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.
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
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.
Diagnosis
DISTINGUISHING FEATURES OF IDIOPATHICFLUSHING 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.
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
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
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
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%
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.
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
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,
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.
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