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 degrees 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.

Current trends in lung transplantation. Lobar transplantation and expanded use of single lungs.

Heart-lung transplantation remains the only therapeutic option for patients with combined end-stage cardiopulmonary disease. Because of the scarcity of heart-lung donors, we have been investigating other surgical alternatives for patients with end-stage vascular and parenchymal lung disease. From June 1989 through June 1991, 48 patients underwent pulmonary transplantation. Seventeen of the 48 patients underwent single lung transplantation. Of the 17 patients in the single lung group, eight patients had pulmonary hypertension and nine had parenchymal lung disease. Four of the 17 patients underwent repair of a cardiac defect with single lung transplantation. One-year actuarial survival was 68%. Pulmonary function has been excellent. The forced expiratory volume in 1 second was 79.6 +/- 13.6 (percent predicted), forced expiratory flow 25%-75% was 72.6 +/- 14.5 (percent predicted), and arterial oxygen tension was 82.8 +/- 10.06 mm Hg when measured at annual follow-up in a group of eight patients without obliterative bronchiolitis. Pulmonary artery pressures of systemic level or greater in the group with pulmonary vascular disease were normal at annual catheterization. Most patients had at least one episode of allograft rejection. Actuarial freedom from rejection at the end of 3 months was 30%. Three of the 17 single lung patients receiving lung lobes were children. Two children received living-related lobe transplants and one neonate received a lobe from a 2-year-old cadaver donor. Single lung transplantation is an effective therapeutic option for selected patients with vascular or parenchymal lung disease. Expanding indications will permit more individuals to receive transplants from the existing donor pool. Living-related and cadaver lobe transplantation will also increase the options available to children in need of lung transplantation.

Effects of microwave radiation on anti-infective factors in human milk.

In intensive care nurseries it has become common practice to use microwave thawing of frozen human milk for more rapid accessibility. Twenty-two freshly frozen human milk samples were tested for lysozyme activity, total IgA, and specific secretory IgA to Escherichia coli serotypes 01, 04, and 06. The samples were heated by microwave for 30 seconds at a low- or high-power setting and then reanalyzed. One-mL aliquots of 10 additional human milk samples were microwaved at low (20 degrees C to 25 degrees C), medium (60 degrees C to 70 degrees C), and high (greater than or equal to 98 degrees C) setting before the addition to each of 1 mL of diluted E coli suspension. E coli growth was determined after 3 1/2 hours of incubation at 37 degrees C. Microwaving at high temperatures (72 degrees C to 98 degrees C) caused a marked decrease in activity of all the tested antiinfective factors. E coli growth at greater than or equal to 98 degrees C was 18 times that of control human milk. Microwaving at low temperatures (20 degrees C to 53 degrees C) had no significant effect on total IgA, specific IgA to E coli serotypes 01 and 04, but did significantly decrease lysozyme and specific IgA to E coli serotype 06. Even at 20 degrees C to 25 degrees C, E coli growth was five times that of control human milk. Microwaving appears to be contraindicated at high temperatures, and questions regarding its safety exist even at low temperatures.

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.

Adjunctive therapy of allergic bronchopulmonary aspergillosis with itraconazole.

Itraconazole is a new orally active antifungal triazole with impressive activity against Aspergillus spp. Six patients with allergic bronchopulmonary aspergillosis (ABPA), aged 14 to 49 years, were treated with oral itraconazole (200 mg twice daily) for a mean of 3.9 months (range, one to six months; three patients continue on therapy). Two patients received two courses. Three patients had underlying cystic fibrosis, and three had severe asthma; four of the six required continuous high-dose systemic prednisone (mean, 43 mg/day; confidence interval [CI], 23 to 63 mg/day) at the start of therapy. In those treated for two months or longer, the mean total serum IgE level fell from 2,462 U/ml (CI, 752 to 4,202 U/ml) to 502 U/ml (CI, 123 to 880 U/ml) during each course, and the mean daily steroid dosage was decreased to a mean of 24 mg/day (CI, 11 to 37 mg/day). All patients experienced improvement in pulmonary function during the trial, with mean FEV, increasing from 1.43 to 1.77L/sec and mean FVC from 2.3 to 2.9 L in those treated for two months or longer. The mean steady-state serum concentration of itraconazole was 5.1 micrograms/ml (range, 1.8 micrograms/ml to 7.3 micrograms/ml); the patient with the lowest concentrations had the least significant clinical response. Cultures of sputum from two of three patients became negative for A fumigatus during therapy. No adverse clinical effects occurred except loss of libido in one patient. We conclude that oral itraconazole may be an effective adjunctive therapy in ABPA, possibly by clearing the airway of Aspergillus, and that randomized trials of this agent are warranted to better define its usefulness in this disorder.

Ulcerative tracheobronchitis after lung transplantation. A new form of invasive aspergillosis.

Invasive aspergillosis is frequently a fatal disease in the setting of immunosuppression, including organ transplant recipients. The fungus usually affects lung parenchyma and may disseminate from there. We have recently noted tracheobronchitis in six patients with heart-lung and lung transplants, three of whom had deep mucosal ulceration and histologic evidence of invasive aspergillosis. This apparently new form of invasive disease is initially limited to the anastomosis site and large airways. Ulceration, necrosis, cartilage invasion, and formation of a pseudomembrane are the pathologic features. In two patients subsequent disseminated aspergillosis occurred with a fatal outcome. In the two single-lung recipients, disease was limited to the transplanted side emphasizing the importance of abnormal local defense mechanisms in the airways of lung transplant recipients. Routine bronchoscopic examination of the airways is important in early detection of this complication. Oral therapy with the new, antifungal agent itraconazole was successful in five of the six patients, with fatal relapse in one. A classification of the various forms of saprophytic, allergic, and invasive forms of aspergillus tracheobronchitis, to include this new entity, is proposed.

