Systemic and Other System Disorders

(1)

Study Population

The incidence of UGI bleeding was retrospectively assessed in a cohort of 19 880 outpatients identified from the Michigan Medicaid billing database with dermatitis and/or asthma treated with corticosten-oids during 1980 to 1984. These diagnoses were

cho-sen because they are common indications for

corti-costeroids and are unlikely to be independently

associated with bleeding. The frequency of UGI

bleeding was assessed within 60 days after each con-ticosteroid prescription. A patient was considered to

have experienced UGI bleeding if he/she was

hos-pitalized during a day of risk and given a discharge diagnosis, including an ICD-9-CM code, compatible with UGI bleeding.

Findings

Forty-five (0.23%) of the 19 880 patients exposed to corticosteroids had a code consistent with UGI bleed-ing within 60 days after a prescription for a corticos-teroid. The incidence of UGI bleeding in patients

without a past history of UGI bleeding who were

exposed to corticosteroids was only 2.8 cases per

10 000 person-months. The rate of UGI bleeding was notably higher in patients receiving anticoagulants and those with a prior history of UGI bleeding (23.0 and 15.9 cases per 10 000 person-months, respective-ly). Other groups with higher rates of UGI bleeding included patients older than 60 years of age, patients with an alcohol-related diagnosis, and patients tak-ing nonsteroidal anti-inflammatory drugs. Patients with “prior abdominal conditions” did not demon-strate higher bleeding rates.

Conclusions

The authors conclude that because the incidence of

UGI bleeding in ambulatory patients with asthma

and/or dermatitis treated with corticosteroids is so

low, prophylactic therapy should be restricted to

high-risk patients, if it is to be used at all.

Reviewer’s Comments

This study does not answer the controversial ques-tion of whether corticosteroid use is associated with an excess risk of UGI bleeding. However, this may not be an important clinical problem since the abso-lute incidence of bleeding is so low. Assuming that

“other abdominal problems” includes peptic ulcer

disease, it would appear that patients with this con-dition are not at higher risk of UGI bleeding when treated with corticosteroids.

Although this was a retrospective study using Medicaid database information, there are advantages to this kind of review. First, I like the idea of con-ducting clinical research from a computer terminal; all of those messy little details of dealing with real patients are eliminated. One can also see the imme-diate advantages of having all of us become part of

one huge central government health care system

(sorry, just kidding).

ALLEN ADINOFF, MD Aurora, CO

Systemic

and

Other

System

Disorders

NATURAL HISTORY OF EOSINOPHILIA-MYALGIA

SYNDROME

Culpepper RC, Williams RG, Mease PJ, Koepsell TD,

Kobayashi JM. Ann Intern Med. 1991;115:437-442 Purpose of the Study

To examine the natural history of the

eosinophffia-myalgia syndrome and to assess the effects of oral

corticostenoids on the course of this disorder.

Study Population

A cohort of 47 patients were reported to the Wash-ington State Department of Health who had met the Centers for Disease Control (CDC) criteria for

eosi-nophilia-myalgia syndrome with onset of symptoms

between July 1 and December 12, 1989. Two of these

47 could not be interviewed, leaving only 45 for the final study. Features of these cases of

eosinophilia-myalgia syndrome were in accordance with the CDC

definitions and included an eosinophil count of

greater than I billion cells per liter, generalized my-algia of sufficient severity to affect activities of daily living, and absence of any infection or neoplasm that could account for the ifiness.

Methods

These 45 patients were followed up with telephone

interviews on four occasions over a period of 12

months after their initial diagnosis of

eosinophiuia-myalgia syndrome. Patients answered questions

about their history of L-tryptophan use, symptom onset and resolution, and maximal severity of each of

their symptoms. Information was collected from

their primary physicians regarding physical exami-nation findings and types/effectiveness of any treat-ments given.

Findings

Patients were predominantly non-Hispanic white women (87%) with an average age of 49 years, all of

whom had taken an L-tryptophan product prior to

disease onset. Symptoms typically progressed from

early onset of myalgia (100%) and fatigue (96%) to

other symptoms such as peripheral edema (93%),

cough or dyspnea (80%), rash (80%), paresthesias or weakness (76%), and scleroderma-like skin changes

(42%). Six patients (13%) recovered completely

within 2 to 5 months of symptom onset. More than

half of the patients who initially presented with my-algia, fatigue, on scleroderma-like skin changes

re-mained symptomatic after 14 months. Symptom

scores reported by the patients for each of their major symptoms improved by at least 40% at the end of the study. There was no statistically significant difference in long-term symptom severity or duration between patients treated or not treated with prednisone. Reviewers’ Comments

Although prednisone did not alter long-term

(2)

severe early manifestations of the disorder as well as exacerbations, oral steroid bursts did offer some ne-lief. Long-term oral steroid use was not advised.

THOMAS M. Fim, MD STANLEY J.SzEFLER, MD Denver, CO

EOSINOPHILIC FASCIITIS ASSOCIATED WITH USE

OF L-TRYPTOPHAN: A CASE-CONTROL STUDY

AND COMPARISON OF CLINICAL AND

HISTOPATHOLOGIC FEATURES

Martin RW, Duffy

J,

Lie JT. Mayo Clin Proc. 1991;66:892-898

Purpose of the Study

The purpose of the study was to investigate the relationship between use of L-tryptophan and the de-velopment of eosinophffic fasciitis.

