Norman J. Lewiston

Cyclosporine and Itraconazole Interaction in Heart and Lung Transplant Recipients

Excerpt Itraconazole is a new triazole antifungal (1-3). The infrequency of serious toxicity makes it particularly appropriate in patients receiving cyclosporine therapy, in whom nephrotoxicity is ...

Fatal myocardial toxicity during continuous infusion intravenous isoproterenol therapy of asthma

We recently utilized continuous infusion intravenous isoproterenol in the treatment of respiratory failure in an 18-yr-old steroid-dependent asthmatic female. Aminophylline, hydrocortisone, aerosolized isoetharine, and oxygen were also administrered. The patient responded to this therapy, with PaCO2 falling from 70 torr to 33 torr in 18 hr. The maximum isoproterenol dosage administered was 0.32 microgram/kg/min. Thirty-six hours following the institution of therapy, while the isoproterenol was being tapered, the patient experienced an increase in respiratory distress followed by cardiac arrest. Postmortem examination revealed multiple small areas of myocardial necrosis. These findings, unusual in asthma, probably were related to the effects of isoproterenol or the combination of isoproterenol and aminophylline on the stressed myocardium. The vulnerability of the hypoxic myocardium to the effects of isoproterenol suggests that careful cardiac monitoring is essential in the management of patients receiving this medication for treatment of respiratory failure secondary to severe asthma.

Allergy to semisynthetic penicillins in cystic fibrosis.

Allergic reactions to anti-Pseudomonal penicillin derivatives are an increasing problem in therapy of cystic fibrosis lung disease. We evaluated 15 patients, ages 12 to 37 years, with documented allergic reactions to carbenicillin, ticarcillin, or piperacillin. Intradermal skin test reactions were positive for benzylpenicillin in seven patients, penicilloyl-polylysine in one, and ticarcillin or piperacillin in eight, for a total of 11 of 11 tested. Results of radioallergosorbent testing to penicilloyl conjugates were positive in eight of 14 patients and equivocal in four others. Overall, skin tests or RAST results were positive in 13 of 15 patients. All patients were desensitized with a semisynthetic penicillin by continuous serial intravenous infusion of 10-fold dose increments, beginning with 10(-6) of the therapeutic dose. Desensitization was successful in 25 of 26 instances. After intravenously administered therapy, maintenance of desensitization with dicloxacillin orally was unsuccessful in four of six patients. We conclude that (1) allergy to semisynthetic penicillins in cystic fibrosis usually is IgE mediated; (2) such allergy can be evaluated by skin testing; (3) it can be safely and in most cases successfully treated by intravenous desensitization; and (4) allergic patients should be desensitized on each subsequent admission for intravenously administered therapy.

Sinus disease in patients with severe cystic fibrosis: relation to pulmonary exacerbation

Four adult cystic fibrosis patients were selected for aggressive surgical management of sinus disease on the basis of severe pulmonary involvement, high frequency of hospital admission, chronic headache, and wheezing unresponsive to conventional treatment. They underwent bilateral Caldwell-Luc procedure with perioperative anti-Pseudomonas antimicrobials. There were substantial improvements in headache and respiratory symptoms and a significant reduction in the frequency of hospital admission after the operation. These findings suggest that sinus disease is associated with pulmonary exacerbation in patients with cystic fibrosis, and strengthens a similar observation in patients with asthma.

PSYCHOLOGICAL FACTORS IN FATAL CHILDHOOD ASTHMA

A review of three recent cases of death due to childhood asthma revealed consistent themes of depression, emotional precipitation of attacks, unsupportive families, and a tendency to deny asthma symptoms. Possible psychosomatic mechanisms are identified as potentially important for the interaction of emotions and asthma.

Trimethoprim-sulfamethoxazole prophylaxis for Pneumocystis carinii infections in heart-lung and lung transplantation--how effective and for how long?

Pneumocystis carinii pneumonia (PCP) is a common clinical problem in the setting of organ transplantation, particularly in heart-lung and lung allograft recipients. Without prophylactic measurements, the incidence of P carinii pneumonia can reach up to 88% of heart-lung transplant recipients. We conducted a retrospective analysis of the Stanford heart-lung and lung transplant experience in order to assess the efficacy of the prophylactic therapy and to try to define the duration of therapy necessary for prevention. During a 9-year period 82 heart-lung and 13 single-lung transplants were performed. Of the patients not on prophylaxis therapy 27% (13 patients) developed P carinii infection as compared with 0% of patients on trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis. The incidence of PCP infection peaked between 3 and 6 months posttransplantation. No case of infection was observed before the 7th week posttransplant. PCP was more common following induction immunosuppression with OKT3 as compared with RATG (P less than 0.05). All cases of infections later than one year posttransplant were associated with recent increase in the immunosuppression regimen with high-dose corticosteroids for treatment of acute or chronic (obliterative bronchiolitis) rejection. Although our study is retrospective and based on various immunosuppressive and diagnostic technique periods, it seems that TMP-SMX is highly effective in preventing PCP infections in heart-lung and lung transplant recipients. Twelve months of therapy is probably a sufficient length of therapy if immunosuppressive therapy is stable. However, whenever augmentation in the immunosuppression regimen is indicated, prophylactic therapy should promptly be restarted.

