Primary Immunodeficiency Diseases in Adults

A 35-year-old woman with pneumococcal bacteremic pneumonia was admitted to her local hospital in 1986. Her initial hospital course was complicated by respiratory insufficiency, disseminated intravascular coagulation, and renal failure, and she was transferred to The Johns Hopkins Hospital for further evaluation and management.

Her medical history was notable for multiple episodes of bronchitis and otitis media in childhood, and a tonsillectomy and adenoidectomy at age 16 years. At age 29 years, she began to experience multiple episodes of sinusitis, a chronic productive cough, and frequent diarrhea. She also had 2 episodes of pneumonia; one, at age 33 years, required hospitalization for intravenous antibiotics to treat Streptococcus pneumoniae, which had been isolated from a sputum culture. During the year preceding her 1986 admission, she developed dyspnea on exertion and intermittent diarrhea and lost 13.5 kg. She had to quit her job and could no longer do her routine housework.

She had no family history of frequent or unusual infections, immunodeficiency, rheumatic or autoimmune disorders, or pulmonary disease. There was no consanguinity.

Physical examination revealed a cachectic woman with bilateral rales and splenomegaly. Laboratory evaluation disclosed a white blood cell count of 9.0×10⁹/L with 0.01 bands, 0.84 polymorphonuclear cells (absolute polymorphonuclear count, 7.56×10⁹/L; reference value, >1.50×10⁹/L), 0.13 lymphocytes (absolute lymphocyte count, 1.17×10⁹/L; reference value, >1.10×10⁹/L), and 0.02 monocytes. The hemoglobin level was 10.8 g/L and the platelet count was 148×10⁹/L. Chest x-ray films confirmed pneumonia and bronchiectasis. Direct visual examination of stool showed Giardia lamblia.

Because of the patient's history of recurrent and severe infections, an immunologic evaluation was performed. The serum IgG level was 1.85 g/L (reference range, 6.90-16.20 g/L), IgA was undetectable (reference range, 0.70-3.80 g/L), and the IgM level was 0.67 g/L (reference range, 0.60-2.60 g/L). Tetanus, diphtheria, and rubella titers were nonprotective despite previous immunizations. The CD4⁺ T-lymphocyte count was 20% (reference range, 34%-56%) and the CD8⁺ count was 26% (reference range, 18%-32%), with a ratio of 0.77 (reference range, 1.1-2.5); her absolute CD4 count was 0.26×10⁹/L (reference value, >0.43×10⁹/L). Serum protein electrophoresis showed hypogammaglobulinemia with no evidence of monoclonal gammopathy.

The diagnosis of common variable immunodeficiency (CVID) was made and intravenous immunoglobulin was initiated at a dose of 400 mg/kg. A course of metronidazole was instituted to treat the G lamblia infection . The patient's symptoms improved slowly and she was discharged after 2 weeks.

She has been treated for the past decade with a monthly regimen of intravenous immunoglobulin. Her general health initially improved, with a weight gain of 13.5 kg, and she was able to return to gainful employment. Although she has not experienced any further episodes of pneumonia, she has continued to develop other infections, including 1 to 3 episodes of bronchitis or sinusitis each year. On one occasion, Escherichia coli was isolated from one of her sinuses during an episode of sinusitis. She has also had several episodes of diarrhea that have been responsive to empiric therapy aimed at eradicating G lamblia. She has continued to experience mild dyspnea on exertion. Her lung function has stabilized with a forced expiratory volume in 1 second (FEV₁) of 0.98 L (37% of predicted), a forced vital capacity (FVC) of 1.41 L (48% of predicted), and an FEV₁/FVC ratio of 0.70 (83% of predicted). She has maintained a stable low lymphocyte count (0.99×10⁹/L) and ongoing mild thrombocytopenia (73×10⁹/L).

Because of the patient's concern, her 3 children underwent immunologic evaluation. All were found to have absent IgA but normal total IgG and IgG subclasses. They remain clinically well.

The primary immunodeficiency diseases are a group of more than 50 disorders in which the underlying defect is intrinsic to the immune system.¹ These disorders affect virtually every functional compartment of the immune system. Although many of the primary immunodeficiency diseases are genetically determined and inherited as single-gene defects, the etiology of some of the diseases remains unknown.

Today's patient represents a dramatic presentation of CVID, one of the many primary immunodeficiency diseases that can affect adults. The following discussion focuses on 2 points that this patient illustrates. First, we discuss her specific primary immunodeficiency disease, CVID, focusing on its clinical presentation, etiology, pathogenesis, and therapy. Second, we review the different types of primary immunodeficiency diseases that can affect adults.