Study Population

Two patients with eosinophuic fasciltis who had

been taking L-tryptophan. Control patients consisted of 60 individuals with various collagen vascular

dis-eases or who had undergone a general medical

ex-amination without systemic disease. Two of these

individuals has used L-tryptophan. A retrospective assessment of clinical features, response to treatment,

and blinded review of biopsy specimens of skin and

fascia in patients who had eosinophilic fasciitis with or without exposure to L-tryptophan was also per-formed.

Findings

There was no difference in the eosinophilic fasciitis seen on biopsy specimens of skin and fascia in pa-tients with the disease who had taken tryptophan. The odds ratio was 19, indicating a 19-fold greater

likelihood of use of L-tryptophan in patients with

eosinophilic fasciitis than in the control group.

Conclusions

This retrospective study confirms the strong

asso-ciation between consumption of L-tryptophan and

the development of eosinophilic fasciitis in some pa-tients. No clinical or histopathologic features were detected that distinguished this disorder on the basis of previous exposure to L-tryptOphan.

This fascinating association between a dietary sup-plement and developing of a systemic disease has been described in many artides. Further data suggest that it was a particular lot of L-tryptophan that led, following ingestion, to the development of eosino-phiic fasciitis. The development of this eosinophiuic disorder may represent varied manifestations of one disease precipitated by a single environmental stim-ulus or it could reflect the spectra of an illness

in-duced by several environmental agents. Thus one

has to ask, are there more L-tryptophans on the ho-rizon?

MARTIN I. SACHS, Pi-iD, DO Rochester, MN

CLINICAL AND IMMUNOLOGIC FOLLOW-UP OF

PATIENTS WHO STOP VENOM IMMUNOTHERAPY

Keating MU, Kagey-Sobotka A, Hamilton RG, Yunginger JW. I Allergy Clin Immunol. 1991;88:339-347

The purpose of the study was to determine

whether a minimal or optimal duration for venom

immunotherapy exists and to determine whether

clinical on immunological parameters exist that are predictive of clinical immunity after venom immu-notherapy was stopped.

Study Population

Fifty-one patients with histories of generalized re-actions to hymenoptera stings and positive venom skin tests were studied. All patients has received

venom immunotherapy to all the venoms originally

producing positive venom skin tests, most receiving mixed vespid and wasp. After 2 to 10 years of venom

immunotherapy all patients had deliberate sting

challenges. If deliberate sting challenges were toler-ated, patients voluntarily stopped venom immuno-therapy and returned annually for additional venom skin tests and deliberate skin challenge. In most pa-tients it was possible to monitor venom skin tests and

venom specific antibody levels before and after

venom immunotherapy was stopped. The ages of the

51 patients studied ranged from 9 to 67, with a mean of 31, and there was a predominance of males.

Findings

One year after venom immunotherapy was

stopped, 49 patients who had previously tolerated deliberate sting challenges while they were receiving

venom immunotherapy now tolerated another

delib-erate sting challenge, whereas 2 patients had gener-alized reactions. Of these 49 nonreactors, 31 returned for deliberate sting challenges at various periods of 2,

3, 4, and 5 years after venom immunotherapy was

stopped. No additional generalized reactions

oc-curred in any of these patients. The 2 individuals with generalized reactions had received venom im-munotherapy for 2 and 4 years, respectively. Both these patients had grade N field sting reactions.

Conclusions

The short-term 1-year, post stopping immunother-apy, risk of recurrence of clinical allergy to stings after venom immunotherapy was higher in patients who experienced grade N field sting reactions before immunotherapy as compared to experiencing grade I to III reactions. In the grade I to III reaction group 0 of 36 responded to a deliberate sting challenge,

whereas in the grade N group 2 of 15 responded to

(3)

The authors conclude that venom immunotherapy should be continued for 5 years in patients with

pre-venom immunotherapy field sting reactions of grade

N severity. Also, because I year after venom

immu-notherapy venom skin test and venom specific IgE

and IgG antibody levels were variable, the authors conclude that venom skin tests and venom specific antibody results do not reliably predict the outcome of deliberate sting challenge or the subsequent

din-ical course in individual patients stopping venom

immunotherapy.

This very important work answers two perplexing

questions. First, are repeated venom skin tests

and/or IgE and IgG specific venom antibody

deter-minations reliable in determining when to stop

venom immunotherapy? The data strongly suggest

that this is not the case. Second, what is the appro-priate length of venom immunotherapy for patients with generalized reactions to insects? The authors

have determined that individuals with a grade N

severity preimmunotherapy sting should be treated

for at least 5 years. If these kinds of sensitivity studies

were performed for various inhalant allergens, we

could determine the appropriate length of immuno-therapy for inhalant allergens.

