Effect of testosterone treatment on the trabecular bone score in older men with low serum testosterone.

The trabecular bone score (TBS) is an indirect measure of vertebral bone microarchitecture. Our objective was to examine the effect of testosterone treatment on TBS. One hundred and ninety-seven hypogonadal men were randomized to testosterone or placebo. After 12 months, there was no difference in the changes in TBS by randomized group. INTRODUCTION: In the Bone Trial of the Testosterone Trials, testosterone treatment increased trabecular volumetric bone mineral density (vBMD) and increased estimated bone strength as determined by finite element analysis. The trabecular bone score (TBS) is an indirect measure of vertebral bone microarchitecture. TBS predicts fracture independent of lumbar spine areal (a) BMD. The objective of this study was to examine the effect of testosterone treatment on TBS compared to its effects on vBMD and aBMD. METHODS: Two hundred and eleven men were enrolled in the Bone Trial of the Testosterone Trials. Of these, 197 men had 2 repeat TBS and vBMD measurements; 105 men were allocated to receive testosterone, and 92 men to placebo for 1 year. TBS, aBMD, and vBMD were assessed at baseline and month 12. RESULTS: There was no difference in the percent change in TBS by randomized group: 1.6% (95% confidence intervals (CI) 0.2-3.9) in the testosterone group and 1.4% (95% CI -0.2, 3.1) in the placebo group. In contrast, vBMD increased by 6% (95% CI 4.5-7.5) in the testosterone group compared to 0.4% (95% CI -1.65-0.88) in the placebo groups. CONCLUSIONS: TBS is not clinically useful in monitoring the 1-year effect of testosterone treatment on bone structure in older hypogonadal men.

Clinical Trials in Veterinary Medicine: A New Era Brings New Challenges.

Randomized clinical trials (RCTs) are among the most rigorous ways to determine the causal relationship between an intervention and important clinical outcome. Their use in veterinary medicine has become increasingly common, and as is often the case, with progress comes new challenges. Randomized clinical trials yield important answers, but results from these studies can be unhelpful or even misleading unless the study design and reporting are carried out with care. Herein, we offer some perspective on several emerging challenges associated with RCTs, including use of composite endpoints, the reporting of different forms of risk, analysis in the presence of missing data, and issues of reporting and safety assessment. These topics are explored in the context of previously reported veterinary internal medicine studies as well as through illustrative examples with hypothetical data sets. Moreover, many insights germane to RCTs in veterinary internal medicine can be drawn from the wealth of experience with RCTs in the human medical field. A better understanding of the issues presented here can help improve the design, interpretation, and reporting of veterinary RCTs.

Correlates of severe or life-threatening toxic effects from trimetrexate.

Trimetrexate, an investigational antifol, has been associated with marked variability in drug tolerance among patients. The agent is extensively protein bound, and hepatic biotransformation plays a major role in its elimination. In early phase II testing, nine of 15 patients who experienced life-threatening or fatal toxic effects from trimetrexate had albumin levels less than or equal to 3.5 g/dL prior to treatment. This prompted a review of the data base on 272 patients entered in phase I clinical trails. The incidence of severe or life-threatening anemia, leukopenia, neutropenia, thrombocytopenia, mucositis, and hepatic toxic effects during the first course of trimetrexate was analyzed according to dose, schedule, prior treatment, and baseline protein and albumin levels. The schedules using doses given by short infusions of 30-60 minutes daily for 5 days or weekly for 3 weeks were generally associated with higher incidence of toxic effects than the schedules using doses given every other week by short infusions or those using continuous infusion. The occurrence of leukopenia and mucositis was dose related. Patients with baseline albumin levels less than or equal to 3.5 g/dL had higher incidence of all types of severe or life-threatening toxic effects than those with albumin levels greater than or equal to 3.6 g/dL, and the differences were significant for the development of anemia, thrombocytopenia, and mucositis. Similar correlations were noted for pretreatment protein levels less than or equal to 6.0 g/dL. The small cohort of patients with leukemia experienced substantial toxic effects and tended to have low protein and albumin levels. Performance status and prior therapy did not emerge as strong predictors of severe toxic effects in the univariate analysis. Multivariate analysis confirmed that the type of cancer (leukemia vs. solid tumor), dose, schedule, and baseline albumin level were significant and independent predictors of severe and life-threatening toxic effects in the phase I patient population. Multivariate analysis including only patients with solid tumors indicated that albumin level, dose, and schedule remained significant predictors of toxic effects. Since normal liver function as reflected by bilirubin and transaminase values were a requirement for eligibility, the results suggest that albumin and protein levels may provide a more sensitive index of hepatic function. Patients with hypoalbuminemia and hypoproteinemia are at increased risk of experiencing severe or life-threatening toxic effects from trimetrexate and should be treated cautiously.