Common variable immunodeficiency is the most common clinically significant primary immunodeficiency disease that can present initially in adult life. Common variable immunodeficiency is used to describe a heterogeneous group of immunologic disorders of unknown etiology, characterized by low levels of serum immunoglobulin and impaired antibody responses.^{2 - 6}

Patients can present with CVID at any age. In a large series of pediatric and adult patients with CVID, there was a bimodal distribution of the age at which the diagnosis was first made, with one peak between 6 and 10 years and another between 26 and 30 years.⁴ Importantly, more than two thirds of the patients were adults (at least 21 years old) when the diagnosis was first made.

The most common clinical presentation of CVID is an increased susceptibility to infection^{2 - 6} (Table 1). Most patients, like the patient presented today, experience recurrent or chronic sinopulmonary infections, or both. The most common respiratory pathogens are encapsulated pyogenic bacteria, such as the pneumococcus and staphylococcus and Haemophilus influenzae type b. Respiratory infections can also be caused by mycoplasma and unencapsulated H influenzae. Patients with CVID can also develop infections at sites other than the respiratory tract. Infectious diarrhea caused by giardia, campylobacter, salmonellae, shigella, and rotavirus can become chronic and lead to significant weight loss, as happened to today's patient. Blood-borne infections such as sepsis, meningitis, septic arthritis, and osteomyelitis are also seen more frequently in patients with CVID than in immunocompetent persons.

Although infections in patients with CVID are most often caused by the same organisms that cause comparable infections in immunocompetent hosts, patients with CVID can also have infections caused by opportunistic organisms such as Pneumocystis carinii, herpes zoster, and a variety of fungi.^{2 - 6} Pathogens that have one clinical expression in an immunocompetent host can have a very different clinical expression in an immunodeficient host. For example, patients with CVID can develop chronic, and often fatal, meningoencephalitis caused by common enteroviruses such as echovirus and coxsackievirus, although less commonly than patients with X-linked agammaglobulinemia.^{5 ,7}

The use of serologic tests to diagnose a specific infectious disease, such as hepatitis or human immunodeficiency virus disease, may not be useful in patients with CVID or other antibody deficiency diseases, because these patients may not generate a normal antibody response to infectious agents.

In addition to their increased susceptibility to infection, patients with CVID can develop a variety of autoimmune and inflammatory disorders.^{2 - 6 ,8} In some patients, the autoimmune or inflammatory disorder is the initial clinical presentation of CVID, preceding the onset of infections by years, while in other patients, autoimmune or inflammatory disorders appear concurrently with, or subsequent to, the increased susceptibility to infection. In a large study of 106 patients with CVID, nearly one quarter developed one or more autoimmune diseases, such as immune thrombocytopenic purpura, autoimmune hemolytic anemia, rheumatoid arthritis, sicca syndrome, systemic lupus erythematosus, autoimmune thyroiditis, vitiligo, or primary biliary cirrhosis.⁴ Interestingly, in this series, autoimmune diseases were seen more often in female than male patients with CVID.⁴

Patients with CVID are also at risk for inflammatory bowel disease.^{2 - 6 ,9} The inflammatory bowel diseases may include Crohn disease, celiac disease, and nodular lymphoid hyperplasia.^{2 - 6 ,9} In one series, symptoms referable to the gastrointestinal tract occurred in more than 50% of patients,² although in most series the prevalence of gastrointestinal symptoms is lower.^{3 - 5} Although some patients' gastrointestinal symptoms can be attributed to infection, they often appear to be related to inflammatory bowel disease.

A syndrome resembling sarcoidosis can also affect patients with CVID. The syndrome is characterized by granulomas in the lung, liver, spleen, and conjunctivae; the granulomas are indistinguishable from those of classic sarcoidosis.¹⁰ Symptoms can include hepatosplenomegaly, immune thrombocytopenic purpura, autoimmune hemolytic anemia, and iridocyclitis.

Once the diagnosis of CVID is suspected based on clinical presentation, laboratory confirmation is relatively simple. The most consistent laboratory abnormality in CVID is low serum IgG levels, with most patients having concurrent deficiencies of IgA and IgM.^{2 - 6} Response to immunization with protein antigens (eg, tetanus) and carbohydrate antigens (eg, pneumococcal capsular polysaccharides) is usually diminished as well. As many as 20% of patients have lymphopenia.^{4 - 5} Most patients have normal numbers of B lymphocytes in their peripheral blood.⁴ Levels of T-lymphocyte subsets are also usually normal. However, in one series, 14 of 38 patients with CVID had elevated levels of CD8⁺ lymphocytes.¹¹

