A comparison of microbiologic flora of the sinuses and airway among cystic fibrosis patients with maxillary antrostomies.

The placement of maxillary antrostomies among cystic fibrosis (CF) patients has been used as a treatment to allow localized antibiotic lavage of infected sinus passages. This procedure is increasingly recommended by lung transplantation centers as a prerequisite prior to accepting a CF patient as a candidate for transplantation. Our study attempts to define the degree of identity between sinus, endotracheal and sputum cultures from 35 patients. The samples (n = 137) were collected within two weeks of each other. An analysis of the microbiologic type, strain, and antibiotic resistance patterns was undertaken. Randomization analysis was performed and a p-value of < 0.05 was considered significant. The results indicated a high degree of correlation between sinus-sputum pairs (n = 55) and endotracheal samples (p < 0.008). This study provides evidence that there is a potential for cross-infection between sinus passages and the lower airway. The localized irrigation of CF sinus cavities post-transplantation may be warranted in an attempt to reduce bacterial counts and potential direct infection of the allograft. However, it is unlikely that this will eliminate this risk because bacterial colonization continues and the CF trachea is another source of infection.

Comparison of a beta-lactam alone versus beta-lactam and an aminoglycoside for pulmonary exacerbation in cystic fibrosis.

UNLABELLED: We determined whether a beta-lactam and an aminoglycoside have efficacy greater than a beta-lactam alone in the management of a pulmonary exacerbation in patients with cystic fibrosis. STUDY DESIGN: Azlocillin and placebo or azlocillin and tobramycin were administered to 76 patients with a pulmonary exacerbation caused by Pseudomonas aeruginosa in a randomized double-blind, third-party monitored protocol. Improvement was assessed by standardized clinical evaluation, pulmonary function testing, sputum bacterial density, sputum DNA content, and time to the next pulmonary exacerbation requiring hospitalization. RESULTS: No significant difference was seen between the 2 treatment groups in clinical evaluation, sputum DNA concentration, forced vital capacity, forced expiratory volume in second 1, or peak expiratory flow rate at the end of treatment (33 receiving azlocillin alone and 43 both antibiotics); adverse reactions were equivalent in each group. Sputum P. aeruginosa density decreased more with combination therapy (P =.034). On follow-up evaluation, an average of 26 days after the end of treatment, all outcome indicators had worsened in both groups. Time to readmission for a new pulmonary exacerbation was significantly longer in the group receiving azlocillin plus tobramycin (P <.001). Treatment-emergent tobramycin resistance occurred in both groups and was more frequent with combination therapy. CONCLUSION: We conclude that the combination of a beta-lactam and an aminoglycoside produces a longer clinical remission than a beta-lactam alone and slightly better initial improvement.

Pediatric tuberculosis: problems in diagnosis and issues in management.

The diagnosis of infection and disease due to Mycobacterium tuberculosis in infants and children presents many clinical challenges. The distinction of infection from disease (tuberculosis) in children is often unclear. There is difficulty in obtaining positive microbiological confirmation of infection in sputum, gastric, tracheal, or bronchial aspirates and in other body fluids in infants and children. Isoniazid is effective in the treatment of infection and prevention of progression of infection to clinical disease. Approximately 50% of children with primary tuberculosis are asymptomatic and are diagnosed as a result of contact investigation. Children become infected from exposure to an adult or adolescent with contagious pulmonary tuberculosis. The results of drug susceptibility tests in the source case in contact with an exposed child can guide the antituberculous chemotherapy. Chemotherapy regimens for treatment of pediatric tuberculosis have become shorter and more intensive with a marked increase in directly observed therapy (DOT).

Genetic and immunologic aspects of cystic fibrosis.

