Robert H. Schwartz

Renal clearance of gentamicin in cystic fibrosis

This study was designed to corroborate previous observations of low serum concentrations of aminoglycosides after usual doses in patients with cystic fibrosis and to investigate possible mechanisms for this change. We studied gentamicin clearance after single and multiple intravenously administered doses in 10 non-acutely ill patients with mild to moderate CF. The data could best be described by a two-compartment model for drug elimination. The mean 1-hour serum concentration, mean volume of distribution, and mean total plasma clearance of gentamicin were not different from those reported for patients without CF. The similarity of the plasma and the renal gentamicin clearances, supported by the observations that greater than 80% of administered drug was excreted in the urine by 4 hours and that negligible amounts were detected in sweat, saliva, or sputum, implies that the kidney is the major route of elimination in patients with mild CF. The correlation of increased plasma gentamicin clearance as NIH score decreases supports the hypothesis that aminoglycoside pharmacokinetics are changed as the severity of disease increases. For patients with mild CF, standard doses of gentamicin (60 mg/m2) will give safe and therapeutic concentrations.

Montelukast reduces peripheral blood eosinophilia but not tissue eosinophilia or symptoms in a patient with eosinophilic gastroenteritis and esophageal stricture

BACKGROUND Eosinophilic gastroenteritis (EG) is an uncommon entity of which the pathogenesis is unclear. As no controlled treatment trials exist, treatment of EG remains largely empiric. Limited results have been achieved with oral cromolyn, ketotifen, and other antihistamines. Oral corticosteroids are effective, but long-term use is complicated by side effects including growth retardation, diabetes, and osteoporosis. OBJECTIVES We sought to determine whether treatment with montelukast would improve symptoms and decrease both peripheral blood and tissue eosinophilia (TE) in a patients with steroid-dependent EG for 20 years complicated by esophageal stricture. METHODS In an unblinded, n = 1 trial, we treated the patient for 5 months with montelukast (20 to 30 mg daily) while his baseline dose of prednisone (10 mg daily) was continued. Complete blood counts and symptoms were monitored weekly. Esophageal biopsies were obtained before and after 5 months of therapy with montelukast. After the posttreatment biopsy was obtained, montelukast was discontinued. Outcome measures included patient symptoms and peripheral and tissue eosinophil counts. RESULTS During treatment with montelukast, the mean peripheral blood eosinophil count fell from 5,064 cells/microL (average 28 determinations over 20 years; range 1,408 to 12,500 cells/microL) to 1,195 cells/microL (average 14 determinations over 16 weeks; range 556 to 2,193 cells/microL), a 76% reduction. The corresponding TE as calculated from esophageal biopsies was 31 eosinophils/high power field before and 70 eosinophils/high power field after treatment. The patient noted no appreciable improvement in esophageal symptoms. CONCLUSIONS Montelukast dramatically reduced peripheral blood eosinophilia, but did not affect TE or symptoms in this patient with severe, long-standing EG complicated by esophageal stricture.

Pulmonary abnormalities in intermediate alpha-1-antitrypsin deficiency.

Pulmonary function studies were carried out in a group of asymptomatic nonsmoking adults with intermediate alpha-1-antitrypsin deficiency who were attending an early disease detection unit in Rochester, N. Y. All subjects were identified by specific protease inhibitor (Pi) typing. Fifteen MZ and 14 MS subjects who had never smoked cigarettes were matched by sex and age to MM controls. Spirometry, static lung volumes, and single breath-diffusing capacity were identical in all Pi type groups with no statistically significant differences noted. Maximal expiratory flow volume curves were obtained in all subjects. MZ subjects demonstrated statistically impaired maximal flow rates at 75%, 50%, and 25% of vital capacity compared to their MM controls. Total pulmonary resistance by the oscillometric method was measured at 3, 5, 7, and 9 cycle/s in the same subjects. Increased frequency dependence of resistance (defined as the difference between total pulmonary resistance at 3 cycle/s and 9 cycle/s) was observed in MZ subjects compared to MM controls. No differences were noted by this method in MS-MM pairs. The data suggest that detectable mechanical abnormalities are present in subjects with the MZ phenotype, even in the absence of established risk factors such as cigarette smoking and high air pollution.

Alpha-1 antitrypsin in childhood asthma.

Alpha-1 antitrypsin (AAT) phenotypes and serum levels were studied in two childhood perennial asthmatic populations. The first was an ambulatory, mostly mild nonsteroid-dependent group living in Rochester, N.Y. The second was a more severe mostly steroid-dependent group residing at an asthma residential treatment center in Denver, Colo. The prevalences of alpha-1 antitrypsin protease inhibitor (Pi) tyes were the same for bothe groups and similar to prevalences in a random population. Alpha-1 antitrypsin serum levels were significantly elevated for the mild nonsteroid-dependent group when compared to the more severe steroid-dependent group. The steroid-dependent group had serum levels similar to a group of nonasthmatic control children. These findings indicate that there is not a strong association of alpha-1 antitrypsin Pi variants such as Pi MZ or Pi MS with more severe asthma. Elevated serum levels in the milk perennial asthmatic group may be the result of chronic inflammatory processes. Normal levels in the sterioid-dependent group may be the result of corticosteroid control of inflammation associated with asthma.

