the Journal of Applied Research
in Clinical and Experimental Therapeutics

Current Issue

Volume 1 - 2001

Volume 2 - 2002

Volume 3 - 2003

Volume 4 - 2004

Volume 5- 2005

Reprint Information

Back to The Journal of Applied Research

©2000-2005. All Rights Reserved. Therapeutic Solutions LLC

Click here for information on how to order reprints of this article.
the Journal of Applied Research
in Clinical and Experimental Therapeutics

Current Issue

Volume 6 - 2006

Volume 5- 2005

Volume 4 - 2004

Volume 3 - 2003

Volume 2 - 2002

Volume 1 - 2001

Reprint Information

Back to The Journal of Applied Research

©2000-2005. All Rights Reserved. Therapeutic Solutions LLC

Click here for information on how to order reprints of this article.

Hypogammaglobulinemia in an Older Male Population



Harsha N. Shantaveerapa, MD

Celso T. Ebeo, MD

Ryland P. Byrd, Jr., MD

Thomas M. Roy, MD


The Veterans Affairs Medical Center

Division of Pulmonary Medicine

PO Box 4000

Mountain Home, TN 37684-4000


The Division of Pulmonary and Critical Care Medicine

James H. Quillen College of Medicine

East Tennessee State University

Johnson City, TN


Key Words: hypogammaglobulinemia, B lymphocytes, corticosteroids



Hypogammaglobulinemia (HGG) is a rare immunodeficiency disorder. However, HGG appears to occur more frequently in the older male veteran population than is reported in the general population. The spectrum of diseases associated with HGG in these patients also differs from those described for the general population. Identifying the patient with HGG is important since appropriate treatment may reduce end organ damage and mortality.



Hypogammaglobulinemia (HGG) is a disorder in which B lymphocytes produce few or no antibodies. The estimated prevalence of HGG in the general population is 0.77/100,000.1 The spectrum of illnesses associated with HGG is broad.2 Recognition of immunodeficiency disorders is important, as appropriate therapy may reduce

long-term morbidity and mortality from recurrent infection.3 The development of

intravenous preparations of gammaglobulin (IVIG) has provided the option of replacement therapy and maintenance of adequate immunoglobulin levels in the physiologic range. Patients treated with IVIG have received clinical benefit as measured by reduced frequency of infections and delayed progression to bronchiectasis and other organ damage.3



The James H. Quillen Veterans Affairs Medical Center (VAMC) is a teaching hospital that provides veteran patients with medical care through a variety of subspecialty clinics. The computerized database was used to identify all patients diagnosed with HGG in the last 5 years. Quantitative immunoglobulin level determinations had been performed at the James H. Quillen VAMC using turbidimetric methods. Subclasses of IgG had been quantitated by nephelometry at a reference laboratory.

The computerized database was also utilized to determine the total number of different patients that had sought medical treatment at the James H. Quillen VAMC during the same 5-year study period. The numbers of distinct patients with chronic obstructive pulmonary disease (COPD) and asthma were also ascertained.

The medical charts of all patients with the diagnosis of HGG were reviewed to determine the etiology of the immunodeficiency. Also recorded were the patients' age and sex, the use of chronic corticosteroids or other immunosuppressive therapy, the presence of recurrent infection, and the patients' quantitative immunoglobulin levels.




During the 5-year study period 37,926 different patients sought medical care at the James H. Quillen VAMC. HGG was suggested and proved in 19 patients and was associated with a variety of disorders (Table). The frequency of documented cases of HGG in our veteran population was 50.1/100,000. All the patients were male with an average age of 63 years.

                 Ten of the patients with HGG fulfilled the American Thoracic Society's definition of chronic bronchitis. Each of these patients with HGG took at least 10 mg/day of oral prednisone for treatment of airflow limitation due to COPD. The oral corticosteroids were thought to be responsible for acquired HGG in these patients. The clinical characteristics of this subgroup have been reported previously.4 Six of these 10 patients also had chronic sinusitis as documented by clinical and radiographic criteria. The James H. Quillen VAMC provided treatment to 5929 COPD patients during the 5-year study period. The frequency of occurrence of HGG in our COPD population was 168.7/100,000.

