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.

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.

Evaluation of the immunologic cross-reactivity of aztreonam in patients with cystic fibrosis who are allergic to penicillin and/or cephalosporin antibiotics.

The immunogenicity, allergenicity, and cross-reactivity of aztreonam were investigated in 19 patients with cystic fibrosis (CF) who are allergic to beta-lactam antibiotics. Skin tests with benzyl-penicilloyl polylysine (BPO), minor determinant mixture, and the drug responsible for the previous allergic reaction were positive for 26%, 53%, and 79% of the patients, respectively. Serum IgG, but not IgE, antibodies to BPO were detected in nine of 14 patients. Eighteen patients whose skin tests with aztreonam were negative were treated. One developed bronchospasm. The others tolerated aztreonam, with an improvement in clinical score greater than or equal to 1 month after treatment (P less than .001). One patient without previous exposure had positive aztreonam skin tests and was later treated uneventfully after iv desensitization. Treatment with aztreonam did not result in IgG or IgE antibody responses in vitro. However, two patients had anaphylactic reactions on reexposure. In patients with CF, allergy to beta-lactam antibiotics is primarily drug-specific. But despite reduced immunogenicity and cross-reactivity, aztreonam should be administered cautiously to patients with CF who are allergic to other beta-lactam antibiotics because it is potentially allergenic with repeated use.

Diuretic effect and disposition of furosemide in cystic fibrosis.

The pharmacodynamics and kinetics of single oral and intravenous doses of furosemide were studied in 9 patients (mean age 18.5 y) with cystic fibrosis. The diuretic effect of furosemide lasted for 6 h after oral administration and 2 h following intravenous injection of the drug. The patients with cystic fibrosis had a more pronounced diuretic response both to the oral and intravenous treatments than that reported in normals. Furosemide caused a marked decrease in urine pH for 5 h following the oral dose and between the 2nd and 3rd h after i.v. injection. The baseline nocturnal urine flow rate in 7 of the 9 patients given furosemide orally was increased by 30.6% compared to that reported in healthy subjects. The bioavailability of furosemide, its mean absorption rate and the mean plasma and urinary elimination half-lives both of the oral and the intravenous drug were similar to those reported in normal subjects. The patients with cystic fibrosis showed, however, about double normal mean total clearance after both the oral and i.v. treatments, and its renal clearance was almost half the plasma clearance. Nonrenal clearance was markedly increased in the patients, which agreed with a considerable decrease in the renal excretion of the drug. The mean apparent volume of distribution was also markedly increased compared to data in the literature. Oral furosemide resulted in a moderate increase in haematocrit and haemoglobin levels in 7 of 9 patients with cystic fibrosis and marked hypokalemia developed in 6 of the 9 patients 6 h after dosing. Pulmonary function tests performed at that time were changed in an inconsistent manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Cystic fibrosis mutations in North American populations of French ancestry: analysis of Quebec French-Canadian and Louisiana Acadian families.

A 3-bp deletion (delta F508) in the cystic fibrosis (CF) gene is the mutation on the majority of CF chromosomes. We studied 112 CF families from North American populations of French ancestry: French-Canadian families referred from hospitals in three cities in Quebec and from the Saguenay-Lac St. Jean region of northeastern Quebec and Acadian families living in Louisiana. delta F508 was present on 71%, 55%, and 70% of the CF chromosomes from the major-urban Quebec, Saguenay-Lac St. Jean, and Louisiana Acadian families, respectively. A weighted estimate of the proportion of delta F508 in the French-Canadian patient population of Quebec was 70%. We found that 95% of the CF chromosomes with delta F508 had D7S23 haplotype B, the most frequent haplotype on CF chromosomes. In the Saguenay-Lac St. Jean families, 86% of the CF chromosomes without delta F508 had the B haplotype, compared with 31% for the major-urban Quebec and Louisiana Acadian families. The incidence of CF in the Saguenay-Lac St. Jean population was 1/895 live-born infants.

