HYPOGAMMAGLOBULINEMIA

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HYPOGAMMAGLOBULINEMIA

Report of an Unusual Variation

Thomas F. Dolan, Jr., M.D., Norman B. McCullough, M.D.

and Lewis E. Gibson, M.D.

National Institutes of Health, National Institute of Allergy and Infectious DLreases

S INCE Bruton1 first described the entity of agammaglobulinemia, numerous

cases have been reported. There are several

recent reviews25 covering the pertinent lit

erature on the clinical syndrome, the physi

ology and the biochemistry of the gamma globulins.

Two major types of agammaglobuline mia, or more properly hypogammaglobu linemia, have been described. The congeni tal type occurs predominately in males and appears to be transmitted as a sex-linked recessive trait, usually becoming manifest within the first few years of life.

Acquired hypogammaglobulinemia occurs in either sex with onset at any time from childhood to old age. In both varieties some

gamma-globulin is detectable in nearly all

cases. The amount present is usually con siderably lower in the congenital type, al though values for the two groups overlap to some extent. The reported values are de pendent upon the method used for deter mination of gamma-globulin; with the im munochemical method the majority of pa tients with the congenital type have concen trations ranging between 0 and 25 m@/100 ml, and the acquired type between 25 and 75 mg/100 ml.

In addition to these entities, cases of

idiopathic and neoplastic dysglobulinemia have been reported.69 These cases show high levels of gamma-globulin, but are characterized by unusual susceptibility to infection.Further, Barandun et al.b0have

studied four patients with normal levels of

gamma-globulin, all of whom resembled pa tients with agammaglobulinemia in their

susceptibility to infections, lack of blood

group isoagglutinins and failure to produce

ADDRESS:(N.B.McC.) Bethesda14, Maryland.

antibody upon challenge with various anti gens. As in their patients with agammaglob ulinemia, these patients also lacked at least two other protein constituents of serum, namely those components designated as betalA and betalM. Immunologically these lattercases appear similarto the case re

ported here.

Clinical History

CASE REPORT

The patient, a boy, was the product of a normal full-term delivery of a healthy gravida IV, pana III, 35-year-old white woman. The mother was well during the entire pregnancy and had had no known radiation or exposure to toxins. The infant appeared normal at birth and until 10 days of age, when purulent drain

age from the umbilicus developed, accom panied by secondary skin abscesses. These le sions responded well to local antibiotic therapy

and he did well until the second month, when

there was onset of severe recurrent furunculosis

often associated with fever. Staphylococcus aureus was isolated from these lesions, and on one occasion blood cultures were postive for

this organism. On physical examination at this

time there was generalized adenopathv and

slight hepatosplenomegaly. The results of lab

oratory tests were unremarkable except for a leukocytosis of 30,000/mm4 with 50% poly

morphonuclear leukocytes. Over a 4-month period, the patient was treated intermittently with a variety of antibiotics, and surgical in cision and drainage of large abscesses were performed on four separate occasions. At age 7 months the patient developed a bout of gastro entenitis which persisted for 2 weeks. At age 8 months he again developed fever and roent

genographic evidence of pneumonitis. He was

treated for 1 month with several different anti

biotics without improvement, when he was

PEDIATRICS, November 1960

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referred to the Clinical Center, National In

stitutes of Health.

Physical examination revealed a small, poorly developed infant. The temperature was 102.6Â°F (39.2Â°C), pulse 120, and respirations

38/minute. The skin was pale, with scat tered pustules over the neck and diaper area.

There was dullness to percussion and decreased

breath sounds over the left upper lung field. The liver was palpated 3 cm below the right costal margin, and the spleen 4.5 cm below the

left. There were no palpable lymph nodes, no

visible posterior pharyngeal lymphoid tissue, and the tonsils were quite small.

Laboratory Findings

Admission roentgenogram of the chest re

vealed infiltrates in the left upper lobe and scattered nodular densities throughout both lung fields. The hemoglobin was 7.5 gm/100

ml; leukocyte count 38,000/mm'; neutrophils 27%, lymphocytes 70% and monocytes 3%; plate lets 264,000/mm3; the erythrocyte sedimenta tion rate, 90 mm/hr (Westergren). The results

of urinalysis were normal; the total blood pro

tein was 6.0 gm/100 ml, and paper electro

phoresis revealed a normal protein pattern.

