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
Division of Pulmonary
PO Box 4000
Mountain Home, TN 37684-4000
The Division of Pulmonary
and Critical Care Medicine
James H. Quillen College of
East Tennessee State
Johnson City, TN
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
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.
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.
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
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
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.
percent (5/19) of our hypogammaglobulinemic patients had cancer. This
percentage of cancer-associated HGG is higher than what has been reported in
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.
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
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
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.
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low levels of lgG2 or lgG3. N Engl J Med 313:720-724, 1985.
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OH, et al: Immunologic and clinical status of blood donors with suboptimal
levels of IgG. J Allergy Clin Immunol 85:769-777, 1990.
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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.
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O: Assessment of the antibody response to pneumococcal vaccine in high-risk
patients. Rev lnfect Dis 3:S184-S197, 1981.
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S, et al: Randomized trial of intravenous immunoglobulin prophylaxis for
patients with chronic lymphocytic leukaemia and secondary
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Cicoia BM, et al: Prophylaxis against infections with low-dose intravenous
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Table. Disorders Associated
Chronic lymphocytic leukemia
Adult HGG (uncertain etiology)