. Additionally, normal healthy children with low IgG2 subclass levels and normal responses to polysaccharide antigens as well as completely asymptomatic individuals with lacking IgG1, IgG2, IgG4 have been reported. A low value of IgG2 in a child may be a temporary finding which normalizes in adulthood. Approximately 10% of males and 1% of females have IgG4 deficiency without significant infections. IgG3 levels may be low with an active infection because it has the shortest half life and the greatest susceptibility to proteolytic degradation. Therefore, IgG subclass measurements are not routinely recommended and treatment with IVIG should be reserved for the patients who have been clearly demonstrated to have impaired responses to both protein and polysaccharide antigens to which they have been immunized.
7. Severe combined immune deficiency (SCID) is a life-threatening syndrome of recurrent infections, oral candidiasis, persistent diarrhea, dermatitis, graft versus host disease after blood transfusion and failure to thrive caused by a number of molecular defects that lead to severe compromise in T cell function with or without B cell dysfunctions. The defects in SCID block the differentiation and proliferation of T cells and in some types, of B cells and natural killer (NK) cells. Immunoglobulin and antibody production are severely impaired even when mature B cells are present. NK cells, a component of innate immunity, are variably affected. The majority of the patients present by age 3 months with unusually severe and frequent common infections such as bacterial otitis media and pneumonia or opportunistic infections including Pneumocystis carinii, and cryptosporidiosis. Viral infections such as herpes simplex, RSV, rotavirus, adenovirus, enterovirus, EBV, CMV are also commonly seen.
The most common defect of SCID is X-linked SCID (XL-SCID), accounting for 50-60% of cases. Adenosine deaminase (ADA) deficiency, accounting for 15% of SCID, is the second common defect. Other defects are purine nucleoside phosphorylase (PNP) deficiencies, IL-7 receptor alpha chain deficiency, recombination activation gene-1 and gene-2 (RAG1, RAG2) deficiency, CD45 deficiency, CD3 deficiency, MHC class I and II deficiency.
SCID is typically diagnosed by clinical features: absence of lymph nodes and tonsils, lymphopenia, absence of a thymic shadow on chest x-ray, abnormal T, B, NK cell enumeration with flow cytometric analysis, abnormal in vivo T cell function studies with skin tests of delayed skin hypersensitivity to tetanus, candida, diphtheria and in vitro lymphocyte function studies by measuring response to phytohemagglutinin (PHA), concanavalin A, pokeweed mitogen, phorbol myristate acetate (PMA) and ionomycin, tetanus and candida.
Skin testing for delayed hypersensitivity (which tests type IV cellular immunity function) is a basic way of testing T cell function. Antigens such as tetanus, candida, trichophyton, and mumps are frequently used because nearly everyone should be positive to all of these; however, occasionally normal young children may have a negative response. A positive response to these intradermal antigens indicates intact T cell function. If no response results from all these antigens, the patient may be "anergic". Thus, this panel of antigens is known as an "anergy panel".
Bone marrow or other stem cell reconstitution is a first-line, specific therapy for almost all forms of SCID. ADA deficiency has specific therapy as an alternative to the transplantation. Polyethylene glycol-treated (PEG) ADA replacement may be administered with improvement but not complete reconstitution of immune function. Currently gene therapy is successful for XL-SCID. Prophylactic antibiotics, IVIG replacement, meticulous skin and mucosal hygienic care, avoidance of exposure to infectious agents, and irradiation of all blood products prior to transfusion are recommended while awaiting stem cell reconstitution. Many patients with SCID are fully reconstituted without complications with bone marrow and other stem cell reconstitution techniques. Patients who are well nourished, uninfected and younger than 6 months prior to transplantation have the best outcomes. Without stem cell reconstitution, it is rare for a patient with SCID to survive.