MARTIN I. SACHS, Pi-D, DO

Rochester, MN

INCREASED RISK FOR ANAPHYLACTOID

REACTION FROM CONTRAST MEDIA IN

PATIENTS ON B-ADRENERGIC BLOCKERS OR

WITH ASTHMA

Lang DM, Alpern MB, Visintainer PF, Smith ST. Ann

Intern Med. 1991;115:270-276 Purpose of the Study

To determine whether patients are at greater risk

for anaphylactoid reactions to intravenous

uro-graphic contrast media if they are receiving (3-adren-ergic blockers or have asthma.

Study Population

Of 29 978 intravenous urographic contrast media

procedures done at the Henry Ford Hospital from July 1987 to June 1988, 63 patients had adverse read-tions, of which 49 were described as anaphylactoid. Methods

Anaphylactoid was defined as occurrence of one or more of the following within 20 minutes after contrast medial infusion: urticaria, angioedema, chest tightness, voice changes, hypotension, syncope while supine, cardiac dysrhythmia or arrest associ-ated with angioedema or urticaria. Charts were

ret-rospectively reviewed in a blinded fashion along

with a control group. For each patient who

experi-enced an anaphylactoid reaction, a control group

consisting of two patients who did not receive pre-treatment and were matched for age, gender, date and type of contrast media procedure were selected.

Asthma was considered present when the chart

doc-umented antiasthma medication use and evidence

compatible with variable airflow obstruction not con-sistent with chronic obstructive pulmonary disease.

Findings

Patients exposed to (3-adrenergic blockers or with

asthma comprised 39% of reactors, compared to 16%

of matched controls. Exposure to (3-blockers was 27%

among reactors and 12% in matched controls.

Asthma was found in 12% of reactors and 4% of

controls; after correction for (3-blocker use, asthma was also associated with an increased risk for ana-phylactoid reaction. Compared with nonasthmatic patients not taking (3-blockers, asthmatic patients were at greater risk for anaphylactoid reactions in-volving bronchospasm. Five of 13 reactors receiving

(3-blockers became hypotensive, and 3 needed

hos-pitalization. Half (7 of 14) of all the reactors experi-ending hypotension were either asthmatic or

receiv-ing (3-blockers. Compared with nonasthmatic

patients not taking (3-blockers, patients exposed to (3-blockers were almost nine times more likely to be hospitalized after an anaphylactoid reaction.

Reviewers’ Comments

This is the first study which has looked at the risk

associated with (3-blocker use or asthma, and

con-trast-nelated anaphylactoid reactions. The results are

intriguing although handicapped by all the faults

associated with a retrospective study. As the authors suggest, a prospective study in these patients to as-sess the risk of contrast-associated anaphylactoid ne-actions after more aggressive prophylactic measures is in order.

THOMAS M. FAME, MD

STArn J.Szw, MD

Denver, CO

CARDIOVASCULAR EFFECTS OF

PSEUDOEPHEDRINE IN MEDICALLY

CONTROLLED HYPERTENSIVE PATIENTS

Mercado DL, Seguin SM, Ardrade WP, Cushner HM.

Arch Intern Med. 1992;152:1242-1245 Purpose of the Study

The purpose of this study was to examine the

safety of sustained-release pseudoephedrine (PE) in hypertensive patients.

Study Population

Twenty-eight patients 27 to 73 years (median age, 63 years) with controlled hypertension participated in a randomized, double-blind, placebo-controlled, crossover study that examined the cardiovascular ef-fects of sustained-release PE. All patients had hyper-tension which was judged to be controlled for at least

3 months prior to study. All but three subjects

re-quired at least one medication, and four were taking three or more medications.

Methods

(4)

Physician-investi-gators measured blood pressure and heart rate for 4

hours after ingestion of the first dose, and at 72

hours. After an 11-day washout, patients were

crossed over to the opposite study medication. Com-pliance was verified with pifi counts and serum drug

levels. Symptom questionnaires were completed by

the volunteers.

Findings

Administration of PE did not result in significant changes in any cardiovascular parameter. A two-fac-ton analysis of variance using drug and repeated measures as variables, however, did demonstrate sta-tistically significant elevations of mean arterial pres-sure and heart rate. Mild disturbances in sleeping pattern and urinary retention in some male subjects were the only significant symptoms detected.

Conclusions

The authors conclude that sustained-release PE ap-pears safe for the majority of medically controlled patients without significant effects on blood pressure or heart rate. There was, however, an upward trend in blood pressure and heart rate which, in a larger population of patients, may prove to be clinically significant.

It remains somewhat confusing that different

re-sults were achieved depending on the statistical test used. It is also unclear why the authors chose to design the study with such a short course of treat-ment (72 hours). Several prior studies have investi-gated the cardiovascular effects of immediate and sustained-release PE in healthy normotensive sub-jects and have reported no significant adverse effects.

ALLEN ADINOFF, MD Aurora, CO

EOSINOPHIL DEGRANULATION IN THE

RESPIRATORY TRACT DURING NATURALLY

ACQUIRED RESPIRATORY SYNCYTIAL VIRUS

INFECTION

Garofalo R, Kimpen JL, Welliver RC, Orga PL. J Pediatr.

1992;120:28-32

This study was undertaken to determine whether

eosinophil cationic protein (ECP) is released into the respiratory tract during respiratory syncytial virus (RSV) infection and to determine the relationship of ECP release to the character and severity of illness.

