Key points

Introduction

Primary immunodeficiencies (PIDs) are a diverse set of immunologic disorders that are intrinsic to the immune system. With the widespread use of high-throughput DNA sequencing, the number of monogenic causes of PIDs has increased dramatically and currently is more than 250 individual genes. Despite these advances in identifying the genetic cause of increasing numbers of PIDs, common variable immunodeficiency (CVID) is by far the most common PID; but the molecular nature of the disorder remains to be defined. Regardless of the cause of a PID, the clinical phenotype is extremely diverse in many cases and may present with autoimmunity or other unusual but serious disorders rather than recurrent infections. In this article, the authors highlight 2 cases of PID that presented with unusual clinical manifestations that led to a delay in diagnosis.

Introduction

Primary immunodeficiencies (PIDs) are a diverse set of immunologic disorders that are intrinsic to the immune system. With the widespread use of high-throughput DNA sequencing, the number of monogenic causes of PIDs has increased dramatically and currently is more than 250 individual genes. Despite these advances in identifying the genetic cause of increasing numbers of PIDs, common variable immunodeficiency (CVID) is by far the most common PID; but the molecular nature of the disorder remains to be defined. Regardless of the cause of a PID, the clinical phenotype is extremely diverse in many cases and may present with autoimmunity or other unusual but serious disorders rather than recurrent infections. In this article, the authors highlight 2 cases of PID that presented with unusual clinical manifestations that led to a delay in diagnosis.

Case 1: autoimmune cytopenias and lung disease

A 17-year-old girl presented to her primary care provider with a 2- to 3-week history of shortness of breath and bruising without known trauma. Her medical history is significant for only allergic rhinitis, which she thinks is worsening, with increased nasal congestion and 3 episodes of sinusitis over the last year. Her only medication is loratadine for symptoms of allergic rhinitis. The remainder of the personal history and family history are unremarkable. Physical examination is remarkable for bruises on the left thigh, left forearm, and right shoulder. Pertinent laboratory findings include the following: hemoglobin (Hgb) 8.1 g/dL, platelets 15,140/μL, and a positive direct Coombs (immunoglobulin G [IgG]). The patient was diagnosed with Evan syndrome and treated with prednisone with a normalization of the platelet count and Hgb.

One year after discontinuing prednisone, the patient again presented with bruising. Hgb was 8.5 g/dL and the platelet count was 11,000/μL. The physical examination was notable for bruising and an enlarged spleen 4 cm below the left midclavicular line. Bone marrow examination revealed large megakaryocytes but no evidence of malignancy. A computed tomography (CT) scan of the abdomen demonstrated splenomegaly, scattered adenopathy, and nodular and ground-glass abnormalities in the lower lungs zones. Based on these findings, a high-resolution CT (HRCT) of the chest was performed that revealed large nodules with ground-glass abnormalities in the lower lung zones and mediastinal adenopathy. PET-CT imaging revealed hypermetabolic lymph nodes in the mediastinum, abdomen, and right inguinal region, with increased uptake in the nodular lesions of the lower lung zones. Biopsy of the right inguinal lymph node revealed noncaseating granulomas but was negative for malignancy. Cultures were negative for routine pathogens, fungi, and mycobacteria. Pulmonary medicine performed a transbronchial biopsy that demonstrated noncaseating granulomas, and a presumptive diagnosis of sarcoidosis was made. The patient was treated with prednisone with resolution of the anemia and thrombocytopenia. However, following 4 months of corticosteroids, there was only a small decrease in the radiographic abnormalities on HRCT of the chest and no changes in the mild restrictive lung disease as determined by complete pulmonary function tests. Corticosteroids were slowly tapered, and other therapeutic options were entertained.

Over the next 2 months the patient had 2 episodes of sinusitis. Clinical immunology was consulted for evaluation of possible immunodeficiency. Quantitative immunoglobulins demonstrated a low IgG (250 mg/dL), absent IgA (<10 mg/dL), and low IgM (12 mg/dL). Postimmunization titers to diphtheria, tetanus, and pneumococcal vaccine polyvalent were nonprotective; the diagnosis of CVID was made. Video-assisted thoracoscopic lung biopsy was performed and demonstrated granulomatous and lymphocytic interstitial lung disease (GLILD). The patient underwent treatment with azathioprine and rituximab, and an HRCT scan of the chest 6 months after beginning immunosuppressive therapy showed marked improvement of the parenchymal abnormalities and pulmonary function.

