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SYSTEMIC

AND

OTHER

SYSTEM

DISORDERS

U-- UIU#U UJ 7

FATAL FOOD-INDUCED ANAPHYLAXIS

Yunginger JW, Sweeney KG, Stumer WQ, et al. JAMA.

1988;260:1 450-1452.

Purpose of Study

The purpose of this paper was to report clinical and

laboratory findings from seven cases of fatal anaphylaxis due to foods.

Study Population

The report was based on the findings from seven patients ranging from 11 to 43 years of age: two female

and five male patients. The cases were evaluated over a

16-month period.

Methods

Serum samples were obtained from six of the seven cases during resuscitation attempts or at autopsy.

Food-specific IgE antibodies were measured by solid-phase radioimmunoassay.

Findings

Elevated levels of IgE antibodies to the incriminated

foods were present in the six cases where the serum was available for study. Three were due to peanut and one

each were due to pecan, crab, and cod. The seventh case

(without serum) was due to peanut. The patients had some features in common: Most were highly atopic; most

reactions occurred away from home; all had previously

had generalized immediate reactions to the food; and none were on fi-adrenergic blocking agents.

Several recommendations are made by the authors. Patients and physicians must be made aware of the potential consequences of severe systemic reactions to

foods. Patients and physicians must know that the im-mediate treatment is injectable, aqueous adrenalin not

oral antihistamines, nor epinephrine by metered-dose

aerosol or in suspension. The patients should have the adrenalin available to them at all times and know how to

administer it. Patients receiving concomitant steroid therapy should be assumed to have adrenal suppression

and treated appropriately during resuscitation. Ingredi-ents of prepared foods must be made available and

pa-tients (and/or their families) must use this information

to try to avoid catastrophic results.

Reviewers’ Comments

Pull the original article and read the seven brief case

reports. This is scary business. We and our patients must treat this with the respect it demands.

ALLEN T. SEGAL, MD

Dallas, TX

ALAN B. GOLDSOBEL, MD San Jose, CA

SERUM SICKNESS-LIKE REACTIONS TO

AMOXICIULIN, CEFACLOR, CEPHALEXIN, AND

TRIMETHROPRIM-SUUFAMETHOXAZOUE

Platt R, Dreis MW, Kennedy DL, Kuritsky JW. J Infect

Dis. 1 988;1 58:474-477.

Purpose of Study

These antibiotics are among the most commonly pre-scribed in the United States for children and adults. Although allergic reactions of various kinds have been

reported for all these antibiotics, serum sickness had been

reported for cefaclor but not for the other antibiotics named. To determine whether this apparent difference

was real and to obtain information on the incidence of

such reactions, the authors undertook an analysis of

reports from the Food and Drug Administration (FDA) Spontaneous Report System.

Methods

The authors received and revised information in the

FDA computer registry from 1972 through 1985. Data

collected also were analyzed from the standpoint of

re-porting bias due to previously published reports of serum sickness to cefaclor and comparative number of prescrip-tions for each drug dispensed.

Findings

There were 638 reports of serum sickness-like reac-tions to cefaclor in the years analyzed; there were 10 to

amoxicillin, 28 to cephalexin, and 51 to

trimethroprim-sulfamethoxazole. Cefaclor also had the largest number of erythema multiforme-type reactors. In contrast, tn-methropnim-sulfamethoxazole had the largest number of

Stevens-Johnson Syndrome reactors (97 vs 2, 7, and 2

for amoxicillin, cefaclor, and cephalexin, respectively)!

No patient with a serum sickness-like reaction died.

Attempts to control for reporting bias still led to the

finding that serum sickness-like reactions are more likely to occur with cefaclor than with other antibiotics listed,

although the incidence of reaction is extremely low (es-timated 1.8 pen 100 000 prescriptions).

Conclusion

The incidence of serum sickness-like reactions to ce-faclor is extremely low, but more common than with the

other antibiotics examined. The apparent lack of reports of serum sickness to the other antibiotics is erroneous,

however. Although the incidence of Stevens-Johnson

re-actions to these antibiotics is extremely low, it is never-theless a more common occurrence with the use of

tn-methnopnim-sulfamethoxazole.

DAVID S. PEARLMAN, MD Aurora, CO

GLUCOSE INTOLERANCE AFTER SHORT-TERM

ADMINISTRATION OF CORTICOSTEROIDS IN

HEALTHY SUBJECTS: PREDNISONE,

DEFUAZACORT, AND BETAMETHASONE

Pagano G, Bruno A, Cavallo-Perin P. Arch Intern Med.

(2)

Purpose of Study

While glucocorticoid-induced glucose intolerance has

been related to systemic steroids, a clear demonstration

of this has been lacking for fluorinated corticosteroids. The purpose of this study was to compare the short-term effects of betamethasone disodium phosphate, predni-sone, and deflazacort, on glucose tolerance when these

steroids were administered at equivalent

anti-inflamma-tory doses to the same healthy subjects.

Study Population

Six healthy subjects (35 ± 3 years of age) were selected on the basis of a normal 75-g oral glucose tolerance test. Subjects received 18 mg of deflazacort, 15 mg of predni-sone, or 1.5 mg of betamethasone disodium phosphate,

12 and 2 hours before the oral glucose tolerance test.

Plasma levels of insulin and C-peptide were also

deter-mined. The study was performed according to a

double-blind, triple crossover design with a 1-month washout

internal among the three tests.

Findings

Fasting plasma glucose levels did not significantly

increase after deflazacort, whereas they increased after

prednisone and betamethasone disodium phosphate (P <

.001). All steroid treatments were associated with signif-icant increases in fasting plasma insulin and C-peptide

levels. During the oral glucose tolerance test, subjects

showed glucose, insulin, and C-peptide levels signifi-cantly higher (as determined by the area of the oral

glucose tolerance tests) than values recorded before

treat-ment (P < .0001). All three parameters were significantly more affected by betamethasone disodium phosphate than prednisone (P < .05), and prednisone was

signifi-cantly more affected than deflazacort (P < .05).

Conclusion

The results suggest that betamethasone disodium

phosphate induces greater glucose intolerance than

pred-nisone and deflazacort.

Reviewer’s Comments

Crucial to the comparison of these three steroids is the acceptance that they were administered in “equivalent anti-inflammatory” dose. Nevertheless, betamethasone disodium phosphate appears to be a highly potent corti-costeroid which is widely used in the authors’ native Italy. Deflazacort seems to have great promise as a prep-aration with diminished adverse effects compared with prednisone and methylprednisolone.

The diabetogenic effects of corticosteroids are due to increased hepatic production and decreased peripheral utilization of glucose. This effect, accompanied by

hyper-insulinemia, has been considered an insulin-resistant state, characterized by a postreceptor defect of insulin

action. The degree of glucose intolerance and insulin

resistance appears to depend on both the dose and dura-tion treatment.

ALLEN D. ADINOFF, MD Aurora, CO

METHOTREXATE-ASSOCIATED HEPATOTOXICITY:

RETROSPECTIVE ANALYSIS OF 210 PATIENTS

WITH RHEUMATOID ARTHRITIS

Shergy WJ, Polisson RP, Caldwell DS, et al. Am J Med.

1 988;85:771 -774.

Purpose of Study

Beginning in the 1980s, methotrexate has been used

successfully to treat rheumatoid arthritis. The magnitude

and severity of short- and long-term methotrexate

tox-icity, however, have not been investigated adequately.

This study was performed to determine the prevalence of hepatotoxicity in patients with rheumatoid arthritis ne-ceiving long-term MTX therapy.