Study Population

Forty-seven patients with documented RSV infec-tion were classffied as having upper respiratory tract illness (URI; 8 patients), bronchiolitis (29), or pneu-monia without wheezing (10). The patients ranged in

age from I through 36 months. An additional 26

children, I to 120 months of age, were also investi-gated. Eighteen of these non-RSV-infected children

had Uffi and 8 had bacterial pneumonia. Patients

with underlying cardiac on respiratory conditions

were excluded, as were patients who received corti-costeroid during the course of their illness. Chest auscultation, respiratory rate, and pulse oximetry were used to rule out lower respiratory tract involve-ment in the URI group.

Methods

Aspirated nasopharyngeal (NP) secretions were

collected within 24 hours of diagnosis. ECP concen-tration was determined using a competitive

radioim-munoassay and expressed as nanograms per

millili-ten of fluid. Mean concentrations of different groups were compared with a two-tailed Student’s t test. Paired t test was used to compare data from matched

pairs. Analysis of frequency was determined by

x

test. Sensitivity, specificity, and positive and negative predictive values for ECP as a marker for bronchioli-tis were calculated from 2 X 2 contingency tables. The correlation of ECP concentration to Pao2 was determined by simple linear regression.

Findings

ECP concentrations were not correlated with age

or gender. Children with bronchiolitis had the high-est ECP concentrations in the NP aspirates. Levels in

children with RSV-URI and RSV pneumonia without

wheezing were comparable. Serial ECP concentra-tions were not measured during different phases of the RSV infection.

When NP secretions contained more than 50

ng/mL of ECP, RSV bronchiolitis could be predicted with a sensitivity of 93% and specificity of 72%. Us-ing the same ECP threshold, the positive predictive value for distinguishing RSV bronchiolitis from other

RSV-related infections was 84.5% and the negative

predictive value was 86.7%.

ECP concentrations were correlated inversely with

Pao when only those patients, regardless of RSV

status, with ECP concentration 50 ng/mL were

in-cluded (correlation coefficient -.35; P < .05). Reviewer’s Comments

Although the authors did not examine bronchial tissue for eosinophilia, previous postmortem studies have shown significant tissue eosinophiia in RSV bronchiolitis. RSV-specific IgE antibody levels are el-evated in bronchiolitis and correlate with the degree of hypoxia. Leukotriene B4, a potent chemoattractant and activator of eosinophils, is found in the respina-tory tracts of infants with bronchiolitis and correlates with disease severity. ECP in bronchial tissues is thought to contribute to sloughing of the overlying mucosa which may in turn expose irritant receptors and decrease bronchial relaxing factors produced by the epithelium.

In this study an ECP concentration of 50 ng/mL in

NP secretions was predictive of RSV bronchiolitis; there was a significant amount of overlap with other

conditions. A prospective study using this level

needs to be done, as does a study looking at ECP

concentrations in RSV disease and subsequent recur-rent wheezing.

(5)

Immunology

PATHOPHYSIOLOGY AND DIAGNOSIS

ROLE OF A STREPTOCOCCAL ANTIGEN IN THE

PATHOGENESIS OF ACUTE POSTSTREPTOCOCCAL

GLOMERULONEPHRITIS

Yoshizawa N, Oshima 5, Sagel I, Shimizu J, Treser G.

I Immunol. 1992;148:3110-3116

The purpose of the study was to describe the

pu-rification and identification of a streptococcal protein (preabsorbing), the antibody response of this protein in patients with acute poststreptococcal glomerulo-nephritis (APSGN), and the action of the protein in inducing glomerular injury.

Methods

Streptococci belonging to M type 12 and I types 1, 4, and 12 were isolated from the pharynx of patients

with APSGN. Electrophoresis techniques were used

to identify a specific protein termed preabsorbing antigen (PA-Ag). Western blot analysis of the isolated protein was done using murmne monoclonal antibod-ies that recognize antigenic determinants shared by nephritis strain-associated streptokinase.

Sera were isolated from 31 patients with APSGN, 36 patients with group A streptococcal upper respi-ratory tract infection without renal disease, and 36

normal adults. Subjects ranged in age from 5 to 45.

Rabbits were immunized with PA-Ag or crude

anti-gen. Complement activation was determined by

im-munoelectrophoresis and by termination of comple-ment fractions 5 through 9.

Findings

Rabbit antisera against PA-Ag and sera of patients with APSGN showed identical precipitation lines by

immunodiffusion. Antibodies to PA-Ag were found

to be present in 30 of 31 patients with APSGN, in 1 of 36 patients with streptococcal infection, and in I of the 36 control subjects. Using electrophoresis tech-niques, it was found that PA-Ag activates the alter-native pathway of complement. Other streptococcal fractions did not activate the complement system.

The identification of the specific antigen responsi-ble for poststreptococcal glomerulonephritis by

im-munological techniques may make this not

un-common disease more readily identifiable. The

therapeutic implications of this study are yet to be identified.

