Epidemiological study of severe febrile reactions in young children in Western Australia caused by a 2010 trivalent inactivated influenza vaccine.

BACKGROUND: The 2010 influenza vaccination program for children aged 6 months to 4 years in Western Australia (WA) was suspended following reports of severe febrile reactions, including febrile convulsions, following vaccination with trivalent inactivated influenza vaccine (TIV). METHODS: To investigate the association between severe febrile reactions and TIV, three studies were conducted: (i) rates of febrile convulsions within 72 h of receiving TIV in 2010 were estimated by vaccine formulation and batch; (ii) numbers of children presenting to hospital emergency departments with febrile convulsions from 2008 to 2010 were compared; and (iii) a retrospective cohort study of 360 children was conducted to compare the reactogenicity of available TIV formulations. FINDINGS: In 2010, an estimated maximum of 18,816 doses of TIV were administered and 63 febrile convulsions were recorded, giving an estimated rate of 3.3 (95% CI 2.6 to 4.2) per 1000 doses of TIV administered. The odds of a TIV-associated febrile convulsion was highly elevated in 2010 (p<0.001) and was associated with the vaccine formulations of one manufacturer-Fluvax and Fluvax Junior (CSL Biotherapies). The risk of both febrile convulsions (p<0.0001) and other febrile reactions (p<0.0001) was significantly greater for Fluvax formulations compared to the major alternate brand. The risk of febrile events was not associated with prior receipt of TIV or monovalent 2009 H1N1 pandemic vaccine. The biological cause of the febrile reactions is currently unknown. INTERPRETATION: One brand of influenza vaccine was responsible for the increase in febrile reactions, including febrile convulsions. Until the biological reason for this is determined and remediation undertaken, childhood influenza vaccination programs should not include Fluvax-type formulations and enhanced surveillance for febrile reactions in children receiving TIV should be undertaken.

Trivalent influenza vaccine and febrile adverse events in Australia, 2010: clinical features and potential mechanisms.

INTRODUCTION: Increased numbers of children presenting with febrile adverse events following trivalent influenza vaccine (TIV) were noted in Australia in 2010. We describe the epidemiology and clinical features of the adverse events and explore the biological basis for the adverse events using an in vitro model. MATERIALS AND METHODS: Children presenting to a tertiary paediatric hospital in 2010 with adverse events within 72 h of TIV were retrospectively reviewed. Demographics, clinical features, physiological variables and outcomes were examined. Plasma cytokine and chemokine levels were examined in a subgroup of children with vaccine-related febrile convulsions. Peripheral blood mononuclear cells of age-matched children were stimulated with different TIV preparations. Inflammatory cytokine and chemokine analysis was performed on cultured supernatants. RESULTS: Vaccine-related febrile adverse events were identified in 190 children. Most occurred in healthy children (median age: 1.5 years) within 12 h of vaccination. Twenty-eight (14.7%) required hospital admission. High temperature ≥39.0 °C (101/190; 53%), vomiting (120/190; 63%) and convulsions (38/190; 20%) were common. All children presenting had received Fluvax(®) or Fluvax Junior(®). In the in vitro model, IFN-α, IL-1ß, IL-6, IL-10, IP-10 and MIP-1α levels were significantly higher when measured at 6 and 24 h in cultures stimulated with Fluvax(®) compared with alternative 2010 TIV preparations. CONCLUSIONS: Numerous febrile adverse events (including febrile seizures) were observed following Fluvax(®) or Fluvax Junior(®) in 2010. Clear differences in cytokine production were observed when peripheral blood mononuclear cells were stimulated with Fluvax(®) compared with alternate TIV preparations. Increased awareness of these potential adverse events is required to ensure earlier detection and prevention in the future.

Association between human rhinovirus C and severity of acute asthma in children.

A new and potentially more pathogenic group of human rhinovirus (HRV), group C (HRVC), has recently been discovered. We hypothesised that HRVC would be present in children with acute asthma and cause more severe attacks than other viruses or HRV groups. Children with acute asthma (n = 128; age 2-16 yrs) were recruited on presentation to an emergency department. Asthma exacerbation severity was assessed, and respiratory viruses and HRV strains were identified in a nasal aspirate. The majority of the children studied had moderate-to-severe asthma (85.2%) and 98.9% were admitted to hospital. HRV was detected in 87.5% and other respiratory viruses in 14.8% of children, most of whom also had HRV. HRVC was present in the majority of children with acute asthma (59.4%) and associated with more severe asthma. Children with HRVC (n = 76) had higher asthma severity scores than children whose HRV infection was HRVA or HRVB only (n = 34; p = 0.018), and all other children (n = 50; p = 0.016). Of the 19 children with a non-HRV virus, 13 had HRV co-infections, seven of these being HRVC. HRVC accounts for the majority of asthma attacks in children presenting to hospital and causes more severe attacks than previously known HRV groups and other viruses.