8. Complement deficiency: Complement proteins are a key component of the innate immune system due to their function of direct lysis of their targets and being an opsonin. Most of the complement deficiency diseases are inherited in an autosomal recessive mode except C1 inhibitor deficiency (autosomal dominant) and properdin deficiency (X-linked). C2 deficiency is the most common defect; however, 50% of individuals with C2 deficiency are asymptomatic. Patients with C1, C4, C2 and C3 deficiencies have a higher incidence of autoimmune diseases such as SLE and encapsulated bacteria infections. Patients with absent factor H and factor I will have excessive consumption of C3; therefore, those patients will have similar infections as those with C3 deficiency states. The most commonly performed test for evaluation of functional complement activity is the CH50 test. APH50 is a useful screening test for the alternative pathway. There is no specific treatment for complement deficiency, except a purified C1 inhibitor preparation for hereditary angioedema due to C1 inhibitor deficiency.
9. WAS is an X-linked recessive disease, caused by a defective gene encoding Wiskott-Aldrich syndrome protein (WASP), which is expressed only in lymphocytes and megakaryocytes. This protein is involved in the reorganization of the actin cytoskeleton in the cells. WAS has a classic presentation with eczema, microcytic thrombocytopenia and recurrent encapsulated infection in a young boy. The initial manifestations often present at birth and consist of petechiae, bruises, bleeding from circumcision or bloody stools. The diagnosis can be made based on the manifestations and immunologic findings including low IgM, high IgA and IgE, poor antibody responses to polysaccharide antigens, moderately reduced number of T cells and variable depression of in vitro T cell function studies. Treatment includes IVIG infusion, irradiated fresh platelet transfusions and splenectomy for bleeding tendency, prophylactic antibiotics after splenectomy, and bone marrow transplantation.
10. Ataxia-Telangiectasia (AT) is an autosomal recessive disorder characterized by sinopulmonary infections, telangiectasia, progressive ataxia and hypersensitivity to ionizing radiation. Immunologic studies reveal combine immunodeficiency consisting of selective IgA and IgG2 deficiency, cutaneous anergy and depression of in vitro T cell function study. Supportive treatment is recommended. Other treatments which may be considered include IVIG and bone marrow transplantation.
11. Hyper-IgE syndrome is characterized by chronic pruritic dermatitis, recurrent staphylococcal infections (skin and respiratory tract), markedly elevated serum IgE, eosinophilia and coarse facial features. The diagnosis may be difficult since there is no clear definition of high IgE levels and IgE levels may fluctuate from time to time. In addition, a high IgE level with eosinophilia is commonly seen in severe atopic dermatitis. Therefore, recurrent staphylococcal infections involving the skin, lungs and joints with other features including a distinctive facial appearance, dental abnormalities and bone fractures are essential for the diagnosis. Treatment with good skin care and continuous antimicrobial therapy such as trimethoprim-sulfamethoxazole are necessary. No specific immunotherapeutic regimen has been successful. The role of IVIG therapy remains to be determined.
12. Chronic granulomatous disease (CGD) is a defect of phagocytic cells with dysfunction of the NADPH oxidase enzyme complex required for the production of reactive oxygen intermediates to destroy microbes. The defect leads to recurrent and uncontrolled catalase-positive organisms including S. aureus, E. coli, Serratia marcescens, Salmonella, Klebsiella spp, Clostridium difficile, Legionella bosmanii, Pseudomonas cepacia, Mycobacterium fortuitum, Chromobacterium, Aspergillus spp, Nocardia spp and Actinomyces spp. The most common infections are lymphadenitis, abscesses of the skin, and of the viscera such as liver. Granuloma formation occurs in CGD because the defect of the intracellular microcidal mechanism causes persistent antigen presentation and induces a sustained cell-mediated response by CD4 T cells, which recruit other inflammatory cells and set up a chronic local inflammation called a granuloma. The diagnosis of CGD can be ascertained by taking advantage of the metabolic defect in the phagocytic cells. A dye called nitro blue tetrazolium (NBT) is pale yellow and transparent. When it is reduced, it becomes insoluble and turns a deep purple color. In normal blood, the NBT is reduced to a dark purple or blue, easily seen in the phagocytic cells. In CGD blood, no dark purple or blue color is seen. Treatment includes short-term treatment of the infections, prophylactic trimethoprim-sulfa, recombinant human interferon-G (enhancing the production of reactive oxygen intermediates) and bone marrow transplantation. This condition is described in further detail in the chapter on neutrophil disorders.
