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A case of common variable immunodeficiency
tion. In R. A. Thompson (ed.), Techniques in clinical immunology, 2nd ed. BlackwellsScientific Publications, Oxford. Gewur'z, H., and Lisbeth A. Suyehira. 1976. Complement. In N. R. Rose and H. Friedman (eds.), Manual of clinical immunology. American Society for Microbiology, Washington, D.C. Lachmann, P. J., and F. S. Rosen. 1979.
P. 105. In M. D. Cooper, et al. (eds.), Immunodeficiency. Springer-Verlag, Berlin. McLean, R. H., and Susan Nilson. 1980. Complement in human diseases. In Noel Rose and P. E. Bigazzi(eds.), Methods in immunodiagnosis, 2nd ed. John Wiley& Sons, New York. Muller-Eberhard, H. J. 1980. Complement reaction pathways, p. 1001. In M. Fongereau and J. Dausset (eds.),
Progress in immunology IV. Academic Press, London. Thompson, R. A. 1981. Assessmentof clinical hypocomplementaemia.In R. A. Thompson (ed.), Techniques in clinical immunology, 2nd ed. Blackwells Scientific Publications, Oxford.
immunoglobulin-bearing cells (1.5 % --normal range = 8-15%); c) Lymphocyte blastogenesis (stimulation indices): phytohemagglutinin (68-normal control = 56), concanavalin A (70--normal control = 55), pokeweed mitogen (45mnormal control = 31). Additional problems identified were chronic sinusitis, arthritis, dysphagia with a normal upper gastrointestinal tract, and anemia that had been treated with long-term vitamin B-12 therapy. The patient was treated for the Haemophilus infection with cephalothin and was placed on a regimen of gammaglobulin. Two years later, she was admitted for a right Caldwell-Luc procedure because of chronic sinusitis. The patient was readmitted six months later with complaints of increased cough, increased sputum production, chills at night, and weight loss. Sputum cultures were positive for H. influenzae. The patient was treated with a course of intravenous ampicillin and after improvement was discharged on amoxacillin. Four months after discharge, the patient developed increased cough with production of yellowish sputum, increased shortness of breath, decreased appetite, diarrhea, and headache. She presented in the emergency room with dyspnea, atrial blood gas of pH 7.46, pO2 of 52 mm Hg, and pCO, of 46 mm Hg on room air. Physical examination revealed a thin female obviously using accessory respiratory muscles to breathe. Lungs had distant breath sounds except at the apices, rales at the right base, and crackles at the left base. The patient
was afebrile, and there was no lymphadenopathy. Diffuse tenderness was noted in the epigastric area. Chest x-ray showed mild cardiomegaly, diffuse pulmonary fibrosis, right pleural scarring, and a right lower-lobe infiltrate. Additional laboratory data included a white blood count of 19,900 with a differential of 8% bands, 74% polymorphonuclear cells, 13% lymphocytes, and 5% monocytes. Sputum cultures revealed an ampicillin-sensitire H. influenzae. The patient was treated with ampicillin intravenously for three days and then was begun on oral amoxacillin. At discharge, the patient's chest x-ray showed improvement of the right lower-lobe infiltrate. A month after discharge, the patient was readmitted for study of a right clavicular abscess. H. influenzae was cultured from the abscess and repeatedly from blood and tracheal aspirates. The blood isolate was shown to be type e by bacterial agglutination. Initially, antibiotic susceptibilities indicated the organism was ampicillin-susceptible. One week later, after repeat susceptibilities, the organism was ampicillin-resistant. The organism also demonstrated resistance to cefamandole. In addition, a stool specimen showed heavy contamination with Giardia lamblia. Sputum cytologies were conclusive for squamous cell carcinoma. Despite extensive antimicrobic therapy, the patient's condition worsened, and she was transferred to the respiratory intensive care unit with respiratory distress and nonresolving H. influenzae pneumonia. She became respi-