Gamma-globulin by the 1/3-saturated am monium sulphate method was 400 mg/100

ml; serum iron, 22 @g/100 ml, and serum iron binding capacity, 320 @g/100 ml. Intermediate strength PPD tuberculin and histoplasmin skin tests were negative. Bone marrow aspiration biopsy showed an increase in lymphocytes,

no plasma cells, and cultures were negative

for bacteria and fungi. Several blood cultures

showed no growth. Nocardia asteroides was

isolated from several specimens of sputum. The

cerebrospinal fluid was normal, including a negative culture.

Hospital Course

The patient was treated daily for 4 months with sulfadiazine, 120 mg/kg, and pencillin,

4.8 million units, orally for 1 month and then

10 million units parenterally for an additional 3 months. There was a gradual reduction in fever, the pneumonia cleared gradually, and the leukocyte count became lower though not

normal. However, there was a slight increase in the hepatosplenomegaly, a persistent anemia

not responding to oral iron therapy, a per

sistently elevated erythrocyte sedimentation

rate and C-reactive protein. Antimicrobial

therapy was discontinued after 4 months. There was no recurrence of pneumonia, and blood, marrow and sputum cultures remained negative for nocardia.Â°

Recurrent furunculosis due to Staphylococ

cus aureus ensued for the next 4 months.

This infection was managed with chloram phenicol and erythromycin therapy plus fre

quent surgical drainage of superficial abscesses.

The patient gradually improved and was dis charged at age 17 months.

He was readmitted 2 weeks later with a

history of fever and diarrhea of 1 day's dura tion. Stool and blood cultures yielded Sal

monella newport, and therapy was started with chloramphenicol and tetracycline, 50 mg/kg

of each drug in daily divided dosage. During

treatment he became afebrile and stools re turned to normal consistency. Blood cultures

became negative, but stool cultures remained

positive.

Treatment of the salmonella infection was

discontinued after 30 days, only to be followed

by a prompt return of fever, gastroenteritis

and positive blood cultures. Again, antibiotic

therapy produced a prompt improvement with

negative blood cultures. During the next 11

months several more attempts were made to

discontinue antibiotics; in each instance there

was prompt recurrence of fever, gastroenteritis

and positive blood cultures. Thereafter he was

treated continuously with tetracycline and

chloramphenicol, 250 mg of each per day in

divided doses. Urine cultures were repeatedly

negative for salmonella, and roentgenograms of

the skeleton on several occasions failed to re

veal a focus of infection.

Immunologic Data

During the second hospitalization it became apparent that the child had an immunologic defect and studies begun at the time of the first admission were repeated and extended.

The pertinent data follow.

The patient was of blood group A, Rh posi

tive. No anti-B isoagglutinins were demon strable at 93@and at 15 months of age. At 17

months of age he was given 0.5 ml of purified

blood group B substance intramuscularly on 2 successive days. One month later the in

0 The details of this patient's nocardiosis are included in another publication: A.M.A. J. Dis.

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819

jections were repeated using twice the amount of B substance. Blood specimens were taken at 14 and 21 days after each attempt at im

munization. No anti-B isoagglutinins were

demonstrable in any of the specimens. He had received immunizing injections

against diphtheria, whooping cough and tet

anus at 4 to 6 months of age; the injections

were repeated at 17 and 18 months. Serum samples taken at 9, 12 and 19 months con

tamed no diphtheria antitoxin as determined

by the rabbit intracutaneous titration method.

A Schick test done at 19 months of age was

positive.

Immunization was attempted against polio

myelitis, mumps and influenza viruses; no neu

tralizing antibodies were demonstrable. After 9 months of chronic infection with

Salmonella newport with several exacerbations,

no agglutinins against this organism appeared. In spite of a variety of acute and chronic

infections, at no time was there lymphadenop

athy.

The bone marrow was examined at 93@and

at 13 months of age. No plasma cells were present in either specimen.

The concentration of gamma-globulin was de.

termined by the 1/3-saturated ammonium sul

phate method on 12 occasions and consistently found to be 400 to 500 mg/100 ml. A single

determination at age 15 months by Tiselius

electrophoresis gave a value of 355 mg/100 ml.

The serum electrophoretic pattern was deter

mined on six occasions between the ages of 9 and 18 months and was essentially normal. At 9 months the values were: alpha,-globulin, 8;

alpha2, 32; beta, 15; and gamma, 7%; and at 173k months: alpha1, 8; alpha2, 25; beta, 17;

and gamma, 8%.