13. Leukocyte adhesion molecule defect (LAD) syndromes are failures of innate host defenses against bacteria, fungi, and other microorganisms resulting from defective tethering, adhesion, and targeting of myeloid leukocytes (PMN, monocytes) to sites of microbial invasion. Killing of microbes is intact, but since the cells can not be mobilized to the point of inflammation and complement-mediated phagocytosis is impaired, the result is a lack of an inflammatory response. The hallmark of the disease is neutrophilia without PMNs in the infected tissue or pus. Histories of delayed separation of the umbilical cord, recurrent bacterial infections, necrotic skin lesions, severe gingivitis, periodontitis, and alveolar bone loss leading to early loss of deciduous and permanent teeth suggest the diagnosis. A definitive diagnosis with flow cytometric analysis reveals a decreased or absence of CD18 and its associated heterodimers: CD11a,CD11b and CD11c in LAD type I and absence of CD15s in LAD type II. Treatment includes continuous antimicrobial therapy, good oral hygiene, white blood cell transfusions and bone marrow transplantation.
Clinical Approach to Suspected Immunodeficiency
The history should include the onset and type of the infections, the frequency, chronicity, severity and the responses to the previous treatments. The associated conditions such as failure to thrive, autoimmune disease, congenital anomalies and family history of consanguinity, fetal wastage and early childhood deaths should be noted. Types of infections and presentations are helpful for differentiation of primary immune defects (Table IV).
Table IV: Typical Clinical Findings in Each Group of Primary Immunodeficiency
Antibody Deficiency Diseases:
. . . . . Presentation after passively acquired maternal antibody wanes (6 months old).
. . . . . Infection with encapsulated bacteria such as Haemophilus influenzae type B, pneumococcus, etc.
. . . . . Recurrent sinopulmonary infection, otitis media.
. . . . . Possible poor growth or failure to thrive.
T-Cell and Combined Immunodeficiency:
. . . . . Presentation in early infancy.
. . . . . Poor growth or failure to thrive.
. . . . . Persistent oral thrush.
. . . . . Opportunistic infection.
. . . . . Presentation in infancy or childhood.
. . . . . Poor wound healing, delayed umbilical cord separation.
. . . . . Gingivitis, abscesses, skin infection, including cellulitis and furunculosis.
. . . . . Early complement deficiency: Sinopulmonary infection, autoimmune disease.
. . . . . Late complement component deficiency: Recurrent infection caused by Neisseria species, including meningococcal and gonococcal infection
Most immunodeficiencies present during infancy or early childhood with the most notable exceptions being common variable hypogammaglobulinemia (CVID), selective IgA deficiency, cyclic neutropenia, and complement deficiencies and some of the secondary immunodeficiencies, which may present later in life. Patients with severe combined immunodeficiency (SCID) suffer major infections very early in life, usually during the first weeks or months of age. Congenital agammaglobulinemia typically presents during the second 6 months of life when maternally transferred antibodies wane. Other immunodeficiencies that present clinically before 5 years of age include Wiskott-Aldrich syndrome (WAS), leukocyte adhesion defects (LAD), chronic granulomatous disease (CGD), hyperimmunoglobulin (Ig)M syndrome, ataxia-telangiectasia (AT), and complement deficiencies.