Case Report
A Case of Common Variable lmmunodeficiency Cinda M. Boyer, Ph.D. John K. Chan, Ph.D. Susan E. Cancelosi, Ph.D. James D. Folds, Ph.D. Clinical Immunology Laboratory Department of Hospital Laboratories North Carolina Memorial Hospital University of North Carolina Chapel Hill, North Carolina 27514
A 60-year-old female first presented at North Carolina Memorial Hospital with a persistent infiltrate of the middle lobe of the right lung. Diagnostic studies indicated chronic obstructive pulmonary disease with sputum cultures positive for Haemophihts influenzae, Klebsiella and Enterobacter. Bronchoscopy showed diffuse erythema, and there was no mass obstructing the right middle lobe. Sputum cytologies were negative for malignancy. The level of a,antitrypsin was normal. Serum protein electrophoresis revealed a marked decrease in immunoglobulins, suggesting immunodeficiencyor plasma cell dyscrasia. A bone marrow aspirate, however, showed no evidence of plasmacytosis. Urine immunoelectrophoresis was normal. Complete blood count included hemoglobin of 14.1, hematocrit of 41, a white blood cell count of 12,500 with 70% polymorphonuclear cells, 21% lymphocytes, 8% monocytes, and 1% eosinophils. Further immunologic studies included a) Immunoglobulin quantitation: IgG (133 mg/dl), IgA (<34 mg/ dl), IgM (<17 mg/dl); b) Lymphocyte typing: E rosette-forming cells (81%0 --normal range = 65-85070), Surface
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rator-dependent and died following cardiac arrest one month after her final admission. This patient history illustrates the features of common variable immunodeficiency. Symptoms of common variable immunodeficiency (acquired agammaglobulinemia) occur relatively late in life, in contrast to the deficiency observed in X-linked agammaglobulinemia, which can be recognized during the first year of life. Patients with acquired agammaglobulinemia are a heterogeneous group. All present with a marked decrease in immunoglobulins of late onset. The extent of the decrease and the distribution of the decrease among the isotypes varies ~vith the patient, however, (2). Usually total immunoglobulins are less than 300 mg/dl with an IgG quantitation of less than 250 mg/dl. IgA and IgM range from undetectable to normal levels. The percentage of peripheral leukocytes bearing surface immunoglobulin ranges from undetectable to normal, though the majority of patients have a normal percentage. There have been increasing reports of cell-mediated defects in these patients, as evidenced by anergy to skin test antigens and abnormalities in the function of T-eell subpopulations. The in vitro finding of increased suppressor activity in the Tcell fraction of patients with common variable immunodeficiency has led to the hypothesis that regulatory cells are responsible for the lack of immunoglobulin production (4). Other possibilities include intrinsic B-cell defects, such as an inability to differentiate at some point along the path from bone marrow stem cells to immunoglobulin-synthesizing and secretory plasma cells. Alternatively, factors required for the differentiation process may be absent. Given the