Further Clinical Course

When it was determined that the patient

was unable to make any measurable antibody, his mother was immunized with a heat-killed suspension of the salmonella responsible for his infection, and he was given a transfusion of her

blood. This did not reult in clearing of the stool of salmonellae nor did it prevent acute

recurrence of illness when antibiotics were withdrawn. Exogenous gamma-globulin was then supplied. Using the figures of Martin et al.,â€• a gamma-globulin fluid compartment of

12% of body weight was assumed and the ap propriate amount of pooled gamma-globulin

was administered to raise the serum level of 400 mg/100 ml already present to 800 mg/ 100 ml. This, likewise, did not change the status of the salmonella infection. However, the furunculosis became less troublesome and the hepatosplenomegaly disappeared. Hence forth for the last year and a half, the gamma

globulin level has been maintained at the above

level by injection of pooled gamma-globulin at

2 to 4-week intervals. Chloramphenicol sup pressive therapy (0.125 or 0.250 gm/day) has also been continued. Some 16 months after the original acute episode Salmonella newport dis

appeared from the stools. Continuous suppres

sive antibiotic therapy has been necessary to control furunculosis and repeated pharyngeal

bacterial infections.

Among additional laboratory studies were: repeated urinalyses, and determination of urea

nitrogen, calcium, phosphorus, sodium, potas sium, chloride, carbon dioxide, alkaline phos phatase and cholesterol in the blood. Results

were all within normal limits. There was no Bence-Jones proteinuria, and an intravenous pyelogram revealed no abnormalities.

The child has continued to have abnormal hematologic findings. There has been a per

sistent anemia not responding to iron therapy,

with hemoglobin values ranging from 7.5 to 11

gm/100 ml. The leukocyte count has remained elevated, ranging from 13,000 to 24,000/mm3,

more usually being 18,000 to 20,000, with a preponderance of lymphocytes ranging from 63

to 87%. The erythrocyte sedimentation rate has

remained elevated from 30 to 50 mm/hr (West ergren). Furunculosis of varying degree has been almost continually present. In spite of this, for the last year he has remained out of the hospital, has gained in height and weight and

appears to be developing normally.

DISCUSSION

This patient presents many variations from the usual findings in hypogamma globulinemia. The level of gamma-globulin in the serum was persistently low, but much higher than that encountered in either con genital or acquired agammaglobulmnemia. When he was first seen, the gamma-globulin

was only slightly below the lower limits of

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820

ing back to birth, and the history of lym phadenopathy at an early age with later disappearance, one is led to speculate on some blocking of the reticuloendothelial system, possibly in the nature of amy loidosis. We have been unable to palpate even a pea-sized lymph node for biopsy and have been reluctant to do a dissection of the neck or groin, since this child has re

peatedly developed abscesses at the site of

venipunctures despite meticulous prepa ration of the skin.

In exhibiting a considerable amount of

gamma-globulin in the serum, lack of blood

group isoagglutinins and failure to produce

antibody upon challenge with various anti

gens, this patient resembles those reported

by Barandun et al.'Â° Whether the beta2A and

beta211 components of serum globulins are

also lacking is not known and the patient is

no longer available to the authors for fur ther study.

Barandun et al.14 have suggsted that the term â€œ¿antibodydeficiency syndromeâ€•

(Antikorpermangelsyndrom) more aptly

describes the fundamental defect in pa tients unable to produce antibodies than do agammaglobulinemia or hypogammaglobu linemia. In view of the qualitative and quantitative differences in gamma-globulin and the variable and multiple deficiencies in serum proteins, which have been re ported in such patients, and particularly the type of case reported here, this sug gestion seems increasingly appropriate.

SUMMARY

An unusual patient, characterized by re current infections, hepatosplenomegaly, low levels of gamma-globulin in the serum (400

mg/100 ml) and lymphocytosis, is described.

The patient had pneumonia due to

Nocardia asteroides followed by chronic

Salmonella newport infection of 16 months' duration, kept in check by continuous anti biotic therapy. No antibodies were pro duced against specific antigenic challenges. The relationship of this case to those of con genital and acquired agammaglobulinemia is discussed.

from chronic infection and, as he became older, a serum gamma-globulin level of 400 mg/100 ml became more abnormal.

None of the known causes of hypo gammaglobulinemia, as cited by Janeway and Gitlin,@ were present, except an ap parent intrinsic failure of the mechanism

for antibody gamma-globulin synthesis as evidenced by absence of palpable lymph nodes, absence of plasma cells in the bone marrow and failure to produce antibodies to antigenic stimuli.