RUSSELL J. Hopp, DO

Omaha, NE

IgG SUBCLASS VALUES IN HEALTHY BLACK AND

WHITE CHILDREN

Ambrosino DM, Black CM, Plikaytis BD. J Pediatr. 1991; 119:875-879

To determine normal IgG subclass values in

healthy children.

Study Population

246 healthy black children aged 6-42 months and

664 white children aged 6-60 months. Methods

Measurement of IgG1, 2, 3, 4 immunoglobulins by

enzyme-linked immunosorbent assay ELISA in the

serum of black children aged 6-42 months vs white

children aged 6-60 months. Comparison was made

of geometric mean values of black and white children

as determined for each 6-month age grouping

be-tween 6 and 42 months. Findings

Geometric mean values for IgGI, 2, and 4 levels

were consistently lower for black children than for

white. The differences were significant for IgG1 sub-class values for those children older than 24 months and IgG2 and 4 values of those children older than 18 months. There were no differences statistically in the IgG3 subclass values.

Conclusions

Young healthy black children have lower IgG1, 2,

and 4 serum concentrations than are found in white children. If normal IgG values based on white chil-dren are used, healthy black children will be errone-ously classified as IgG subclass deficient.

This study may have import also for Native

Amer-ican children, who have lower serum IgG2 and 4

responses to Haemophilus influenza type B capsular polysaccharide than white children have. This immu-nologic impairment is correlated with a very high incidence of H influenzae invasive infections in this population from the polysaccharide and capsulide pathogens. The results of this study contradict a pre-vious study of the relationship of raised

immunoglo-bulin subclass concentrations which had much

smaller numbers. The reasons for the difference in

black and white children are not documented, but

the authors signify that socioeconomic status, nutri-tion, environmental exposures, and, possibly genet-ics could play a role.

CHRISTOPHER RANDOLPH, MD Waterbury, CT

LYMPHOCYTE SUBSETS IN HEALTHY CHILDREN

DURING THE FIRST FIVE YEARS OF LIFE

Denny T, Yogev R, Gelman R. JAMA. 1992;267:1484-1488 Purpose of the Study

(6)

in children and to assess whether these phenotypes change relative to age in children.

Study Population

Two hundred eight healthy children aged1 month to 5 years who were participating in a Haemophilus

influenzae conjugate vaccine trial were studied. No patients had been ill or had a history of signs or symptoms consistent with immune abnormalities. No patients had been vaccinated within the previous week. Ninety-two percent of the children were His-panic.

Methods

Simultaneous, direct, two-color immunofluores-cence and standard flow cytometric techniques were used for monoclonal antibody staining and lympho-cyte subset analysis.

Findings

CD4 and CD8 lymphocyte counts were highest in

the youngest children and declined with age. The percentile of CD4 lymphocytes was highly age-de-pendent, decreasing with age up to 5 years. The

per-centile of CD8 lymphocytes mildly increased with

age.

Conclusions

Children in this study had much higher CD4

lym-phocyte counts than normal values for adults. The

percentile of CD4 lymphocytes was also higher than

normal adult values and both declined with age.

Even at 5 years of age, children’s levels were higher than reported adult normal values. These values

need to be considered when evaluating children for

human immunodeficiency virus infection, risk for

opportunistic infection, and treatment with medica-tions such as zidovudine.

Airi B. GOLDSOBEL, MD San Jose, CA

PROGNOSTIC SIGNIFICANCE OF IMMUNOLOGIC

CHANGES IN 675 INFANTS PERINATALLY

EXPOSED TO HUMAN IMMUNODEFICIENCY

VIRUS

de Martino M, Tovo PA, Galli L. J Pediatr. 1991;119:702-709

To determine the significance of immunologic changes vs outcome.

Study Population

Six hundred seventy-five children born to human

immunodeficiency virus (HN) infected mothers

with HN type I: 58 symptom-free (P1), 203 with

symptoms (P2), and 414 uninfected subjects.

Methods

Immunologic parameters including neutrophil, lymphocyte, and I-cell subset numbers and

immu-noglobulin levels were evaluated from birth to age 2 years in 675 children born to HN-infected mothers (P1 and P2 classes) and 414 uninfected subjects.

Findings

P2 patients, even at birth to I month of age, had lower CD4 positive lymphocytes and higher IgA and 1gM values than the P1 and uninfected children had.

Increased IgG values from 1 month to 6 months of

age and increased CD8 positive lymphocyte numbers at 13 to 24 months of age were also observed. The P1 population of children differed from uninfected chil-dren only at 13 to 24 months of age, and they were noted to have decreased CD4 positive and increased CD8 positive lymphocytes. Progressed immunologic alterations were found in those P2 patients with se-vere clinical deterioration and in those who died. One hundred sixty-four preselected children (25 P2,

15 P1, 124 uninfected children) who had been

fol-lowed sequentially from birth and initially classified as indeterminate (P0) up to 6 months of age were

further evaluated. P2 patients during the I- to

6-month period had higher immunoglobulin and

lower CD4 lymphocyte values than P1 and

unin-fected children. No difference was obtained between P1 and uninfected children.

Conclusion

Infants with perinatally acquired HN type I infec-tion have immunologic abnormalities that correlate with their clinical setting. These abnormalities are predictive of their clinical prognosis but not their infection status.