LEARNING OBJECTIVES: Reading this article will enable the readers to reinforce their knowledge of the pathophysiology of cystic fibrosis (CF), the pathogenesis of the lung disease, the criteria for diagnosis, and CF genotype/phenotype relationships. The focus of this review is on the genetic and immunologic aspects of CF. DATA SOURCE: Relevant articles, current texts, data presented at the annual North American Cystic Fibrosis Conferences and distributed to the Directors of CF Centers by the CF Foundation were reviewed. A MEDLINE database using subject keywords was searched from 1987 to date. Background information derived from the author's 33 years of clinical experience at three of the CF Foundation's CF Care, Teaching and Resource Centers was also included. STUDY SELECTION: Since CF is an inherited disorder, the genetic aspects are emphasized. With the cloning of the CF gene, DNA analysis has assumed an important role in confirming the clinical diagnosis and in the improved understanding of the pathophysiology of this disorder. Although DNA testing is highly specific, it is not very sensitive. RESULTS: Cystic fibrosis gene structure and function are described briefly. The pathophysiology of CF, as it relates to the CF gene defect, and the current knowledge of the pathogenesis of the lung disease are reviewed. The criteria for the diagnosis proposed by the Clinical Practice Guidelines for CF are discussed. Problems of establishing the diagnosis and the importance of correlations of laboratory and clinical findings in CF are emphasized. CONCLUSIONS: As a multisystem disorder, CF can masquerade as other disorders, including allergic respiratory disease. Primary care physicians often refer patients to allergists/immunologists because of recurrent respiratory problems. This review discusses the genetic heterogeneity of CF.

Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%.

Cystic fibrosis (CF)--an autosomal recessive disorder caused by mutations in CF transmembrane conductance regulator (CFTR) and characterized by abnormal chloride conduction across epithelial membranes, leading to chronic lung and exocrine pancreatic disease--is less common in African-Americans than in Caucasians. No large-scale studies of mutation identification and screening in African-American CF patients have been reported, to date. In this study, the entire coding and flanking intronic sequence of the CFTR gene was analyzed by denaturing gradient-gel electrophoresis and sequencing in an index group of 82 African-American CF chromosomes to identify mutations. One novel mutation, 3120+1G-->A, occurred with a frequency of 12.3% and was also detected in a native African patient. To establish frequencies, an additional group of 66 African-American CF chromosomes were screened for mutations identified in two or more African-American patients. Screening for 16 "common Caucasian" mutations identified 52% of CF alleles in African-Americans, while screening for 8 "common African" mutations accounted for an additional 23%. The combined detection rate of 75% was comparable to the sensitivity of mutation analysis in Caucasian CF patients. These results indicate that African-Americans have their own set of "common" CF mutations that originate from the native African population. Inclusion of these "common" mutations substantially improves CF mutation detection rates in African-Americans.

Flexible fiberoptic rhinoscopy in the diagnosis of nasal polyps in cystic fibrosis.

The incidence of nasal polyps in patients with CF in various studies varies from 6.7% to 48%. Fiberoptic rhinoscopy, a safe and minimally invasive diagnostic procedure, has the major advantage over routine physical examination of the nares because of the ability to examine the nose beyond the nasal vestibule. In examinations of both nostrils of 34 patients with CF age 4-30 years, nasal polyps were detected by rhinoscopic examination, but missed by physical examination in 17 (25%) of the nostrils. In 7% (5/64) of the nostrils in this series, rhinoscopy ruled out polyps that were reportedly identified on physician examination. This study confirms that even a careful physical examination of the nose is often inadequate to uncover significant nasal pathology such as nasal polyps.

Pregnancy in patients with cystic fibrosis.

With increasing life span of patients with CF, more women with CF are becoming pregnant and others are seeking information about the risks involved during pregnancy and delivery. A striking limitation of the available information is the lack of large prospective studies of pregnant patients with CF matched for age and disease severity compared with their non-pregnant cohorts. A study investigating the effect of pregnancy on morbidity and mortality is being completed by the Cystic Fibrosis Foundation. We recommend that all women with CF be offered contraceptive measures and counseling on the maternal and fetal risks of pregnancy, including the genetic risks for the child. The issue of who will raise the child in the event of subsequent morbidity or maternal mortality should ideally be prospectively discussed.

Successful prenatal management of hydrops, caused by congenital cystic adenomatoid malformation, using serial aspirations.

