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
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;66:892-898Purpose 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.
Reviewer’s Comments
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
Purpose of the Study
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
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.
Reviewer’s Comments
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
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.
Reviewer’s Comments
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
Purpose of the Study
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.
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
Purpose of the Study
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.
Reviewer’s Comments
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
Purpose of the Study
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.
Reviewer’s Comments
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
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
Purpose of the Study
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.
Reviewer’s Comments
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
Purpose of the Study
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.
Reviewer’s Comments
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
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.
Reviewers’ Comments
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
Purpose of the Study
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
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.
Reviewers’ Comments
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.
Reviewer’s Comments
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: 1432-1438Purpose of the Study
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
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.
Reviewer’s Comments
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