This study is limited by the small number of

af-fected children who were followed sequentially for more than a few months. A longer duration longitu-dinal study, ie, for more than a year, with larger numbers of infected patients vs controls is essential to verify further the reliability of immunologic changes as an indicator of clinical outcome.

CHRISTOPHER RANDOLPH, MD

Waterbury, CT

TREATMENT

RESULTS OF THE NATIONAL INSTITUTE OF

ALLERGY AND INFECTIOUS DISEASES

COLLABORATIVE CLINICAL TRIAL TO TEST THE

PREDICTIVE VALUE OF SKIN TESTING WITH

MAJOR AND MINOR PENICILLIN DERIVATIVES IN

HOSPITALIZED ADULTS

Sogn DD, et al. Arch Intern Med. 1992;152:1025-1032

(7)

Study Population

Eight centers cooperated in the National Institute of Allergy and Infectious Diseases trial of the predic-tive value of skin testing with major and minor pen-idillin derivatives.

Methods

Hospitalized adults were tested (prick and intrad-ermal) with a major-determinant (octa-benzylpenicil-loyl-octalysine) and a minor-determinant mixture (potassium benzylpenicillin, benzylpenicilloate, and benzylpenicilloyl-N-propylamine). if the

minor-de-terminant mixture component gave a positive test,

further tests were performed with each of the three separate components. Patients then received a ther-apeutic course of penicillin and were observed, for 48 hours, for adverse reactions compatible with an IgE-mediated or accelerated allergy.

Findings

Patients ranged in age from 21 to 97 years old.

Among the 726 history-positive patients, 566 with

negative skin tests received penicillin and only 7 (1. 2%) had possibly IgE-mediated reactions; none were

life-threatening. Among 600 history-negative

pa-tients, 568 with negative skin tests received penicillin and none had a reaction. Only 9 of the 167 positive skin test reactors received a penicillin agent and then usually by cautious incremental dosing (“desensiti-zation”). Two (22%) of these 9 patients had reactions compatible with IgE-mediated immediate or acceler-ated penicillin allergy; both were positive to the two skin test determinants. No significant adverse events were felt to be due to the skin-testing procedure.

Conclusions

These data corroborate previous data about the

negative predictive value of negative skin tests to

these materials. The reaction rate in skin test-positive patients was significantly higher than in those with negative skin tests, demonstrating the positive pre-dictive value of positive tests to both major and mi-nor determinants. The number of patients positive only to the major-determinant or only to the minor-determinant mix was too small to draw conclusions about the positive predictive value of either reagent alone.

I wish the study had included patients in the pe-diatric age group. Nevertheless, it is comforting to know that this study corroborates the results found previously. It is not clear why these workers went to all the trouble. Rumor has it that the investigators

were hoping the results might persuade the Food

and Drug Administration to approve the

minor-de-terminant mixture for use in clinical testing. The

ma-jor-determinant mixture used seems similar to the

commercially available Pre-Pen (penicillolyl-polyly-sine).

ALLEN ADINOFF, MD Aurora, CO

FREQUENCY OF ADVERSE REACTIONS TO

HEPATITIS B VACCINE IN 43 618 PERSONS

McMahon BJ, Helminiak C, Wainwright RB, Bulkow L, Trimble B, Wainwnight K. Am J Med. 199292:254-256 Purpose of the Study

The purpose of this study was to determine the

incidence of adverse reactions to hepatitis B plasma-derived vaccine.

Study Population

This was a sample of Alaska natives (43 618) who received 101 360 doses of hepatitis B vaccine.

Methods

All adverse reactions, excluding transient fever, myalgia, or soreness lasting less than 3 days, were

reported. An intradermal skin test was developed

and administered to patients who had experienced an adverse event (such as rash or arthritis) associated with the first vaccine injection, before the next

im-munization was scheduled. Heptavax (Merck Sharp

and Dohme), 0.1 mL of a 1:10 dilution (using normal saline) of vaccine, was administered in the forearm

and interpreted immediately and at 48 hours to

de-ted erythema and induration. Records for the entire population were reviewed for Guillain-Barr#{233} syn-drome (GBS).

Findings

Possible adverse reactions occurred in 39 persons. The most frequent adverse reactions were myalgia/ arthralgia lasting longer than 3 days (14), skin rashes (8), and dizziness (7). No increased incidence of GBS was found in the vaccinees. Skin tests, performed in 13 persons who experienced an adverse event asso-ciated with the first vaccine injection, were positive in 5. Two persons with urticaria associated with the vaccine had negative skin tests, although I patient

with an “arthus reaction” had a positive skin test

reaction. Six of the persons with negative skin tests

and 8 persons who did not undergo skin testing

re-ceived additional doses of vaccine without any

ad-verse reactions. Six persons had positive skin test reactions, and in all these, the vaccination series was discontinued.

