ACTUAL OR STANDARD BICARBONATE

201

development stimulation should be incorporated tine treatment of

into the

Tropical Metabolism Research Unit, University of the West Indies, Kingston 7, Jamaica

TABLE I-BICARBONATE REPORTING BEFORE AND AFTER OF ALL-ELECTRODE BLOOD-GAS ANALYSER

rou-

PEM.

(79

ACQUISITION

LABORATORIES)

SALLY GRANTHAM-McGREGOR MARIE STEWART CHRISTINE POWELL

Thomas Coram Research Unit,

University of London,

W. N. SCHOFIELD

London WC1

PERINATAL INFECTION BY EPSTEIN-BARR VIRUS

SIR,—de The has suggested that perinatal infection by the Epstein-Barr (EBV) is an important risk factor for the development of Burkitt’s lymphoma.! We have been interested in the possibility of perinatal infection by EBV for some time and have looked for intrauterine infection by testing umbilical-cord blood for EBV-transformed cells. Lately we have been testing uterine cervical secretions as a possible source of EBV. We would like to record our negative findings. Umbilical-cord blood collected at birth was tested for EBVtransformed cells.2 In 1973, one of us reported the presence of EBV-transformed cells in 1/696 specimens of cord blood;3 the infected newborn showed normal growth and development by the age of 24 months.’ Since then, we have tested over 2000 additional specimens of cord blood collected at the University of California at Davis Medical Center; none contained EBVtransformed cells. We have recently tested uterine cervical secretions from 55 women attending family-planning clinics in Honolulu. The secretion was collected by a cotton swab which was then placed immediately in 3 ml of nutrient medium. The specimen was processed and tested for EBV.4 None of the specimens contained EBV. The median age of these women was 20 (range 16-38). 13 were in the first, 2 in the second, and 2 in the third trimester of pregnancy; 10 were up to six weeks post partum; 15 were on birth-control pills 11 had intrauterine devices fitted, Our negative findings accord with those of Visintine et al.5

and Joncas et al.6 Department of Medical Mircobiology, University of California, Davis, California 95616, U.S.A. Department ofPediatrics, John A. Burns School ofMedicine, University ofHawaii at Manoa, Honolulu, Hawaii

R. SHIHMAN CHANG

DEXTER S. Y. SETO

TABLE

II-CLINICIANS’ PREFERENCES,

SIR,—After

many years of

blood-gas analysis

on tono-

metered blood and reporting bicarbonate as standard bicarbonate this department purchased a fully automatic all-electrode analyser. We chose a ’Corning 175’ (Corning Medical Ltd) which prints out actual bicarbonate. The change in reporting disturbed both laboratory and hospital staff. Corning Medical tell us that standard bicarbonate is the European custom while most Americans report actual bicarbonate. We wondered if the pattern had changed since the introduction of fully automatic blood-gas analysers in Britain in 1973. About 100 selected laboratories were sent a circular, and 79 replied. Of the 91 instruments recorded only 5 were of the tonometer type. There was a shift in reporting practice when allelectrode blood-gas analysers were introduced, standard bicar1. de Thé G. Is Burkitt’s

lymphoma related to perinatal infection by EpsteinBarr virus? Lancet 1977; i: 335-38. 2 Chang RS, Hsieh M-W, Blankenship W. Initiation and establishment oflymphoid cell lines from the blood of healthy persons. J Nat Cancer Inst 1971; 47:469-77. 3 Chang RS, Blankenship W. Spontaneous in-vitro transformation of leuko4

cites from a neonate. Proc Soc Exp Biol Med 1973; 144: 337-39. Chang RS, Lewis JP, Reynolds Rd, Sullivan MJ, Neuman J. Oropharyngeal excretion of Epstein-Barr virus by patients with lymphoproliferative disorders and by recipients of renal homografts. Ann intern Med 1978; 88:

34-40. 5. Visintine AM, Gerber P, Nahmias AJ. Leukocyte transforming agent (Epstein-Barr virus) in newborn infants and older individuals. J Pediatr 6

1976; 89: 571-75. Joncas J, Boucher J, Granger-Julien M, Filion C. Epstein-Barr virus infection in the neonatal penod and in childhood. Can Med Assoc J 1974; 110: 33-37.

(21

BE=base excess.

bonate being reported (alone or in combination) by 75% of laboratories before the change and by 56% afterwards, the corresponding figures for actual bicarbonate being 27% rising to

52% (table i).

Surprisingly few clinicians had expressed a preference for the way in which bicarbonate should be reported. Of those that had, most preferred base excess with or without standard bicarbonate (table n). When asked to record the advantages claimed for preferences laboratories sent in a wide range of comments, from a recital of the virtue of calculating the patient’s pK to "Anything for a quiet life". The following is a selection; we do not necessarily agree with them: versus actual (A) bicarbonate.-S is under standard many assumptions are made on S; is only way to consider treatment and diagnosis logically; accustomed to S in U.K. and naturally reluctant to accept A; S is useful because it gives non-ventilatory element of acid-base state; changed to A on advice of medical staff committee; surprisingly, no comment from clinicians on change to A, though base excess still reported; differences between S and A too small, even in acute respiratory failure, to affect clinical manage-

Standard

ACTUAL OR STANDARD BICARBONATE

WHEN EXPRESSED

LABORATORIES)

conditions;

(S)

too

ment.