Study Population

A retrospective review of all patients undergoing liver

biopsy for methotrexate monitoring during a 10-year

period was performed. A total of 538 biopsies were per-formed in 399 patients, 259 of whom had inflammatory

arthritis.

Findings

No evidence of cirrhosis was defined in the patients

with rheumatoid arthritis; however, six patients with rheumatoid arthritis had histologic evidence of fibrotic liver disease (2.9% of the group with rheumatoid

arthni-tis). Of the 6 patients, 5 were obese and 3 had glucose

intolerance; 1 patient admitted to alcohol usage. Only 1

patient with fibrotic liven disease had elevated liver

func-tion tests, and 1 patient showed a declining serum albu-mm level. Patients with abnormal liven biopsies had a mean cumulative dose and duration of methotrexate of 1495 mg and 32 months, respectively.

Conclusion

Although the prevalence of MTX hepatotoxicity in patients with RA was low, a small but definite risk of hepatic fibrosis, not predictable by laboratory screening,

still exists.

Reviewer’s Comments

The use of MTX in the treatment of steroid-requiring

asthmatics has been demonstrated to be of benefit. Its

use in the future will likely increase so we all might well

become familiar with the potential adverse effects.

ALLEN D. ADINOFF, MD Denver, CO

ANTIBODIES TO EPSTEIN-BARR VIRUS-SPECIFIC

DNase AND DNA POLYMERASE IN THE CHRONIC

FATIGUE SYNDROME

Jones JF, Williams M, Schooley RT, Robinson C,

Glaser R. Arch Intern Med. 1 988;1 48:1957-1960.

Purpose of Study

(3)

in-fection and the chronic fatigue syndrome (CFS) by

as-saying for antibodies acting against EBV-specific DNase

and DNA polymerase, which are expressed only during virus replication.

Study Population

Seven groups of subjects were studied: group 1: 25 healthy EBV-senopositive medical students; group 2: 5

healthy seropositive individuals olden than 65 years;

group 3: 14 individuals with CFS and high titers to EBV early antigen; group 4: 5 patients with AIDS-related complex; group 5: 4 patients with primary infectious

mononucleosis; group 6: 4 individuals with CFS and low or no antibodies to EBV; and group 7: 6 patients with CFS and extremely high anti-early antigen and viral

capsid antigen titers.

Findings

All 6 individuals in group 7 had elevated antienzyme

antibodies. Another 5 individuals also had elevated levels

of DNA polymenase antibodies, although 3 of these were only slightly above the 95% confidence limits established

(group 1): 2 geriatric patients, 2 patients with acute

mononucleosis, and 1 patient with CFS and low

anti-EBV titers. The 6 individuals in group 7 had severe

illnesses: one died of bone marrow failure; three

devel-oped fatal lymphoma; 2 had pneumonia.

Conclusion

The authors acknowledge that their original

hypothe-sis was only “partially fulfilled”: antienzyme antibodies indicating active viral replication were not found in pa-tients with uncomplicated CFS. Nevertheless, the

pa-tients with extraordinarily high antibody titers to viral capsid antigen and early antigen also had high levels of antibodies to EBV-specific DNase and DNA polymerase.

These antibody profiles are similar to those in patients

with nasopharyngeal carcinoma. Patients with chronic

EBV and this antibody profile might be in another illness

category at risk for malignant disease.

Reviewer’s Comments

Maybe we can not put the EBV-chronic fatigue

syn-drome “connection” to rest. A recent placebo-controlled

study found no benefit to patients with EBV and CFS

treated with acyclovir. Assuming the CFS is based on an

organic illness, it appears much more likely that it

rep-resents a similar response of the host to a variety of different stimuli, including EBV, cytomegalic inclusion

virus, herpes, and measles virus.

In addition, the patients with the very high antienzyme antibody titers (group 7), in fact, did not fulfill diagnostic

criteria for CFS since they had other diseases accounting for their chronic fatigue. Nevertheless, the results suggest

that EBV may be responsible for malignancies in addition to nasopharyngeal carcinoma and Burkitt lymphoma.

ALLEN D. ADINOFF, MD Denver, CO

YEAST CONNECTION AMONG 100 PATIENTS WITH

CHRONIC FATIGUE

Renfro U, Feder HM Jr, Lane TJ, Manu P, Matthews

DA. Am J Med. 1 989;86:1 65-168.

Purpose of Study

Patients with the “yeast connection” are characterized

by fatigue a multiple systemic symptoms. The purpose of this study was to compare patients with chronic fatigue

who believed they had the yeast connection to those with chronic fatigue without the yeast connection.

Study Population

One hundred consecutive patients with a chief com-plaint of chronic fatigue were evaluated in a specialty clinical setting. A complete history was obtained, and a detailed review of systems and a complete physical

ex-amination were performed. A detailed psychiatric

evalu-ation was also obtained.

Findings

Eight patients believed that their fatigue was due to

chronic candidiasis. Of these eight, seven had psychiatric

diagnoses that were judged to underlie their fatigue (5

had major depression and 2 had somatization disorders). Of the remaining 92 patients with chronic fatigue, 59 (64%) had underlying psychiatric diagnoses. The only variables that yielded statistically significant differences were that patients with the yeast connection were more

likely to have seen a nonmedical caretaker and were likely

to be taking larger quantities of vitamins. Psychiatric

referral was offered to the 7 yeast connection patients with a psychiatric diagnosis, and all refused. One of these

patients insisted on a tongue biopsy to rule out Candida,

which was performed elsewhere and was negative.

Conclusion

From this study and a review of the literature, the authors were unable to identify findings that are specific

for the yeast connection.

Reviewer’s Comments

For anyone who finds the results of this study a sun-pnise, we have a special deal going this week on bridges in the Brooklyn area. Physicians who might likely en-counter patients with the “yeast connection” must make

themselves familiar with the concepts its proponents espouse as well as the position statement by the American

Academy of Allergy and Immunology. This study is im-portant in that it notes a very high incidence of

psycho-pathology in patients with chronic fatigue. It also

under-lies the poor prognosis many of these patients have who refuse to address a dysfunctional belief system. Never-theless, most of these patients did not meet current definitions for the “chronic fatigue syndrome” since they carry psychiatric diagnoses felt responsible for their fa-tigue.

(4)

Diagnosis

DISTINGUISHING FEATURES OF IDIOPATHIC

FLUSHING AND CARCINOID SYNDROME

POLYMERASE CHAIN REACTION COMPARED WITH

CONCURRENT VIRAL CULTURES FOR RAPID

IDENTIFICATION OF HUMAN IMMUNODEFICIENCY

VIRUS INFECTION AMONG HIGH-RISK INFANTS

AND CHILDREN

Edwards JR, Ulrich PP, Weintraub PS, et al. J Pediatr.

1 989;1 15:200-203.

Study Population

Twenty-five high-risk infants and children aged 5 weeks to 8 years born to either intravenous drug-abusing

mothers or known to be human immunodeficiency virus (HIV)-infected comprised the study population. There

were four groups of infants based on Centers for Disease Control criteria: group I HIV positive by culture, group

II indetenminant, group III asymptomatic infants HIV

and antibody negative born to HIV-positive mothers, group IV healthy infants born to senonegative mothers.

Methods

Serial HIV autobody determinations by standard en-zyme-linked immunosonbent assay followed by Western Blot for confirmation and HIV culture were performed.

For polymenase chain reaction blood polymorphonuclear

cells were isolated and DNA extracted, denatured, an-nealed, and extended with primers using DNA

polymer-ase; after amplification oligomen probes were used to assay for integrity of complimentary sequences.