Hyposecretion of |[beta]|-Adrenergically Induced Sweating in Cystic Fibrosis Heterozygotes

ABSTRACT.: In order to determine if expression of the eystic fibrosis gene can be detected in heterozygotes, we determined sweat responses induced by local stimulation with cholinergic and β-adrenergic agents for 20 heterozygotes, 19 age- and sex-matched controls, and five subjects with cystic fibrosis. Active sweat glands were counted and sweat droplets were collected in constant bore capillaries and measured optically. Kach subject was tested two to six times. The central finding was that the sweat response of carriers was significantly lower than controls to β-adrenergic stimulation (P= 0.0013, two-tailed r test; P < 0.02, Mann-Whitney U). while cystic fibrosis homozygotes did not sweat at all. In contrast, the cholinergic sweat responses did not differ between carriers and controls. For both groups the correlation between cholinergic and (1- adrenergic sweating was positive, but a linear regression of β-adrenergic sweat responses as a function of cholinergic sweat responses yielded slopes that were significantly different for the two groups. The ratio of β-adrenergic to cholinergic sweating was plotted for each subject; the mean ratio of the carriers was approximately half of the mean for the controls (P = 0.0002 using r test or P<0.002 using the Mann-Whitney U). Our results confirm previous studies and provide new evidence that carriers have, on average, a β-adrenergically stimulated secretory response that is significantly reduced relative to the control response.

Heart-lung transplantation in infants, children, and adolescents☆☆☆

We have performed heart-lung transplantation in 10 children for the preoperative diagnoses of primary pulmonary hypertension (4), complex congenital heart disease with pulmonary hypertension (4), pulmonary atresia (1), and cystic fibrosis (1). Ages ranged from 4 months to 18 years. There were 15 episodes of pulmonary rejection, with an occurrence rate of 1.67 episodes per patient. Pulmonary infections occurred frequently, with an occurrence rate of 3.3 episodes per patient. The actuarial survival rate at 1 and 2 years was 78% and 47%, respectively. Patient attrition between 1 and 2 years was attributable to the complications of obliterative bronchiolitis, which has effected 71% (5/7) of the long-term survivors. Four of the 5 surviving children have minimal physical limitation and are in functional class I. These data support continued investigation into heart-lung transplantation in children and set the stage for further program development into single-lung transplantation in children.

Altered Antibody Isotype in Cystic Fibrosis. Possible Role in Opsonic Deficiency

ABSTRACT. Patients with cystic fibrosis (CF) whose respiratory tracts are colonized with Pseudomonas aeruginosa (PA) may develop a specific opsonic deficiency for alveolar macrophage phagocytosis of PA. We examined the possible role of altered antibody (Ab) isotype in this phenomenom by measuring serum levels and distribution of IgG and IgG subclass Ab (IgGl, IgG2, IgG3, and IgG4) to the major opsonic immunodeterminant, serotype-specific lipopolysaccharide (LPS), by means of enzyme-linked immunosorbent assays employing monoclonal secondary antibodies, and comparing these results to the serum opsonic capacity in an in vitro murine alveolar macrophage phagocytic assay. Twenty-one patients with CF who were colonized with PA had approximately a 30-fold elevation of PA LPS IgG Ab levels and higher IgG subclass 1-4 Ab compared to 10 uncolonized patients with CF and 11 healthy controls (p<0.05-0.0005 depending on the isotype). Colonized patients with CF had a shift in PA LPS Ab distribution toward IgG3 compared to uncolonized patients with CF (p<0.02). A surprising finding was that uncolonized patients with CF had lower levels (p<0.05) and proportion (p<0.002) of PA LPS IgG2 Ab than controls, with an apparent shift to higher levels and proportion of PA LPS IgG4 (p<0.01). Serum from colonized patients with CF showed diminished opsonic capacity for phagocytosis of PA compared to uncolonized patients and controls (p<0.005), with 42% showing inhibitory activity. Functional Ab was also found to be inhibitory at high (> 500 ng/ml) concentrations. Serum opsonic capacity appeared to include a noncomplement cofactor for optimal activity. Levels of PA LPS IgG4 but not IgGl-3 subclass Ab correlated inversely with opsonic capacity. We conclude that high levels of PA LPS IgG4 Ab may be inhibitory to normal pulmonary clearance of PA in colonized patients with CF, and that high levels of functional antibodies may also contribute to this specific acquired deficiency. The role of deficient IgG2 Ab responses to PA LPS and possibly other polysaccharide antigens in CF requires further study.

The Effect of Nutritional Additives on Anti-Infective Factors in Human Milk

It has become a common practice to supplement human milk with a variety of additives to improve the nutritive content of the feeding for the premature infant. Twenty-two freshly frozen human milk samples were measured for lysozyme activity, total IgA, and specific IgA to Escherichia coli serotypes 01, 04, and 06. One mL aliquots were mixed with the following: 1 mL of Similac, Similac Special Care, Enfamil, Enfamil Premature Formula, and sterile water; 33 mL of Poly-Vi-Sol, 33 mg of Moducal, and 38 mg of breast-milk fortifier, and then reanalyzed. Significant decreases (41 % to 74%) in lysozyme activity were seen with the addition of all formulas; breast-milk fortifier reduced activity by 19%, while no differences were seen with Moducal, sterile water, or Poly-Vi-Sol. No differences were seen in total IgA content, but some decreases were seen in specific IgA to E. coli serotypes 04 and 06. E. coli growth was determined after 3 1/2 hours of incubation at 37°C after mixing. All cow-milk formulas enhanced E. coli growth; soy formulas and other additives preserved inhibition of bacterial growth. Nutritional additives can impair anti-infective properties of human milk, and such interplay should be considered in the decision on the feeding regimen of premature infants.