Criteria for monitoring carcinoembryonic antigen: variability of sequential assays at elevated levels.

Fifty-five patients with advanced cancer and elevated plasma carcinoembryonic antigen (CEA) levels greater than 20 ng/mL (Roche assay) were monitored by clinical parameters for disease activity and a daily plasma specimen was obtained and stored frozen. In 45 patients with evaluable metastatic lesions, 35 were stable; five had progressive disease; and five had regressive disease. Plasma CEA in patients with stable disease showed an overall coefficient of variation of 13%. The CV did not differ according to various quantitative CEA levels from less than 100 ng/mL to greater than 1,000 ng/mL. The coefficient of variation in responding and progressive disease patients ranged from 13% to 63%. An analysis of CEA variability relative to the baseline CEA level was possible using the formula square root 2 times the variability about the mean; this yields a value of +/- 36% representing the range within which approximately 95% of sequential CEA levels would lie in the absence of a clinical change in disease. In 225 CEA determinations in stable disease patients, 6% demonstrated an increase beyond this level (36%) and none demonstrated a decrease of 36% or more from the baseline level. This study establishes guidelines for the boundaries of change in plasma CEA that may be applied as a criterion (in conjunction with standard objective disease parameters) for determination of tumor response to therapy.

Plasma clearance of carcinoembryonic antigen following hepatic metastatectomy.

Four patients with isolated hepatic metastases from primary colonic cancer presented with elevated plasma carcinoembryonic antigen (CEA) levels and underwent surgical metastatectomy . Plasma levels were monitored at two to six hour intervals in the immediate postoperative period and daily measurements were obtained for an extended period thereafter, up to 34 days. CEA clearance demonstrated a two-phase decrement with an initial rapid decay followed by a logarithmic decline with plasma half-lives of 66, 75, 150, and 208 hours. The first phase decline of 63% to 89% in circulating CEA levels immediately following tumor removal may reflect the fact that the plasma CEA is in dynamic equilibrium with the tumor CEA. The kinetics of the second-phase decline of CEA is variable and may be related to the quantitative circulating pool or to pathophysiologic processes influencing CEA metabolism or secretion in the liver. Quantitative assessment of tumor CEA content by immunoperoxidase techniques suggests a direct relationship between tissue levels and circulating plasma levels. The study of CEA kinetics may help in understanding the biology of tumor marker production and improve the capacity for clinical monitoring of plasma levels in conjunction with tumor therapy.

A comparison of carboplatin plus methotrexate versus methotrexate alone in patients with recurrent and metastatic head and neck cancer.

Patients with recurrent and metastatic squamous cell carcinoma of the head and neck (SCCHN) were stratified by performance status, extent of disease, and prior radiotherapy and subsequently randomized to receive carboplatin (CBDCA; Bristol-Myers, Wallingford, CT) administered intravenously (IV) monthly, initially at doses of 400 mg/m2 in combination with methotrexate (MTX) given IV weekly at doses of 40 mg/m2 or MTX alone at the same dose/schedule. Significant dose-limiting myelosuppression required CBDCA dose reductions to 300 mg/m2 and, subsequently, 200 mg/m2. Nonhematological toxicities were not significant. Our study objective was to determine whether CBDCA plus MTX produce a substantial improvement in response rate over single-agent MTX. A response rate of 50% (complete [CR] plus partial response [PR]) for CBDCA plus MTX compared with 25% for MTX was specified as the difference to be detected. We employed a two-stage study design for randomized trials that allowed for early termination of studies involving relatively ineffective treatment regimens. With this design, the study could be closed after the first stage (20 patients entered onto each treatment arm) if the number of responders to CBDCA plus MTX were not superior to MTX. Five of 20 patients responded to treatment in each arm, and we were able to conclude that the addition of CBDCA to MTX is unlikely to result in a twofold increase in response rate compared with MTX alone in this group of patients. This two-stage design represents a simple and efficient method of testing the relative efficacy of new combinations containing at least one active agent against a suitable control arm in this disease. It addresses scientific and ethical issues of continuing testing with relatively ineffective treatments, and at the same time provides a reliable method for identifying very active regimens likely to represent significant therapeutic advances.