Findings

All patients had 100% concordance for gag-specific primer pair in between HIV cultures both positive and negative and polymenase chain reaction. Two of six

in-fants with indeterminant status for HIV in group II were known to be HIV 1 positive, first confirmed by

polymer-ase chain reaction and later by culture. One patient had

initial HIV 1 positively confirmed at 1 month of age by culture and subsequently 4 negative cultures and polym-erase chain reaction.

Reviewer’s Comments

This study demonstrates the essential utility of polym-erase chain reaction with peripheral blood mononuclear

cell lysates for identification of HIV infection in virus-infected infants. Initial culture positivity followed by negativity may be secondary to low numbers of circulat-ing copies of provinal DNA of mononuclear cells and/or

a change in the viral genome.

CHRISTOPHER RANDOLPH, MD

Waterbury, CT

Aldrich UB, Moattari AR, Vinik Al. Arch Intern Med.

1 988;1 48:2614-1618.

Purpose of Study

The clinical and biochemical profiles of 11 patients

with idiopathic flushing were compared with those of 8 patients with cancinoid syndrome.

Study Population

Nineteen patients whose major complaint was repeated episodes of flushing were evaluated. Laboratory evalua-tion was extensive and included whole blood on plasma

measurements of senotonin, gastrointestinal hormones

(eg, vasoactive intestinal peptide), and neunohormones (eg, substance P), as well as 24-hour urine collections for 5-hydroxyindoleacetic acid. When clinically indicated,

patients were treated with a somatostatin analog, SMS

201-995.

Findings

Carcinoid tumors were found in 8 patients, but despite

extensive studies, no cause for flushing was identified in the other 11 patients. Patients with idiopathic flushing

were more often women, had a longer duration of symp-toms, and were younger. Palpitations, syncope, and

hy-potension occurred only in patients with idiopathic

flush-ing, and wheezing and abdominal pain occurred only with carcompod syndrome; diarrhea occurred in both types of patients. Elevated senotonin levels were present primarily

in carcinoid syndrome. Increased levels of urine

5-hy-droxyindoleacetic acid were specific for cancinoid

syn-drome but insufficiently sensitive to detect all cases. Abnormalities of gut and vasoactive peptides failed to

distinguish the two conditions. Flushing in cancinoid syndrome patients responded uniformly to SMS 201-995

(Sandostatin), but only one third of the patients with idiopathic flushing.

Conclusion

Patients with idiopathic flushing have features that distinguish them from individuals with flushing from

other causes, such as cancinoid syndrome,

postmenopau-sal state, chlorpropamide-alcohol flush, panic attacks, medullary thyroid carcinoma, and automatic epilepsy.

Reviewer’s Comments

I found this to be a useful review of the differential

diagnosis of flushing and discussion of all of those gas-trointestinal and neuropeptides we occasionally hear

about but aren’t quite sure what they all do. Symptoms of flushing may also be seen in patients with anaphylaxis.

Unfortunately, the symptom of prunitus was not men-tioned in any of these patients. Measurements of serum levels of mast cell-specific tryptase may have identified patients with idiopathic anaphylaxis or mastocytosis.

(5)

INTERFERON-y IN THE DIAGNOSIS AND

PATHOGENESIS OF PELVIC INFLAMMATORY

DISEASE

Grifo JA, Jeremias J, Ledger WJ, Witkin SS. Am J

Obstet Gynecol. 1 989;1 60:26-31.

Purpose of Study

The study addressed the questions of whether serum levels of intenferon--y might aid in the diagnosis of pelvic

inflammatory disease (PID) and if interferon-fly played a

role in the mechanisms of PID.

Study Population

Forty-eight consecutive women seeking evaluation for pelvic pain were studied. PID was diagnosed if cervical motion tenderness, white blood cell counts in cervical

mucus, and a negative pregnancy test were found on if patients had positive cervical cultures for Neisseria gon-orrheae or Chiamydia trachomatis. Intenferon-’y in sera was quantitated by an enzyme-linked immunosorbent

assay. Sera were also analyzed for their ability to inhibit

Candida albicans-induced lymphocyte proliferation.

Findings

Of the 48 patients studied, 29 (60%) had PID and 19

(40%) had a variety of other problems. In patients with

PID, interferon--y was “positive” in 19 (66%) but positive

in only 3 (16%) of the women without PID (P < .025).

The sensitivity was 66% and specificity 84%. More

stnik-ing was the almost complete lack of overlap between the

groups: interferon-gamma for PID group was 10 to 800

U/ml vs non-PID group 17 to 22 U/ml (means and SD not given). C albicans-induced proliferation by control lymphocytes was inhibited by 11 of 28 sena (39%) from patients with PID, but only 1 of 19 sena (5%) without

PID(P<.025).

Conclusion

Intenferon-y production is frequently associated with

PID. The authors speculate that local production of in-terferon-y at sites of PID may activate suppressor T

lymphocytes (via induction of Ia antigen expression)

which might enable anaerobic bacteria to proliferate and

induce a prolongation of infection and further tissue

damage. Alternatively Ia expression causes cells to lose

“self” status, rendering them susceptible to attach by autologous T cells. The resultant inflammatory response could magnify tissue damage and create conditions

con-ducive for the development of additional secondary infec-tions.

Reviewer’s Comments

A major problem with this study is the lack of

defini-tion of a “positive” level for interfenon-y. It is unfortunate that further analysis of the data was not done since there was very little overlap of intenfenon-y levels between those with and without PID. It appears that a

interferon-y level >22 U/ml was diagnostic of PID.

ALLEN D. ADINOFF, MD Denver, CO

DIAGNOSIS OF SULFONAMIDE HYPERSENSITIVITY

REACTIONS BY IN VITRO “RECHALUENGE” WITH

HYDROXYLAMINE METABOLITES

Rieder MJ, Uetrecht J, Shear NH, et al. Ann Intern Med.

1 989;1 10:286-289.

Purpose of Study

The purpose of this study was to determine whether differences in in vitro detoxification of sulfonamide-re-active metabolites can be detected among the lympho-cytes from controls, patients with sulfonamide

hypersen-sitivity reactions, and patients with nonhypersensitivity

reactions to sulfonamide agents.

Study Population

Peripheral blood lymphocytes were obtained from 46 normal volunteers and 76 patients referred to the Adverse

Drug Reaction Clinic at the Hospital for Sick Children

and Sunnybrook Medical Center for assessment of

ad-verse reactions of sulfonamide agents. Thirty-one

pa-tients had clinical histories consistent with a diagnosis

of hypersensitivity reaction, whereas 45 patients had

clinical histories felt to be inconsistent with a diagnosis of hypersensitivity reaction.

Methods

The detoxification capacity for reaction products of

sulfonamide metabolism has been assessed by the use of

munine microsomes with an activating system to metab-olize the parent sulfonamide to an electrophilic interme-diate, and lymphocytes are used as the target tissue.

Lymphocytes are used because they possess all of the

major detoxification pathways, and their inability to me-tabolize the parent drug makes possible the isolated study of detoxification. The oxidative metabolism of sulfon-amide agents by cytochrome P-450 enzymes produces a

reactive metabolite toxic to lymphocytes. Previous stud-ies have suggested that the hydroxylamine metabolite of the parent drug is the toxic intermediate. Lymphocytes

from three groups of patients (controls, patients with a history of sulfonamide hypersensitivity, and patients with nonhypersensitivity reactions of sulfonamide agents) were assayed with tetrazolium to assess them for differences in toxicity from the hydroxylamine derivative of sulfamethoxazole.