The James H. Quillen VAMC provided treatment to 338 unique asthmatics during the 5-year study period. Two asthmatic patients were identified with HGG. Both of these patients were also on 10 mg/day or more of chronic oral corticosteroids to control airway inflammation and symptoms of their asthma. Since no other immunologic disorder could be identified in these two patients, the corticosteroids were thought to be the cause of their HGG. Both asthmatics suffered from chronic sinusitis.

                 Of the remaining patients with HGG, five of them had neoplasms. Each of these patients had their HGG diagnosed prior to treatment of their cancer with immunosuppressive agents. The final two patients had no obvious comorbid illnesses but both suffered recurrent sinopulmonary infections.




The frequency of observed HGG is higher in the veteran population than that of the general population.1 The reason for this is not clear. T-cell mediated immunity appears to decline with age.2,5 The average age of our veteran patients with HGG was 63 years, which is older than the mean age of the general population with HGG (29 years).2 The average age of the general US and veteran populations are 36 and 58 years, respectively.

                 Twelve of our 19 (63%) HGG patients were being treated with at least 10 mg/day oral prednisone for respiratory diseases, either chronic bronchitis or asthma. While uncommon, one of the adverse effects of corticosteroid therapy is HGG. An average daily dose as low as 5 mg/day has been associated with HGG.6 The mechanisms involved in immunoglobulin deficiencies induced by corticosteroids are complex. A reduction in the synthesis of immunoglobulins may occur because corticosteroids potentiate prostaglandin-mediated inhibition of B-lymphocyte function, inhibit macrophage antigen processing function, and inhibit T helper cell function.7,8 Interference with B cell function alone, however, may not be sufficient to cause a reduction in antibody levels.9 Corticosteroids also increase the catabolism of immunoglobulins.10,11

Comorbid illnesses are often seen in the veteran patient and may contribute to HGG in the population. There were nearly 6000 COPD and over 300 asthma patients who received their care at the James H. Quillen VAMC during the study period. While the exact number of steroid-dependent COPD and asthmatic patients could not be determined by our computerized database, we suspect that the prevalence rate for HGG among our respiratory patients may be greater than 168.7/100,000. Our study group represented only those patients with a clinical presentation of HGG. The vast majority of our respiratory patients were not screened with a laboratory analysis of their immunoglobulins.

There is a large body of literature linking immunodeficiency disorders with

hematologic and solid malignancies. A high incidence of lymphoid and gastric carcinoma in patients with HGG has been reported.2,12-14 Hypogammaglobulinemic patients have a fivefold increase in the risk of cancer when compared to the non-hypogammaglobulinemic population.13 The literature, however, has not addressed the issue of cancer risk in patients with steroid-induced HGG. To date, none of our 12 patients with steroid-induced HGG has been diagnosed with malignancy.

                 Twenty-six percent (5/19) of our hypogammaglobulinemic patients had cancer. This percentage of cancer-associated HGG is higher than what has been reported in the general

population (15%).2 The reason for this observation may be due to age of the veteran patient and the increased incidence of cancer in the older population.

In the general population, patients with HGG have an associated autoimmune disease

in 22% of the cases.2 None of our veterans who had been diagnosed with HGG had a known autoimmune disorder. Since autoimmune diseases are more common in women, there may

have been a selection bias based on the male gender of our study population.2

Judicious use of antibiotics has been advocated in the treatment of recurrent sinopulmonary infections in respiratory patients.6,15 However, encouraging reports document a response to IVIG therapy in selected COPD and asthmatic patients with HGG.15-18 Patients with recurrent upper and lower respiratory infections and an impaired response to pneumococcal vaccination appear to benefit the most from IVIG.19 While none of our cancer patients with

HGG experienced recurrent sinopulmonary infections, prophylactic IVIG has also been shown to offer a protective effect against infections in patients with malignancy.20,21



Not only does the frequency rate of HGG in the veteran population appear to be higher than what is reported for the general population, but the patients are older and have a different clinical disease spectrum when compared with the general population. Steroid-induced HGG and cancer-associated HGG account for a higher percentage of illnesses linked with HGG in the veteran population. These observations imply that IVIG may have a greater role in the treatment of the veteran patient population. Resources should be directed so that further study can be undertaken to determine which patients benefit from IVIG therapy and whether IVIG therapy would decrease the overall medical costs of caring for these patients by reducing the number of emergency room visits and hospital admissions.