heterogeneity in the presentation of patients with common variable immunodeficiency, it is probable that a number of defects are represented in the population. The clinical manifestations associated with common variable immunodeficiency in the respiratory tract include recurrent infections, chronic lung disease, and chronic sinusitis. Pneumococci, H. influenzae, and other pyogenic organisms are the agents commonly involved in the respiratory infections. Some common associated gastrointestinal disorders include malabsorption, pernicious anemia, chronic diarrhea, and infection with Giardia lamblia. Patients may present with autoimmune disorders such as systemic lupus erythematosus, idiopathic thrombocytopenic purpura, dermatomyositis, hemolytic anemia, or a rheumatoid arthritis-like disorder. In addition, patients with common variable immunodeficiency have an increased risk o f lymphoreticular malignancy and nonlymphoreticular malignancy, especially of the gastric epithelium (2). The patient described here possessed the cardinal feature of decreased immunoglobulin levels of late onset. The percentage of circulating B lymphocytes was also below normal. Both the number o f T lymphocytes and their proliferative response to the T-cell mitogens concanavalin A and phytohemagglutinin were normal. A subset of human B cells may also be stimulated by phytohemagglutinin. Interestingly, the proliferative response to pokeweed mitogen was normal. Pokeweed mitogen induces proliferation in both B cells and a subset o f T cells, as well as a polyclonal immunoglobulin response. The reduced proportion of surface immunoglobulin-bearing cells had no
apparent effect on the proliferative response to pokeweed mitogen. The effect of pokeweed mitogen on the synthesis of immunoglobulins was not measured. The most serious manifestation of common variable immunodeficiency in this patient was her recurrent H. influenzae infections superimposed on chronic lung disease. H. influenzae type e, resistant to both ampicillin and cefamandole, was isolated in the final episode. Unencapsulated strains of H. influenzae are commonly isolated from the upper respiratory tracts of healthy people. The organism may be carried in the lower respiratory tract, but only in patients with chronic lung disease (1). Rarely, capsulated strains are found in the upper respiratory tracts of healthy people. The presence of a capsule is usually associated with pathogenicity. Of the six capsular types (a thru e), type b is most often isolated in cases of invasive disease in adults and children. In 26 cases of adult bacteremic pneumonia, 20 were type b, 3 were type f, 1 was type c, l was type d, and I was unencapsulated (3). To our knowledge, this is the first report of a type e H. influenzae bacteremic pneumonia in a patient with common variable immunodeficiency.
References 1. Haemophilus influenzae pneumonia in adults. 1972. Br. Med. J. 2:672. 2. Hermans, P. E., J. A. Diaz.buxo,
andJ. D. Slobo. 1976. Idiopathic lateonset immunoglobulin deficiency. Am. J. Med. 61:221-237. 3. Quintiliani, R., and P. Hyams. 1971. The association of bact eremicHemophilus influenzae pneumonia in adults with typable strains. Am. J. Med. 50:78 !-786. 4. Waldmann, T. A., et al. 1974. Role of suppressor T cells in pathogenesis of common variable hypogammaglobulinemia. Lancet 2:609-613.
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P. 105. In M. D. Cooper, et al. (eds.), Immunodeficiency. Springer-Verlag, Berlin. McLean, R. H., and Susan Nilson. 1980. Complement in human diseases. In Noel Rose and P. E. Bigazzi(eds.), Methods in immunodiagnosis, 2nd ed. John Wiley& Sons, New York. Muller-Eberhard, H. J. 1980. Complement reaction pathways, p. 1001. In M. Fongereau and J. Dausset (eds.),
Progress in immunology IV. Academic Press, London. Thompson, R. A. 1981. Assessmentof clinical hypocomplementaemia.In R. A. Thompson (ed.), Techniques in clinical immunology, 2nd ed. Blackwells Scientific Publications, Oxford.