A randomized study of oral nutritional support versus ad lib nutritional intake during chemotherapy for advanced colorectal and non-small-cell lung cancer.

One hundred ninety-two patients with previously untreated metastatic cancer (102 non-small-cell lung cancer [NSCLC]; 90 colorectal cancer) were randomized to receive either ad lib nutritional intake (control group) or specific nutritional intervention during a 12-week study period when chemotherapy was administered. Those patients randomized to nutritional interventions were counselled to take oral nutrients with caloric intake equal to 1.7 to 1.95 times their basal energy expenditure, depending on their pretreatment nutritional status ("standard" group). An augmented group was counselled to have a caloric intake equivalent to that of the standard group but with 25% of calories provided as protein and additional supplements of zinc and magnesium. Counselling increased caloric intake in both tumor types but reduced weight loss in the short term only for lung cancer patients. Ninety-three NSCLC patients were evaluable for tumor response to vindesine and cisplatin. Overall, only 20.4% of the patients responded, and there were no significant differences in response rates, median time to progression, or overall duration of survival between the nutrition intervention groups and the control group. The tumor response rate to time-sequenced 5-fluorouracil (5-FU) and methotrexate in the 81 evaluable patients with colorectal cancer was only 14.8%, and no significant differences in tumor response rates were noted between the three groups. Furthermore, the median time to progression and overall duration of survival were not different for the control, standard, and augmented groups. Nutritional interventions using dietary counselling had no impact on the percent of planned chemotherapy dose administered, the degree of toxicity experienced by patients, or the frequency of treatment delays. A multivariate prognostic factor analysis demonstrated that for lung cancer, the percent of weight loss, serum albumin concentration, and presence of liver metastases were significant (P less than .05) and independent prognostic variables for survival duration. For colorectal cancer, serum albumin, alkaline phosphatase, lactic dehydrogenase (LDH) levels, and percent targeted caloric intake (TCI) were significant independent predictors of survival duration.

On the use of laboratory markers as surrogates for clinical endpoints in the evaluation of treatment for HIV infection.

There are strong ethical and practical reasons for hastening decision-making about the efficacy of new treatments for human immunodeficiency virus (HIV) infection. One strategy is to use early markers of disease progression, such as CD4+ lymphocyte levels, as surrogates for ultimate clinical endpoints, such as the development of acquired immune deficiency syndrome (AIDS) or death, in the evaluation of new therapies. We used a simple model of transitions among three health states (well; alive but with an adverse marker; and having experienced a definitive clinical endpoint) to examine the extent to which treatment comparisons based on the surrogate endpoint predict ultimate clinical benefits. With parameters chosen to model the treatment of HIV infection, computer simulations of clinical trials demonstrated substantial time savings by use of the surrogate endpoint. However, reliance on the surrogate led to serious overestimates of ultimate clinical benefit if treatment entailed delayed toxicity or had only transient beneficial effects. Likewise, reliance on the surrogate led to serious underestimates of ultimate clinical benefit when the treatment had no effect on the transition from well to the marker state but did reduce the rates of transition from the marker state to the ultimate clinical endpoint and directly from the well state to the ultimate clinical endpoint.

Comparative safety of two recombinant hepatitis B vaccines in children: data from the Vaccine Adverse Event Reporting System (VAERS) and Vaccine Safety Datalink (VSD).