Certain physical findings alert one to the possibility of primary immune deficiency. Failure to thrive secondary to recurrent infections is commonly seen in some antibody deficiencies and combined T and B cell deficiencies. Persistent sinopulmonary infections, especially ear drainage, pneumonia or bronchiectasis, are seen in antibody deficiencies, T and B cell deficiencies and complement deficiencies. Absence or scanty lymphoid tissue such as tonsils and lymph node suggests X-linked agammaglobulinemia (XLA), SCID or complete DiGeorge anomaly. Chronic eczematous rash are found in hyper-IgE syndrome and WAS. Recurrent skin infection with oral ulcers, periodontitis or gingivostomatitis are associated with phagocytic cell defects such as CGD and LAD. Failure or delayed umbilical cord separation is a clinical clue of LAD. Recurrent mucosal candidiasis suggests T cell deficiencies such as SCID and AIDS. Adenopathy and hepatosplenomegaly is frequently encountered in HIV infection.
Several congenital and hereditary conditions with musculoskeletal abnormalities are associated with immunodeficiency. These include Bloom syndrome, Fanconi anemia, trisomy 21, Turner syndrome, short-limbed skeletal dysplasia, cartilage-hair hypoplasia, Shwachman syndrome and ectodermal dysplasia. Classical findings of some specific syndromes should be carefully noted including DiGeorge syndrome (micrognathia, hypertelorism, low-set ears, shortened upper lip philtrum, mandibular hypoplasia, a bifid uvula, an antimongolian slant of the eyes, notched ear pinnae, high arched palate, fish-shaped mouth and congenital heart disease), AT (telangiectasis on bulbar conjunctiva, skin, the bridge of the nose, the ears and antecubital fossa), and Chediak-Higashi syndrome (partial albinism, photophobia).
The proper choice of laboratory tests is based on a careful history and physical examination which target specific suspected immunodeficiency possibilities. A complete blood count is an initial screening test. The number of neutrophils, lymphocytes, abnormalities of white blood cells or red blood cell morphology, numbers and morphology of platelets should be noted. Abnormal CBC findings may point out to a specific disease such as: 1) Lymphopenia (less than 2,000) in XLA, SCID, WAS, AT, DiGeorge, malnutrition and AIDS. 2) Neutropenia in hyper IgM syndrome, cyclic neutropenia, drug-induced neutropenia, Shwachman syndrome and autoimmune-mediated neutropenia. 3) Eosinophilia in WAS, and hyper-IgE syndrome. 4) PMN cells with large cytoplasmic granules in Chediak-Higashi syndrome. 5) Thrombocytopenia in WAS. 6) Howell-Jolly bodies in asplenia. 7) Leukocytosis with few neutrophils in the inflammatory lesions of LAD.
Certain culture results may point out a specific immune defect such as: 1) Encapsulated bacteria in antibody, T cell and complement deficiencies. 2) Opportunistic organisms in T cell deficiencies. 3) Recurrent staphylococcus infections in CGD, LAD and Hyper IgE syndrome. 4) Recurrent catalase-positive organism infections in CGD.
In blood chemistry, a decreased globulin fraction suggests hypogammaglobulinemia, malnutrition, or protein loss. An elevated globulin level is seen in HIV infection, certain autoimmune diseases, hepatitis, myeloma or chronic infections.
If the defect of B cells or humoral immunity defect is suspected, measurements of isohemagglutinins, immunoglobulin levels of IgG, IgA, IgM, specific antibody levels against of diphtheria, tetanus, H. influenzae and pneumococcus, and B cell enumeration (CD19) by a flow cytometer are needed. It should be noted that normal levels of IgG, IgM and IgA in children are lower than that in adults. A second test for specific antibody levels is required after having a booster dose of the vaccine if the first test result is low. Measurement of IgG subclass levels should not be used as a screening test and may not yield any more useful information than a total serum IgG level with specific antibody titers. In a suspected immunodeficiency case with eczema, IgM and IgE measurement are appropriate to evaluate hyper-IgE syndrome, WAS and atopic dermatitis.
