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The authors take a case-based look at 10 immune disorders, and review when to suspect a primary immunodeficiency in a child with frequent infections and how to confirm the diagnosis.
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The authors take a case-based look at 10 immune disorders, reviewing when to suspect a primary immunodeficiency in a child with frequent infections.
In the five decades since Ogden Bruton described agammaglobulinemia, knowledge of immune function has grown exponentially. More than 95 inherited immunodeficiency disorders have now been identified.1,2 Over the last two decades, professional and public awareness of immunodeficiencies has increased dramatically, mainly due to discovery of the human immunodeficiency virus.
Selective IgA deficiency
Common variable immunodeficiency
Hyperimmunoglobulinemia E syndrome
Chronic mucocutaneous candidiasis
Severe combined immunodeficiency syndrome
Chronic granulomatous disease
Pediatricians are often faced with a child who has a history of frequent infections. Such a case raises challenging questions: Is the frequency of the infections alarming? Is this presentation a true case of primary immunodeficiency? Should this child receive an immune work-up?
To familiarize the pediatrician and family physician with the warning signs of primary immunodeficiency, we present key characteristics of several of these disorders in a series of clinical vignettes. (For a general review of primary immunodeficiency syndromes, we refer the reader to several excellent reviews.1,36) When there is a high index of suspicion for an immunodeficiency, we recommend a full work-up of the patient and his family performed by a physician specializing in immune system-mediated diseases.
The immune system can be divided into four "arms": B-cell, or humoral, immunity; T-cell, or cellular, immunity; the phagocytic system; and the complement system. Within the last decade, substantial progress has been made in understanding the function of these arms. Many primary immunodeficiency disorders are due to a single gene mutation that leads to a defect in function or interaction of these arms. Table 1 lists the major primary immunodeficiency disorders.
With some children who have a primary immunodeficiency, the condition goes undiagnosed and they succumb to overwhelming infection during the first two years of life. Of those children whose condition is diagnosed, about 50% have a B-cell defect, 20% have a combined B- and T-cell defect, and 10% have a pure T-cell defect; phagocytic defects, followed by complement defects, account for the remaining percentages.7 Clinical presentation varies with the type of defect; T-cell and B-cell disorders, for example, each present in a characteristic manner (Tables 2 and 3).
Onset of symptoms usually between 4 and 5 months of age
Recurrent infections with viral, fungal, or mycobacterial pathogens
Opportunistic infection (e.g., Pneumocystis carinii pneumonia)
Failure to thrive, fatal in childhood
Fatal infection as a consequence of a live virus vaccine or BCG
Graft versus host disease caused by blood product transfusions
Increased incidence of malignancy
Onset of symptoms delayed to about 7 to 9 months of age, when maternally transferred antibodies wane, or until later years or decades (common variable immunodeficiency)
Recurrent infections with encapsulated bacteria
Chronic or recurrent sinusitis, otitis media, pneumonia, bronchiectasis
Lymphadenitis or abscess formation (except in X-linked agammaglobulinemia)
Hematogenous spread leading to septicemia, meningitis, and osteomyelitis
No fungal or viral infections (except enteroviral infection)
No severe growth impairment; can survive into adulthood with treatment
Hypoplasia or aplasia of peripheral lymph nodes (X-linked agammaglobulinemia)
Lymphoid hyperplasia, hepatosplenomegaly (common variable immunodeficiency and, sometimes, hyper-IgM syndrome)
Increased risk of autoimmune processes and allergies
The following 10 warning signs of a possible primary immunodeficiency should not be overlooked8:
A boy who was healthy until the age of 7 months is brought to you at 16 months with a four-day history of diarrhea. His medical history is significant for multiple episodes of otitis media. Since his 6-month check-up, he has dropped on the growth curve from the 75th percentile to below the 50th percentile in height and weight. On physical examination, he has purulent ear discharge, absent tonsils, no palpable lymph nodes, rhonchi over the left lower lobe, and increased bowel sounds.
