Spontaneous resolution of profound hypogammaglobulinemia.

ABSTRACT: A 3-month-old, full-term female infant was hospitalized with pneumonia and bronchiolitis. Laboratory studies revealed a profoundly low level of IgG (41 mg/dL) and low level of IgA (<6.67 mg/dL). Other causes of immunodeficiency were ruled out, and there was no evidence of protein loss to account for the low immunoglobulin levels. The immunoglobulin levels normalized over time. Our patient had a transient hypogammaglobulinemia of infancy, with severely low IgG and low IgA levels. We found no other reports of cases with such low values of IgG that proved to be transient.

TRANSIENT HYPOGAMMAGLOBULINEMIA of infancy (THI) is characterized by an abnormal delay in the onset of immunoglobulin synthesis. Some groups describe it as a rare disorder, (1,2) but others have reported THI to occur more commonly. (3-5) The onset is usually at 3 to 6 months of age, and immunoglobulin levels usually normalize by 2 to 5 years of age. There are no definite criteria for diagnosis, but most patients have IgG levels [greater than or equal to]2 standard deviations below normal for their age, and they may also have low levels of IgA and IgM as well. Circulating B-cell values are normal, as are production of specific antibody to diphtheria and tetanus. Most cases of THI are discovered because of recurrent sinopulmonary infections. Rarely do the patients have severe infections, and some are asymptomatic.

The degree of hypogammaglobulinemia varies, but extremely low IgG levels are rarely reported. (6) We report a case of THI with extremely low IgG and IgA levels.

CASE REPORT

A 4-month-old black female infant was referred for evaluation of hypogammaglobulinemia. She had been born at 39 weeks' gestation, weighing 5 lb 13 oz. She had been well until 3 months of age, when she was hospitalized for respiratory syncytial virus-negative bronchiolitis and pneumonia. She had persistent wheezing. She was discharged home with albuterol syrup but was rehospitalized 1 1/2 weeks later for recurrent wheezing and pneumonia. She was treated with intravenous antibiotics, nebulized albuterol, corticosteroid, and oral theophylline. Quantitative IgG was low at 41 mg/dL, IgA level was <6.67 mg/dL, and IgM level was normal at 34 mg/dL. A sweat chloride measurement was normal.

The infant was referred to us for an immunologic workup and evaluation of persistent pneumonitis and wheezing. She weighed 5.1 kg (15th percentile for age) and was 57 cm long (<5th percentile). On examination, small tonsils were present There was no thrush. The lungs had coarse breath sounds and rhonchi. Hepatosplenomegaly was not present. Small cervical and inguinal lymph nodes were palpated. The patient did not have diarrhea. Quantitative immunoglobulin measurements again revealed a low IgG level of 43 mg/dL, an IgA level of <6.67 mg/dL, an IgM level of 38 mg/dL, and an IgE level of 0.6 IU/mL (Table 1). In both the patient and her mother, results of enzyme-linked immunosorbent assay for human immunodeficiency virus were negative. Complement CH50 was normal at 279 U/mL (normal, 100 to 300 U/mL). Lymphocyte subset analysis revealed normal percentages and absolute values for CD2m GD3, CD4, and CD8, with a normal CD4-to-CD8 ratio of 1.26 (Table 2). The CD19 level was elevated, and CD56 level was normal. Result s of mitogen stimulation studies with phytohemagglutinin, pokeweed, and concanavalin A were all normal (Table 3). Total serum protein was low at 5.3 g/dL (normal, 6.3 to 8.3 g/dL), but serum albumin was normal at 3.7 g/dL (normal, 3.5 to 5.1 g/dL). Urinalysis was unremarkable. A chest radiograph revealed hyperinflation and a mildly enlarged cardiac silhouette, but no pulmonary infiltrates. Initial cardiology evaluation was normal.

By 5 months of age, the patient had a croup-like cough and stridor. Subsequent evaluation revealed a pulmonary artery sling, with an aberrant origin of the right subclavian artery. She had a surgical repair, with resolution of the stridor, but continued to have reactive airways disease with wheezing. She had few infections after that time.

The patient had a protective titer to tetanus toxoid (>5.05 IU/mL) and diphtheria toxoid (>0.450 U/mL) after two diphtheria-pertussis-tetanus immunizations (at 5 months of age). By 21 months, IgG, IgA, and IgM levels were all normal for age (Table 1). At 2 years 10 months, she was immunized to Streptococcus pneumoniae. She had a greater than fourfold rise in titer to types 1, 4, and 8, and a titer >200 ng/mL (less than a fourfold increase) to types 3, 12F, 18C, 19F, and 23F. Levels of IgG subclasses were as follows: IgG1 435 mg/dL, IgG2 60 mg/dL, IgG3 29 mg/dL, and IgG4 <9 mg/dL.

DISCUSSION

We searched MEDLINE for "transient hypogammaglobulinemia." We limited our search to reports written in the English language.

Our patient had an extremely low level of IgG initially, which gradually increased into the normal range for her age. By 11 months of age, IgG level was 202 mg/dL, and IgA and IgM levels were in the normal range for the patient's age. She was clinically well, with few infections after she was initially found to have viral bronchiolitis and pneumonitis. She had an elevated level of mature B cells (CD19). She had normal production of specific antibody to diphtheria and tetanus toxoids and to S pneumoniae. T-cell subset levels and results of mitogen stimulation studies were also normal. Although IgG4 was undetectable, the clinical significance of its absence remains uncertain even in healthy adults.

