Immunodeficiency in Congenital Chyluria

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Reprint requests to (W.C.A.) Department of Pediatrics, Arkan-sas Children’s Hospital, 804 Wolfe St. Little Rock, AR 72201.

American Academy of Pediatrics.

792 PEDIATRICS Vol. 66 No. 5 November 1980

lmmunodeficiency

in

Congenital

Chyluria

Chronic thoracic duct drainage in the experimen-tal animal has been employed to deplete thymic dependent lymphocytes with resultant cellular im-mune deficiency.’3 The human clinical correlate is the patient with chylothorax or even more analo-gous, chronic chyluria. The most common cause of

chyluria worldwide is filariasis. Other causes include trauma, tuberculosis, neoplasms, infections, lym-phactic aneurysm, and thoracic duct stenosis.4 We recently evaluated a child with this defect, giving us the opportunity of evaluating the effect of chronic T-cell depletion on immune reactivity.

CASE REPORT

J.K. is a 6-year-old Korean boy who was adopted at 2 years of age. Family history is unknown. He received recommended immunizations including the live viruses:

polio, measles, mumps, and rubella. He did not develop clinical chickenpox after his adoption although he was exposed on numerous occasions. He remained relatively

free from both major and minor infections during early childhood. His only hospitalization was for tonsillectomy and adenoidectomy, recommended because his tonsils were felt to be excessively large. He often attended day-time nursery schools where he was exposed to other children with febrile illnesses and “colds.” He was

de-scribed as having milder episodes of fever and upper

respiratory infections than other children. At 4 years of

age, his mother began to notice “white” urine and the

child complained of being unable to void. He was initially admitted for a urinary tract infection and needed bladder

catheterization for inability to void on several occasions. A 24-hour urine collection that was milky in appearance resulted in his referral for further evaluation.

Initial physical examination revealed a well developed and nourished oriental boy with no physical abnormali-ties. There was neither hepatosplenomegaly nor periph-era! edema. Lymph nodes (5- to 7-mm) were noted in the

right inguinal and left anterior cervical areas. Height and

weight were at the 50th percentile for age. Laboratory

values showed a hematocrit of 42%, a WBC of 4,200 with

50% polymorphonuclear leukocytes, 36% lymphocytes, 7% monocytes, 2% band cells, and 5% eosinophils on

peripheral smear. Electrolytes were normal, blood urea nitrogen was 8 mg/100 ml, serum creatinine was 0.6 mg/ 100 ml, and serum albumin was 4.9 gm/100 ml with a total protein of 6.4 gm/100 ml. Creatinine clearance was

1 18 ml/min/1.73 sq m. Urine contained 1.9 gm of

lipopro-tein per 24 hours with 5.6% -yglobulins and chylomicrons on electrophoresis. Thick blood smears were negative on

three occasions. Filariasis titer was less than 1:32 (inter-preted as negative). A normal sized thymus was evident on chest x-rays. Lymphangiogram was attempted with the microdissection microscope, but no lymphatic vessels were identified. Dye in the feet took four months to clear.

A lymphoscan was performed and showed no inguinal

lymph nodes. After several hours, the isotope was noted in the kidneys and bladder. There was no flow into the liver. Diagnostic impression was congenital absence of lower extremity lymphatic vessels with cisterna chyli reflux although chyluria was not noted until 4 years of age.

Evaluation of immune function is summarized in the Table. Total leukocyte and differential counts were com-pleted by routine methodology. Quantitative immuno-globulin levels were assessed by laser nephelometry and total hymolytic complement (CH,oo) measurement by radial diffusion using Quantiplates (Kallested Lab). Lym-phocytes in peripheral blood were separated on a Hy-paque-Ficoll gradient and in vitro lymphocyte stimulation by the mitogens, phytohemagglutinin, pokeweed, and concanavalin A, was determined by micromethods pre-viously described.5 Five concentrations of each mitogen were used with the maximum stimulation recorded in this report. Antigen stimulation of lymphocytes was accom-pushed as previously described6 using three concentra-tions of moniia and tetanus antigens. Average control counts per minute averaged approximately

1,200

and little variation was observed during the course of these studies. For skin testing, a

1:100

dilution of moniia was first employed and this was followed by testing with a 1:10 dilution if reactions were less than 10 mm of erythema, or induration, or both. Tetanus toxoid antigen was used undiluted. In large screening studies, 64% of children more than 5 years of age demonstrated positive responses to moniia and 55% reacted to this tetanus toxoid prepa-ration.6 Percentages and absolute numbers of circulating lymphocytes with receptors for C’b (erythrocyte-anti-body complement rosettes) and for sheep red blood cells (E rosettes) were determined according to methods de-tailed elsewhere.5 For studies of urinary lymphocytes,

only cells which excluded trypan blue dye were counted; viability ranged from 64% to 82%.