Conclusions

The authors conclude that hepatitis vaccine is safe

and most adverse reactions are coincidental. No

re-lationship appeared to exist between the type of ad-verse reaction and the presence of a positive skin test. Reviewer’s Comments

I seem to be seeing more and more patients

re-ferred for evaluation of possible adverse reactions to vaccines and, therefore, found this article useful. The skin test results were not a major focus of this study, and certain details which would be useful to aller-gists are not included. Nevertheless, a negative skin test response in a patient with an apparent adverse vaccine reaction seemed to have useful predictive

value. Because a second vaccine dose was not given

(8)

its predictive value. Alaska natives were studied as

part of a mass vaccination program directed at a

group who apparently have a high incidence of acute hepatitis B infection and a high carrier rate.

ALLEN ADINOFF, MD

Aurora, CO

ENDOTHELIAL LEUKOCYTE ADHESION

MOLECULE-i (ELAM-1) MEDIATES

ANTIGEN-INDUCED ACUTE AIRWAY

INFLAMMATION AND LATE-PHASE AIRWAY

OBSTRUCTION IN MONKEYS

Gundel RH, Wegner CD, Torcellini CA, Clarke CC,

Haynes N, Rothlein R, Smith Letts LG. J Clin Invest.

199188:1407-1411 Purpose of the Study

Allergen exposure often elicits a two-phase bron-choconstrictive response characterized by a mast cell

mediated immediate asthmatic response within 10 to

15 minutes, followed by a late asthmatic response (LAR) 4 to 6 hours after exposure. The development of the LAR is associated with an influx of

inflamma-tory cells (polymorphonuclear leukocytes EPMNsI)

into the airway. Adhesion molecules present on

white blood cells and the vascular endothelium are thought to play a role in the process of white blood cell accumulation at sites of local inflammation. This

study examined the role of ELAM-I (an adhesion

glycoprotein) in the development of acute airway

inflammation and the LAR in a primate model.

Methods

Bronchial challenges with Ascaris suum were

ad-ministered to sensitized monkeys. Prior to and at

various times after the bronchial challenge, broncho-alveolar lavage with bronchial biopsies and measure-ment of respiratory resistance were performed.

Findings

Examination of the baseline bronchoalveolar

lay-age fluid showed a large percentage of esosinophils

but very few PMNs. Six hours after the challenge

there was a significant increase in the number of

PMNs and a fall in the number of eosinophils. By 7

days, the values for both eosinophils and PMNs had

returned to baseline. The number of PMNs also

con-related with the severity of the LAR.

Immunohis-tochemical staining of the bronchial biopsy

sped-mens showed increases in ELAM-1 expression at 6

hours which was confined to the vascular endothe-lium. Pretreatment with intravenous antibodies against ELAM-I inhibited both the influx of PMNs and the development of the LAR, whereas treatment

with ICAM-l (another adhesion molecule) had no

effect on either parameter.

Conclusions

(1) The rapid influx of PMNs associated with the

LAR occurs largely through an endothelial ELAM-I

dependent process. (2) The significant correlation

be-tween the degree of PMN influx and magnitude of

the LPR suggests an effector role for the PMN in the

LAR. (3) ICAM-1 does not appear to be the predom-inant adhesion protein involved in the acute airway inflammatory response.

Recently, more emphasis has been placed on the role of inflammation in the pathogenesis of asthma.

This study provides direct evidence for the role of

inflammatory cells (ie, neutrophils) in producing the LAR. It also demonstrates that adhesion molecules present on the vascular epithelium are upregulated following allergen exposure and that they promote the accumulation of inflammatory cells into the air-way. Additional research in this area wifi provide further insight into the pathogenesis of asthma and may allow for improved treatment.

JOSEPH D. SPAHN, MD STANLEY J. SZEFLER, MD Denver, CO

CYTOKINE REGULATION OF IMMUNOGLOBULIN

SECRETION BY NEONATAL LYMPHOCYTES

Spawski JB, Lipsky P.J Clin Invest. 1991;88:967-977

Neonates are deficient in their ability to produce

immunoglobulin (Ig), with deficiencies in both

I- and B-cell function noted. In an attempt to better understand this problem, the authors evaluated the ability of neonatal lymphocytes to produce

immuno-globulin following stimulation with immobilized

an-ti-CD3 monoclonal antibody (MAb) in the presence or absence of added cytokines.

Methods

Mononuclear cells were isolated from cord blood of healthy newborns at the time of delivery and fur-then purified into B and I lymphocytes. Affiquots of the neonatal B cells and irradiated T cells were incu-bated with immobilized anti-CD3 MAb in the pres-ence or absence of supplemental intenleukin-2 (IL-2), IL-4, or IL-6. The supernatants were removed on day

15 and analyzed for immunoglobulin secretion.

Sim-ilar studies were performed using B and I cells from healthy adult donors.

Findings

Stimulation of adult lymphocytes with anti-CD3

MAb proved a very strong stimulus for Ig

produc-tion of all isotypes (and without the need for added cytokines). Neonatal lymphocytes failed to produce Ig with anti-CD3 stimulation alone but could

pro-duce Ig if exogenous cytokines were added. The

(9)

Conclusions

Neonatal lymphocytes failed to produce Ig when

stimulated with anti-CD3, a powerful inducer of

adult B cells. Previous studies have revealed that

neonatal I cells are unable to support Ig production

by neonatal on adult B cells. It has been unclear

whether this inability is due to deficient I-cell pro-duction of cytokines or secondary to other intrinsic aspects of I-cell immaturity. This study demonstrates that the addition of cytokines are sufficient to sup-port Ig production. Of note, no selective

isotype-spe-dfic changes were noted following stimulation of

any of the cytokines or combination of cytokines

studied. Thus, although the neonatal I cells were

deficient in the production of cytokines required for Ig secretion, they were able to respond to supplemen-tal cytokines as noted in the ability of B cells to now produce 1g.