BACKGROUND: Preliminary review of data from the Vaccine Adverse Event Reporting System (VAERS), 1991-1994, revealed that more serious adverse events were reported in children who received a specific brand of recombinant hepatitis B (HepB) vaccine. OBJECTIVE: To compare the post-marketing safety experience of the two recombinant HepB vaccines licensed for use in infants and children in the United States. DESIGN: Review of a case series derived from passive surveillance data in the national VAERS. A retrospective cohort study using data from one health maintenance organization participating in Vaccine Safety Datalink (VSD), a computerized record linkage system. POPULATIONS STUDIED: U.S. children, ages birth-10 years for whom adverse events after HepB vaccine were reported to VAERS, 1991-1994. Children, ages birth-6 years, who received HepB vaccine at Kaiser Permanente Medical Care Program, Northern California, 1991-1994. MAIN OUTCOME MEASURES: VAERS reporting rates for each vaccine by manufacturer were calculated from the numbers of reported events occurring within 30 days of HepB vaccination and the number of doses distributed by the manufacturers. VSD event rates for each vaccine were calculated from the numbers of hospitalization or emergency room visits within 30 days of HepB vaccination and the number of vaccine doses administered to the cohort. RESULTS: In VAERS, higher rates of serious events (i.e., life threatening or resulting in hospitalization or permanent disability) were reported in children who received Vaccine A vs. Vaccine B (relative risk [RR]: 3.13-8.18, P < 0.01), particularly by those vaccinated in the private (RR: 7.62-28.58, P < 0.01), but not public sector (RR: 2.12, P = 0.19). Similar types of events were reported in recipients of both vaccines. In contrast, analysis of VSD data showed no significant difference in rates of hospitalization or ER visits in children who received either HepB vaccine (RR: 0.96-1.25, P > 0.05). CONCLUSIONS: Our investigation reveals that it is unlikely there is a true difference between rates of serious events temporally associated with the two HepB vaccines in children. This study demonstrates the dual roles played by VAERS and VSD in providing a more complete picture of the post-marketing safety profile of childhood vaccines, and underscores the importance of using other analytic studies to evaluate findings from passive surveillance systems of adverse events.

Recombinant hepatitis B vaccination of neonates and infants: emerging safety data from the Vaccine Adverse Event Reporting System.

OBJECTIVES: To evaluate the postmarketing safety of recombinant hepatitis B (HB) vaccine given to neonates and infants in the US. METHODS: US reports associated with HB vaccination and received between January 1, 1991, and May 31, 1995, by the national Vaccine Adverse Events Reporting System (VAERS) were reviewed as a case series. RESULTS: During 1991 through 1994, 12,520 (32%) VAERS reports were received for events temporally associated with administration of HB vaccine, of which 14% were received for neonates and infants. More reports described serious outcomes for neonates (< 0.1 year old) than for other age groups (40% vs. 6 to 15%). HB alone was administered to 58 (97%) neonates; review of these reports did not reveal unexpected serious events. Among infants (0.1 to 0.9 years old) 192 (9%) received HB vaccine alone and 1469 (66%) received HB in combination with diphtheria-tetanus-pertussis (DTP) vaccine. Similar serious adverse events reported in neonates and infants included fever, agitation and apnea. Events reported for infants receiving HB/DTP and DTP alone were similar and differed from reports filed for infants receiving HB vaccine alone, suggesting that these events may be associated with use of DTP vaccine. CONCLUSIONS: This review shows no unexpected adverse events in neonates and infants given HB vaccine despite use of at least 12 million doses of vaccine given in these age groups. Although VAERS lacks the ability to distinguish coincidental events from true vaccine reactions, this database represents the largest case series of events temporally associated with HB vaccination of neonates and infants.

Syncope after immunization.

OBJECTIVE: To describe the individual characteristics, clinical features, and morbidity associated with syncope following immunization. DESIGN: Large case series. SETTING: United States, 1990 through 1995. SUBJECTS: Reports to the national Vaccine Adverse Event Reporting System (VAERS), a passive surveillance system. An additional 3 reports of head injury (documented by medical records) were obtained through the National Vaccine Injury Compensation Program. MAIN OUTCOME MEASURES: Syncope, syncope and hospitalization, or syncope and head injury within 12 hours of vaccination. RESULTS: A total of 697 cases of syncope after vaccination was reported. Age younger than 20 years was reported for 77.4%; 57.5% were female. Hospitalization was reported in 9.6%. Of the 571 syncope events with known time, 511 occurred 1 hour or less after vaccination. Of these, 323 (63.2%) occurred 5 minutes or less, 454 (88.8%) occurred 15 minutes or less, and 500 (97.8%) occurred 30 minutes or less after vaccination. Tonic or clonic movements, which have been associated with the anoxia of vasovagal syncope, were reported in 30.4% of syncopal episodes occurring 15 minutes or less after and in 12.8% of those occurring 15 minutes or longer after vaccination (P < .001). Six patients suffered skull fracture, cerebral bleeding, or cerebral contusion after falls; 3 of these patients required neurosurgery. Falls occurred 15 minutes or less after vaccination, in or near the clinic or office. Ages ranged from 12 to 28 years; 5 of 6 were male. Follow-up revealed substantial residual impairment in 2 patients. CONCLUSIONS: Prevention of injury from syncope after vaccination and of syncope itself may be possible in many cases. Vaccinators should be aware that patients exhibiting presyncopal signs and symptoms around the time of immunization need to be evaluated carefully and may need to be assisted to sit or lie down after immunization until free of symptoms.