Cellular immunodeficiencies or T cell disorders can be screened in vivo with the use of the delayed hypersensitivity skin test (DHST) including Candida albicans (1:100), tetanus toxoid (1:100), trichophyton (1:30), tuberculin (5TU and 250TU) and mumps (i.e., the anergy panel). An induration of 10mm or more to one antigen or more than one antigen of indurations of 5mm or more indicates normal cell-mediated immunity. Approximately 90% of normal adults show a good response to at least one antigen when three to five antigens are applied. However, DHST may be difficult to evaluate in infants because such immunity has not yet been acquired or because of insufficient sensitization. Other tests for T cell disorders are T cell enumeration including CD3 (pan T), CD4 (helper T cell), CD8 (cytotoxic T cell) by a flow cytometer and in vitro assays for T cell functions such as lymphocyte proliferation to mitogens (phytohemagglutinin, concanavalin-A) and antigens (candida, tetanus, mumps, PPD, streptokinase or toxic shock syndrome toxin). Normally T cells constitute 55% to 80% of peripheral blood lymphocytes, with an absolute count of at least 1,000cells per cu-mm, and the number of CD4 cells is 1.5 to 2 times the CD8 cells. Higher absolute numbers of T-cell subsets and CD4 cells are commonly seen in normal infants and children.
Two screening tests for complement deficiencies are total hemolytic assay, CH50 for the classical pathway and AH50 for the alternative pathway. In a disseminated meningococcemia case or when terminal complement deficiency is suspected, AP50 and properdin levels are indicated if CH50 is normal. If CH50 is completely or partially absent, measurement of C3 and C4 levels is recommended. Normal C3 and C4 levels with low CH50 indicate deficiency of one of the other classic pathway components. If low levels of C3 and C4 are found, increased complement consumption is likely.
Determining the number and morphology of circulatory neutrophils, and assessing the oxidative metabolism by the nitroblue tetrazolium (NBT) test or chemiluminescence test, can screen phagocytic function in clinical practice. If a chemotaxis defect is suspected, a Boyden chamber test is recommended. Adhesion molecules such as CD11 a,b,c/ CD18 on granulocytes should be evaluated if LAD suspected.
1. The least likely recurrent infection caused by primary immune deficiency is:
. . . . . a. Recurrent otitis media
. . . . . b. Recurrent bacterial skin infection
. . . . . c. Recurrent bacterial pneumonia
. . . . . d. Recurrent osteomyelitis
. . . . . e. Recurrent urinary tract infection
2. Which one is considered as a characteristic of transient hypogammaglobulinemia of infancy (THI)?
. . . . . a. Normal IgG
. . . . . b. Normal IgM
. . . . . c. Normal IgA
. . . . . d. Normal IgD
3. Which one is the most likely diagnosis of an 18 year old female who presents with a history of recurrent sinopulmonary infection, low IgG and IgA and ITP?
. . . . . a. X-linked agammaglobulinemia
. . . . . b. Severe combined immunodeficiency
. . . . . c. Common variable immunodeficiency
. . . . . d. Ataxia-telangiectasia
. . . . . e. Cystic fibrosis
4. A 7 month old infant with a history of failure to thrive, recurrent oral candidiasis, and Pneumocystis carinii pneumonia is being evaluated. Which of the following is the least useful diagnostic test?
. . . . . a. Immunoglobulin levels and functional antibody
. . . . . b. Enumeration of T cells and lymphocyte proliferation assay
. . . . . c. Anti-HIV antibody
. . . . . d. Delayed type hypersensitivity skin test
. . . . . e. Nitroblue tetrazolium test and phagocytic tests
5. A mother brings her son, a 6 year old boy with severe eczema, recurrent bacteria skin infections and history of staphylococcal pneumonia for evaluation of immunodeficiency. Initial tests reveal normal CBC and platelets, 50,000 IU of IgE, normal IgG, IgM and IgA levels. Which one is the most likely diagnosis?