Eventual diagnosis: X-linked agammaglobulinemia. XLA is an X-linked, recessive, B-cell immune deficiency caused by a mutation in the Bruton tyrosine kinase (Btk) gene. Btk is a tyrosine kinase responsible for intracellular signaling that maps to position Xq22. Female carriers can be identified through detection of the defective Btk gene. Prenatal genetic analysis and diagnosis is possible from chorionic villous or amniocentesis samples. Analysis of maternal female relatives is useful to identify other carriers, although about a third of cases will be new mutations without carriers among the maternal grandmother and aunts. Onset of bacterial infections usually follows the decline of maternal antibodies transported across the placenta (late part of the first year of life). Infections occur mainly in the sinopulmonary tract, lungs, conjunctiva, gastrointestinal tract, and joints.
The most common pathogens are Haemophilus influenzae, Staphylococcus aureus, and Streptococcus pneumoniae. On physical examination, lymphoid tissue is typically absent. Untreated boys experience repeated pulmonary infections leading to bronchiectasis. Arthritis is often a complaint and is caused by bacterial infection. Because T-cell function is adequate, control of fungal and viral infections is usually normal. Enteroviruses are the only viral pathogens that are poorly controlled, despite therapy; in some patients, this poor control manifests as chronic meningoencephalitis.
Laboratory evaluation reveals a nearly normal or normal white blood cell count; near or total absence of M, E, and A serum immunoglobulins; and variable but low levels of IgG. The diagnosis is confirmed by flow cytometry, which reveals normal T-cell counts and absence of B cells. Genetic confirmation is possible but usually unnecessary for treatment. Therapy consists of intravenous immunoglobulin (IVIG) infusions. At times, recurrent sinopulmonary infection requires antibiotic prophylaxis.
Key points for XLA
A 4-year-old girl complains of bilateral ear pain. Her medical history is relevant for approximately four ear infections a year, a history of tympanostomy tube insertion, and several episodes of sinusitis. Family history reveals a healthy mother, father, and two older siblings. A physical examination finds purulent drainage from tympanostomy tubes.
Eventual diagnosis: Selective IgA deficiency. The most common form of primary immune deficiency, selective IgA deficiency has a reported incidence of between 1:500 and 1:700 in North America and Europe, with a lower prevalence in Japan and Southeast Asia.9 Selective IgA deficiency is defined as a serum IgA level below 5 mg/dL, with IgM and IgG levels in the normal range. Many affected people are asymptomatic. Among those who aren't, sinusitis and otitis media are the predominant clinical expressions of the condition. Diarrhea and malabsorption are often present as well. Some IgA-deficient persons also have an IgG subclass deficiency, and may be more susceptible to infection and autoimmune connective tissue disease.
Selective IgA deficiency can be associated with drugs, including phenytoin, sulfasalazine, hydroxychloroquine, and d-penicillamine. The deficiency occurs in males and females and has been observed to cluster in families, inherited in an autosomal recessive pattern in some and in a dominant pattern with variable penetrance in others. Therapy is seldom needed, although, at times, a prophylactic regimen for sinopulmonary infection is helpful. Patients in whom IgA is completely undetectable may have severe reactions to blood or blood derivatives, which contain IgA, because anti-IgA IgE antibodies may form.
Key points for selective IgA deficiency
Selective IgA deficiency and common variable immunodeficiency (CVID) share a tendency to autoimmunity and have been found in first-degree relatives, suggesting a relationship.
CVID is characterized by a marked reduction in levels of IgG and IgA, and a low or normal level of IgM. Specific antibody production is moderately or severely reduced, but auto-antibodies are detected relatively frequently, implying an incomplete block of antibody production. The defect is presumed to be in B cells, although some patients exhibit a variable degree of T-cell dysfunction. The incidence is estimated to be 1 in 10,000 to 100,000 people. Onset of clinical symptoms is usually between 1 and 5 years and 16 and 20 years of age.2 CVID is equally distributed between the sexes.