Antinuclear antibodies and anticytoplasmic antibodies in bronchial asthma.

The presence of antinuclear antibodies and anticytoplasmic antibodies was evaluated in the sera of 50 patients with bronchial asthma and 35 matched control subjects with miscellaneous medical diseases with the use of an indirect immunofluorescent assay with HEp-2 cells as substrate. The results were compared to age, sex, atopic status, dose, and duration of the antiasthmatic medication, immunotherapy, severity of the disease, and presence or absence of myalgia. The patients had mild to moderate asthma. The incidence of fluorescent anticytoplasmic antibodies (FACA) in the sera of patients with asthma was statistically significant (p = 0.02) in comparison to FACA in the sera of the control subjects. The combined incidence of fluorescent antinuclear antibodies (FANA) and FACA was found to be significantly higher among atopic subjects with asthma (p = 0.03) and the subjects with asthma and with myalgia (p less than 0.05). The 20% incidence of FACA in this group of subjects with asthma was significantly greater (p less than 0.0001) than the reported 2.7% incidence of FACA in a group of patients with various rheumatologic diseases. Variables, such as dose and duration of antiasthma medications and immunotherapy did not appear to influence the presence of FANA and FACA in their sera. The significance of positive FANA and FACA in this group of subjects with asthma is not known and needs to be evaluated by long-term studies.

Renal handling of beta 2-microglobulin in patients with cystic fibrosis.

We evaluated the renal handling of beta 2-microglobulin (beta 2-M) and creatinine in healthy outpatients (n = 6), normal children hospitalized for infections treated with antibiotics (not including an aminoglycoside) (n = 4); outpatients with cystic fibrosis (CF; n = 12), and hospitalized patients with CF (n = 6) who received a 10- to 14-day course of antibiotic treatment that included an aminoglycoside. The serum beta 2-M concentrations in the normal outpatients (2020.1 +/- 276.6 micrograms/L) were significantly lower (p less than 0.05) than those observed for outpatients (2833.3 +/- 202.6 micrograms/L) or patients with CF (2861.8 +/- 340.5 micrograms/L. There were no significant differences found for creatinine clearance or fractional excretion of beta 2-M when subjects without CF were compared with those with the disease. Furthermore, no significant differences were observed in hospitalized patients with CF when creatinine clearance and fractional excretion of beta 2-M were compared between the initiation and conclusion of aminoglycoside treatment. Glomerular filtration and proximal tubular reabsorption of beta 2-M were not altered in patients with CF. These findings do not support a global defect in proximal renal tubular reabsorption as the underlying cause for altered aminoglycoside clearance in patients with CF.

Duration of the suppressive effect of tricyclic antidepressants on histamine-induced wheal-and-flare reactions in human skin.

The antihistaminic properties of the tricyclic antidepressants have been recognized since these compounds were first developed. Antidepressants, which are equally effective for treating depression or used in the treatment of chronic urticaria, have varying in vitro antihistaminic properties. We compared the duration of H1-receptor blockade by two tricyclic antidepressants, doxepin (the most potent antihistamine) and desipramine (the least potent antihistamine), in a single dose, double-blind, noncrossover study. After baseline prick test with histamine phosphate 1:1000 by Multitest (Lincoln Diagnostics, Decatur, Ill.), the suppression of cutaneous histamine-induced wheal-and-flare responses were measured daily for 7 days in 33 healthy volunteers who were randomly administered a single 25 mg dose of oral desipramine or doxepin. Significant differences in the suppression of the wheal-and-flare responses to histamine between the two drugs were noted (p less than 0.05) during the first 3 days. Desipramine suppressed the wheal for 2 days and flare for 1 day. Doxepin suppressed the wheal for 4 days and flare for 6 days. Our results suggest doxepin should be withheld for at least 7 days before allergy skin testing.