One of the most important goals in the differential diagnosis of CVID is the exclusion of hypogammaglobulinemia secondary to other disorders. For example, it is essential to exclude hypogammaglobulinemia secondary to loss of immunoglobulins and other serum proteins in the stool or urine. Hypogammaglobulinemia may also be associated with chronic lymphocytic leukemia, thymoma (Good syndrome¹ ), or other lymphoreticular malignancies.^{2 - 6} In addition, it is important to exclude hypogammaglobulinemia secondary to the effects of drugs such as phenytoin or cyclophosphamide. Finally, other primary immunodeficiency diseases must be excluded. For example, rare cases of X-linked agammaglobulinemia present relatively late in life and may initially be confused with CVID.¹²

The cause of CVID is unknown. Because the disorder is probably the consequence of a variety of causes, a single etiology is unlikely.⁶ However, much evidence supports a genetic predisposition to the disorder, at least in some patients. For example, in 10% of patients, CVID or a related primary immunodeficiency disease (IgA deficiency) is found in more than one family member,⁴ as it was in today's patient. In families in which multiple members are affected, the pattern of inheritance of the immunodeficiency does not conform to strict mendelian rules. In some families, the immunodeficiency can appear to skip a generation, and in others, one family member may have IgA deficiency while another may have CVID,^{4 ,13} suggesting variable expressivity and penetrance of a disease susceptibility gene. In fact, studies have shown that susceptibility to either CVID or IgA deficiency may be linked to specific alleles of class II and class III genes of the major histocompatibility complex,^{14 - 15} suggesting that these alleles, or alleles of closely linked genes with which they are in linkage disequilibrium, are somehow involved in the pathogenesis of CVID and IgA deficiency. It should be noted, however, that a more recent study has failed to confirm an association between specific major histocompatibility complex haplotypes and CVID.¹⁶

Just as CVID probably has a number of causes, it is also likely that a number of pathogenetic mechanisms are responsible for the development of hypogammaglobulinemia. In some patients there is evidence consistent with an intrinsic defect in B-lymphocyte function, and in others there is evidence that the hypogammaglobulinemia is the consequence of abnormalities in the interactions of T lymphocytes and their lymphokines with B lymphocytes (reviewed in Sneller et al⁶ ).

Although CVID is likely the result of a variety of underlying defects in the immune system, because all patients have hypogammaglobulinemia and functional antibody deficiency, the cornerstone of treatment of CVID is replacement therapy with immunoglobulin preparations containing IgG. Until 1982, the preparations of immunoglobulin licensed for use in the United States could be given only by intramuscular injection. Because only limited volumes of immunoglobulin can be injected intramuscularly at any one time, replacement therapy was limited and it was difficult to maintain the patient's IgG levels in the normal range. However, with the introduction of IgG preparations that can be administered intravenously, patients are now able to receive enough immunoglobulin to sustain their IgG levels in the normal range. Several studies have shown that the success of therapy, whether determined by the number of infections or the degree to which the patient's pulmonary function improves, is directly related to the trough level of serum IgG attained by the replacement therapy.^{17 - 18} The usual dose of immunoglobulin is 400 mg/kg given in a single monthly infusion, but some patients need higher doses or more frequent infusions to control symptoms.

In addition to immunoglobulin replacement therapy, management should include early and aggressive antibiotic therapy for infections, ongoing treatment of autoimmune and inflammatory diseases, and surveillance for malignancy.

The prognosis of CVID depends, at least in part, on how early the disorder is diagnosed and treated. If therapy is initiated before infections have caused structural damage to the lung or other organs, the patient may be expected to do well. However, if therapy is delayed until after recurrent pulmonary infections have caused irreversible bronchiectasis and fibrosis, the patient may continue to have problems, much like today's patient.

Prognosis is also related to whether patients develop autoimmune or inflammatory disorders or malignancies associated with CVID. Patients with CVID are more likely to develop malignancies than the general population, with some estimates as high as 5 to 10 times the normal risk.^{4 - 5 ,19} The most common malignancies involve the lymphoid system (eg, lymphoma) or the gastrointestinal tract (eg, gastric carcinoma), with the risk increasing with advancing age.^{4 - 5 ,19}

Because many of the primary immunodeficiency diseases were first described in infants and children, these disorders were initially considered diseases characteristic of, if not confined to, childhood. It has become increasingly clear, however, that these disorders are as common in adults as in children. There are at least 3 situations in which physicians who care for adults may see patients with primary immunodeficiency diseases. First, several of the primary immunodeficiency diseases can present at any age, and commonly have their initial clinical presentation in adults. Second, as molecular genetic analysis of some of the primary immunodeficiency diseases has advanced, it is evident that many of the disorders that characteristically present initially in childhood may have a mild enough phenotype to allow initial clinical presentation in adulthood. Finally, effective treatments exist for the overwhelming majority of the disorders, allowing survival of many, if not most, children with primary immunodeficiency diseases into adult life.