Common variable immunodeficiency

CVID is the most common PID to be followed by a clinical immunologist and requires regular therapy. Recent data from the European Society for Immunodeficiencies (ESID) registry and the United States Immunodeficiency Network registry showed that CVID accounted for 20% to 30% of all reported PIDs. The estimated prevalence of CVID has been estimated at between 1:10,000 and 1:100,000 of the population. The wide variation in the prevalence of the disease is likely multifactorial, but underdiagnosis likely contributes to these discrepancies. The diagnosis of CVID is frequently delayed with studies reporting a median of 5 to 9 years from the onset of symptoms to the diagnosis of CVID.

Definition and laboratory test results’ abnormalities

The diagnostic criteria for CVID based on a recent international consensus document are summarized in Box 1 . The current guidelines to diagnosis CVID do not require the typical clinical manifestations (eg, recurrent infections, autoimmunity) to be present in a patient at the time of the diagnosis, a feature that is not present in alternative diagnostic criteria. The enumeration of lymphocyte subsets in patients with CVID reveals several abnormalities. In contrast to congenital agammaglobulinemias, B cells are typically present in peripheral blood. However, in approximately 10% of patients, B cells are profoundly reduced or absent, which may portend a poorer prognosis. B-cell subset analysis is useful in identifying patients at risk to develop complications of the disorder. For example, low numbers of isotype class switched B cells (CD27 ⁺ , IgM ^– , IgD ^– ) in peripheral blood correlates with an increased risk of multisystemic granulomatous disease and splenomegaly. T-cell abnormalities are common and may include T-cell lymphopenia, anergy, and poor response to mitogens. A subset of patients with CVID may have profoundly reduced numbers of CD4 T cells (<200 cells per microliter). These patients are much more likely to have noninfectious and infectious complications of CVID and are at risk for increased mortality.

Cause

CVID is a clinical syndrome with a common laboratory phenotype. The protean clinical manifestations of CVID likely represent the many heretofore-unidentified causes of the disorder. Many reserve the diagnosis of CVID to those PIDs that meet the international criteria (see Box 1 ) and for which no monogenic cause has been found. Depending on the ethnicity of a population, CVID is familial in approximately 5% to 25% of the cases. Heterozygous mutations in the transmembrane activator and calcium-modulator and cyclophilin-ligand interactor (TACI) gene are found in 5% to 10% of patients and are associated with a dramatically increased risk to develop CVID, whereas homozygous mutations of TACI invariably lead to a CVID-like disorder. Interestingly, in contrast to patients with CVID and heterozygous mutations in TACI, patients with homozygous mutations do not have autoimmune complications typically found in CVID. With the increasing use of high-throughput DNA sequencing, there are several monogenic disorders that share many of the features of CVID (eg, CD19 deficiency, CTLA4 deficiency, Inducible T cell costimulator deficiency). Consequently, many clinical immunologists perform either targeted gene sequencing or whole-exome sequencing in patients with CVID with an unusual clinical phenotype (eg, severe clinical phenotype, early age of onset).

Clinical manifestations

The onset of the clinical manifestations of CVID is highly variable. In the United States, the mean age for the diagnosis of CVID is the third decade of life. In contrast, data from the ESID registry found that more than 30% of patients with CVID had an onset of disease at less than 10 years of age, with 38% of males diagnosed before 10 years of age. Regardless of these differences, CVID should be considered in any person with unusually severe, frequent, or chronic infections who is greater than 2 years of age.

Recurrent upper and/or lower respiratory tract infections (RTIs) (bronchitis, sinusitis, otitis media, and pneumonia) are a hallmark of CVID occurring in greater than 90% of such patients. Encapsulated bacteria ( Haemophilus influenzae, Streptococcus pneumoniae ) and atypical bacteria ( Mycoplasma or Ureaplasma spp) are common pathogens. As most clinical laboratories do not culture for Mycoplasma sp and serology cannot be used to reliably diagnose infection in antibody-deficient patients, antimicrobial therapy for RTIs should include coverage for atypical pathogens. Opportunistic infections are uncommon in patients with CVID unless T-cell counts are profoundly reduced. Gastrointestinal (GI) tract infections with bacteria pathogens similar to those in immunocompetent hosts are common. Infections with Giardia lamblia may be particularly severe and difficult to treat and often require a longer duration of therapy than in an immunocompetent host. Recently, chronic norovirus infection has been implicated in the enteropathy that occurs in CVID.

