Primary immunodeficiency diseases in adults

Once seen as children's diseases, one-fourth of cases are now diagnosed in adulthood.


The classic perception is that primary immune deficiency only affects children. However, the diagnosis of primary immunodeficiency diseases (PIDDs) in adults is growing in incidence. In fact, with the advent of superior diagnostic tools and antimicrobial therapies, more than a quarter of all PIDDs are diagnosed in adulthood (11. García JM, Gamboa P, de la Calle A, Hernández MD, Caballero MT, García BE, et al. Committee of Immunology of the Spanish Society of Allergology and Clinical Immunology. Diagnosis and management of immunodeficiencies in adults by allergologists. J Investig Allergol Clin Immunol. 2010;20:185-94. [PMID: 20635783]).

There is an increasing role for hospitalists in the care of PIDD patients, given the inherent complexity of the pathophysiology, diagnosis, and treatment. Primary care and hospitalist physicians are often the first to detect history and physical exam findings that may indicate aberrancies in the immune system. A better understanding of immune diseases may ameliorate diagnostic delay, and early diagnosis could significantly decrease morbidity resulting from recurrent infections.

The most common causes of PIDD in adults are antibody deficiencies, which account for over half the cases (Table 1). Therefore, antibody defects will be the focus of this review. Those affected classically have increased susceptibility to recurrent sinopulmonary bacterial infections with encapsulated bacteria such as Haemophilus influenzae and Streptococcus pneumoniae. However, the clinical presentation can vary significantly depending on the specific immune defect, ranging from nearly asymptomatic to fulminant, life-threatening infections. Common variable immune deficiency (CVID) has heterogeneous presentations, and autoimmunity (particularly idiopathic thrombocytopenia purpura, or ITP) may herald the diagnosis. More recently, awareness is being raised about a subset of individuals affected by CVID with a primary gastrointestinal phenotype (22. Daniels JA, Lederman HM, Maitra A, Montgomery EA. Gastrointestinal tract pathology in patients with common variable immunodeficiency (CVID): a clinicopathologic study and review. Am J Surg Pathol. 2007;31:1800-12. [PMID: 18043034]).

Various forms of deficiency

Immunoglobulin A (IgA) deficiency is the most common PIDD affecting adults, ranging from 1 in 100 to 1 in 1,000 in European, African, and Middle Eastern populations to much less in Asian populations. IgA deficiency is defined as decreased or absent levels of serum IgA with normal IgG and IgM levels in patients older than age 4 (33. Al-Herz W, Bousfiha A, Casanova JL, Chapel H, Conley ME, Cunningham-Rundles C, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2011;2:54. [PMID: 22566844]). Those with serum IgA levels of less than 7 mg/dL are described as having selective IgA deficiency. Individuals with serum IgA levels greater than or equal to 7 mg/dL but less than 2 standard deviations below normal have partial IgA deficiency (44. Yel L. Selective IgA deficiency. J Clin Immunol. 2010;30:10-6. [PMID: 20101521] doi:10.1007/s10875-009-9357-x).

Clinical findings in IgA deficiency are heterogeneous, but most (85% to 90%) lack any symptoms. Manifestations include recurrent sinopulmonary and gastrointestinal tract infections and increased risk of noninfectious states, such as allergic diseases, autoimmunity, and celiac disease (55. Singh K, Chang C, Gershwin ME. IgA deficiency and autoimmunity. Autoimmun Rev. 2014;13:163-77. [PMID: 24157629]). Selective IgA deficiency places patients at risk for anaphylaxis to blood products including intravenous immunoglobulin (IVIG). A subset of patients may develop further antibody deficiencies, such as specific antibody deficiency or CVID.