Symptoms are mainly caused by the hypogammaglobulinemia and manifest as repeated sinusitis and pneumonias. Complications, including bronchiectasis, lymphoid interstitial pneumonia, and giardiasis, occur occasionally. CVID has been associated with a sprue-like syndrome, gastric atrophy, and hemolytic and pernicious anemia. Among patients with CVID, there is an increased incidence of autoimmune disease, including celiac disease, thyroiditis, rheumatoid arthritis, and autoimmune thrombocytopenia, as well as an increased risk of lymphoma and gastric carcinoma. Tonsils and lymph nodes are present and, at times, enlarged.
Therapy consists of gammaglobulin replacement, antibiotics, and treatment of complications. Patients with CVID and an undetectable level of IgA may react to IVIG and other blood and blood-derived products for the same reason that IgA-deficient patients with an undetectable level of IgA do. The prognosis for patients with CVID is good, except for those affected by an autoimmune disease or malignancy.
Key points for CVID
A 3-year-old boy has a history of recurrent sinusitis since he was 1 year old. He has had several episodes of pneumonia. During the most severe episode, he required ventilatory support; bronchoalveolar lavage revealed Pneumocystis carinii. The WBC count is normal during these infections.
Eventual diagnosis: Hyper-IgM syndrome. This condition is characterized by a normal or elevated IgM level; usually low serum IgE and IgA levels; variable, but usually low, IgG level; and recurrent sinopulmonary infections. The syndrome has two known forms: X-linked and autosomal recessive. The X-linked form affects promotion by T cells of isotype switching in B cells. The abnormality is in the gene for CD 40 ligand (CD 154), which is expressed on the surface of activated T cells; CD 40 (its receptor) is on the surface of B cells. This interaction leads to stimulation of B cells and plays a critical role in isotype switching (from IgM to other isotypes). The autosomal recessive form is caused by a defect in the gene for activation-induced cytidine deaminase (AID), an mRNA editing enzyme. Although the exact function of AID is poorly understood, the mutation also results in a failure of isotype switching. (There is another, heterogeneous subgroup of patients with hyper-IgM syndrome; these patients have an elevated IgM level with immunodeficiency of an unknown etiology.10)
Clinically, X-linked hyper-IgM patients tend to be sicker than those who are autosomal recessive, usually leading to a diagnosis before 5 years of age. Infections typically start in the first two years or so of life and are characterized by sinopulmonary bacterial infection, mainly with pyogenic strains. Some patients have lymphoid hyperplasia. X-linked hyper-IgM patients have frequent noninfectious complications of cytopenia or autoimmune disease and may also have opportunistic infections.
In the autosomal recessive group, onset of recurrent otitis and sinusitis typically occurs within the first two years of life. Patients are not usually given a diagnosis of immunodeficiency until about the second or third decade, however. Lymphoid hyperplasia is more common than in the X-linked group, because B cells are stimulated but cannot work efficiently. This group does not have an increased risk of cytopenia, autoimmune disease, or opportunistic infection.
Treatment is IVIG therapy, which often decreases the serum IgM level and often leads to regression of lymphoid hyperplasia, as well as improvement of the neutropenia. Bone marrow transplant has been used in the treatment of one child,11 and may be the treatment of choice in young children with X-linked hyper-IgM syndrome because of high morbidity and mortality.
Key points for hyper-IgM syndrome
A 10-year-old boy has repeated skin, lung, and sinus infections. He has severe eczema that has become superinfected numerous times, and his abscesses often require incision and drainage; several cultures grew S aureus. When you observe the child you get the impression that he has coarse facial features.
Eventual diagnosis: hyperimmunoglobulinemia E syndrome. Recurrent, severe staphylococcal abscesses of the skin, viscera, sinuses, middle ears, and lungs characterize this syndrome. Although a few early descriptions of this disorder emphasized the presence of "cold" abscesses, in our experience most cutaneous abscesses in these patients have typical calor, rubor, et tumor.12 The staphylococcal pneumonias are almost always followed by development of pneumatoceles. The syndrome is also characterized by an extremely elevated IgE level (usually greater than 2,000 IU/mL) that may vary over time.