1. Baumgart KW, Britton WJ, Kemp A, et al: The spectrum of primary immunodeficiency disorders in Australia. J Allergy Clin Immunol 100:415-423, 1997.

2. Cunningham-Rundles C: Clinical and immunologic analysis of 103 patients with common variable immunodeficiency. J Clin lmmunol 9:22-33, 1989.

3. Baumgart KW, Cook MC: Therapeutic applications of intravenous immunoglobulin. Aust J Hosp Pharm 23:148-151, 1992.

4. Ahmed Z, McCoskey EH, Byrd RP Jr, Roy TM: Acquired hypogammaglobulinemia in male veterans with corticosteroid dependent chronic bronchitis. Fed Pract 17:10-14, 2000.

5. Pisciotta AV, Westing DW, DePray C, Walsh B: Mitogenic effect of phytohaemagglutinin at different ages. Nature 215:193-194, 1967.

6. Hamulus DL, Young RM, Peter JB, et al: Hypogammaglobulinemia in asthmatic patients Ann Aller 68:472-481, 1992.

7. Posey WC, Nelson HS, Branch B, et al: The effect of acute corticosteroid therapy for asthma on serum immunoglobulin levels. J Allergy Clin Immunol 62:340-348, 1978.

8. Galand P, Crevon MC, Emilie D, et al: Effect of hydrocortisone on the in vitro human antibody response with monocytes and prostaglandins. Clin Immunol Immunopathol 29:403-414, 1983.

9. Fauci AS, Dale DC, Balow JE: Corticosteroid therapy: Mechanisms of action and clinical considerations. Ann Intern Med 84:304-315, 1976.

10. Baxter JD, Harris AW: Mechanism of glucocorticoid action: General features, with reference to steroid-mediated immunosuppression. Transplant Proc 7:55-65, 1975.

11. Butler WT, Rossen RD: Effect of corticosteroids on immunity in man. I. Decreased IgG concentration caused by 3 or 5 days of high dose methylprednisolone. J Clin Invest 52:2629-2640, 1973.

12. Cunningham-Rundles C, Siegal FP, Cunningham-Rundles S, et al: Incidence of cancer in 98 patients with common varied immunodeficiency. J Clin Immunol 7:294-299, 1987.

13. Kiniin LJ, Webster ADB, Bird AG, et al: Prospective study of cancer in patients with hypogammaglobulinemia. Lancet 1:263-265, 1985.

14. Hermaszewski RA, Webster ADB: Primary hypogammaglobulinemia: A survey of clinical manifestations and complications. Quart J Med 86:31-42, 1993.

15. Sweinberg SK, Wodell RA, Grodofsky MP, et al: Retrospective analysis of the incidence of pulmonary disease in hypogammaglobulinemia. J Allergy Clin Immunol 88:96-104, 1991.

16. Bjorkander J, Bake B, Oxelius VA, et al: Impaired lung function in patients with IgA deficiency and low levels of lgG2 or lgG3. N Engl J Med 313:720-724, 1985.

17. Nahm MH, Macke R, Kwon OH, et al: Immunologic and clinical status of blood donors with suboptimal levels of IgG. J Allergy Clin Immunol 85:769-777, 1990.

18. Herer B, Labrousse F, Mordalet-Dambrine M, et al: Selective IgG subclass deficiencies and antibody responses to pneumococcal capsular polysaccharide antigen in adult community- acquired pneumonia. Am Rev Respir Dis 142:854-857, 1990.

19. Landesman SH, Schiffman O: Assessment of the antibody response to pneumococcal vaccine in high-risk patients. Rev lnfect Dis 3:S184-S197, 1981.

20. Boughton BJ, Jackson N, Lim S, et al: Randomized trial of intravenous immunoglobulin prophylaxis for patients with chronic lymphocytic leukaemia and secondary hypogammaglobulinemia. Clin Lab Haematol 17:75-80, 1995.

21. Musto MS, Specchia CF, Cicoia BM, et al: Prophylaxis against infections with low-dose intravenous immunoglobulins (IVIG) in chronic lymphocytic leukemia. Results of a crossover study. Haematologica 8:121-126, 1996.


Table. Disorders Associated with Hypogammaglobulinemia




        Mean Age

Chronic bronchitis






Chronic lymphocytic leukemia



Non-Hodgkin's lymphoma



Gastric adenocarcinoma



Adult HGG (uncertain etiology)