Specific antibody deficiency occurs in about 8% of adults who report a history of 3 or more episodes of community-acquired pneumonia (66. Ekdahl K, Braconier JH, Svanborg C. Immunoglobulin deficiencies and impaired immune response to polysaccharide antigens in adult patients with recurrent community-acquired pneumonia. Scand J Infect Dis. 1997;29:401-7. [PMID: 9360257]). It is characterized by suboptimal responses to polysaccharide vaccines and infections in light of normal QUIGS (quantitative immunoglobulin values for IgA, IgM, and IgG). Immune responses to polysaccharide antigens rely on T cell-independent pathways for antigen processing. Since absent responses to polysaccharide antigens are common in CVID, severe combined immune deficiency (SCID), and other immune deficiencies, the diagnosis of specific antibody deficiency can only be made in the context of an otherwise normal immune evaluation. The diagnosis is typically prompted by a suggestive history of recurrent sinopulmonary infections and is confirmed by measurement of impaired response to vaccine on post-immunization titers. One subtype demonstrates a normal initial response to immunization, but this effect is temporary and titers rapidly regress by approximately 6 months due to defects in memory B cells.

Patients with suggestive histories who are found to have low pneumococcal titers should receive the unconjugated 23-valent polysaccharide vaccine. Post-immunization titers should be performed 4 to 6 weeks later. A serotype-specific IgG titer equal to or greater than 1.3 µg/mL or a 2-fold increase in antibody titers over baseline levels is considered protective in all age groups, and normal adults should be protected for at least 70% of the serotypes (77. Orange JS, Ballow M, Stiehm ER, Ballas ZK, Chinen J, De La Morena M, et al. Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2012;130:S1-24. [PMID: 22935624]). If a suboptimal response is noted, patients should receive the conjugated 13-valent pneumococcal vaccine. If post-immunization titers are still not protective, the patient should receive a second conjugated vaccine as a booster 4 to 8 weeks later and post-immunization titers should be repeated.

Failure to respond to the unconjugated polysaccharide vaccine is diagnostic of specific antibody deficiency, even if response to conjugated vaccine is intact. Specific antibody deficiency is due to a defect in T cell-independent responsiveness to polysaccharide antigens, and the use of the conjugated protein enlists T-cell participation in antigen processing.

The most clinically significant PIDD in adults is CVID, which affects as many as 1 in 25,000 individuals in the general population (88. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92:34-48. [PMID: 10413651]). It is a diagnosis of exclusion, characterized by both quantitative and functional deficiencies. Serum IgG levels are markedly decreased (typically ≤450 mg/dL), as are IgA and/or IgM (at least 2 standard deviations below the mean) and concurrent impaired antibody responses to vaccinations (99. Cunningham-Rundles C. How I treat common variable immune deficiency. Blood. 2010;116:7-15. [PMID: 20332369], 1111. Agarwal S, Cunningham-Rundles C. Autoimmunity in common variable immunodeficiency. Curr Allergy Asthma Rep. 2009;9:347-52. [PMID: 19671377]).

The presentations are often complex and variable. In addition to a history of increased susceptibility to infections, the clinical picture is often complicated by autoimmune and inflammatory conditions. The treatment of autoimmune disease is complicated by the concurrent primary immunodeficiency. Complications may include pulmonary, gastrointestinal, rheumatologic, hematologic, and dermatologic manifestations. Malignancies, particularly lymphoma, are common.

Diagnosis by exclusion

Case 1: A 33-year-old woman was in generally good health until she presented with acute-onset prolonged flu-like symptoms followed by hepatitis secondary to Epstein-Barr virus (EBV), significant weight loss, and recurrent fevers. She continued to develop intermittent fevers after discharge, and she was readmitted 11 months later for sepsis with EBV/cytomegalovirus viremia. She had no history of recurrent infections, and her family history was noncontributory. Her immune workup revealed pan-hypogammaglobulinemia (IgG <35 mg/dL, IgM <6 mg/dL, IgA <7 mg/dL), and she was given a diagnosis of CVID and started on IVIG.