Neonatal deaths after hepatitis B vaccine: the vaccine adverse event reporting system, 1991-1998.

OBJECTIVE: To evaluate reports of neonatal deaths (aged 0-28 days) after hepatitis B (HepB) immunization reported to the national Vaccine Adverse Event Reporting System (VAERS). DESIGN: Case series; review of autopsy reports. SETTING: Voluntary reports submitted to VAERS, a passive surveillance system, from the US population. PATIENTS: All US neonates (0-28 days of age) whose deaths after HepB vaccination given alone were reported to VAERS, occurring from January 1, 1991, through October 5, 1998. INTERVENTION: None (observational database). RESULTS: Of 1771 neonatal reports, there were 18 deaths in 8 boys and 9 girls (1 patient unclassified). The mean age at vaccination for these 18 cases was 12 days (range, 1-27 days); median time from vaccination to onset of symptoms was 2 days (range, 0-20 days); and median time from symptoms to death was 0 days (range, 0-15 days). The mean birth weight of the neonates (n = 15) was 3034 g (range, 1828-4678 g). The causes of death for the 17 autopsied cases were sudden infant death syndrome for 12, infection for 3, and 1 case each of intracerebral hemorrhage, accidental suffocation, and congenital heart disease. CONCLUSION: Few neonatal deaths following HepB vaccination have been reported, despite the use of at least 86 million doses of pediatric vaccine given in the United States since 1991. While the limitations of passive surveillance systems do not permit definitive inference, these data suggest that HepB immunization is not causing a clear increase in neonatal deaths.

Results of second-look laparotomy in patients with early-stage ovarian carcinoma.

One hundred twelve patients with early (FIGO stage I and II) ovarian carcinoma had a second-look laparotomy performed after comprehensive surgical staging and randomization into clinical protocols. Of the 95 patients who were asymptomatic before second-look laparotomy, only 5% had positive findings. In contrast, 53% of the 17 patients with findings that suggested recurrence or bowel obstruction had disease at second-look laparotomy. Overall, only 13% of the entire group of 112 patients had recurrent disease at second-look laparotomy. Asymptomatic patients with early ovarian carcinoma who have undergone careful initial surgical staging followed by appropriate adjuvant therapy can be spared a routine second-look operation.

Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection.

The efficacy of combined radiation and fluorouracil as adjuvant therapy for pancreatic cancer is suggested by a prospective randomized study conducted by the Gastrointestinal Tumor Study Group (GITSG). Twenty-two patients randomized to no adjuvant treatment and 21 to combined therapy were analyzed. Neither life-threatening toxic reaction nor death due to toxic effect was encountered. The study was terminated prematurely because of an unacceptably low rate of accrual combined with the observation of increasingly large survival differences between the study arms. Median survival for the treatment group (20 months) was significantly longer than that observed for the control group (11 months). Four patients, three in the treated and one in the control group, have survived five years or longer following surgery. The extent of the tumor and initial performance status were significantly and independently related to survival.

Biostatistics in clinical trials: Part 2. Determining sample sizes for clinical trials.

The appropriate sample size for a clinical trial depends on the objectives of the trial. For Phase II trials, the recommended sample size is generally in the neighborhood of 25-40 patients, regardless of the choice of design. Sample sizes for Phase III trials are much more variable, ranging from less than a hundred to thousands of patients. The methodology of sample size determination for Phase III trials depends on the type of endpoint that is to be the primary focus of analysis. Tables of sample sizes for a variety of situations are presented. Use of sequential designs may reduce the required sample size by permitting early termination of trials whose results become definitive prior to completion of patient entry.

Do large, simple trials have a place in the evaluation of AIDS therapies?