Although the pruritic rash seen in these patients is not typical of atopic dermatitis, confusion often arises because very severe atopic dermatitis can also be associated with an extremely high serum IgE level. However, allergic symptoms are usually absent in patients with hyperimmunoglobulinemia E syndrome, despite their elevated IgE level. Also, true furuncles are unusual in atopic dermatitis, although superinfection of the eczematoid rash can occur.
Patients are also noted to have delayed shedding of primary teeth and coarse facial features, the cause and mechanism of which is not well understood.
Laboratory findings reveal an extremely high level of IgEin some patients, 5,000 IU/mL. Blood and sputum eosinophilia is marked. Antibody responses to vaccinations and boosters are abnormal in many patients. Chemotaxis abnormalities are observed in some patients but, even in these patients, may not be present consistently.
The cause of the disorder is unknown. The presence of excessive eosinophils may indicate that the pathology is eosinophil mediated. The variable defect in phagocytic function indicates that phagocytic function is not the basic problem. The fact that both sexes and members of successive generations are affected suggests that this disorder is autosomal dominant with an incomplete penetrance.
Treatment consists of long-term therapy with a penicillinase-resistant antibiotic. A supplemental antifungal medication is often needed for specific infections. Thoracic surgery is often required for removal of pneumatoceles if they are superinfected or affect lung function. Prognosis is guarded but, with chronic antibiotic treatment, long-term survival is likely. The leading cause of death is a decline in pulmonary function.
Key points for hyperimmunoglobulinemia E syndrome
A female newborn is the product of a full-term pregnancy and was born by spontaneous vaginal delivery with Apgar scores of 9 and 9 at one and five minutes, respectively. Seizures began in the newborn nursery. On physical examination, she appears dysmorphic, with a short philtrum, micrognathia, and downward slant of the eyes. Heart exam reveals a grade 4/6 murmur. A complete blood count is remarkable for a low WBC count with a markedly depressed number of lymphocytes.
Eventual diagnosis: DiGeorge syndrome (congenital thymic hypoplasia). This disorder is a complex congenital malformation resulting from dysmorphogenesis of the third and fourth pharyngeal pouches. Patients have hypoplasia of the thymus, hypoparathyroidism, congenital heart disease, and abnormal facial features such as fish mouth, short philtrum of the upper lip, micrognathia, hypertelorism, downward slant of the eyes, and low-set ears. Neonatal hypocalcemic seizures usually raise suspicion of the diagnosis.
The syndrome is variable, typically presenting with hypoplasia rather than total aplasia of the parathyroids and thymus. Thymic hypoplasia can lead to cellular immunodeficiency, because the total number of peripheral T cells is severely depressed and the cells proliferate poorly to allogeneic cells and mitogens. B-cell numbers are normal, and antibody response can be relatively intact if there is sufficient T-cell function for T-cell help. If profound T-cell impairment is present but unrecognized, fatal graft-versus-host disease can result if nonirradiated blood is administered (such as before corrective heart surgery). If the thymic hypoplasia is partial, the child will have few or no life-threatening infections.
Diagnosis is made based on the clinical picture, low number of circulating WBCs, and flow cytometry (absence or low numbers of T cells). The molecular basis for the disease is microdeletions from chromosome 22q11.2.
The partial form of the condition requires no immunologic treatment. The severe form requires treatment once hypoparathyroidism and cardiovascular problems have been controlled. Some patients have been treated with bone marrow transplantation; others have been reconstituted with transplantation of fetal thymus.13
Key points for DiGeorge syndrome
An 18-year-old girl has had chronic, recurrent nail infections and oral thrush since 5 years of age. Most of these infections have been resistant to conventional antifungal therapy. Last year she was diagnosed with hypoparathyroidism. She has had lung and sinus infections throughout her life.