New workforce, practice, and payment reforms essential for improving access to pediatric subspecialty care within the medical home

T HE AVAILABILITY OF pediatric subspecialty care is critically important to the heal th and wel l being of infants, children, and adolescents. Moreover, timely collaboration with pediatric subspecialists is an essential element of the standard of care for children: the community-based medical home. The medical home model of care, with a generalist physician as the leader, has been shown to produce considerable economic and patient-level benefits. In this model, primary care practice teams coordinate all care for a patient, including subspecialty care. Unfortunately, lack of access to pediatric subspecialty care within the medical home has reached crisis proportions in the United States owing to several interrelated factors: an insufficient number of pediatric subspecialists, dramatically increasing demand for pediatric subspecialty care, a fragmented system of pediatric primary and specialty care, and inadequate f inancing of medical education and collaborative primary and specialty pediatric care through the medical home. In the United States, approximately 28 000 medical and surgical pediatric subspecialists serve 80 million children and youth. The ratio of board-certified pediatric subspecialists to children in each of the 31 specialties is hazardously low. Although the number of pediatric subspecialists has increased in the last decade, far too few physicians are being trained in nearly every pediatric subspecialty. For example, the American Board of Pediatrics reports that in 2007 there were only 19 first-year fellows in developmental behavioral pediatrics, 24 in adolescent medicine, and 26 in pediatric rheumatology. Compounding the pipeline problems are increasing retention difficulties, a growing retirement rate, the tendency of younger physicians to limit their hours of practice, and the overall shortage of physicians. Furthermore, as the elderly population grows, the availability of adult specialists, many of whom care for children in areas where pediatric subspecialists are unavailable, is eroding. In addition to the problem of a shrinking workforce, demand for pediatric subspecialty care has reached unprecedented levels. During the last few decades, the incidence and prevalence of certain chronic conditions, such as attention-deficit/ hyperactivity disorder, asthma, depression, and obesity, have dramatically increased. Furthermore, the survival of infants and children with complex, formerly fatal conditions has become commonplace. Advances in medical and surgical care, technology, and drugs have clearly created new benefits and stresses on our pediatric care delivery systems. Changes in families’ knowledge and preferences for referral to specialty care are resulting in higher rates of referrals to pediatric subspecialists. Also affecting higher rates of specialty referral is the lack of adequate primary care capacity, resulting in a reduced amount of time that physicians can devote to identifying and managing chronic conditions. Underlying these obvious supplyand-demand problems is the worsening fragmentation between primary and specialty pediatric care. Despite the supporting evidence, resources to enable primary care practices to provide this level of care are not generally available. Lack of recognition of the importance of the medical home as the base of care coordination from the standpoint of reimbursement along with the absence of organized and efficient systems for referral, consultation, and collaborative care at the community and regional levels result in worsening fragmentation. Fragmentation is also aggravated by the uneven geographic distribution of pediatric subspecialists, the everchanging insurance and health plan enrollment of families, and the shifting composition of plans’ provider networks. Inadequate financing of graduate medical education and the lack of financing for continuing medical education for primary care providers further compromises access to pediatric subspecialty care within the medical home. Because payment for graduate medical education is a function, in part, of the percent of inpatient days attributable to caring for Medicare patients, hospitals serving children are at a distinct disadvantage. While a separate graduate medical education program operates for children’s hospitals, it is subject to low annual appropriations. In addition, the graduate medical education program is structured to discourage subspecialty training in favor of primary care training by counting fellows in subspecialty training at lower levels than resident physicians in their initial specialty training. Moreover, no funding sources are available to support primary care providers who are interested in pursuing additional specialized training. Equally significant is inadequate third-party payment. Between one-third to one-half of all children (depending on their age) are insured by Medicaid or the State Children’s Health Insurance Program, and children with special

Serum α1-Antitrypsin Types: Elastase Inhibition Versus Trypsin Inhibition

Elastase and trypsin were compared for the assay of human serum α1-antitrypsin. (1) For distinguishing MM and MZ types, the combination of concentration and elastase inhibitory capacity was

964 ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (ABPA) WITH LOW SERUM IgE