Findings

The lymphocytes from patients with a history of

hy-persensitivity reactions showed markedly increased tox-icity to increasing concentrations of hydroxylamine

com-pared with those from controls and patients with a history

of nonhypersensitivity reactions. These differences were highly significant (P < .01). No difference was found

between the toxicity shown by the lymphocytes from

controls and that shown by the lymphocytes from

(6)

Conclusion

Metabolic differences in the production and

detoxifi-cation of reactive metabolites of sulfonamide agents are important determinants of hypersensitivity reactions to

these agents. These results suggest that the hydroxyl-amine derivative of sulfamethoxazole may be a reactive

metabolite mediating these reactions. Of further interest

is that cells of parents of patients with hypersensitivity reactions to sulfonamides show toxicity intermediate be-tween patient and control values, suggesting that the defect in detoxification may have a genetic basis. It

appears that the use of sulfonamide hydnoxylamines is

useful in the diagnosis and study of the pathogenesis of

hypersensitivity reactions to sulfonamide agents.

MICHAEL C. HOLLIE, MD

STANLEY J. SZEFLER, MD

Denver, CO

ANTICONVULSANT HYPERSENSITIVITY SYNDROME:

IN VITRO ASSESSMENT OF RISK

Shear NH, Spielberg SP. J C/in Invest. 1 988;82:1

826-1832.

Purpose of Study

The purpose of this study was to demonstrate the value of an in vitro lymphocyte toxicity assay in evaluating

patients with suspected hypersensitivity to phenytoin,

canbamazepine, and/or phenobanbital (aromatic anticon-vulsants).

Definition

The “anticonvulsant hypersensitivity syndrome”

(ACHS) is a rare (1:10 000 exposure), delayed process beginning with fever about 3 weeks after initiation of drug therapy, followed by a nash and lymphadenopathy,

often followed by internal multiorgan disease including hepatitis, nephnitis, pneumonitis, and hematologic

ab-normalities, sometimes leading to severe morbidity on

death.

Study Population

The study group consisted of 53 adult patients with

suspected ACHS. Parents of seven study-group patients were examined separately. Control subjects included 49 healthy volunteers never exposed to anticonvulsants and

10 patients with seizure disorders treated chronically with phenytoin without adverse symptoms.

Methods

In the in vitro lymphocyte toxicity assay, each subject’s peripheral blood lymphocytes were isolated and

incu-bated with either phenytoin, carbamazepine, or pheno-barbital in the presence of mouse hepatic microsomes, which metabolize these anticonvulsants to arene oxides,

presumably toxic to lymphocytes. Hypothetically, arene

oxides may be metabolized further by lymphocyte epoxide

hydrolases (enzymes) to nontoxic metabolites if this

de-toxification mechanism is not defective. Following

incu-bation, percent of dead lymphocytes above baseline was

determined.

Findings

Patients with a clinical history suggestive of ACHS had a significantly higher percentage of lymphocyte

cy-totoxicity in the previously described in vitro assay than

control subjects (P < .001). Of 50 study-group patients

40 demonstrated significant lymphocyte cytotoxicity in the presence of all three aromatic anticonvulsants.

Clin-ically, 7 of 10 study-group patients developed ACHS when given all three aromatic anticonvulsants. Parents of 7

patients with ACHS had an intermediate degree of lym-phocyte cytotoxicity when compared with patients with

ACHS and controls. All three study groups were

statis-tically distinct (P < .001).

Conclusions

These investigators demonstrated that patients with

ACHS were identifiable by this in vitro lymphocyte

tox-icity assay. A mechanism for ACHS and the lymphocyte toxicity assay was proposed: patients susceptible to

de-veloping ACHS are defective in enzymes necessary to degrade toxic metabolites of aromatic anticonvulsants to

their nontoxic products. The common occurrence of

cross-reactivity between these anticonvulsants, in vivo and in vitro, suggests that they share a common metabolic pathway. This is most likely not utilized in valproic metabolism, an anticonvulsant that was well-tolerated by

patients with ACHS. Finally, parents of patients with

ACHS had an intermediate degree of lymphocyte cyto-toxicity in this assay, suggesting an autosomal

codomi-nant inheritance pattern to this syndrome.

ANDREW LIU, MD

STANLEY J. SZEFLER, MD Denver, CO

Treatment

DIETARY REPLACEMENT IN PRESCHOOL-AGED

HYPERACTIVE BOYS

Kaplan BJ, McNicol J, Conte RA, Moghadam HK.

Pediatrics. 1989;83:7-17.

Purpose of Study

The purpose of this study was to establish the role of

dietary factors in hyperreactivity.

Study Population

Included in the study were 24 hyperactive preschool-aged boys whose diagnosis was consonant with the

diag-nostic and statistical manual mental disorder. Their ages

(7)

Methods

The study consisted of 10 weeks which encompassed 3 weeks of a baseline or the child’s normal diet followed by

3 weeks of an equivalent or placebo diet and 4 weeks of

a diet called “The Alberta Children’s Hospital Diet,” which eliminated food dyes, flavors, preservatives,

mon-osodium glutamate, chocolate, and caffeine with de-creased amounts of simple sugar, as well as specific foods

which parents had indicated might be a problem, ie, milk and dairy products. Environmental controls and reduced

inhalant exposure were recommended, but not enforced. Study personnel were blinded to design and irrelevant

food detractors such as dyes or specific instructions

re-garding time and the quantity of food were given to prevent knowledge of the study intent or design. A food attitude questionnaire was administered both to the pan-ents and children with and those without attention deficit

disorder or hyperactivity.

Multivaniant and univaniant analyses of variance were

used on all repeated measures with the Greenhouse-Geiser adjustment of degrees of freedom and the Tukey

method of multiple comparisons for significant treatment

effects at the level of .05.

Findings

Approximately 42% of children (10 of 24) exhibited a

50% improvement in behavior as a result of the Alberta Children’s Diet with an additional 16% (4 of 24)

exhib-iting a 12% improvement of placebo effect. The remain-ing 42% (10 of 24) were unresponsive to dietary

interven-tion. Changes in behavior were rated on the basis of scores obtained from an abbreviated questionnaire on

which parents recorded symptoms for hyperactivity, with an extra set of questions specific to individual children. Notably, analysis of behavioral change at daycare on the

questionnaire had no significant effect on treatment, but the authors attribute this to the high turnover nate and

absenteeism rate of daycane workers. This meant that children were not evaluated consistently with a single

rater. Parental bias was eliminated by demonstrating that the Food Attitude Questionnaire showed no difference in

the parents of responders and nonrespondens.

Reviewer’s Comments

Replacement studies such as this indicate higher re-sponse rate than challenge studies which demonstrate

only 0% to 10% of the subjects respond to a challenge substance. This may be related to the fact that replace-ment diets are broader interventions than challenge

stud-ies which often focus on specific classes of substances. This suggests that there may be individual differences

and sensitivity to various food substances that are of major importance in the area of hyperactivity. Indeed, a

recent report suggests that behavioral changes can be demonstrated by challenges of a wider variety of foods included in the present study, ie, oats, peanuts, wheat,

grapes, and bananas. Only night awakening corresponded with behavioral changes, but also halitosis and latency to

sleep onset tended to improve.

Flaws in this study include the inability to rule out

parental bias entirely and failure to exclude children with inhalant allergy which may have accounted for some of

the symptomatology ofthe so-called hyperactive children.