immunoglobulin-bearing cells (1.5 % --normal range = 8-15%); c) Lymphocyte blastogenesis (stimulation indices): phytohemagglutinin (68-normal control = 56), concanavalin A (70--normal control = 55), pokeweed mitogen (45mnormal control = 31). Additional problems identified were chronic sinusitis, arthritis, dysphagia with a normal upper gastrointestinal tract, and anemia that had been treated with long-term vitamin B-12 therapy. The patient was treated for the Haemophilus infection with cephalothin and was placed on a regimen of gammaglobulin. Two years later, she was admitted for a right Caldwell-Luc procedure because of chronic sinusitis. The patient was readmitted six months later with complaints of increased cough, increased sputum production, chills at night, and weight loss. Sputum cultures were positive for H. influenzae. The patient was treated with a course of intravenous ampicillin and after improvement was discharged on amoxacillin. Four months after discharge, the patient developed increased cough with production of yellowish sputum, increased shortness of breath, decreased appetite, diarrhea, and headache. She presented in the emergency room with dyspnea, atrial blood gas of pH 7.46, pO2 of 52 mm Hg, and pCO, of 46 mm Hg on room air. Physical examination revealed a thin female obviously using accessory respiratory muscles to breathe. Lungs had distant breath sounds except at the apices, rales at the right base, and crackles at the left base. The patient
was afebrile, and there was no lymphadenopathy. Diffuse tenderness was noted in the epigastric area. Chest x-ray showed mild cardiomegaly, diffuse pulmonary fibrosis, right pleural scarring, and a right lower-lobe infiltrate. Additional laboratory data included a white blood count of 19,900 with a differential of 8% bands, 74% polymorphonuclear cells, 13% lymphocytes, and 5% monocytes. Sputum cultures revealed an ampicillin-sensitire H. influenzae. The patient was treated with ampicillin intravenously for three days and then was begun on oral amoxacillin. At discharge, the patient's chest x-ray showed improvement of the right lower-lobe infiltrate. A month after discharge, the patient was readmitted for study of a right clavicular abscess. H. influenzae was cultured from the abscess and repeatedly from blood and tracheal aspirates. The blood isolate was shown to be type e by bacterial agglutination. Initially, antibiotic susceptibilities indicated the organism was ampicillin-susceptible. One week later, after repeat susceptibilities, the organism was ampicillin-resistant. The organism also demonstrated resistance to cefamandole. In addition, a stool specimen showed heavy contamination with Giardia lamblia. Sputum cytologies were conclusive for squamous cell carcinoma. Despite extensive antimicrobic therapy, the patient's condition worsened, and she was transferred to the respiratory intensive care unit with respiratory distress and nonresolving H. influenzae pneumonia. She became respi-
Case Report
A Case of Common Variable lmmunodeficiency Cinda M. Boyer, Ph.D. John K. Chan, Ph.D. Susan E. Cancelosi, Ph.D. James D. Folds, Ph.D. Clinical Immunology Laboratory Department of Hospital Laboratories North Carolina Memorial Hospital University of North Carolina Chapel Hill, North Carolina 27514
A 60-year-old female first presented at North Carolina Memorial Hospital with a persistent infiltrate of the middle lobe of the right lung. Diagnostic studies indicated chronic obstructive pulmonary disease with sputum cultures positive for Haemophihts influenzae, Klebsiella and Enterobacter. Bronchoscopy showed diffuse erythema, and there was no mass obstructing the right middle lobe. Sputum cytologies were negative for malignancy. The level of a,antitrypsin was normal. Serum protein electrophoresis revealed a marked decrease in immunoglobulins, suggesting immunodeficiencyor plasma cell dyscrasia. A bone marrow aspirate, however, showed no evidence of plasmacytosis. Urine immunoelectrophoresis was normal. Complete blood count included hemoglobin of 14.1, hematocrit of 41, a white blood cell count of 12,500 with 70% polymorphonuclear cells, 21% lymphocytes, 8% monocytes, and 1% eosinophils. Further immunologic studies included a) Immunoglobulin quantitation: IgG (133 mg/dl), IgA (<34 mg/ dl), IgM (<17 mg/dl); b) Lymphocyte typing: E rosette-forming cells (81%0 --normal range = 65-85070), Surface
120