Anti-bacterial IgE in the antibody responses of house dust mite allergic children convalescent from asthma exacerbation.

BACKGROUND: Atopic sensitization to the house dust mite (HDM) is associated with altered antibody responses to the nasopharyngeal colonizing bacterium Haemophilus influenzae and children admitted to the emergency department for asthma exacerbation have reduced IgG responses to HDM allergens. OBJECTIVE: To investigate anti-bacterial and anti-allergen antibody responses during convalescence from asthma exacerbation and differences found in exacerbations associated with and without viral infection. RESULTS: IgE antibodies to the P6 bacterial antigen increased in 60% of sera during convalescence and for many children achieved titres as high as IgE titres to allergens. In contrast IgE anti-HDM titres declined during convalescence. The anti-bacterial IgE titres were the same in subjects with and without virus infection while the anti-HDM IgE declined more rapidly in virus-infected subjects. IgG titres to the major HDM allergens showed no consistent increase and the overall IgG anti-HDM titres even declined in subjects without a virus infection. Anti-bacterial IgG antibodies in contrast to IgE did not change. Patients with frequent episodic or persistent asthma had similar IgE anti-bacterial titres to patients with infrequent asthma during the acute phase, although they had reduced IgG titres to both the bacteria and the HDM. CONCLUSIONS: During the period following an acute exacerbation of asthma there was a marked and specific increase in anti-bacterial IgE compared with a reduced IgE response to HDM. This provides further support for the concept of T-helper type 2 responses to bacterial antigens playing a role in asthma pathogenesis.

Is atropine needed with ketamine sedation? A prospective, randomised, double blind study.

OBJECTIVE: To compare atropine with placebo as an adjunct to ketamine sedation in children undergoing minor painful procedures. Outcome measures included hypersalivation, side effect profile, parental/patient satisfaction, and procedural success rate. METHODS: Children aged between 1 and 16 years of age requiring ketamine procedural sedation in a tertiary emergency department were randomised to receive 0.01 mg/kg of atropine or placebo. All received 4 mg/kg of intramuscular ketamine. Tolerance and sedation scores were recorded throughout the procedure. Side effects were recorded from the start of sedation until discharge. Parental and patient satisfaction scores were obtained at discharge and three to five days after the procedure, with the opportunity to report side effects encountered at home. RESULTS: A total of 83 patients aged 13 months to 14.5 years (median age 3.4 years) were enrolled over a 16 month period. Hypersalivation occurred in 11.4% of patients given atropine compared with 30.8% given placebo (odds ratio (OR) 0.29, 95% confidence interval (CI) 0.09 to 0.91). A transient rash was observed in 22.7% of the atropine group compared with 5.1% of the placebo group (OR 5.44, 95% CI 1.11 to 26.6). Vomiting during recovery occurred in 9.1% of atropine patients compared with 25.6% of placebo patients (OR 0.29, 95% CI 0.09 to 1.02). There was a trend towards better tolerance in the placebo group. No patient experienced serious side effects. CONCLUSION: Ketamine sedation was successful and well tolerated in all cases. The use of atropine as an adjunct for intramuscular ketamine sedation in children significantly reduces hypersalivation and may lower the incidence of post-procedural vomiting. Atropine is associated with a higher incidence of a transient rash. No serious adverse events were noted.

Adverse skin and joint reactions associated with oral antibiotics in children: the role of cefaclor in serum sickness-like reactions.