CHRISTOPHER RANDOLPH, MD

Waterbury, CT

OLIGOANTIGENIC DIET TREATMENT OF CHILDREN

WITH EPILEPSY AND MIGRAINE

Egger J, Carter CM, Soothill JF, Wilson J. J Pediatr.

1989;1 14:51 -58.

Purpose of Study

These authors have previously reported treatment of migraine (Lancet. 1983;2:865) and hyperkinesis (Lancet.

1985:1:940) with the oligoantigenic diet. This study ne-ports the results of treatment of children with a

combi-nation of migraine and epilepsy.

Study Population

Forty-five children (aged 2 to 16 years) with migraine

headaches and poorly controlled epilepsy were enrolled

in the study. They had a variety of types of seizures, with

a variety of etiologies.

Methods

The patients were put on a 4-week trial of an “oligoan-tigenic diet” consisting of 2 meats, 2 starches, 2 fruits, 8 vegetables, water, pure seasonings, calcium, and vitamins. If there was symptomatic improvement on the diet, new

foods were reintroduced singly to see which foods

pro-yoked symptoms. If there was no improvement on the

first diet, a second 4-week trial of different foods was done. Double-blind, placebo-controlled studies of

offend-ing foods were done in 16 patients.

Findings

Of 45 children, 40 improved. Twenty-five became

sei-zure-free on dietary treatment. It is not stated how many had improvement of headaches. Double-blind,

placebo-controlled studies in 16 patients demonstrated the

occur-nence of seizures upon ingestion of the suspected food in

8 patients, and of placebo in one. Skin-prick testing to

the suspected foods was not helpful.

Reviewer’s Comments

This is a somewhat confusing study. It is disappointing that the effect of diet upon the migraine headaches was not delineated. It is quite surprising that such a hetero-geneous population showed improvement.

MARY ELLEN FRIEDMAN, MD

(8)

EFFECT OF CONTINUOUS INTRAVENOUS INFUSION

OF ZIDOVUDINE (AZT) IN CHILDREN WITH

SYMPTOMATIC HIV INFECTION

Pizzo PA, Eddy J, Falloon, J, et al. N EngI J Med.

1988;319:889-896.

Study Population

Twenty-one children, aged 14 months to 12 years, with

symptomatic human immunodeficiency virus (HIV) in-fection (Class P2) were treated with continuous intrave-nous infusions of zidovudine (AZT).

Methods

Patients were randomly assigned to one of four AZT

treatment groups. Six hours after a single bolus infusion of AZT, continuous intravenous infusion was begun at

one of four dose levels: level 1, 0.5 mg/kg/hour (360 mg/ m2/day); level 2, 0.9 mg/kg/hour (650 mg/m2/day); level

3, 1.4 mg/kg/hour (1000 mg/m2/day); and level 4, 1.8 mg/ kg/hour (1300 mg/m2/day). Adverse effects and efficacy of AZT were assessed by examination of neuropsychiat-nc, hematologic, hepatic, and immunologic studies.

Findings

The mean duration of follow-up of these patients was

60 weeks in level 1; 52 weeks in level 2; 36 weeks in level

3; and 30 weeks in level 4. The dosage schedules selected were based on in vitro data which suggested that

concen-tnations of >1 mol/L optimally inhibited HIV replication. After the bolus dosage of AZT, the biexponential

half-lives were 10 and 92 minutes. Plasma levels fell below 1 mol/L 1.5 hours after the dose. With continuous infusions

of AZT, the mean steady-state levels were 1.9 mol/L for level 1; 2.8 mol/L for level 2; 3.1 mol/L for level 3; and 4.5 mol/L for level 4. The mean cerebrospinal fluid to plasma ratio for AZT was 0.24. The major dose-limiting

adverse drug effect was bone marrow suppression result-ing in neutnopenia, which was found predominantly in

levels 3 and 4. Based on adverse side effects, the authors recommended a dosage between 0.9 to 1.4 mg/kg/hour.

Of 21 patients 5 died in the trial; 3 from infections and 1 secondary to myocanditis. Other nonfatal infections

also occurred, principally indwelling catheter infections. Thirteen patients were able to be examined for effects of

AZT on neuropsychological development. Before AZT

treatment, 8 of the 13 had clinical evidence of encepha-lopathy and 5 were in the normal range. Verbal and

performance IQ scores improved in all 13 patients. CD4 cell numbers increased by >25% oven baseline in 15 of 21 patients. The most dramatic improvement was noted in patients who had CD4 cells greater than 200/mm3

before beginning AZT. Three of these patients (30%) had increases of 500 or more cells. Subjective improvements,

such as weight gain, increased activity, and increased appetite, were also noted in the majority of patients.

Conclusion

The Centers for Disease Control estimate that there will be 3000 new cases of pediatric AIDS by 1991. For

this ever-increasing problem, this study indicated that

AZT is an effective drug in the treatment of human

immunodeficiency virus infection in children, especially

in improving neuropsychiatnic development. Further-more, improvement of immune function, which was

in-dependent of the neuropsychiatnic improvement, was most striking in patients with pretreatment CD4 cell numbers above 200 cells/mm3. Thus, treatment with AZT may be more successful before immunologic

deteniora-tion. Further studies will need to be conducted to

deter-mine whether continuous infusion of AZT is superior to

intermittent oral dosing. If so, then development of a sustained-release oral preparation would be the next log-ical step.

ALAN KNUTSEN, MD

St. Louis, MO

THE INFLUENCE OF HUMAN IMMUNODEFICIENCY

VIRUS (HIV) INFECTION ON ANTIBODY

RESPONSES TO INFLUENZA VACCINES

Nelson KE, Clements MU, Miotti P, Cohn 5, Polk BF.

Ann Intern Med. 1 988;1 09:383-388.

Purpose of Study

This study was performed to ascertain whether sub-jects infected with human immunodeficiency virus (HIV)

generally develop protective hemagglutination inhibition antibody responses to inactivated influenza vaccines.

Study Population

Persons with the acquired immunodeficiency

syn-drome (AIDS) (n = 25) or the AIDS-related complex (n = 14), and HIV-seropositive men with only

lymphade-nopathy or no symptoms (n = 27) were recruited from Johns Hopkins Hospital outpatient and inpatient serv-ices and the SHARE project (Study to Help the AIDS

Research Effort). Controls were HIV-senonegative ho-mosexual men (n = 22) and HIV-seronegative

heterosex-uals (n = 16).

Methods

Subjects were immunized with inactive vaccines

con-taming 15 ;g of each of the following influenza virus hemagglutinins: A/Taiwan/1/86 (H1N1), A/Mississippi/ 1/85 (H3N2), A/Chile/183 (H1N1), and B/Ann Arbor/

1/86. Blood was collected from each subject immediately

before immunization and 4 weeks afterward for antibody measurements.

Findings

Fourfold or greater antibody responses occurred less frequently in subjects with HIV infections than in

HIV-seronegative controls. Protective levels (1:64 on greater) of hemagglutination inhibition antibodies were attained

by 94% to 100% of HIV-seronegative controls, 52% to 89% of HIV-seropositive asymptomatic subjects, and 13%

(9)

by an inactivated virus vaccine, might stimulate T-cell activation and subsequent HIV replication in infected

persons, levels of serum p24 antigen, an HIV cone protein,

were assayed before and after immunization. No increase in the prevalence on level of serum HIV p24 antigen or clinical deterioration was detected among HIV-infected

persons after influenza immunization.