Some have described a deficiency of helper T cells as the underlying cause of THI. (4) Cano et al (9) found absent specific viral antibodies in 9 of 11 patients; in all but 2, specific antibodies to viruses subsequently developed.

Usually patients with THI do well clinically with no intervention. They rarely have severe infections. [gamma]-Globulin therapy is usually not necessary. Patients who have moderate to severe infections, such as pneumonia or meningitis, may require treatment with intravenous [gamma]-globulin on a temporary basis. Short-term use of [gamma]-globulin infusions in one study (9) did not appear to delay the spontaneous resolution of THI.

[gamma]-Globulin treatment was considered in our patient's case because IgG levels were extremely low. However, this was not instituted because good antibody-forming capacity was seen and levels of IgG steadily improved, consistent with the diagnsosis of THI.

Our patient's clinical course was relatively typical, but it was remarkable for the extremely low initial level of IgG, which was lower than in previous reports of THI we could identify. Tiller and Buckley (1) included one patient with a serum IgG level of 50 mg/dL at 3 months of age in their series. Siegal et al (4) reported an IgG level of 60 mg/dL in one patient in their series. Benderly et al (6) reported a case in which the patient had an initial serum IgG level of 40 mg/dL at 1 year of age; however this patient had a persistent IgA deficiency of <5 mg/dL at 3 years of age.

Our case illustrates that even a profoundly low level of IgG may prove to be transient. It remains to be seen if the resolution of this child's hypogammaglobulinemia will be long-lasting.

References

(1.) Tiller TL Jr, Buckley RH: Transient hypogammaglobulinemia of infancy: review of the literature, clinical and immunologic features of 11 new cases, and long-term follow-up. J Pediatr 1978; 92:347-353

(2.) Dressler F, Peter HH, Muller W, et al: Transient hypogammaglobulinemia of infancy, five new cases, review of literature, and redefinition. Acta Paediatr Scand 1989; 78:767-774

(3.) Hayakawa H, Iwata T, Yata J, et al: Primary immunodeficiency syndrome in Japan. I. Overview of a nationwide survey on primary immunodeficiency syndrome. J Clin Immunol 1981; 1:31-39

(4.) Siegal RL, Issekutz T, Schwaber J, et al: Deficiency of T-helper cells in transient hypogammaglobulinemia of infancy. N Engl J Med 1981; 305:1307-1311

(5.) McGeady SJ: Transient hypogammaglobulinemia of infancy: need to reconsider name and definition. J Pediatr 1987; 110:47-50

(6.) Benderly A, Pollack S, Etzioni A: Transient hypogammaglobulinemia of infancy with severe bacterial infections and persistent IgA deficiency. Isr J Med Sci 1986; 22:393-396

(7.) Denny T, Yogev R, Gelman R, et al: Lymphocyte subsets in healthy children during the first 5 years of life. JAMA 1992; 267:1484-1488

(8.) Yabuhara A, Kawai H, Komiyama A: Development of natural killer cytotoxicity during childhood: marked increases in number of natural killer cells with adequate cytotoxic abilities during infancy to early childhood. Pediatr Res 1990;28:316-322

(9.) Cano F, Mayo DR, Ballow M: Absent specific viral antibodies in patients with transient hypogammaglobulinemia of infancy. J Allergy Olin Immunol 1990; 85:510-513

TABLE 1

Serial Immunoglobulin Levels

               Patient's Value
Age       IgG, mg/dL         IgA, mg/dL  IgM, mg/dL

3 mo          41                <6.67          34
4 mo          43                <6.67          38
6 mo         130                <6.67          35
11 mo        202                   13          41
21 mo        627                   23          72
33 mo        534                   18          66
4 yr         689                   28          86
                  Reference Ranges (*)
AGe            IgG, mg/dL   IgA, mg/dL  IgM, mg/dL

2 wk to 6 mo    165-781        0-101      14-106
7 mo to 23 mo   208-1,164     13-127      27-178
2 to 5 yr       407-1,187     17-191      34-206

(*)Normal ranges for the University of Mississippi Medical Center.
TABLE 2

In Vitro Lymphocyte Analysis at Diagnosis (Age, 4 Mo)

                                 Cells/[mm.sup.3]

Subset    Lymphocytes  Absolute No.        Reference Range (*)

CD3           71%         5,065                2,280-6,450
CD4           39%         2,782                1,690-4,600
CD8           31%         2,212                  720-2,490
CD56           4%           285                  319-935 (+)
CD19          18%         1,284                  500-1,500

(*)Reference ranges (except for CD56). (7)

(+)Reference range. (8)
TABLE 3

Results of Mitogen Stimulation Studies

                       Counts Per Minute

Mitogen             Patient       Control

Phytohemagglutinin  11,232         9,867
Pokeweed             7,327         3,528
Concanavalin A      12,712         4,660

RELATED ARTICLE: KEY POINTS

* Transient hypogammaglobulinemia occurs during infancy and early childhood.

* Transient hypogammaglobulinemia is an abnormal delay in the onset of adequate immunoglobulin synthesis, which resolves spontaneously over time.

* Our patient had a profoundly low level of IgG, much lower than other cases of transient hypogammaglobulinemia reported in the literature.