OBJECTIVE: To review presentations to Princess Margaret Hospital Emergency Department (PMH ED) with adverse joint and skin reactions associated with the use of oral antibiotics, to describe the clinical course of children with cefaclor-related serum sickness-like reactions (cefaclor SSLR) and compare these with cases reported to the Adverse Drug Reactions Advisory Committee (ADRAC). METHODS: Twelve-month retrospective review of presentations to a tertiary paediatric ED (42,000 visits annually) via an ED computer database search and review of medical charts of children presenting with joint or skin reactions. Telephone interviews were conducted with the caregivers of children with cefaclor SSLR. RESULTS: Adverse skin or joint reactions occurred in 150 children; 70 after cefaclor alone, 10 after cefaclor in combination with other antibiotics and 70 after other antibiotic courses. SSLR occurred in 44 children; 32 after cefaclor alone, five after cefaclor in combination with other antibiotics and seven after other single antibiotics. In children with cefaclor SSLR, otitis media was the most common indication (59.4%), another 18.8% had viral illnesses. Prolonged sequelae occurred in four children, a situation not previously reported. Sixty reports of paediatric cefaclor SSLR were made to ADRAC during the study period, none originated from PMH ED. CONCLUSIONS: Cefaclor was associated with 53.3% of oral antibiotic related skin and joint adverse reactions and 84.1% of SSLR. The indications for its use in paediatric illness require careful reconsideration. ADRAC data under-represents the incidence of cefaclor SSLR.

Croup.

The management of mild to severe croup has undergone dramatic changes in the last 5 years, primarily due to the increased understanding of the benefits of treating it with steroids. Steroids have been used in the treatment of croup for many years, but, until recently, their use has remained controversial. Earlier studies were often not blinded or used inappropriate outcome measures, such as respiratory rate, which have not proven appropriate. Two attempts to review the literature in 1980 and 1989 cautiously supported the use of steroids. Despite these recommendations many practitioners continued to view croup in most cases as a benign self-limited condition, and since steroids have potential side-effects, their use was not considered justified. More recently, however, a number of developments such as the successful use of the inhaled steroid budesonide and oral dexamethasone have reinforced the argument for using steroids. Recent work has also shown that both inhaled and systemic steroids work by 1 hour and dramatically reduce morbidity and hospitalization time. The demonstration that an oral dose of 0.15 mg/kg dexamethasone is as effective as larger doses has made the use of systemic steroids more acceptable to many practitioners. All children with croup severe enough to be admitted to hospital should receive steroids. Two recent studies have shown that steroids also benefitted children who presented to emergency departments for treatment, but whose croup was not considered severe enough for admission. The type of steroid, the dose, and the mode of administration will need to be decided by the attending clinician.

Sixteen years of croup in a Western Australian teaching hospital: effects of routine steroid treatment.

STUDY OBJECTIVE: To describe the experience of croup at Princess Margaret Hospital for Children (PMH), the only tertiary pediatric hospital in Western Australia, from 1980 through 1995 with reference to the introduction of routine steroid treatment in the ICU in 1989, in the general hospital wards from 1989 through 1993, and in the emergency department observation ward in 1993. METHODS: Information on the numbers of children with croup presenting to PMH from 1980 through 1985 who were admitted to the general wards, the ICU, and the observation ward; intubation rate; and length of stay was obtained from a combination of state health records, hospital statistics, logbooks, and computer records. RESULTS: The numbers of children who presented to and were admitted to PMH with croup were similar for all years of the study period. Since 1989, the annual number of children intubated (1980-1989 average, 8; 1990-1995 average, 4) and total ICU days for croup (1980-1989 average, 129; 1990-1995 average, 24) has decreased dramatically. The annual percentage of children transferred to the ICU (1980-1989 average, 11.6%; 1994-1995 average, 2.6%) and the average length of stay for PMH (1980-1989 average, 2.03 days; 1994-1995 average, 1.1 days) decreased every year from 1989 through 1994, coincident with increasing use of steroids for croup in the general wards. The change of policy from no steroids to compulsory use of steroids in the observation ward coincided with an increase in the percentage of children discharged home directly from the observation ward (to 97% from 80%). CONCLUSION: The introduction of steroids at PMH coincided with a dramatic decrease in measures of severity for children admitted to hospital with mild to severe croup. All children hospitalized with croup should receive steroid therapy.

Efficacy of a small single dose of oral dexamethasone for outpatient croup: a double blind placebo controlled clinical trial.