Congenital cystic adenomatoid malformation (CCAM) is a lung lesion that is now commonly diagnosed in utero with fetal ultrasonography. The described treatment of this lesion includes observation with treatment delivery, a single aspiration, thoraco-amniotic shunts, and fetal resection. This patient had an in utero diagnosis of a Stocker type I CCAM associated with hydrops. Fetal resection was not an option because of patient refusal. The fetus was treated with multiple serial aspirations. There was marked improvement of the anasarca, and subsequently the baby was born without respiratory distress. On the second day of life the CCAM began to expand, and the right lower lobe was resected. The baby's postoperative course was uneventful. CCAM with hydrops is associated with a high mortality rate. Current recommended therapy for these lesions is fetal resection or thoracoamniotic shunt. The authors' patient was treated with serial fetal thoracocenteses, with an excellent outcome. This therapy may be an alternative to fetal surgery or an adjunct to fetal surgery in selected cases.

Four new adenosine deaminase mutations, altering a zinc-binding histidine, two conserved alanines, and a 5' splice site.

Three new missense mutations (H15D, A83D, and A179D) and a new splicing defect (573 + IG-->A) in the 5' splice site of intron 5 were among six mutant adenosine deaminase (ADA) alleles found in three unrelated patients with severe combined immunodeficiency disease, the most common phenotype associated with ADA deficiency. When expressed in vitro, the H15D, A83D, and A179D proteins lacked detectable ADA activity. The splicing defect caused skipping of exon 5, resulting in premature termination of translation and a reduced level of mRNA. H15D is the first naturally occurring mutation of a residue that coordinates directly with the enzyme-associated zinc ion. Molecular modeling based on the atomic coordinates of murine ADA suggests that the D15 mutation would create a cavity or gap between the zinc ion and the side chain carboxylate of D15. This could alter the ability of zinc to activate a water molecule postulated to play a role in the catalytic mechanism. A83 and A179 are not directly involved in the active site, but are conserved residues located respectively in alpha helix 4 and beta strand 4 of the alpha/beta barrel. Replacement of these small hydrophobic Ala residues with the charged, more bulky Asp side chain may distort ADA structure and affect enzyme stability or folding.

Resting energy expenditures measured by indirect calorimetry are higher in preadolescent children with cystic fibrosis than expenditures calculated from prediction equations.

OBJECTIVE: This study compared measured resting energy expenditures to resting energy expenditures calculated using Harris-Benedict equations (HBEs) and the Cystic Fibrosis Consensus Committee equations (CFCCEs). DESIGN: We studied 31 preadolescent boys and girls with cystic fibrosis who ranged in age from 3.25 to 12.75 years old. The patients were afebrile and not in pulmonary distress. Measured resting energy expenditures were determined using a portable metabolic measurement cart with fully automated calibration and data management. The measured resting energy expenditures obtained were compared with values obtained using HBEs and CFCCEs. RESULTS: For each patient, the measured resting energy expenditure value was above the predicted resting energy expenditure values derived from HBEs (P < or = .0001) and CFCCEs (P < or = .01). APPLICATIONS: The HBEs and the CFCCEs underestimated the energy expenditures of the study population by 13% and 8%, respectively. These findings support the usefulness of the measurement of energy expenditures in determining the energy needs of preadolescent patients with cystic fibrosis. In clinical practice, the resting energy expenditures would be multiplied by activity coefficients to determine the total daily energy expenditures of this population.

Interstitial lung disease in children.

Interstitial lung disease in children is a heterogeneous group of disorders of both known and unknown causes that share a common histologic characteristic (i.e., inflammation of the pulmonary interstitium that may resolve completely, partially, or progress to derangement of alveolar structures with varying degrees of fibrosis). The inflammatory process, evoked as a result of injury to alveolar epithelium and/or the endothelium, is responsible for alveolar wall thickening that is the histologic marker of ILD. This article extrapolates some of the known pathogenic mechanisms of ILD from adult and animal models and applies this information for a better understanding of the pathogenesis of ILD in children. The clinical manifestations vary and are often subtle and nonspecific. There is no consensus on specific criteria for the clinical diagnosis of ILD in children. There are no pathognomonic laboratory criteria for the diagnosis of ILD in children other than the characteristic findings on histologic examination of the lung. It is important to make the diagnosis early to minimize lung damage. Therapy is directed toward the reduction of the inflammatory response to minimize or prevent the progression to fibrosis. ILD suffers from lack of uniform guidelines for diagnostic evaluation, therapy, and prognostic indicators essential for critical monitoring of disease activity. No one medical center has enough cases of ILD in children to allow objective evaluation of a significant number of cases with adequate longitudinal follow-up to determine guidelines for optimal management and to identify accurate prognostic indicators. The organization of a multicenter approach will guide us towards a better understanding of ILD in children.