Eventual diagnosis: Chronic mucocutaneous candidiasis. CMC is a selective defect in T-cell function characterized by chronic candidiasis of the mucous membranes, skin, and nails. Fungal infections usually present by 5 years of age. Candida rarely penetrates the dermis, and patients are not usually susceptible to Candida sepsis. Some patients have involvement of the esophagus, leading to dysphagia and nutritional problems. Most patients develop an autoimmune endocrinopathy by adulthood (Addison's disease, hypothyroidism, diabetes, and pernicious anemia).14
T-cell numbers are normal. In vitro proliferative responses to mitogens are normal but often weak or absent to Candida antigen. B-cell immunity is variable, and some patients require IVIG therapy.
Patients usually do not respond to a topical antifungal agent and instead require aggressive therapy with a systemic antifungal medication. Ultimately, a novel antifungal agent or amphotericin B needs to be used. Bone marrow transplant has been used with success, but even though the prognosis for patients with CMC is not good, outcomes are not uniformly poor enough to justify routine use of bone marrow transplantation.
Key points for CMC
An 11-month-old boy is brought to your clinic because of tachypnea and irritability. Birth weight was 3.5 kg. He appeared perfectly well until 4 months of age, when he developed a runny nose and dry cough that never seemed to go away. At 5 months of age, he had two ear infections that were treated with amoxicillin and seemed to respond. A chest radiograph showed pneumonia, which resolved with clarithromycin. Oral thrush and a candidal diaper rash that developed during therapy were attributed to the antibiotics. He was also noted to be gaining weight poorly and was falling off the curve for his age on the growth chart.
On examination, he is tachypneic and has oral thrush, small tonsils, a clear nasal discharge, and coarse breath sounds over both lungs. His white count is 3.7 x 103 cells/µL and absolute lymphocyte count, 0.55 x 103 cells/µL. Lab results show decreased immunoglobulin levels and profoundly decreased T-cell numbers. Lymphocyte mitogen proliferative responses are nearly absent.
Eventual diagnosis: Severe combined immunodeficiency syndrome. SCID is fatal unless detected and treated early in life. These patients lack functioning T cells and B cells. A wide variety of defects cause this syndrome; in a percentage of the affected population, the genetic basis remains unknown.
Infants usually become ill during the first few months of life because they lack cellular and humoral immunity. Symptoms typically include, but are not limited to, persistent oral thrush, ear infections, failure to thrive, chronic diarrhea, pneumonia, and sepsis. Patients may have all the characteristics listed in Tables 2 and 3. They may also have a perinatal rash resembling measles or atopic dermatitis, the result of a graft-versus-host reaction caused by transplacentally transferred maternal lymphocytes.
SCID should be suspected when the lymphocyte count is persistently low and immunoglobulins are decreased. The diagnosis is confirmed by flow cytometry and absent proliferative response of lymphocytes to mitogen and antigen stimulation, which confirms the markedly depressed T- and B-cell function.
Antibiotic treatment for specific infectious diagnoses should be pursued aggressively. Precautions must be taken to minimize the possibility of lethal complications; for example, do not administer live viral vaccines, and give only irradiated, leuko-depleted blood products.
Definitive treatment is immunoreconstitution by bone marrow transplant. Gene therapy for two of the genetic types of SCID has been attempted and has been successful for one type.15 Enzyme replacement therapy, by polyethylene glycol-conjugated adenosine deaminase (PEG ADA), is possible in the autosomal recessive SCID caused by adenosine deaminase deficiency (observed in about 15% of SCID infants16).
Key points for SCID
A 1-year-old boy has severe eczema on his arms, legs, and trunk and purulent drainage from his left ear. At the time you examine him, he is afebrile. His mother reports that he bruises easily and has had a multitude of ear infections. He was admitted to the hospital once for bloody diarrhea and was noted to have a mildly decreased platelet count.