. . . . . a. Atopic dermatitis
. . . . . b. Wiskott-Aldrich Syndrome
. . . . . c. Hyper-IgE syndrome
. . . . . d. Chronic granulomatous disease
. . . . . e. Leukocyte adhesion defect
6. Which one is a true association of a primary immune deficiency and an abnormal hematologic finding?
. . . . . a. Leukocyte adhesion defect and thrombocytopenia.
. . . . . b. Hyper-IgM syndrome and neutropenia.
. . . . . c. Wiskott-Aldrich syndrome and gigantic platelets.
. . . . . d. Chronic granulomatous disease and large cytoplasmic granules in PMNs.
. . . . . e. Hyper-IgE syndrome and mastocytosis.
7. Which one is the characteristic infection in patients with terminal complement (C5-C9) deficiency?
. . . . . a. MRSA
. . . . . b. Pneumocystis carinii
. . . . . c. Meningococcus
. . . . . d. Catalase-positive organisms
. . . . . e. Herpes viruses
8. A contraindicated vaccine in an isolated IgA deficiency patient is:
. . . . . a. OPV
. . . . . b. Varicella
. . . . . c. Influenza
. . . . . d. MMR
. . . . . e. None of the above
9. IVIG replacement is indicated in all of the following, except:
. . . . . a. X-linked agammaglobulinemia (XLA)
. . . . . b. X-linked hyper-IgM syndrome
. . . . . c. Chronic granulomatous disease (CGD)
. . . . . d. Wiskott-Aldrich syndrome (WAS)
. . . . . e. Common variable immunodeficiency
10. PCP prophylaxis with trimethoprim-sulfamethoxazole is recommended in:
. . . . . a. X-linked agammaglobulinemia (XLA)
. . . . . b. X-linked hyperIgM syndrome
. . . . . c. Chronic granulomatous disease (CGD)
. . . . . d. Wiskott-Aldrich syndrome (WAS)
. . . . . e. Hyper-IgE syndrome
1. Schiff RI, Harville TO. Chapter 2- Primary and Secondary Immunodeficiency Diseases. In: Bierman CW, Pearlman DS (eds). Allergy, Asthma and Immunology from Infancy to Adulthood, third edition. 1996, Philadelphia: W.B. Saunders Company, pp. 20-54.
2. Conley ME, Stiehm ER. Chapter 9-Immunodeficiency Disorder: General Considerations. In: Stiehm ER (ed). Immunologic Disorders in Infants & Children, fourth edition. 1996, Philadelphia: W.B. Saunders Company, pp. 201-252.
3. Tangsinmankong N, Bahna SL, Good RA. The immunologic workup of the child suspected of immunodeficiency. Ann Allergy Asthma Immunol 2001;87(5):362-370.
4. Paul ME, Shearer WT. Chapter 33- Approach to the Evaluation of the Immunodeficient Patient. In: Rich RR, Fleisher TA (eds). Clinical Immunology, Principles and Practice, second edition. 2001, St. Louis: Mosby, pp. 33.1-33.11.
5. Smart BA, Ochs HD. The molecular basis and treatment of primary immunodeficiency disorders. Curr Opin Pediatr 1997;9:570-576.
6. Notarangelo LD, Hayward AR. X-linked immunodeficiency with hyper-IgM (XHIM). Clin Exp Immunol 2000;120:399-405.
7. Buckley RH. The hyper-IgE syndrome. Clin Rev Allerg Immunol 2001;20:139-154.
8. Buckley RH. Immunoglobulin G subclass deficiency: fact or fancy? Curr Allergy Asthma Rep 2002;2:356-360.
9. Bonilla FA, Geha RS. Primary immunodeficiency diseases. J Allergy Clin Immunol 2003;111:S571-S581.
Answers to questions
1.e, 2.c, 3.c, 4.e, 5.c, 6.b, 7.c, 8.e, 9.c, 10.b