Management options: SCIDS with adenosine deaminase deficiency.

Of the currently available options for the treatment of ADA deficiency, the treatment of choice remains transplantation of bone marrow from an HLA identical donor. When an HLA-identical donor is not available, haploidentical BMT or enzyme replacement needs to be considered and evaluated on an individual basis. Haploidentical BMT may be potentially curative, but this form of therapy is not without risks, especially in severely ill patients or in patients requiring cytoablation. The ability to utilize PEG-ADA even in ill patients, is certainly an advantage over haploidentical BMT. Polyethylene glycol-adenosine deaminase enzyme replacement usually entails a shorter time of hospitalization, but is very expensive for long-term treatment. The expense will increase as the patient requires higher doses of the enzyme replacement with increasing weight. Although PEG-ADA enzyme replacement therapy has been shown to be effective without significant risks to patients with SCIDS, there is increasing concern that this form of therapy may be jeopardized due to expense for long-term treatment in the current era of managed care and health care reforms. The use of PEG-ADA enzyme replacement is associated with decreased morbidity and mortality when compared with haploidentical BMT transplantation. There have been only two deaths among the 29 patients treated with PEG-ADA. In contrast, the 2-year survival for BMT in ADA deficient patients is quite variable ranging from 0% to 66%.(ABSTRACT TRUNCATED AT 400 WORDS)

Evaluation of the wheezing infant.

Wheezing is a very common symptom or sign in the infant. The evaluation of the underlying cause of the wheezing is difficult and requires a thorough assessment of several factors in the history and physical examination and a basic understanding of the pathophysiology of wheezing. With the increased availability of infant pulmonary function equipment, the evaluation of serial pulmonary function studies in infants with wheezing should prove helpful in continued assessment of the reversibility of their airway obstruction using bronchodilators and the effect of antiinflammatory pharmacologic agents on long-term hyperresponsiveness of the airways. Wheezing-associated respiratory tract infections in infancy ("wheezy bronchitis") and asthma share common risk factors, including history of exposure to environmental tobacco smoke, but the link between these two entities is still controversial. Each infant who presents with wheezing should be assessed individually with a thorough history and physical examination and an evaluation of the likelihood of asthma versus other underlying causes of wheezing such as cystic fibrosis, aspiration syndromes, congenital anomalies, or environmental factors such as exposure to passive tobacco smoking.

Skin test reactivity to whole body and fecal extracts of American (Periplaneta americana) and German (Blatella germanica) cockroaches in atopic asthmatics.

Forty-six atopic asthmatic subjects aged 3 to 58 years attending the allergy clinic of a university hospital were evaluated for prick skin test reactivity with commercially available extracts of cockroach (CCE) and house dust (HD). Additionally, skin testing was performed with American cockroach whole body (AWBE) and fecal extracts (AFE) as well as German cockroach whole body (GWBE) and fecal extracts (GFE) prepared in our laboratory. Commercial cockroach extract was prepared from American, German, and Oriental cockroach whole bodies. Skin test reactivity to the different extracts were as follows: 83% to HD, 70% to CCE, 70% to AWBE and/or GWBE, 63% to AWBE, 57% to GWBE, 63% to AFE and/or GFE, 52% to AFE, 50% to GFE, 48% to both AWBE and GWBE, and 39% to both AFE and GFE. The subjects with positive skin tests to AWBE and/or GWBE (70%) were the same individuals who showed skin test reactivity to CCE (70%). Subjects from lower income families (less than $10,000) had a significantly higher skin test reactivity to cockroach allergens than those from families with an annual income of $11,000 to $24,000 (P = .04). These results demonstrate the significance of cockroach sensitization in atopic asthmatics, suggest the importance of fecal cockroach allergens, and support earlier observations of shared interspecies allergens between American and German cockroach whole bodies.