Conclusions

Because of the poor antibody responses to influenza

vaccines among HIV-infected subjects, even in many with no or minimal symptoms, alternative strategies for

pre-venting influenza, such as booster doses of influenza

vaccine, prophylaxis with amantadine, on both should be

considered.

MICHAEL C. HOLLIE, MD

STANLEY J. SZEFLER, MD Denver, CO

PREVENTION OF GIANT CORONARY ARTERY

ANEURYSMS IN KAWASAKI DISEASE BY

INTRAVENOUS ‘y-GUOBUUIN THERAPY

Rowley AH, Duffy CE, Schulman ST. J Pediatr.

1989;1 13:290-294.

Purpose of Study

This report looks at the authors’ experience with

in-travenous -y-globulin (IVGG) in the treatment of Kawa-saki Disease with respect to the prevention of coronary

artery aneurysms, especially giant coronary artery aneu-rysms, which have been associated with morbidity and

mortality.

Study Population

All children treated for Kawasaki Disease at a single medical center between January 1979 and July 1987 were examined for coronary artery abnormalities. One hundred and eighty-seven patients were identified. Male/

female ratio was 1.5 to 1.0. The mean ages for IVGG-treated and nontreated patients were 33.5 and 30 months,

respectively. Asian children were ovenrepnesented in this sample.

Methods

Patients were divided into three groups corresponding to different treatment protocols: group 1, patients not

treated with -y-globulin (before 1984); group 2, patients

who received IVGG plus aspirin or aspirin alone

(Decem-ben 1985 to August 1985); group 3, patients diagnosed and treated within 10 days of the onset of their illness with aspirin plus IVGG in doses of either 400/mg/kg/day

for 4 days on 2 g/kg as a single dose. For the purpose of this review the patients were analyzed as to whether on

not they received IVGG. Demographic features for each group were similar. Echocardiograph reports performed 1 to 3 months after the onset of the acute illness were reviewed as well as the most recent follow-up studies.

The videotapes of equivocal studies were reviewed in a

blinded fashion by one of the authors. Lumen

enlarge-ment -.-3 mm or 1.5 times as large as adjacent vessel indicated coronary artery aneurisms, and internal diam-eter -8 mm indicated giant coronary artery aneunisms.

Findings

Only 3 of 68 patients treated with IVGG vs 39 of 119

patients (33%) not treated with IVGG developed cono-nary artery aneunism abnormalities (P .001). No patient treated with IVGG developed giant coronary artery

aneunisms. Fifteen of twenty-six patients under 1 year of

age not treated with IVGG developed coronary artery aneunism (58%). Only 4 patients under 1 year of age received IVGG. Two of these patients developed coronary artery aneunisms, although one of the two had coronary artery aneunism before IVGG treatment. Follow-up data indicate that most lesions regress with time. Thirty-three

of forty-one patients with coronary artery aneunism

(80%) either resolved completely or regressed on follow-up examinations at 1 to 5 years after the acute illness. Five of seven patients with giant coronary artery

aneur-ism showed no change at follow-up, but two patients with giant coronary artery aneunism showed only mild

regres-sion.

Conclusion

This large sample size supports other studies indicating that IVGG prevents giant coronary artery aneunism. Up

to 71% of patients with giant coronary artery aneunism as a consequence of Kawasaki Disease develop

obstruc-tive arterial lesions and are at risk for myocandial infarc-tion (Nakano H, et al. J Pediatr. 1986;108:198).

Admin-istration of IVGG within the first 10 days of illness with Kawasaki Disease decreases the overall incidence of con-onary artery aneunism and may prevent the formation of giant coronary artery aneurism.

MICHAEL S. KAPLAN, MD Los Angeles, CA

INTRAVENOUS IMMUNOGUOBULIN TREATMENT OF

PREGNANT PATIENTS WITH RECURRENT

PREGNANCY LOSS CAUSED BY

ANTIPHOSPHOUIPID ANTIBODIES AND Rh

IMMUNIZATION

Scott JR, Branch DW, Kochenour NK, Ward K. Am J

Obstet Gynecol. 1 988;1 59:1055-1056.

Purpose of Study

The study reports the use of immunoglobulin (Ig) in

the treatment of two pregnant patients.

Study Population

A 23-year-old woman had experienced six fetal deaths. Anticandiolipin IgG antibodies were 27.5 SD above the mean and partial thromboplastin time was 38 seconds.

(10)

of intravenous IG 400 mg/day for 5 days at 8 and 14 weeks gestation. IgG antiphospholipid antibody levels

and partial thromboplastin time decreased to near normal

levels after the infusions, where they remained during

the nest of the pregnancy. Severe eclampsia developed at

30 weeks gestation requiring delivery by cesarean section

of a healthy 1140-g infant. A 25-year-old Rh-negative

woman who, because of religious convictions, had refused

previous prenatal care had had seven pregnancies which

ended in fetal deaths due to severe erythroblastosis

fe-talis. During hen eighth pregnancy, a 30-week gestational

infant survived after three intrauterine and nine complete

exchange transfusions. In a ninth pregnancy, she was

given intravenous Ig as above at 20 weeks gestation. A

fetal transfusion of Ig was given at 27 weeks. At 36 weeks,

a 2200-g infant was delivered and given one exchange

transfusion.

Findings

These case reports confirm the usefulness of this treat-ment in pregnant patients with these disorders.

Reviewer’s Comments

More and more we have come to see the use of Ig for

immunosuppression, not immunoreplacement. The mechanisms are yet to be established but likely include

antibody suppression via antiidiotypic antibodies. High-dose Ig has been reported to lower the inhibitor activity

in one nonpregnant patient with lupus anticoagulant and improve the clinical outcome in severely Rh-sensitized

women.

Immunology

ALLEN D. ADINOFF, MD Denver, CO

IDENTIFICATION OF A HISTAMINE-RELEASE

INHIBITORY FACTOR PRODUCED BY HUMAN

MONONUCLEAR CELLS IN VITRO

Alam R, Grant JA, Left-Brown MA. J C/in Invest.

1 988;82:2056-2062.

Purpose of Study

Histamine is a major factor in allergic inflammation

and an important immunomodulator including

immuno-suppressive effects such as stimulating the synthesis of inhibitory lymphokines. These investigators evaluated the effects that histamine may have on the synthesis of

histamine-release inhibitory factor by mean human mononuclear cells.

Methods

Human mononuclear cells were isolated from the ve-nous blood from healthy donors and allergic patients. Generation of histamine-release inhibitory factor and histamine-releasing factor(s) from human mononuclear

cells was evaluated in the presence of various concentra-tions of histamine and concanavalin-A.

Findings

Human mononuclear cells from healthy subjects pro-duce a histamine-release inhibitory factor upon stimula-tion with histamine and the mitogen concanavalin-A. The histamine-release inhibitory factor specifically

in-hibits histamine-release factor-induced histamine-release

from basophils.

Conclusion

The authors propose that specific inhibition of

hista-mine-releasing factor(s) by the endogenous cytokine

his-tamine-neleasing inhibitory factor may be an important

physiological mechanism for regulating basophils and mast cells. They suggest that histamine-releasing

inhib-itory factor may be one of the major molecules preventing allergic sensitization, and maybe (when feasible) its ad-ministration might reverse allergic reactions.

GARY RACHELEFSKY, MD Los Angeles, CA

INDUCTION OF ALLERGEN-SPECIFIC IgE AND IgG

RESPONSES BY ANTI-IDIOTYPIC ANTIBODIES

Nagpal 5, Shanthi KN, Kon R, et al. J Immunol.

1989;1 42:3411-3415.