Base excess.-Base

excess gives deviation from normal at a glance; of calculation for corrective treatment with base excess; base excess normal values are easier to remember: specific request for A and S but not base excess, because base excess may mislead the clinician to give bicarbonate when really this will correct itself once the primary cause is dealt with.

ease

Actual bicarbonate is calculated from Henderson-Hasselbach equation using pH and PC02; it represents whole-blood bicarbonate. standard bicarbonate is the concentration in whole blood which has been equilibrated at 37°C at a PC02 of 40 mm Hg with oxygen to give full saturation of the hmmoglobin ; by obtaining a value under these conditions the effect of altered respiration is eliminated, i.e., changes in standard are due only to effect of metabolic factors. Clearly, U.K. laboratories have switched to all-electrode analysers, and this has been accompanied by a swing from reporting standard to actual bicarbonate. Only a quarter of clinicians have voiced an opinion on their preference-but were the rest even asked? Clinicians seem to prefer standard bicarbonate and base excess-but is this because of tradition or from conviction? Where clincians did state a preference, 16 laboratories gave it and 5 did not-is this an acceptable percentage of satisfaction? Did the manufacturers ask U.K. cus-

202 what they wanted, or are we in the main subject to the dictates of the Americans? Acid-base interpretation is difficult and reporting style is still very much a personal choice, based on tradition, conviction, or--dare we suggest it-guesswork. We shall be interested,to see the reaction of clinical readers of The Lancet to the appearance of these figures. tomers

We thank Dr F. P. Woodford of the D.H.S.S. London for providing laboratory statistics, Mrs M. McGarry for typing, and, above all, our colleagues who answered our questions. Fife Area

Laboratory, Kirkcaldy, Fife KY2 5AG

A. LAWRIE B.P. GOLDA

SEVERE COMBINED IMMUNE-DEFICIENCY DISEASE IN PATIENT WITH &agr;1-ANTITRYPSIN DEFICIENCY

SIR,-Severe combined immune-deficiency disease (SCID) has an incidence of 0-2-1 per 100 000 live births. The disease is heterogeneous’ with autosomal recessive, X-linked, and sporadic forms and a variety of arrests of T-cell maturation.2 The association of a deficiency of adenosine deaminase in 20% of cases of SCID3 has underlined the importance of enzyme pathways in the control of lymphocyte maturation and differentiation. &agr;1-antitrypsin (alA T) deficiency (Pi type ZZ) occurs in about 1 in 7700 individuals in a White North American population. SCID and alA T deficiency together thus would be expected by chance in about 1 in 770 million individuals. Since protease activity and protease inhibitors have been linked to certain lymphocyte responses,4-7 the association of these two conditions may not be fortuitous. A 9-month-old White male, the first-born of a non-consanguineous marriage, had a normal prenatal and early postnatal history. From the age of 8 weeks he had episodes of eczema and diarrhoea. 1 month before admission he had fever, diarrhoea, and hepatomegaly. Laboratory tests suggested immune deficiency and he was referred here. We found him to be chronically ill, malnourished, and below the third percentile in weight. He had jaundice, oral candidiasis, generalised oedema, and enlarged lymph glands, liver, and spleen. He was anaemic. (Hb 8.7g/dl) with a white-blood-cell count of 4100/µl

(50% neutrophils, 19% eosinophils, 27% lymphocytes, 4% monocytes.) His early course in hospital was characterised by profuse watery diarrhoea and picorna/parvo virus was identified in his stools. He was in respiratory distress and papovavirus was isolated from tracheal secretions. An open lung biopsy was done but no organisms wereidentified. Humoral and cell-mediated immune status were assessed.1 Serum-proteins were measured by cellulose-acetate electrophoresis. Pi typing was carried out by isoelectric focusing in a polyacrylamide gel and by Fagerhol’s acid-starch gel electrophoresis with crossed immunoelectrophoresis,8 and OjAT was measured by electroimmunoassay.9 1. Gelfand EW, Biggar WD, Orange RP. Immune deficiency: evaluation, diagnosis and therapy. Pediat Clin N Am 1974; 21: 745-76. 2. Gelfand EW, Dosch HM, Shore A. The role of the thymus and thymus microenvironment in T-cell differentiation. In: Golde DW, Cline MJ, Metcalf D, Fox CF, eds. Hematopoietic cell differentiation. New York: Aca-