OBJECTIVE: To assess the efficacy of a single dose of oral dexamethasone 0.15 mg/kg in children with mild croup not admitted to hospital. DESIGN: Double blind, randomised, placebo controlled clinical trial. SETTING: The emergency department of a tertiary paediatric hospital. SUBJECTS: 100 children aged 4-122 months presenting with mild croup. INTERVENTION: A single oral dose of dexamethasone 0.15 mg/kg or placebo. MAIN OUTCOME MEASURE: Return to medical care with ongoing croup. RESULTS: Baseline characteristics of the two treatment groups were similar. Eight children (all from the placebo group) returned to medical care with ongoing croup, one being admitted. There was no reported difference in duration of croup symptoms, duration of viral symptoms, or rate of return to medical care for other reasons. CONCLUSION: Oral dexamethasone in a dose of 0.15 mg/kg is effective in reducing return to medical care with ongoing croup in children with mild croup.

Oral and inhaled steroids in croup: a randomized, placebo-controlled trial.

It was the objective of this study to compare the efficacy of oral dexamethasone and inhaled budesonide in children hospitalized with croup, using a three-way, double blind, randomized, placebo-controlled clinical trial design. The trial was carried out in the Emergency Department Observation Ward of a tertiary pediatric hospital. The subjects for the study were 80 children (age range 5 to 158 months) who were hospitalized with croup. Children received either 2 mg of nebulised budesonide, dexamethasone syrup (0.6 mg/kg) or a placebo. Median duration of hospitalization was shorter for children treated with dexamethasone (12 hr) and budesonide (13 hr) compared to placebo (20 hr) (P < 0.03). There was no significant difference in hospitalization time between children treated with dexamethasone and budesonide. Median time to a croup score of < or = 1 was shorter for children treated with dexamethasone (2 hr) or budesonide (3 hr) compared to those who received placebo (8 hr) (P < 0.01). Croup scores for both steroid groups were significantly lower than the placebo group by 1 hr and remained so subsequently. The croup scores did not differ significantly in the 2 steroid treated groups. Six of the 30 children (20%) in the placebo group required adrenaline after the first hour compared to none of the 50 children in the steroid treated groups (P < 0.02). We conclude that oral dexamethasone and inhaled budesonide are both effective in reducing symptoms and duration of hospitalization in children with croup.

Oral dexamethasone in the treatment of croup: 0.15 mg/kg versus 0.3 mg/kg versus 0.6 mg/kg.

The objective of this study was to compare the efficacy of a single dose of oral dexamethasone of varying sizes in 120 children hospitalized with croup in two sequential double blind, randomized, controlled clinical trials (Trials A and B). The study was conducted in the Emergency Department Observation Ward of a tertiary pediatric hospital. One hundred and twenty children (age range 6 to 160 months) hospitalized with croup participated. Baseline characteristics for the two groups in each trial were similar. In Trial A 60 children received either 0.6 or 0.3 mg/kg dexamethasone syrup; in Trial B 60 children received either 0.3 or 0.15 mg/ kg dexamethasone syrup. Duration of hospitalization, reduction in croup scores, and adrenaline usage were evaluated. Median duration of hospitalization was similar for children in Trial A (7 and 8 hr), and in Trial B (9 and 9 hr). Croup scores following treatment did not differ and were significantly lower than initial scores for all groups and in each trial. Other outcome measures were similar for the two groups in each trial, including need for nebulized adrenaline, numbers of patients admitted to intensive care, rate of return to medical care with reoccurrence of croup, and readmission to hospital with croup following discharge from hospital. We conclude that oral dexamethasone in a dose of 0.15 mg/kg is as effective as 0.3 or 0.6 mg/kg in relieving symptoms and results in a similar duration of hospitalization in children with croup.

Evaluation of SaO2 as a predictor of outcome in 280 children presenting with acute asthma.

STUDY OBJECTIVES: To evaluate the initial measurement of arterial oxygen saturation (SaO2) as a predictor of outcome in acute childhood asthma compared with other factors of past and present asthma history. DESIGN: Prospective observational double-blind study. SETTING: The emergency department of an urban pediatric hospital with a 1988 annual census of 50,000 children. TYPE OF PARTICIPANTS: Two hundred eighty children with recurrent wheezing that was diagnosed by a physician as asthma, who presented to the ED with wheezing. INTERVENTION: SaO2 was measured on arrival in the ED, and a detailed history of the present attack and past asthma was recorded. Children were treated according to then-current practice guidelines. Parents were contacted by telephone to determine the outcome of the attack; a "poor outcome" was defined as admission to hospital or re-presenting with ongoing symptoms to receive medical care if sent home from the ED. A "worst outcome" was defined as receiving IV aminophylline and steroids after failing to respond to repeated bronchodilation and oral steroids. MEASUREMENTS AND MAIN RESULTS: The proportion of children at each percent SaO2 who had a poor outcome increased with decreasing SaO2 (r = .97). Likelihood ratios for a poor outcome were 35 (confidence interval [CI], 11 to 150) for an SaO2 of 91% or less compared with 96% or more and 4.2 (CI, 2.2 to 8.8) for an SaO2 of 92% to 95% compared with 96% or more. An SaO2 of 91% or less predicted with a sensitivity of 100% and a specificity of 84% those children with a worst outcome who required IV therapy. Other factors of current or past asthma history failed to predict outcome. CONCLUSION: We have shown that in acute childhood asthma, the initial level of SaO2 reflects severity as it predicts the likelihood of poor outcome. This predictive quality of SaO2 is independent of current or past clinical factors.