Method for rapid evaluation of topically applied agents to cystic fibrosis airways.

The proposal is to target a single maxillary sinus for treatment with agents designed to reverse or ameliorate the cystic fibrosis (CF) defect in airway mucosa, with the opposite sinus serving as a control. Selected CF patients have undergone maxillary antrostomy and antibiotic lavage to help relieve severe pulmonary disease and chronically impacted and infected sinuses. After treatment, the mucosa in the maxillary sinuses of these patients are accessible and can be bathed with fluids introduced via the stomas with procedures that restrict the fluid to a single sinus. The ability of an agent to reverse mucosal pathology can therefore be determined easily with the mucosa of the contralateral sinus serving as a control. Electrophysiological properties, amounts and composition of fluid and mucus, immune functions, and bacterial colonization can be measured accurately and repeatedly. The consistent observation that sinus involvement in CF is near universal and bilaterally symmetric offers a unique opportunity for a simultaneous within-subject, double-blinded control paradigm. This approach should speed evaluation of any agent designed to improve airway mucosal function.

beta-adrenergic sweat responses in cystic fibrosis heterozygotes with and without the delta F508 allele.

Cystic fibrosis (CF) causes early death for most homozygotes, yet has a carrier frequency among Caucasians of about 4-5%, suggesting a heterozygote advantage. The major defect in the CF gene is a three-base deletion leading to loss of a phenylalanine residue at position 508 (delta F508) that accounts for about 68% of CF alleles in the North American population; the remaining 32% appears to consist of a large assortment of mutations. Sweat secretion in response to beta-adrenergic stimulation is completely lacking in CF homozygotes and is reduced to 1/2 normal in heterozygotes. To determine if this secretory process is affected by different CF alleles, we used the polymerase chain reaction technique with DNA obtained from peripheral leukocytes to determine retrospectively the presence or absence of the delta F508 allele in 20 CF heterozygotes for whom sweat responses to beta-adrenergic stimulation had previously been determined. Twelve of 20 subjects (60%) were positive for the delta F508 mutation. The variance in sweat responses was not reduced in the delta F508 group relative to the non-delta F508 group, but a gender/allele interaction was noted.

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.

Clinical significance of hyperbilirubinemia in patients with pulmonary hypertension undergoing heart-lung transplantation.

Hyperbilirubinemia is commonly observed in long-standing pulmonary hypertension and is thought to be the result of chronic right ventricular failure and subsequent liver congestion. To evaluate the clinical significance of preoperative hyperbilirubinemia, we reviewed the cases of 62 patients with pulmonary hypertension (31 primary and 31 Eisenmenger's syndrome) who underwent heart-lung transplantation between 1981 and 1990 at Stanford. Bilirubin levels higher than 1.0 mg/dl were noted in 58% of patients, and bilirubin levels higher than 2.0 mg/dl were noted in 23% of patients. Indirect hyperbilirubinemia accounted for 66% to 87% of the total bilirubin and tended to fluctuate with diuretic therapy. It was associated with polycythemia, reticulocytosis, and mild elevations of liver enzymes. Early postoperative mortality in patients with total bilirubin levels greater than 2.1 mg/dl, bilirubin levels greater than 1 mg/dl but less than 2.0 mg/dl, and levels less than 1 mg/dl was 58%, 27%, and 16%, respectively (p less than 0.05). In those with high bilirubin levels, four patients had severe hemorrhage as part of their terminal event. Cardiac cirrhosis was found at autopsy in 75% of the early deaths of patients with high bilirubin. We conclude that hyperbilirubinemia is a late manifestation of pulmonary hypertension. The mechanism of hyperbilirubinemia is probably the result of the combination of increased hemolysis and decreased uptake by the chronically congested liver. Patients with pulmonary hypertension and hyperbilirubinemia appear to be at greater surgical risk during heart-lung transplantation.

Selection and evaluation of recipients for heart-lung and lung transplantation.

Heart-lung and lung transplantation is being successfully performed with increasing frequency in patients with end-stage cardiopulmonary and pulmonary disease. Transplantation must now be considered as a therapeutic option in selected patients, and physicians are required to understand the principles involved for determining suitable candidates and operative procedures of choice. Indications, contraindications, and choice of operation with respect to underlying disease are discussed herein, as are methods of evaluation and appropriate timing for transplantation. Special considerations regarding specific patient populations are also addressed. In properly selected patients, heart-lung and lung transplantation provide a viable therapeutic option in those with end-stage disease who are unresponsive to conventional management.

Obliterative bronchiolitis.

The mass of evidence suggests that OB is a manifestation of allograft rejection in the time period later than that usually associated with acute postoperative rejection. Respiratory infection may serve to amplify (and possibly trigger) this process. A maintenance immunosuppression regimen utilizing cyclosporine A, prednisone, and azathioprine appears to be much more effective than an earlier regimen utilizing only the first two drugs. Aggressive surveillance utilizing prospective measurement of pulmonary function and arterial blood gases and a willingness to look for histologic evidence of OB with the earliest symptomatology has lowered significantly the mortality and the morbidity of this disorder at Stanford and elsewhere. We believe that the current ability to treat and even reverse this serious complication brightens the prospect of heart-lung and lung transplantation for assuming a role in the medical practice of the future.

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.