This study furthers our understanding of the

mechanisms responsible for the neonate’s inability to

produce immunoglobulin following stimulation with

antigen. It also further emphasizes the importance of I- and B-cell interaction. There are obvious clinical implications to this research in that immunotherapy with specific cytokines could boost an ill neonate’s humoral immune response.

JOSEPH D. SPAHN, MD

STANLEY J. SzEFLER, MD Denver, CO

PARALLEL REGULATION OF IL-4 AND IL-5 IN

HUMAN HELMINTH INFECTIONS

Mahanty 5, AbramsJS, King CL, Limaye AP, Nutman TB.

J Immunol. 1992;148:3567-3571 Purpose of the Study

The purpose of the study was to investigate the

relationship between cytokine production and the increased levels of serum IgE and peripheral

eosino-philia commonly accompanying human helminth

infections. Study Population

Peripheral blood mononuclear cells from normal

subjects and individuals with eosinophilia and hel-minth infections were studied.

Methods

Peripheral blood mononuclear cells were isolated using Ficoll-Hypaque density gradient centrifuga-tion. Levels of cytokines were measured from super-natants of peripheral blood mononuclear cells after

stimulation with pokeweed mitogen. Cytokine levels

in cell supernatants were measured by

enzyme-linked immunosorbent assay using monoclonal

anti-bodies. Findings

The mean serum IgE concentration in the nine

sub-jects infected with helminth was 960 ng/mL. The

average number of eosinophils per microliter was

1459. The IgE level for the normal controls was 31

ng/mL, and the mean number of eosinophils per

microliter was 103. Production of interleukin-3 (IL-3)

in infected individuals was twofold higher than in

uninfected individuals, IL-4 was fourfold higher, and IL-S was sixfold higher. There was no increased pro-duction of interferon gamma or granulocyte macro-phage colony-stimulating factor (GM-CSF). There

were an increased number of CD4 cells secreting

IL-4 and IL-S in the infected individuals, while the

numbers of cells secreting interferon gamma and

GM-CSF were similar. There was a correlation

be-tween IL-4 and IL-S secretion in the group as a

whole, suggesting that the production of IL-4 and IL-S increases proportionately and in parallel.

Studies using mice have clearly shown that CD4

cells are capable of producing a THI (minimal IL-4/ IL-5) or a IH2 (IL-4 and IL-S) cytokine profile. Some preliminary work has shown that similar cytokine profiles may be pertinent to allergic and asthmatic human subjects. This report would suggest that pan-asitic infections likewise can induce a TH3 cytokine

profile from CD4 cells. The question remains

whether all human subjects would, when exposed to

parasitic infections, produce IL-4 and IL-S in excess amounts, thus increasing their IgE and eosinophil counts, or whether some subjects are genetically pre-disposed to do so. This question is also pertinent to allergic subjects, although questions about the anti-genic properties of parasites vs pollen is obviously left begging.

RUSSELL J. Hopp, DO

Omaha, NE

IL-4 CONTROLS THE SELECTIVE

ENDOTHELIUM-DRIVEN TRANSMIGRATION OF

EOSINOPHILS FROM ALLERGIC INDIVIDUALS

Moser R, Fehr

J,

Bruijnzeel PLB. J Immunol. 1992;149: 1432-1438

The purpose of the article was to characterize the transendothelium migration of circulating

eosino-phils from normal and allergic subjects utilizing a

human umbilical vein endothelium cell model.

Methods

Eosinophils from allergic and nonallergic donors were placed in contact with a single layer of human

umbilical vein endothelium cells cultivated on an

extracellular matrix provided by human fibroblasts.

Findings

(10)

macrophage colony-stimulating factor, IL-3, or IL-4. Eosinophils from allergic subjects spontaneously penetrated the IL-4-activated vascular constructs. IL-4 selectively induced eosinophil layer penetration

whereas IL-4, IL-I, and tumor necrosis factor all

shared the capacity to induce eosinophil adherence to endothelium cells. The effect of IL-4 could be spe-cifically blocked using an IL-4-specific neutralizing monoclonal antibody. Antibodies against

intracellu-lar adhesion molecule-i (ICAM-1) and VCAM-1

were also able to inhibit the eosinophil transmigra-tion. Furthermore, eosinophil transmigration across

IL-4 vascular constructs was strongly inhibited by

blockage of endothelium messenger RNA synthesis.

It is quite evident that the eosinophilia present in nasal secretions and sputum of allergic and asthmatic subjects is accomplished by a complex array of

cel-lular and mediator interaction and provides a key

area for future research and potentially therapeutic manipulation.

RUSSELL J. Hopp, DO

(11)

1993;92;336

Pediatrics