rator-dependent and died following cardiac arrest one month after her final admission. This patient history illustrates the features of common variable immunodeficiency. Symptoms of common variable immunodeficiency (acquired agammaglobulinemia) occur relatively late in life, in contrast to the deficiency observed in X-linked agammaglobulinemia, which can be recognized during the first year of life. Patients with acquired agammaglobulinemia are a heterogeneous group. All present with a marked decrease in immunoglobulins of late onset. The extent of the decrease and the distribution of the decrease among the isotypes varies ~vith the patient, however, (2). Usually total immunoglobulins are less than 300 mg/dl with an IgG quantitation of less than 250 mg/dl. IgA and IgM range from undetectable to normal levels. The percentage of peripheral leukocytes bearing surface immunoglobulin ranges from undetectable to normal, though the majority of patients have a normal percentage. There have been increasing reports of cell-mediated defects in these patients, as evidenced by anergy to skin test antigens and abnormalities in the function of T-eell subpopulations. The in vitro finding of increased suppressor activity in the Tcell fraction of patients with common variable immunodeficiency has led to the hypothesis that regulatory cells are responsible for the lack of immunoglobulin production (4). Other possibilities include intrinsic B-cell defects, such as an inability to differentiate at some point along the path from bone marrow stem cells to immunoglobulin-synthesizing and secretory plasma cells. Alternatively, factors required for the differentiation process may be absent. Given the
heterogeneity in the presentation of patients with common variable immunodeficiency, it is probable that a number of defects are represented in the population. The clinical manifestations associated with common variable immunodeficiency in the respiratory tract include recurrent infections, chronic lung disease, and chronic sinusitis. Pneumococci, H. influenzae, and other pyogenic organisms are the agents commonly involved in the respiratory infections. Some common associated gastrointestinal disorders include malabsorption, pernicious anemia, chronic diarrhea, and infection with Giardia lamblia. Patients may present with autoimmune disorders such as systemic lupus erythematosus, idiopathic thrombocytopenic purpura, dermatomyositis, hemolytic anemia, or a rheumatoid arthritis-like disorder. In addition, patients with common variable immunodeficiency have an increased risk o f lymphoreticular malignancy and nonlymphoreticular malignancy, especially of the gastric epithelium (2). The patient described here possessed the cardinal feature of decreased immunoglobulin levels of late onset. The percentage of circulating B lymphocytes was also below normal. Both the number o f T lymphocytes and their proliferative response to the T-cell mitogens concanavalin A and phytohemagglutinin were normal. A subset of human B cells may also be stimulated by phytohemagglutinin. Interestingly, the proliferative response to pokeweed mitogen was normal. Pokeweed mitogen induces proliferation in both B cells and a subset o f T cells, as well as a polyclonal immunoglobulin response. The reduced proportion of surface immunoglobulin-bearing cells had no
apparent effect on the proliferative response to pokeweed mitogen. The effect of pokeweed mitogen on the synthesis of immunoglobulins was not measured. The most serious manifestation of common variable immunodeficiency in this patient was her recurrent H. influenzae infections superimposed on chronic lung disease. H. influenzae type e, resistant to both ampicillin and cefamandole, was isolated in the final episode. Unencapsulated strains of H. influenzae are commonly isolated from the upper respiratory tracts of healthy people. The organism may be carried in the lower respiratory tract, but only in patients with chronic lung disease (1). Rarely, capsulated strains are found in the upper respiratory tracts of healthy people. The presence of a capsule is usually associated with pathogenicity. Of the six capsular types (a thru e), type b is most often isolated in cases of invasive disease in adults and children. In 26 cases of adult bacteremic pneumonia, 20 were type b, 3 were type f, 1 was type c, l was type d, and I was unencapsulated (3). To our knowledge, this is the first report of a type e H. influenzae bacteremic pneumonia in a patient with common variable immunodeficiency.
References 1. Haemophilus influenzae pneumonia in adults. 1972. Br. Med. J. 2:672. 2. Hermans, P. E., J. A. Diaz.buxo,
andJ. D. Slobo. 1976. Idiopathic lateonset immunoglobulin deficiency. Am. J. Med. 61:221-237. 3. Quintiliani, R., and P. Hyams. 1971. The association of bact eremicHemophilus influenzae pneumonia in adults with typable strains. Am. J. Med. 50:78 !-786. 4. Waldmann, T. A., et al. 1974. Role of suppressor T cells in pathogenesis of common variable hypogammaglobulinemia. Lancet 2:609-613.
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