The effect of age on oxygen desaturation during histamine inhalation challenge in normal infants.

Arterial oxygen saturation (SaO2) is usually measured during inhalation challenges in infants as desaturation has been demonstrated with provoked bronchoconstriction. We wished to examine whether measurement of SaO2 would provide a simple noninvasive indicator of respiratory function (RF) changes occurring during inhalation challenge in infants. Histamine inhalation challenges were performed longitudinally in 22 normal healthy infants at 4 and 26 weeks of age. RF was measured by calculating maximum forced expiratory flow at functional residual capacity (VmaxFRC) using the rapid thoracic compression technique. Airway responsiveness was assessed using histamine; the provoking concentration (PC) was that which caused a fall in VmaxFRC of at least 40% from baseline. The provocative concentration for an exact fall of 40% in VmaxFRC (PC40) from baseline was derived by linear interpolation. SaO2 was continuously monitored by pulse oximetry. One month old infants had higher SaO2 levels throughout the inhalation challenge in comparison to their SaO2 levels at 6 months of age. Significant falls in SaO2 were observed at the PC at both ages. However, at the age of 26 weeks the infants had greater median falls in SaO2 [PC, 4.5% (95%CI: 3.0, 7.0)] compared to the response at age 4 weeks [3.0% (95%CI: 1.0, 4.0) (P < 0.01)]. Median falls in VmaxFRC at the PC were not different between the ages. These results indicate an age-dependent discordance between airway and SaO2 response in healthy infants during histamine-induced bronchoconstriction.

A comparison of a bodyweight dose versus a fixed dose of nebulised salbutamol in acute asthma in children.

OBJECTIVE: To compare the efficacy of salbutamol as a fixed dose Ventolin Nebule (2.5 mg) and as variable dose respirator solution (0.1 mg/kg bodyweight). DESIGN: Multicentre, randomised, double-blind, parallel group comparison. SETTING: The Emergency Departments of the Royal Children's Hospital, Melbourne, Victoria; Princess Margaret Hospital for Children, Perth, Western Australia; and The Children's Hospital, Sydney, New South Wales. PATIENTS: Ninety-nine children between four and 12 years of age who presented to the Emergency Departments with mild to moderate acute asthma from May to December 1990. INTERVENTIONS: Children enrolled in the study were randomly allocated to one of two groups. Group 1 received one Nebule (2.5 mg salbutamol in 2.5 mL aqueous solution) delivered by wet nebulisation. Group 2 received salbutamol (approximately 0.1 mg/kg bodyweight) diluted with saline to 2.5 mL, delivered by identical wet nebulisation. MAIN OUTCOME MEASURES: (i) Clinical score; (ii) pulse oximetry; and (iii) peak expiratory flow rate (PEFR) where possible--measured before, and at 15 and 30 minutes after treatment with salbutamol. RESULTS: The clinical score significantly improved in both treatment groups after 15 minutes (P < 0.001), but the difference between the two treatments (adjusted for covariates) was not significant (P = 0.97). Both preparations of salbutamol produced a significant increase in oxygen saturation after 15 minutes (P < 0.05), while the difference between the two treatments (adjusted means) was not significant (P = 0.46). Peak flow measurements were available for 65 of the 99 patients. Both preparations of salbutamol produced highly significant (P < 0.001) improvements in PEFR at 15 minutes after treatment. The difference in peak flow rates between the two treatment groups (adjusted means) was not significant (P = 0.89). The study had a power of 0.8 to detect differences between treatments of 9% PEFR (percentage predicted), 0.8% oxygen saturation and 0.77 units of clinical score. CONCLUSIONS: A fixed dose of nebulised salbutamol is as efficacious as a salbutamol dose calculated for bodyweight in children with mild to moderate acute asthma.