Several primary immunodeficiency diseases commonly have their initial clinical presentation in adulthood (Table 2). For example, in one series of adult patients with CVID, the onset of symptoms referable to immunodeficiency developed at a mean age of 31 years, but the diagnosis was made at a mean age of 42 years.² A later study,⁴ mentioned earlier, which included children and adults, showed that there were 2 peak ages of diagnosis, one in the first decade of life and the other in the third decade. Other primary immunodeficiencies involving the humoral immune system, such as IgA deficiency, IgG subclass deficiency, or a combination of both, may also present initially in adults.^{20 - 21} Finally, the initial clinical manifestation of many of the complement deficiencies may also be in adult life. For example, C2 deficiency, one of the most common inherited defects of the complement system, is diagnosed most often in adults.²² It should be noted that when a primary immunodeficiency presents initially in adults, it can represent an immune defect that has developed during adult life, as best illustrated by CVID (formerly called acquired hypogammaglobulinemia). Alternatively, it may be a defect that has been present since birth but is most likely mild and does not produce symptoms until adulthood, as best illustrated by some of the genetically determined complement component deficiencies.

There are isolated patients with primary immunodeficiency diseases whose first clinical presentation has been in adulthood, even though these disorders traditionally present initially in infants and young children. In some patients, the delayed onset of symptoms is probably related to a milder clinical phenotype of the genetic defect. Perhaps one of the best examples is adenosine deaminase deficiency, which classically presents as severe combined immunodeficiency disease in infants and is fatal if untreated.²³ However, milder phenotypes of adenosine deaminase deficiency, diagnosed in older children and adults, are the result of specific mutations leading to partial deficiency of this enzyme.^{24 - 25} Wiskott-Aldrich syndrome, an X-linked disorder classically described by the triad of eczema, thrombocytopenia, and immunodeficiency, is yet another primary immunodeficiency disease that may be severe and, if untreated, fatal in children, but has also been diagnosed in a milder form in adults.²⁶ Another example is X-linked agammaglobulinemia, an inherited form of agammaglobulinemia in which B lymphocytes do not mature normally and cannot produce sufficient amounts of immunoglobulin. Even though the majority of patients with X-linked agammaglobulinemia present in infancy or early childhood,²⁷ there are isolated patients with documented disease who present initially well into adulthood.¹²

In addition to differences in mutations leading to milder phenotypes, differences in environmental pressure or in compensatory immunologic mechanisms may also result in late presentation of a congenital immunodeficiency. For example, a 69-year-old man who presented with his first serious clinical infection, sepsis caused by Pseudomonas cepacia, was diagnosed as having the X-linked form of chronic granulomatous disease.²⁸ The diagnosis was considered because the patient's grandson had died of pneumonia with the same organism 9 years earlier, at the age of 5 years. The specific mutation shared by this adult and his grandson was identical and allowed some residual enzyme activity. Presumably, differences in environmental pressures and in the genetic backgrounds of the child and his grandfather may have accounted for the discrepancy in the time of their clinical presentations.

The third way in which primary immunodeficiency can affect adults is through the survival of infants and children with these diseases into adulthood. Advances in therapy have led to improved long-term outcomes for diseases that had previously been considered to be fatal in many infants and children. These improved outcomes have been the result of advancement in supportive therapy (eg, antibiotics), replacement therapy (eg, immunoglobulin replacement, enzyme replacement), and "curative" procedures (eg, bone marrow transplantation). For example, severe combined immunodeficiency disease, a disorder characterized by defective T- and B-lymphocyte function resulting from several genetic defects, was once a fatal disorder in most affected infants,²⁹ but now is "curable" by bone marrow transplantation.³⁰ Similarly, as the molecular genetic basis of the various forms of severe combined immunodeficiency disease is elucidated, specific enzyme replacement therapy and gene therapy are made possible, such as has become available for adenosine deaminase deficiency.^{31 - 33} Another example is chronic granulomatous disease, a defect in phagocyte killing function, which was initially described as "fatal granulomatous disease of childhood."³⁴ Life expectancy has been markedly improved by aggressive management of infections with antimicrobial agents and surgery as needed, by prophylactic antibiotics, and by interferon gamma therapy.³⁵ X-linked agammaglobulinemia is another example of a previously fatal disorder in which early and appropriate therapy with intravenous immunoglobulin has enabled patients to survive into adulthood.^{5 ,27}

Physicians may be called on to diagnose and treat adults with a number of primary immunodeficiency diseases. The major clinical clues to these diseases are an increased susceptibility to infection and unusually high rates of autoimmune disorders and inflammatory disorders. Physicians who care for adults should maintain a high index of suspicion for primary immunodeficiency diseases because early diagnosis should improve long-term prognosis and may have important consequences for genetic counseling.