The patient was placed on a low fat diet and followed over the ensuing year. Weight gain and growth were normal. Chyluria was increased in the recumbent position and proteinaceous clots often occluded the urethra in the morning. This was successfully treated with 1 gm ascorbic acid a day. Three years after the onset of symptoms, the

chyluria has decreased, urinary total protein and total lipoprotein were too low to be measured, and only occa-sional lymphocytes can be demonstrated in the urine. However, the patient has now developed lymphedema of both lower extremities. Immune studies were repeated and were essentially unchanged from those presented in the Table. Lymphocyte counts have ranged from

1,396

to

3,357/cu mm.

DISCUSSION

Although many measurements of host defense were decreased, this patient appears to be relatively

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Laboratory Values

Tetanus toxoid (1:1), 3 mm; streptokinase-streptodornase (4-10 units), 2 mm;

moniia (1:10), 13 mm; mumps, 6 mm; phytohemagglutinin, 3 mm

Phytohemagglutinin, 22 (31-68); pokeweed mitogen, 26 (19-47); concanavalin A,

19 (36-65)

Tetanus toxoid, 1.9 (>3.0); moniia, 2.2 (>3.0) 1,512/cu mm (>1,500/cu mm)

46% (55%-81%); 696/cu mm (1,650-2,430/cu mm)

7.5

x

105/ml

57%

14%

Phytohemagglutinin, 4.9; pokeweed mitogen, 1.5; concanavalin A, 0

* Normal values are shown in parentheses.

t

Expressed as a stimulation index = counts per minute in cultures containing mitogen or antigen divided by counts per

minute for lymphocytes incubated with medium alone.

t

EAC, Erythrocyte-antibody complement. TABLE. Immunologic Studies*

EXPERIENCE AND REASON 793

Immune Function Cell-mediated immunity

Skin tests

Mitogen stimulationt

Antigen stimulation

Absolute lymphocyte counts E rosetttes Humoral immunity EACt rosettes IgG IgA 1gM Tetanus antibody Rubella antibody

Varicella zoster antibody Total hemolytic complement

Urine lymphocyte studies Total lymphocytes E rosettes

EAC rosettes

Mitogen stimulationt

31% (14%-23%); 469/cu mm (420-690/cu mm)

387 mg/100 ml (688-1,875) 48 mg/100 ml (53-292) 83 mg/100 ml (60-225)

0.04 IU (>0.01) 1:20 (>1:10)

1:8 (>1:2)

55 CHl( units (25-83)

free from those diseases associated with immune deficiency. Results of assays for cell-mediated

im-munity were most consistently depressed. No skin

test responses demonstrated induration 10 mm

while stimulation with two of three mitogens was

below control values; specific antigen stimulation

was negative and quantitation of circulating thymic dependent (T) lymphocytes demonstrated a re-duced population. Loss of T-cells into the urine would account for these findings with calculated daily losses for this patient ranging from 1

x

i0 to 5 x 10 cells per day. However, recurrent or severe viral infections and difficulty with live virus

vac-cines or fungal infections were not evident.

Normally, the lymphatic cells of the gastrointes-tinal tract flow into the cisterna chyli where they are joined by the lymphatic cells from the lower extremities. From there, the lymph flows into the thoracic duct and the venous system to the liver where lipoproteins are metabolized. In this patient, no lymphatic cells were demonstrable in the lower extremities. On lymphoscan, no inguinal nodes were demonstrable and the dye did not collect in the liver as expected. Instead, the dye was collected in the kidneys and excreted by the urine. Because of the presence of chylomicrons and lipoprotein in the

urine, it would appear that the intestinal lymphatic vessels were intact. The presence of chyluria

mdi-cates that cisterna chyli reflux through the

peri-nephric lymphatic vessels was present. We were

unable to determine from our studies if the thoracic duct was patent, but in other reported cases of chyluria secondary to filariasis, no thoracic duct blockage has been demonstrated and the lymphatic flow into the kidney is a pressure phenomenon. In

all likelihood, these were congenital lesions that were manifested later in life in this particular child.