The influence of a family history of asthma and parental smoking on airway responsiveness in early infancy.

BACKGROUND: Airway responsiveness to inhaled nonspecific bronchoconstrictive agents has been demonstrated in normal, healthy infants. However, it is unknown whether airway responsiveness is present from birth or if it develops as a result of subsequent insults to the respiratory tract. To investigate this question, we assessed airway responsiveness in 63 normal infants at a mean age of 4 1/2 weeks. METHODS: Respiratory function was measured with use of the partial forced expiratory flow-volume technique to determine the maximal flow at functional residual capacity (VmaxFRC). The infants inhaled nebulized histamine at sequentially doubled concentrations (0.125 to 8.0 g per liter), until a concentration was reached at which the VmaxFRC fell by 40 percent from the base-line value (PC40) or until a concentration of 8.0 g per liter was reached. We also assessed maternal serum levels of IgE, cord-serum levels of IgE, the infants' skin reactivity to several allergens, and the parents' responsiveness to histamine and obtained family histories of asthma and smoking. RESULTS: Airway responsiveness was increased in infants with a family history of asthma (n = 19; median PC40, 0.78 g per liter; 95 percent confidence interval, 0.44 to 1.15; P less than 0.01), parental smoking (n = 13; median PC40, 0.52 g per liter; 95 percent confidence interval, 0.43 to 5.40; P less than 0.05), or both (n = 20; median PC40, 0.69 g per liter; 95 percent confidence interval, 0.37 to 2.10; P less than 0.05), as compared with the infants with no family history of asthma or smoking. The infants with no family history of asthma or smoking had a median PC40 of 2.75 g per liter (95 percent confidence interval, 1.48 to 4.00). No significant relations were detected between the immunologic variables and the PC40 in the infants. CONCLUSIONS: This study indicates that airway responsiveness can be present early in life and suggests that a family history of asthma or parental smoking contributes to elevated levels of airway responsiveness at an early age.

Time course of change in oxygen saturation and peak expiratory flow in children admitted to hospital with acute asthma.

The time course for recovery of the arterial oxygen saturation (SaO2) in acute childhood asthma is unknown. Serial measurements of SaO2 were made in 47 children during an acute attack of asthma that required admission to hospital. Adequate serial peak expiratory flow (PEF) measurements were possible in 28 children (mean age 8.3 years; group A), but not in the other 19 children (mean age 3.2 years; group B). Measurements of PEF and SaO2 were recorded twice daily before and 30 minutes after they had received salbutamol by nebuliser. Initial SaO2 values (mean (SD) %) were similar in groups A and B at 92.2 (3.5) and 92.4 (2.9). For the children in group A, PEF plateaued 36 hours after admission and SaO2 plateaued 12 hours later. Mean PEF improved after each dose of nebulised salbutamol during the first 36 hours, whereas mean SaO2 increased only after the first dose. SaO2 increased more rapidly in group B. Length of hospital stay was not related to initial SaO2 or PEF values. These data suggest that in children admitted to hospital for acute asthma arterial oxygen saturation is low at admission, recovers more slowly than airway function, reflects bronchodilatation with salbutamol only when SaO2 is low, and recovers more rapidly in younger children than in older children.

Response of normal infants to inhaled histamine.

The age at which nonspecific bronchial hyperresponsiveness (BHR) is first seen in humans is unknown, though both genetic and environmental factors have been implicated in its development. The current study aimed to establish whether BHR to histamine can be demonstrated in normal infants. Twelve infants, mean age of 7.8 months (range, 3 to 18 months), were studied. None had any history of a previous significant respiratory illness. Respiratory function was monitored using the maximal flow at function residual capacity (VmaxFRC) obtained with the forced expiratory flow-volume technique. Histamine was inhaled in doubling concentrations from 0.125 to 8 g.L-1. A greater than 30% fall in VmaxFRC was considered a response. All infants responded to histamine, the geometric mean concentration for their response being 1.4 g.L-1. Associated transient changes for the group were an increase in respiratory rate (p less than 0.02) and a fall in SaO2 (p less than 0.001). Forced expiratory flow-volume curves were concave in all infants after the last dose of histamine. We speculate that humans are born with "bronchial hyperresponsiveness" and that genetic or environmental factors determine which infants lose it thereafter.