It is important to emphasize that CVID is a diagnosis of exclusion and that other defined causes of hypogammaglobulinemia must be ruled out before making the diagnosis (99. Cunningham-Rundles C. How I treat common variable immune deficiency. Blood. 2010;116:7-15. [PMID: 20332369]). This patient was given a diagnosis of CVID due to profoundly low immunoglobulin levels of multiple subtypes, but further immune studies also revealed CD4 lymphopenia of 113 cells/µL (normal range, 493 to 1,666 cells/µL), absent B cells, depressed NK cell function, and abnormal lymphocyte proliferation to mitogens. Although a small percentage of patients with CVID will have absent or low B lymphocytes, the additional findings are atypical of CVID and should prompt additional investigations. For instance, an underlying genetic defect such as in hemophagocytosis lymphohistiocytosis may have predisposed her to acquire an EBV infection and a secondary immunodeficiency.

Malignancy is another likely possibility. The patient's initial bone marrow biopsy was described as active EBV infection-associated bone marrow changes, although reevaluation was consistent with diffuse large B-cell lymphoma. Due to religious preferences, the patient declined a stem-cell transplant and succumbed to adenovirus septic shock within months.

Despite increasing numbers of individuals diagnosed with primary immune defects, secondary etiologies remain the leading cause of immunodeficiency in adults. Infectious diseases (HIV, CMV, EBV) and malignancy (B-cell malignancies, chronic lymphocytic leukemia, Good's syndrome, and non-Hodgkin lymphoma) are well-described causes of secondary hypogammaglobulinemia. Medication exposures can also be responsible. Glucocorticoids are by far the most common offending agent, although biologics, antimalarials, captopril, carbamazepine, gold salts, phenytoin, and other antiepileptics have also been implicated. Finally, systemic disorders that result in either hypercatabolism or increased loss of immunoglobulins, such as in protein-losing enteropathy, must also be ruled out (1010. Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol. 1999;93:190-7. [PMID: 10600329]). In the case presented above, one must question why a healthy 33-year-old woman would suddenly develop a profound, combined immunodeficiency and disseminated EBV infection. Thus, malignancy is a more likely diagnosis.

Hyperimmunoglobulin M syndromes

The hyperimmunoglobulin M syndromes are a heterogeneous group of disorders characterized by defects in class switch recombination with or without defects in somatic hypermutation. The disease is defined by the inability of B cells to effectively communicate with T cells through CD40 (on B cells) and CD40 ligand (on T cells). This interaction is an absolute requirement for class switching from IgM, the default pathway, to IgG, IgA, or IgE. Mutations can reside in genes encoding CD40L and CD40, as well as activation-induced deaminase (AID) and uracil N-glycosylase (UNG) within B cells that play a direct role in class switching. The inheritance of these genetic mutations can be X-linked or autosomal recessive. Patients with hyper-IgM experience recurrent sinopulmonary infections but also have an increased susceptibility to opportunistic infections, severe neutropenia, and complications with autoimmunity. Pneumocystis jiroveci pneumonia is a presenting feature in about 40% of patients, and irreversible biliary tract complications with Cryptosporidium species is a common reason for early morbidity and mortality.

Case 2: A 22-year-old man originally presented in childhood with Evans syndrome (ITP with autoimmune hemolytic anemia) and was diagnosed with CVID as a young adult. He was treated with IVIG for his hypogammaglobulinemia and had been receiving infliximab and chronic prednisone for Evans syndrome for many years. He presented in respiratory failure at our institution with anasarca, 3+ pitting edema in all extremities, clubbing of all digits, splenomegaly, and petechiae. Immunoglobulin levels while on monthly replacement were IgG, 297 mg/dL; IgA, <8 mg/dL; and IgM, 1,450 mg/dL (1,810 mg/dL on repeated testing). Flow cytometry revealed a normal number of B cells, all of which were immature, and no evidence of class-switched cells. A T-cell panel showed CD4 lymphopenia (278 cells/µL), low memory CD4 cells, and increased activated CD8 cells. Bone marrow biopsy was negative for leukemia/lymphoma. The patient was found to have cryptogenic cirrhosis with severe hypoxemia secondary to intrapulmonary shunting from hepatopulmonary syndrome.