Purpose of Study

The purpose of this study was to explore idiotypic,

anti-idiotypic, and anti-anti-idiotypic responses to

allen-gens. Furthermore, this study elaborates that

anti-anti-idiotypic (a-a-Id) antibodies resemble idiotypic antibod-ies and their ability to combine with the allergen.

Study Population

Sera from 19 patients with immediate reactions (nau-sea, vomiting, hives, hypotension) after the ingestion of

cooked shrimp were used. Serum from a 36-year-old male

with a 1 1-year history of adverse reactions to shrimp was

used for the isolation of shrimp allergen-specific idiotypic antibodies. The sera used in this study were from patients

all demonstrating positive skin test reactions to shrimp

and contained shrimp-specific Ig antibodies

demon-strated by radioallengosorbent test.

Methods

Shrimp extract was prepared by standard means. The major shrimp allergen designated Sa-II was purified by a

series of separation steps including ammonium sulfate,

anion exchange, chromatography, etc. BALB/c mice were

immunized with affinity-purified human idiotypic

anti-bodies directed against a high-purified shrimp allergen.

The generated anti-idiotypic antibodies were then

(11)

mice with affinity-purified allergen-specific anti-idiotypic antibodies produced anti-anti-idiotypic antibodies.

Findings

(1) Mouse anti-idiotypic antibodies recognized

shrimp-specific human idiotypic antibodies of the IgE isotype from 18 of 20 individuals. (2) Mouse anti-idiotypic

anti-bodies recognized shrimp-specific human idiotypic

anti-bodies of the IgG isotype from 14 of 20 shrimp-sensitive patients. (3) A high percentage of individuals sensitive to shrimp share the same idiotypes. (4) Immunization of

BALB/c mice with affinity-purified allergen-specific

anti-idiotypic antibodies induced anti-allergen-specific, anti-idiotypic antibodies, induced anti-allergen IgE, and

IgE responses in the absence of the allergen. (5) The demonstration of shared idiotypes on IgG and IgG

anti-bodies in the sera of shrimp-sensitive patients supports

the use of allergen-specific anti-idiotypic antibodies as surrogate allergens.

Conclusion

Although as clearly and openly stated by the authors that the anti-idiotypic antibody and anti-anti-idiotypic

responses were reported in mice, the results support the

concept that similar events may occur in humans. This study nicely demonstrates the regulation of the immune response via a network of idiotypic antibodies,

anti-idiotypic antibodies, and anti-anti-idiotypic antibodies in the regulation of human IgE response to allergen. This

study was performed carefully, and the results suggest

that anti-idiotypic antibodies have the potential to re-place native allergens in the immunodiagnosis of allergic

diseases.

MARTIN I. SACHS, PHD, DO

Rochester, MN

THE FREQUENCY OF ANTINUCLEAR ANTIBODY

(ANA) IN CHILDREN BY USE OF MOUSE KIDNEY

(MK) AND HUMAN EPITHELIAU CELLS (HE-2) AS

SUBSTRATES

Arroyave CM, Giambrone MJ, Rich KC, Walaszek M. J

Allergy C/in Immunol. 1 988;82:741 -744.

Purpose of Study

This study was performed to determine in a normal

pediatric population the frequency of antinuclear anti-body.

Study Population

The sera of 241 normal children and 10 children with

systemic lupus erythematosus were evaluated.

Methods

The sera in increasing dilutions were combined with

mouse kidney and human epithelial cells for detection of positive antinuclear antigens. Radial immunodiffusion

was used to defect antibodies to Sm, RNP, SS-A, SS-B,

Scl-70.

Findings

Eight patients, 5 female and 3 male subjects,

demon-strated positive antinuclear antibodies. The antinuclear antibodies were positive in 5, 2, and 1 subjects at 1:5, 1:10, and 1:20 serum dilutions, for mouse kidney and for

human epithelial cells. Antinuclear antigens were positive in 4, 2, and 1 subjects at 1:10, 1:20, and 1:40 dilutions,

respectively, HE-2 cells. All the antinuclear antibodies

were a speckled pattern, and one subject had a positive

test with both substrates. No antibodies for any other nuclear antigens were detected in any subjects. All 10

subjects with systemic lupus erythematosus had a spec-kled antinuclear antibody pattern at a 1:80 or greaten

titer. As a pediatric screening measure, the authors sug-gest the use of antinuclear antibody determination with

a cutoff of 1:20 mouse kidney and 1:40 HE-2 cells.

Reviewer’s Comments

The authors have attempted to establish the frequency

of positive antinuclear antibodies in a normal pediatric population, which is valuable for clinical interpretation

of antinuclear antibody results in children.

RUSSELL J. Hopp, DO

Omaha, NE

FAMILIAL DEFECT IN THE SURFACE EXPRESSION

OF THE T-CEUL RECEPTOR-CD3 COMPLEX

Alarcon B, Regueiro JR, Arnaiz-Villena A, Terhorst C.

N Eng/ J Med. 1988;319:1203-1209.

Study Population

In this study, 2 brothers, one 11 months old and the

other 6 years old, were found to have a severe T-cell immunodeficiency related to a deficiency of the CD3-T-cell receptor (CD3-TCR).

Findings

The propositus was an 11-month-old boy with recur-rent Gram-negative bacterial and viral infections,

he-molytic anemia, and failure-to-thrive, who subsequently

died at 3 years of age. On autopsy, thymic epithelium was present but there was severe depletion of thymocytes. In

addition, Hassall corpuscles were absent. His older brother has had repeated episodes of acute asthma, but

not increased frequency of infections. Immunologic

eval-uation of the patient revealed nearly absent CD3 lym-phocytes, 8% (N 71 to 89), but normal percentages of

CD2, CD4, and CD8 cells. The T-cell receptor, identified

by monoclonal antibodies to the a/fl proteins, was also

markedly decreased, 4% (N 40 to 80). In vitro lympho-proliferative responses to stimulations with phytohemag-glutinin, tetanus toxoid, allogeneic mononuclear cells,

(12)

brother had similar immunologic laboratory results. In

particular, the a/fl hetenodimer of the T-cell receptor was

markedly reduced, 3% (N 40 to 81); however, the -y/5 heterodimer was normal, 6% (N 3 to 9). CD3-positive lymphocytes were only 1%. In vitro T-cell studies of the

brother also revealed marked immunodeficiency.

The CD3 complex is composed of 4 proteins, -y, #{244},,

chains, noncovalently linked to the T-cell receptor. Re-cently, the CD3-w protein has been identified, which is only associated transiently with the CD3 complex during

its assembly in the endoplasmic reticulum. Further

bio-chemical studies of the brother’s T-cells revealed that the

CD3- chain was markedly decreased, whereas the other

proteins of the CD3-T-cell receptor complex were present intracellularly. The deficiency of the CD3- chain

pre-vented transport of the complex to the cell surface.

Conclusion

Although patients with severe combined

immunodefi-ciency syndrome share a common clinical picture, the

underlying defects are heterogeneous. Specific enzyme

deficiencies of the purine salvage pathway, adenosine

deaminase, and purine nucleoside phosphorylase, are two known metabolic defects leading to severe T-cell

defi-ciency. This is the first report of a severe T-cell

immu-nodeficiency associated with selective impairment of the expression of the CD3-T-cell receptor complex.

ALAN KNUTSEN, MD

St. Louis, MO

CHARACTERIZATION OF GP12O BINDING TO CD4

AND AN ASSAY THAT MEASURES ABILITY OF

SERA TO INHIBIT THIS BINDING

Schnittman SM, Lane HC, Roth J, et al. J Immunol.