demic Press, 1978:277-93. 3. Meuwissen HJ, Pickering RJ, Pollara B, Porter FH, eds. Combined immunodeficiency and adenosine deaminase deficiency. New York: Academic Press, 1975. 4. Matter A. A study of proteolysis as a possible mechanism for T-cell mediated target cell lysis. Scand J Immunol 1975; 4: 349-56. 5. Arora PK, Miller HC, Aronson LD. &agr;1-antitrypsin is an effector of immunological stasis. Nature 1978; 274: 589-90. 6. Hatcher VB, Oberman MS, Lazarus GS, Grayzel AI. A cytotoxic proteinase isolated from human lymphocytes. J Immunol 1978; 120: 665-70. 7. Lipsky J, Berninger RW, Hyman LR, Talamo RC. Presence of alpha-1-antitrypsin on mitogen stimulated human lymphocytes. J Immunol 1979; 122: 24-26. 8. Cox DW, Celhoffer L. Inherited variants of alphal-antitrypsin: A new allele PIN. Can J Genet Cytol 1974; 16: 297-303. 9. Laurell CB. Electroimmuno assay. Scand J Lab Clin Invest 124: 21-23.

1972; 29 suppl

Serum immunoglobulins were: IgG 200, IgA <10, IgM <10 mg/dl and IgE <10 ng/ml. There was no antibody response to diphtheria-tetanus-pertussis-polio vaccines. 20-25% of the peripheral-blood mononuclear cells stained for surface immunoglobulins. Skin tests for delayed hypersensitivity were negative ; lymphocytes failed to proliferate in response to mitogens or allogeneic cells; less than 5% of lymphocytes formed rosettes

sheep red blood-cells. After incubation of bone-marrow or peripheral-blood mononuclear cells with 100-300 ;j.g/ml thymosin (kindly provided by Dr C. Joseph, Hoffmann-La Roche, Nutley, New Jersey) 15-25% of’ the cells

with cells

formed E-rosettes. Cellulose-acetate electrophoresis indicated an abnormally low peak in the &agr;1 region. Further study revealed that the patient was Pi type ZZ; the concentration of &agr;1AT was high for Pi type ZZ (34% of a normal serum pool) as often happens in -such children with liver disease. Both parents were Pi type MZ. The association of inherited deficiencies of adenosine deaminase and purine nucleoside phosphorylase with immune deficiency is now well established. In addition, we have delineated four groups of SCID on the basis of their ability to respond in vitro to incubation with thymic epithelial monolayers, epithelial-derived factors, cell extracts, or drugs such as theophylline.2 This SCID patient is the only one (of more than twenty studied) whose precursor T-cells responded in vitro to thymosin. Parenteral thymosin therapy was followed by improvement both immunologically (normal E-rosette numbers, lymphocyte proliferative responses to mitogens and allogeneic cells, delayed-hypersensitivity response to Candida albicans) and clinically, with amelioration of the diarrhoea, elimination of the picorna/parvo virus, and weight gain. We do not know if the &agr;&sfgr;AT deficiency in this SCID patient is causal or fortuitous. Abnormal immune function is not characteristic of &agr;1AT deficiency, and we know of no mechanism linking &agr;1AT to impairment in immune responses. However, surface protease activities have been implicated in lymphocyte blastogenesis’ and cell-mediated cytotoxicity,6 so the possible association of these two rare disorders warrants further investigation.

Supported by grants from the Medical Research Council and Health and Welfare of Canada (606-1239-44). Division of Immunology,

Department of Pediatrics, and Research Institute, Hospital for Sick Children, Toronto, Ontario M5G 1XB, Canada

(MT-4875)

E. W. GELFAND D. WILSON Cox M. T. LIN H.-M. DOSCH

GENETICS OF ACQUIRED AND CONGENITAL ADRENAL HYPERPLASIA

SIR,—New et al.’ described

a kindred in which a phenotypinormal sibling demonstrated HLA antigen haplotypes which were identical with those of an older sister who had the acquired form of virilising adrenal hyperplasia (AVAH). They concluded that this condition is genetically different from congenital adrenal hyperplasia of the classical variety, the latter showing a close linkage with the HLA-B locus on chromosome 6. We have studied the HLA haplotypes of a family with a daughter exhibiting acquired adrenal hyperplasia. The girl was taller than her peers when aged 5, with acne and a ravenous appetite. At the age of 7 pubic and axillary hair appeared, and at 8 years 7 months her height was in the 80th percentile and weight was in the 95th percentile. At that time she had pubic hair equivalent to Tanner stage in and clitoromegaly without labial fusion or a urogenital sinus. There was no breast development. Blood-pressure was 100/60 mm Hg

cally

MI, Lorenzen F, Pang S, Gunczler P, Dupont B, Levine LS. "Acquired" adrenal hyperplasia with 21-hydroxylase deficiency is not the same genetic disorder as congenital adrenal hyperplasia. J Clin Endocrinol

1. New

Metab

1979; 48: 356-59.