Eventual diagnosis: Wiskott-Aldrich syndrome. WAS is an X-linked immunodeficiency characterized by eczema, susceptibility to infection, and thrombocytopenic purpura with small, defective platelets.1 Wiskott-Aldrich syndrome protein (WASP) is involved in the actin polymerization process and believed to be responsible for maintaining the integrity of the cytoskeleton.3 The gene encoding for WASP was identified in 1994 and mapped to Xp11.22; a wide variety of mutations have been identified. Children with WAS may exhibit excessive bruising or bloody diarrhea. Early in life, eczema is prominent, as well as susceptibility to infection caused by encapsulated bacteria and pneumococci. Later in life, infection by opportunistic organisms may occur.
Immunoglobulin levels are variable in these patients. Usually, IgM is low and IgA, IgG, and IgE are elevated. Antibody response to polysaccharide antigens is impaired and blood-group isohemagglutinins are absent.1 T-cell function may be intact initially but declines with time. Patients often have autoimmune cytopenia and vasculitis. The most frequent cause of death is lymphoma (induced by Epstein-Barr virus). In the modern era, the death from infection and bleeding once seen is uncommon.
Treatment is usually supportive, with antibiotic therapy as needed and monthly IVIG infusion. Often, splenectomy is required in patients with uncontrolled bleeding due to hypersplenism.
Successful bone marrow transplantation from HLA-identical siblings or an HLA-matched unrelated donor have been performed after conditioning with irradiation and chemotherapy.5 In older children, transplantation has been hampered by the presence of pre-existing infection; the prognosis for transplant is probably better early in life, before multiple infections are established. If the mutation is known to be in the family, prenatal diagnosis of WAS can be made by chorionic villous sampling or amniocentesis.
Key points for WAS
A 1-year-old boy refuses to use his right leg. He has had a fever for the last two days. On physical examination, he has enlarged inguinal nodes and splenomegaly. His medical history includes lymphadenitis, and several abscesses that required incision and drainage and grew Klebsiella sp. A radiograph of the hip revealed findings consistent with osteomyelitis.
Eventual diagnosis: Chronic granulomatous disease. CGD is a neutrophil defect characterized by impaired intracellular killing of bacterial and fungal organisms. X-linked and autosomal recessive forms exist. Patients are susceptible to catalase-positive organisms (S aureus, Escherichia coli, Pseudomonas sp, Klebsiella sp, Proteus sp, Salmonella sp) and fungi, mainly Aspergillus. The neutrophils cannot produce hydrogen peroxide and the other superoxides required to kill catalase-positive organisms.
Symptoms often manifest early in life, although there have been reports of patients who did not exhibit symptoms until after the first decade of life. Common presenting symptoms include lymphadenopathy (often with drainage), granuloma formation, abscesses, osteomyelitis, and hepatosplenomegaly. Lymphadenitis with Serratia is almost pathognomonic for this disorder. Some patients have gastrointestinal obstruction caused by granulomatous inflammation of the mucosa in the gastric antrum or small bowel.
Diagnosis is made on the basis of the clinical picture and the respiratory burst assaya flow cytometric assay of the ability of neutrophils to reduce a non-fluorescent compound to fluorescent form in the presence of a stimulus to the neutrophil respiratory burst. In some centers, this test has replaced nitroblue tetrazolium (NBT) dye reduction.
Early and aggressive treatment of infections with antibiotics is necessary. In the absence of microbiologic diagnosis, therapy to cover staphylococcal and gram-negative organisms should be used empirically. Invasive and deep tissue fungal infections are frequently encountered and require aggressive antifungal therapy with amphotericin or another potent antifungal agent. Studies have suggested at least limited benefita reduction in the number of serious infectionswith IFN-g-therapy.17 Many patients survive into the third decade of life.
Key points for CGD
The authors thank Loretta Rudloff, DO, for her input and help in the preparation of the manuscript of this article.
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Majed Koleilat, Larry Williams, Michael Ryan. Read the warning signs of primary immunodeficiency.