1988;141 :4181-4186.

Methods

This study characterizes the binding of I-labeled gpl2O

to CD4 cells and describes an assay system that measures a potentially relevant form of immunity to human

im-munodeficiency virus (HIV) infection; in other words,

the blocking of HIV binding to CD4-positive cells.

Findings

The binding of gpl2O to CD4-positive cells was inhib-ited by soluble CD4 and by monoclonal antibody to T4A but not to T3 or T4. The majority of HIV-positive sena

could inhibit binding at dilutions of 1:100 to 1:1000. There was no correlation in binding inhibition in this assay and

clinical stage of HIV infection. The binding inhibition titer was correlated with the titer of anti-gpl6O and the titer of anti-gpl2O antibodies determined by Western blot

dilution.

Conclusion

As with previously described neutralizing antibodies and other forms of immune response to HIV, it is unclear

what role antibody blocking of HIV binding to CD4 cells may play in active immunity to HIV in infected individ-uals. This activity may prove to have some value in protection against initial HIV infection and, thus, the

assay may be of use in monitoring vaccine trials. The assay described by the authors was highly sensitive and

specific in measuring this important binding of HIV to CD4-positive cells. Perhaps the most significant aspect of this study is its ability to shed light on the initial step

in infection with HIV, namely the specific binding of the viral envelope glycoprotein (gpl2O) to the CD4 molecule

found on certain T cells and monocytes.

MARTIN I. SACHS, PHD, DO Rochester, MN

CORNEAL ALLOGRAFT REJECTION FOLLOWING

IMMUNIZATION

Steinemann TL, Koffler BH, Jennings CD. Am J

Ophthalmol. 1 988;1 06:575-578.

Purpose of Study

The purpose of this study was the retrospective review

of five cases who developed corneal allograft rejection

after routine immunizations.

Study Population

This study included five patients, all females, aged 33

to 84 years with no other contributing health factors.

Methods

This is a retrospective review of five patients who developed allograft rejection within 1 day to 8 weeks after receiving a routine immunizations.

Findings

Case 1 was a 33-year-old woman who received a tetanus toxoid booster after having received a corneal transplant 9 months before. Within 4 days she experienced signs of

graft rejection, successfully treated with oral and topical

steroids. The patient underwent a second keratoplasty

and 6 months later received part 1 of a Hepatitis B vaccine with signs of rejection within 24 hours. She was

treated successfully with topical steroids. The patient

received part 2 of Hepatitis B, again developed signs of graft rejection, and was treated successfully. Case 2, an

84-year-old woman, underwent a keratoplasty 14 months

before receiving an influenza vaccine. Within 5 weeks the patient developed signs of graft rejection. Case 3 is a 73-year-old who underwent keratoplasty 3 weeks before re-ceiving an influenza vaccine and developed graft rejection within 1 month of the immunization. Case 4, a 69-year-old woman, received a corneal transplant 4 months before

immunization with influenza vaccine and developed graft

rejection. Case 5 is a 72-year-old woman who received an

influenza vaccine 6 months before graft rejection of a

corneal graft.

(13)

expression and subsequent recognition of antigens of the

major histocompatibility complex of the cornea. The recommendation by the authors was that allograft

pa-tients be treated with increased topical corticosteroids both before and after immunization.

Reviewer’s Comments

The temporal relationship between immunization and onset of symptoms is highly variable in the group of

patients reviewed. Because the incidence of graft

rejec-tion in these patients is reported to be as high as 35%,

the relationship between vaccine and graft rejection may just be coincidental. The proposed association, though, is of interest and should be evaluated prospectively.

ALMA M. HERRERA, MD Washington, DC

TRANSFUSION INDUCES BLOOD DONOR-SPECIFIC

SUPPRESSOR CELLS

Quigley RU, Wood KJ, Morris PJ. J Immunol.

1 989;1 42:463-470.

Study Population

Inbred male LEWIS-RT1, blood group D Agouti-RT1, and Wistar Albino Glaxo-RT1 rats between 8 and 10 weeks of age were used in the study.

Methods

Lymphoid cells were harvested from transfused and untreated rats. These cells were either (a) transferred to

lightly irradiated syngeneic hosts which were

subse-quently challenged with a kidney allograft or (b) titrated as regulator cells into naive, unidirectional, mixed lym-phocyte culture such that the regulator and responder populations were syngeneic.

Findings

In the LEW to DA strain combination, the adoptive

transfer of thonacic duct lymph node cells from DA

animals transferred with LEW blood 7 days previously

into syngeneic DA lightly irradiated host resulted in the

indefinite survival of LEW kidney allografts. In contrast, spleen cells had no effect on renal allograft survival. The

indefinite survival of LEW kidney allografts with lymph

or lymph cells was blood donor-specific and dose-depend-ent. The addition of lymph node on thoracic duct

lymph-derived regulator cells harvested from DA rats transfused

with LEW blood to a unidirectional, mixed lymphocyte

culture resulted in a specific depression of the

prolifera-tive response when compared with the proliferation of these same cells without the addition of these regulator

cells or with the addition of lymph node-derived on tho-nacic duct-derived regulator cells from a DA nat

trans-fused with a third-party blood. The depression of the

proliferative response observed in vitro was blood donor-specific. These in vitro findings were confirmed in two other strain combinations, LEW-PVG and DA-PVG.

Conclusion

Thus, the authors have demonstrated that a single blood transfusion results in the induction of donor-spe-cific suppressor cells detectable both in vivo, and in an

in vitro assay, namely the challenge with a kidney

allo-graft and in vitro using a unidirectional mixed lympho-cyte culture. Interestingly enough, the identification of donor-specific suppressor cells identified by using mono-clonal antibodies was found only in lymph node and thoracic duct lymph following the blood transfusion.

Sup-presson cells were not detected in the spleen following transfusion. The authors are presently investigating the hypothesis that this is a kinetic event and that the spleen

would harbor suppressor lymphocytes at a later date.

MARTIN I. SACHS, PHD, DO Rochester, MN

CORRECTION OF THE MOLECULAR DEFECT IN B

LYMPHOCYTES FROM X-LINKED

AGAMMAGUOBULINEMIA BY CELL FUSION

Schwaber J, Koenig N, Girard J. J C/in Invest.

1 988;82:1 471-1476.

Purpose of Study

The investigators relate their success in restoring func-tional immunoglobulin synthesis in vitro to defective B

lymphocytes from a patient with the minor phenotype of

X-linked agammaglobulinemia (XLA) through cell

fu-sion.

Methods

One XLA patient’s B lymphocytes were fused with

mouse myeloma cells in the presence of “HAT” selection

media to isolate hybnidomas. Hybnidoma proteins,

mRNA, and genomic DNA were analyzed with human cDNA probes and nucleotide sequencing to demonstrate homology to human immunoglobulin genes and gene products.

Findings

The XLA B lymphocyte were unable to synthesize whole immunoglobulin heavy chains (D-JH-C without

VH). Interestingly, hybnidomas of XLA B lymphocytes

were able to synthesize and secrete full-length heavy

chains (VH-D-JH-C) and functional immunoglobulin in vitro. Furthermore, immunoglobulin isotype switching,

arrested in XLA B lymphocytes, was restored in hybni-domas, allowing for their production of viable IgG.

Fi-nally, these hybnidoma-pnoduced heavy chains were of

human, not mouse, origin.

Conclusion

The B lymphocyte defect in the minor phenotype of XLA is amenable to connection by cell fusion in vitro.

The resulting production of full-length immunoglobulin

References

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