Would trials enrolling large numbers of patients and that would require the collection of a relatively small amount of baseline and follow-up data be useful in evaluating treatments for AIDS? It seems worth considering whether widely available large, simple trials, especially those focused on optimizing dosage regimens of existing drugs, could serve the dual purpose of answering important patient management questions and improving the access of indigent populations to marketed therapies.

Low-dose heparin for prevention of venous thromboembolism in total hip arthroplasty and surgical repair of hip fractures.

Sixty-seven hip-arthroplasty and fifty-two hip-fracture patients participated in a placebo-controlled randomized double-blind study on the effects of low-dose heparin prophylaxis in the prevention of venous thromboembolism. In this study, a positive thromboembolic event meant a positive test by: (1) daily 125I-fibrinogen scanning, (2) contrast venography on the tenth postoperative day, or (3) radionuclide perfusion lung scan in confirmation of suspected clinical pulmonary emboli. Nineteen (59.4 per cent) of thirty-two placebo-treated arthroplasty patients showed evidence of a thromboembolic event in contrast with eight (22.9 per cent) of thirty-five heparin-treated patients (p less than 0.003). Heparin-treated arthroplasty patients required mean blood transfusions of 4.7 units, contrasted with a mean 3.2-unit transfusion requirement for placebo-treated patients (p less than 0.05). The incidence of observed bleeding complications was higher among the heparin-treated patients. Of the twenty-three placebo-treated patients with fracturs, 39.1 per cent had a thromboembolic event, while 41.4 per cent of the twenty-nine who received heparin showed evidence of thromboembolism, demonstrating that low-dose heparin afforded no protection, nor did it affect the incidence of bleeding complications or transfusion requirements in fracture patients.

The complicated task of monitoring vaccine safety.

Vaccination is an essential component of modern public health programs and is among our most cost-effective medical interventions. Yet despite vaccines' clear effectiveness in reducing risks of diseases that previously attacked large proportions of the population, caused many deaths, and left many people with permanent disabilities, current vaccination policies are not without controversy. Vaccines, like all other pharmaceutical products, are not entirely risk-free; while most known side effects are minor and self-limited, some vaccines have been associated with very rare but serious adverse effects. Because such rare effects are often not evident until vaccines come into widespread use, the Federal government maintains ongoing surveillance programs to monitor vaccine safety. The interpretation of data from such programs is complex and is associated with substantial uncertainty. A continual effort to monitor these data effectively and to develop more precise ways of assessing risks of vaccines is necessary to ensure public confidence in immunization programs.

Association between bronchoalveolar lavage cytologic features and airway reactivity in horses with a history of exercise intolerance.

OBJECTIVE: To correlate indices of airway reactivity to bronchoalveolar lavage (BAL) fluid cytologic features in horses with a recent decline in exercise tolerance. ANIMALS: 20 actively working horses from 2 to 24 years old. PROCEDURE: Bronchoalveolar lavage fluid samples were obtained and analyzed. Forced oscillatory mechanics (1-7 Hz) technique was used for measurements of total respiratory system resistance (RRS), compliance (CRS), and resonant frequency (fres). Changes in RRS (1 Hz) during histamine challenge were used to generate histamine dose-response curves, from which the provocative concentrations that evoked a 75 or 100% increase in baseline RRS (PCRRS75 and PCRRS 100, respectively) were determined. Age, sex, baseline lung mechanics, and BAL cytologic findings were correlated with PCRRS75 and PCRRS100. RESULTS: No horse of the study had clinical signs or history of obstructive pulmonary disease or increased percentage (> 7%) of neutrophils in bronchoalveolar lavage fluid samples. Mean (+/- SEM) RRS, CRS, and fres were 0.67 +/- 0.06 cm of H2O/L/s, 0.52 +/- 0.04 L/cm H2O, and 2.46 +/- 0.02 Hz, respectively. There was no correlation between age or sex, and RRS, CRS, fres, PCRRS75, or PCRRS100. There was a significant correlation (rs = -0.78, P < 0.001) between percentage of BAL fluid mast cells and PCRRS75 or PCRRS100, but correlation with other cell types and indices of airway reactivity were not observed. CONCLUSION: The strong association between mast cell percentage in BAL fluid and airway reactivity in this group suggests that mast cell products may contribute to bronchospasm, airway wall thickening, and/or loss of elastic recoil, which underlie airway hyperreactivity. Alternatively, mast cells may contribute to nonspecific airway reactivity in horses through unknown mechanisms.