Elevated serum IgE is helpful in making the diagnosis of ABPA and in monitoring the onset of exacerbation and response to therapy. ABPA occurs frequently in patients with cystic fibrosis (CF). They also develop high total serum IgE.A 20 yr. old non-asthmatic woman with CF who smoked marihuana developed fever, chest pain and expectoration of brown flecks. She had a ligularinfiltrate, blood(1500/mm3) and sputum(50%) esoinopilia.Sputum cultures were positive for Aspergillus fumigatus (Af). A previously negative immediate skin test to Af became positive (1:10,000 w/v). She developed serum precipitins to antigens from two Af sources and to Aspergillus species isolated from her marihuana.Septate hyphae were seen in a left upper lobe bronchial brushing. Culture grew Af. Three mos. prior to the acute illness IgE was 9 IU/ml. Serum IgE rose to 16 and 29 IU/ml. during 10 days when the Dx of ABPA was being considered. With prednisone Rx symptoms disappeared, chest infiltrate cleared, culture for Af became negative, Af precipitin tests became negative and IgE fell to 6 IU/ml. The immediate skin test to Af remained positive 3 mos. after Dx. Af RASTs were negative 4 yrs. and 3 mos, prior to the illness, at the time of acute illness and at 3 mo. intervals after onset. Serum skin sensitizing antibody could not be detected by P-K passive transfer and skin testing at 2 hrs. and 48 hrs.Elevated total serum IgE does not always accompany acute ABPA. Early diagnosis may need to be made using less restricted criteria.

Pathogenesis of deficient serum ?1-antitrypsin in the type ZZ homozygote

Why is the serum α1-antitrypsin activity in the type ZZ (deficient) individual only one-tenth that of the type MM (normal) individual? To determine whether the explanation is simply decreased concentration or also decreased specific activity, the specific activity was determined for ZZ and MM sera. Four ZZ sera had a mean specific activity of 0.665±0.170 sd mg of trypsin inhibited per milliliter of serum and 20 MM sera had a mean specific activity of 0.573±0.157 sd. Hence the lower activity of ZZ serum is due entirely to its lower concentration of α1-antitrypsin. This lower concentration, in turn, could be due to decreased entry into or increased removal from the circulation. Increased removal in ZZ could be due to an increased intrinsic lability or to an accelerated removal mechanism. At acid pH (4.6–6.6) and at elevated temperatures (54–58 C), the activity of ZZ sera was not more labile than that of MM sera. An accelerated removal mechanism may also be unlikely in view of the reported finding that labeled α1-antitrypsin had the same removal rate when injected into an MM or a ZZ individual. If the lower concentration is not due to increased removal, it must be due to decreased entry into the circulation. This could be the result of a decreased rate of synthesis or secretion. The fact that antitrypsin accumulates in the hepatic parenchymal cells of the ZZ individual favors a defect in hepatic secretion.

758 CYSTIC FIBROSIS (CF) IN A LARGE KINDRED

Consanguineous matings increase the chance for the appearance of homozygous autosomal recessive disease. When the frequency of a recessive gene in the population is high, as with CF, the finding of consanguinity among the parents need not be common. There have been few reports of consanguinity in CF families.In four families, 6 of 21 children with documented CF can trace their roots back 6 and 7 generations to a common ancestor who was born in 1789 in Lorraine, France. Since 1833 when this patriarch came to the U.S. there have been over 5,000 descendants. Most have lived in upstate New York.The parents of the CF proband are distant cousins (4 and 5 generations removed) via two lines of descent.Two other CF children in a second family and one in a third family are cousins. They are also second cousins to the proband. Each parent pair contains a sibling descended from the patriarch via a second line of descent. The opposite spouses, not of the same lineage, are also siblings.Two other CF children in a fourth family are related to the other CF individuals via a third line of descent.The inherited nature of CF is evidenced by;(1)four CF families with common ancestry, and (2)brothers and sisters having children with CF. Autosomal recessive inheritance is evidenced by; (1) consanguinity in parents of the proband, (2) first cousins with CF, and (3)a 29% CF incidence when the expected incidence is 25%.

ACCEPTANCE OF CARRIER TESTING AND FETAL DIAGNOSIS OF CYSTIC FIEROSIS (CF) IN AMISHMENNONITE AND HUTTERITE CF KINDERDS

This study examined the attitudes, feelings, and knowledge of 37 parents, 29 adult siblings, 126 aunts and uncles, and 30 cousins of 50 CF-affected individuals in 2 large inbred kindreds (Amish-Mennonite and Hutterite) prior to the availability of carrier testing and fetal diagnosis by DNA marker linkage analyses. Data was ascertained by selfadministered questionnaires. Some responses could be compared to 2 non-inbred CF populations studied by Kaback et al. (California) and Steele et al. (Pittsburgh).Knowledge of the recurrence risk of CF changed planned family size (51% - present study vs 48% - Kaback et al.). Families continued to reproduce when other than the first child had CF (50% - present study vs. 15% - Steele et al.). The majority incorrectly identified the recurrence risk for CF to carrier parents (57%) and felt that carrier screening (61%) and fetal diagnosis (56%) should be done. The majority also felt that CF might be a possible reason for pregnancy termination (54%).Despite our preconceived notions that these populations would not consider fetal diagnosis and carrier testing, our survey suggests that these optional procedures, which are now available may influence reproductive decisions in these families.