Despite depressed IgG and IgA levels and history of ITP, which occurs in 5% to 8% of patients with CVID, it is important to note that this patient's IgM level was persistently over 5 times the upper limit of normal (1111. Agarwal S, Cunningham-Rundles C. Autoimmunity in common variable immunodeficiency. Curr Allergy Asthma Rep. 2009;9:347-52. [PMID: 19671377]). Once malignancy is ruled out, this should prompt consideration of other immune defects. Elevated IgM can occur in light of chronic active liver disease, but in this patient it may have been the etiology of his primary immunodeficiency.

Evaluation of PIDDs

The initial evaluation of primary immunodeficiency begins with a detailed patient history and physical exam. Special attention should be paid to recurrent sinopulmonary infections that necessitate antibiotics, recurrent abscesses, a family history of immunodeficiency, use of intravenous antibiotics for infections, and history of failure to thrive thrive (see more on this online) .

Laboratory evaluation should be completed in a stepwise fashion beginning with a complete blood count with differential and metabolic panel to evaluate for overall lymphocyte and neutrophil counts, as well as any metabolic derangements that may indicate organ damage. Specific immune workup begins with quantifying serum immunoglobulins as well as measuring titers to tetanus, Streptococcus pneumoniae, Haemophilus influenzae B, and hepatitis B. These results provide a helpful overall picture of immunoglobulin production and reflect the ability of B- and T-cells to interact in generating specific antibodies to antigenic stimuli either from natural exposure or immunizations. Vaccination and post-immunization titers are warranted if titers are not protective (Table 2). Lymphocyte function can be measured by quantifying proliferative responses to various stimuli that act through either antigen-dependent or independent pathways.

Abnormalities in initial immune studies or a suggestive history in the setting of normal preliminary investigations should prompt collaboration with an immunologist for further evaluation. Additional immunodeficiencies, most of them relevant to the adult population, are briefly reviewed in Table 3.

We are increasingly relying on advanced testing modalities. Flow cytometric analyses to detect protein expression can be essential to characterize many immune defects. B-cell phenotyping using cell surface markers that identify mature memory population can identify those at increased risk for complications in CVID and may guide clinicians in targeting therapy (1212. Cunningham-Rundles C. The many faces of common variable immunodeficiency. Hematology Am Soc Hematol Educ Program. 2012;2012:301-5. [PMID: 23233596]). Additional specialized studies for functional analyses, immunophenotyping, and gene sequencing are also available for appropriate cases. Whole exome sequencing in conjunction with functional assays is gaining clinical relevance in the diagnosis of atypical PIDDs.

Although the patient presented in the second case had laboratory findings and a clinical presentation consistent with that of hyper-IgM syndrome, he did not demonstrate any of the known mutations associated with this syndrome, since genetic studies for mutations involving CD40L, CD40, UNG, and AID were all negative. The patient died before functional studies were performed or complete exome sequencing was obtained.

Case 2 presents the possibility of a novel genotype for hyper-IgM syndrome and illustrates the importance of pursuing multiple investigations concurrently for patients with unusual primary immune deficiency syndromes. Flow cytometric analysis evaluating CD40L and CD40 expression would have been immensely helpful in addition to the genotype data.

Conclusions

Primary care and hospitalist physicians are playing increasing roles in the initial evaluation and long-term care of patients with PIDD.

Antibody defects account for most cases of PIDD in the adult population and classically manifest with recurrent sinopulmonary infections. ITP and other forms of autoimmunity are common associations, and enteropathy is an increasingly recognized comorbid condition. Individuals with CVID are at heightened risk for hematologic, intestinal, and dermatologic malignancies.

Abnormalities in initial immune studies or a suggestive history in the setting of normal results should prompt collaboration with an immunologist.

Flow cytometry assays and whole genome sequencing, which were once considered only research-based tools, are rapidly becoming the standard of care.