The constant lymphocytosis is in con trast to that observed in patients with agam maglobulinemia. Young et al.@3 have oh served lymphopenia. Good and Zak2 have observed extremes of leukopenia and leuko

cytosis and also cyclic neutropenia. In view

of the absence of adenopathy, it is difficult to understand the consistently elevated leu kocyte counts. Although there has been a relative neutropenia, absolute neutrophil counts have always been within the normal range. The possibility of a chronic lymphatic leukemia or preleukemic state has been seri ously considered, but there is no evidence for this on repeated hematologic and bone marrow examinations.

Janeway and Gitlin3 comment on the lack of infections with gram-negative en teric bacilli, but the salmonellosis in this patient has been rather unique in its dura tion. Unless receiving specific antimicrobial therapy, he was symptomatic and had posi tive blood cultures for a period of over a year.

Splenomegaly is rather uncommon in congenital agammaglobulinemia, although we have observed it in several other cases. The fact that this disappeared after pro longed antimicrobial therapy suggests the possibility that it may have been due to nocardia or other infection in the spleen.

By employing ordinary laboratory tests the true nature of this patient's metabolic defect was not realized for many months. Not until repeated life-threatening infec tions occurred was the real nature of the defect detected.

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821

REFERENCES

1. Bruton, 0. C.: Agammaglobulinemia. PEDI

ATRICS, 9:722, 1952.

2. Good, R. A., and Zak, S. J.: Disturbances

in gamma-globulin synthesis as â€œ¿experi ments of nature.â€• PEDIATRICS, 18:109,

1956.

3. Janeway, C. A., and Gitlin, D.: The gamma globulins. Advances in Pediat., 9:65, 1957.

4. Gitlin,D., Gross,Paul A. M., and Jane

way, C. A.: The gamma-globulins and their clinical significance. I. Chemistry, immunology and metabolism. II. Hypo gammaglobulinemia. New England J.

Med., 260:21; 72, 1959.

5. Gross,Paul A. M., Gitlin,D., and Jane

way, C. A.: The gamma-globulins and

their clinical significance. III. Hyper gammaglobulinemia. IV. Therapeutic

uses of gamma-globulins. New England

J. Med.,260:121;170,1959.

6. Brem, T. H., and Morton, M. E.: Defective serum gamma-globulinformation.Ann. Int. Med., 43:465, 1955.

7. Lawson,H. A.,eta!.:Observationson the antibody content of the blood in patients with multiple myeloma. New England J. Med.,252:13,1955.

8. Janeway, C. A., et al.: Hypergamma

globulinemia associated with severe re

current and nonspecific infection. Am.

J. Dis.Child.,88:388,1954.

9. Zinneman, H. H., and Hall, W. H.: Re current pneumonia in multiple myeloma and some observations on immunologic response.Ann.Int.Med.,41:1152,1954.

10. Barandun, S., Cottier, H., and Hassig, A.: New aspects of agammaglobulinemia

and antibody deficiency syndrome. In:

Immunopathology. 1st International Symposium, 1958, Ed. by Pierre Grabar

and Peter Miescher, pp. 60-69, Basel, Schwabe, 1958.

11. Martin,C. M., et al.:Studieson gamma globulin. I. Distribution and metabolism of antibodies and gamma-globulin in hypogammaglobulinemicpatients.J. Lab. & Clin.Med.,49:607,1957.

12. Oberman, J. W., et al.: Electrophoretic analysis of serum proteins in infants and children. I. Normal values from birth to adolescence. New England J. Med., 255:743, 1956.

13. Young, I. I., Wolfson, W. Q., and Cohn, C.: Studiesinserumproteins.Agammaglob ulinemia in the adult. Am. J. Med., 19: 222, 1955.

14. Barandun, S., Buehler, H., and Hassig, A.: Das Antikorpermangelsyndrom. Schweiz. med. Wchnschr., 86:33, 1956.

CIBA FOUNDATION STUDY GROUP No. 4:

Vmus VIRULENCE AND PATHOCENICITY,

G. E. W. Wolstenholme, and C. M. O'Con

nor,Eds. Boston,Little,Brown and Co., 1960,114 pp.

This book contains the papers presented by

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This small book contains a wealth of in formation for the investigator interested in virology. It likewise will stimulate the non

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1960;26;817

Pediatrics

Thomas F. Dolan, Jr., Norman B. McCullough and Lewis E. Gibson