Chronic thoracic duct drainage in the

experimen-tal animal, usually a rodent, has demonstrated vary-ing degrees of cellular immune deficiency that is rapidly restored following cessation of this proce-dure.3 Therefore, experimental results have sup-ported the ability of bone marrow reserves to rap-idly reconstitute such losses. The human model, as demonstrated in the present case, is perhaps even

more efficient. Additional data are provided by experience from neonates with chylothorax who do not appear to manifest cellular immune deficiency7

and by children with intestinal lymphangiectasia who retain humoral defense, but demonstrate some depression of cellular reactivity. Calculated daily T-cell losses in the present patient represent between 0.1% and 8% of his total pooi of circulating

lympho-cytes. Certainly, a large store of mature thymic

dependent lymphocytes reside in the spleen and lymph nodes, and these can enter the peripheral circulation to replace such losses. These, in turn, must be restored by replication or production of new lymphocytes in the bone marrow. The effi-ciency of this system is best tested by the microbial

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794 PEDIATRICS Vol. 66 No. 5 November 1980 challenge endured by any young child. This case, therefore, clearly demonstrates extensive reserve capacity for cell-mediated immunity in the human.

WATSON C. ARNOLD, MD

RUSSELL W. STEELE, MD

Department of Pediatrics

University of Arkansas for Medical Sciences and Arkansas Children’s Hospital

Little Rock

REFERENCES

1. McGregor DD, Gowans JL: The antibody response of rats depleted of lymphocytes by chronic drainage from the

tho-racic duct. J Exp Med 117:303, 1963

2. Gowans JL, Uhr JW: The carriage of immunologic memory by small lymphocytes in the rat. J Exp Med 124:1017, 1966

3. McGregor DD, Gowans JL: Survival of homografts of skin in rats depleted of lymphocytes by chronic drainage from the thoracic duct. Lancet 1:629, 1964

4. Wiggelinkhuizen J, Landman C, Greenberg E: Chyluria. Am J Dis Child 124:99, 1972

5. Steele RW, Britton HA, Anderson CT, et al: Severe

corn-bined imrnunodeficiency with cartilage-hair hypoplasia: In vitro response to thymosin and attempted reconstitution. Pediatr Res 10:103, 1976

6. Steele RW, Suttle DE, LeMaster PC, et al: Screening for cell-mediated immunity in children. Am J Dis Child 130: 1218, 1976

7. Koffler H, Papile L, Burstine RL: Congenital chylothorax: Two cases associated with maternal polyhydramnios. Am J Dis Child 132:638, 1978

SMOKING AND ANTISOCIAL BEHAVIOR-URGENCY FOR ACTION

The important and encouraging fact is that among an increasing number of people it is becoming socially embarrassing to be a smoker. Those very people who once received you in an office solid with cigarette smoke, who smoked

cigars over your dinner, who blew pipe smoke at you in the elevator, are beginning to be embarrassed by their habits. The social pressure now is not always on the side of the smoker; rather it is the smokers who are starting to apologize. This is a very healthy sign . . . . Individuals and governments are coming to realize that, while smoking is something that only individuals can do, it affects the health and the quality of life of everyone, and it is therefore a matter for society to deal with.

It is a matter that society must deal with, because new recruits are constantly

being drafted into the cohorts of the smokers-witness the large numbers of very young children who are beginning to smoke, witness the increasing numbers

of women who smoke. For the first time last year in the United States of America there were more smokers among the teenage girls than among the

boys . . . . Unless we act very quickly, this sinister trend will soon become generalized not only in the developed countries, but in the developing countries too.

Submitted by Student

From H. Mahler, Address to the Fourth World Conference on Smoking and Health, Stockholm, June 18-21, 1979.

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1980;66;792

Pediatrics

Watson C. Arnold and Russell W. Steele