There has been a marked decline in mortality due to infection with the use of high-dose antibody replacement therapy. In contrast, morbidity and mortality due to noninfectious complications has appreciably increased. Noninfectious complications are extremely common and occur in more than 60% of patients with CVID and include chronic lung disease, GI tract disease, liver disease, autoimmune disease, and cancer. Autoimmune cytopenias are especially common and complicate 29% of patients with CVID. Autoimmune thrombocytopenia is the most common, but Coombs-positive autoimmune hemolytic anemia and autoimmune neutropenia occur as well. GI complications include chronic enteropathy and inflammatory bowel disease. The risk to develop B-cell lymphomas is increased in CVID and similar to individuals infected with human immunodeficiency virus type 1 (HIV-1). These lymphomas are due to EBV in only a minority of cases. Increased risk of early mortality in CVID is found in patients with functional or structural lung disease, GI tract disease, liver disease, and B-cell lymphomas.

The pulmonary complications of CVID are diverse and a major cause of morbidity and mortality. With the use of HRCT scans of the chest as a mandatory screen for pulmonary disease, clinically significant pulmonary disease was found to be present in more than one-third of patients. Bronchiectasis is the most common and may be present in as many as 60% of patients as determined by HRCT of the chest. Gamma globulin replacement therapy markedly reduces pyogenic lung infections. However, gamma globulin only contains IgG; some studies suggest that antibody replacement will not fully prevent the development of bronchiectasis. Therapy for bronchiectasis is similar to those patients with bronchiectasis without immunodeficiency and emphasizes the mobilization of secretions. Based on studies of patients with bronchiectasis without immunodeficiency that showed decreased infectious exacerbations, chronic azithromycin prophylaxis is frequently used in patients with CVID and bronchiectasis.

Diffuse interstitial lung disease (ILD) occurs in 20% to 30% of patients with CVID and includes GLILD, cryptogenic organizing pneumonia (COP), and B-cell lymphomas, which include bronchus-associated lymphoid tissue lymphomas or higher-grade B-cell lymphomas. Apart from COP, which seems to respond to corticosteroid therapy, other forms of diffuse ILD are resistant to corticosteroid therapy and do not respond to gamma globulin replacement therapy.

Granulomatous disease, which can occur in virtually any organ but most commonly in the lung, spleen, liver, bone marrow, and/or GI tract, is reported to occur in approximately 10% to 25% of patients with CVID. As standard screening tests for granulomatous disease are infrequently performed, the diagnosis may be significantly delayed or missed altogether. GLILD is the pulmonary manifestation of a multisystemic granulomatous disease. The diagnosis of GLILD is based on the constellation of histopathologic findings that typically occur in the same biopsy and include non-necrotizing granulomas, lymphocytic interstitial pneumonitis (LIP), and follicular bronchiolitis. GLILD is not specific to CVID and has been reported in other PIDs, including CTLA4 haploinsufficiency, lipopolysaccharide responsive beigelike anchor protein (LRBA) deficiency, and hypomorphic mutations of the recombinase activating 1 (RAG1) gene. The natural history of GLILD in CVID is not clearly defined, and some think that progressive pulmonary disease may not occur. In contrast, the authors reported that GLILD leads to progressive impairment and early mortality with moderate to severe pulmonary fibrosis in nearly 50%.

The constellation of findings of non-necrotizing granulomas and mediastinal adenopathy led to the belief that GLILD was a form of sarcoidosis in patients with CVID. It is now established that the two disorders are distinct disorders with unique pathologic, radiographic, and clinical findings. GLILD is a macronodular disease with a lower lung zone predominance, whereas sarcoidosis is typically micronodular with an upper lung zone predominance. Follicular bronchiolitis and LIP are much more predominant in GLILD compared with sarcoidosis. Other features characteristic of GLILD include a high prevalence of autoimmune cytopenias, frequent presence of hepatosplenomegaly, lack of spontaneous remission of lung disease, and failure to respond to corticosteroid therapy.

The cause of GLILD is unknown, but the occurrence in other PIDs characterized by autoimmunity suggests that this may be a common response of the lung to immune dysregulation. It has been reported that the overproduction of tumor necrosis factor-α (TNF-α) may lead to the granulomatous disease in CVID. TNF-α antagonists have been reported to successfully treat patients with GLILD, lending further support to this hypothesis. In a retrospective study of 7 patients, rituximab/azathioprine therapy was found to markedly improve the radiographic abnormalities on HRCT of the chest and pulmonary function of patients with CVID and GLILD. This approach needs to be validated in a properly controlled, placebo-controlled, prospective study.

Replacement gamma globulin, administered either subcutaneously or by vein, is the treatment of choice for all patients with CVID. A typical starting dosage of gamma globulin is 400 mg/kg to 600 mg/dL per month. Although measurement of serum IgG is useful, the doses of gamma globulin are increased to prevent serious infections. Patients with granulomatous disease, bronchiectasis, or marked splenomegaly require a higher dose of gamma globulin to prevent infection compared with patients without these complications.