A CASE OF RECURRENT ACUTE HAEMORRHAGIC CYSTITIS ASSOCIATED WITH SALBUTAMOL AND BECLOMETHASONE USE IN A PAEDIATRIC PATIENT

Abstract

12 September 2011 Dear Editor, Inhaled salbutamol in combination with corticosteroids is important in first-line management of asthma. Rare case report and case control studies have associated salbutamol inhalation with pain in the bladder (incidence of 3.0%) and voiding difficulties (incidence less than 1%).1 Adverse drug reactions (ADRs) affecting the urinary system have never been described for inhaled beclomethasone. No cases of haemorrhagic cystitis have been described with these drugs in paediatric population and only one case has been reported in an adult.2 Here we describe the case of a 9-year-old Caucasian girl, EB, treated for acute asthma control and cough with inhaled salbutamol (6 mg/day) and beclomethasone (0.8 mg/day) for 5 days. She had no history of chronic asthma or seasonal allergies. During the last day of therapy with salbutamol and beclomethasone, she experienced haemorrhagic cystitis that remitted 2 days after β2 agonist and corticosteroid withdrawal. The urine culture was negative. The clinical history indicated that the child already had an episode of haemorrhagic cystitis 5 years before the present occurrence, with suprapubic pain, vesical tenesmus, burning sensation upon urination, which required emergency treatment. When she presented herself to the emergency department, she had been taking salbutamol (6 mg/day) for asthma and bronchitis for the previous 8 days. The patient was not taking any other drug treatment. The urinalysis showed micturition with haematuria, leukocytes and activity of esterases, while the urine culture was negative (Table 1). The child was hospitalised for 3 days, and salbutamol treatment immediately withdrawn. On the third day of hospitalisation, a follow-up urinalysis showed the absence of macroscopic and microscopic haematuria, and there was an improvement of dysuria and general condition of the patient. Similarly, negative for haematuria was a further urinalysis carried out 5 days after patient dismissal. The clinical picture described earlier is compatible with a case of haemorrhagic cystitis. Intermittent haematuria, associated with upper respiratory infection, may be also compatible with IgA nephropathy, thin basement membrane disease or hypercalciuria. The clinical data, the fact that renal function (Table 1) and blood pressure (120/75 breaths per minute) were in the norm, the absence of proteinuria in follow-up urinalyses with total remission of microscopic haematuria and the absence of a family history of micro-haematuria without renal failure since both parents were negative for haematuria at urinalysis, appear to rule out thin basement membrane disease. Hypercalciuria can be excluded with certainty only on testing a spot calcium/creatinine ratio or 24-h urinary calcium excretion in the urine. Based on clinical symptoms, absence of abnormal calciuria in initial (Table 1) and follow-up urinalyses, with normal creatinine blood values, hypercalciuria was, however, considered unlikely, and the previous tests were not carried out. IgA nephropathy can not entirely be ruled out since it may occur in at least 50% of cases with normal IgA levels and normal blood pressure. However, this appears a less likely possibility since the IgA values in the child were below normal values (Table 1) in the absence of familial haematuria. Analysis with the Naranjo adverse drug reaction probability scale indicates the present ADR as ‘possible’, an inference reinforced by positive de-challenge and re-challenge and the fact that the patient did not receive any salbutamol in the four years between the two episodes. Active salbutamol in the urinary tract can increase plasminogen activator activity and tissue- and urokinase-type plasminogen activator levels and down-regulate plasminogen activator inhibitor-1 expression and secretion. This activates the fibrinolytic system that may lead to haemorrhages.3 Moreover, β2 adrenergic receptor stimulation in platelets increases generation of nitric oxide, a vasodilating messenger that potently inhibit platelets adhesion and aggregation and has been associated in experimental in vivo models to development of haemorrhagic cystitis.4 It is therefore possible these mechanism contributed to the observed haemorrhagic reaction. β2 is the most abundant adrenergic receptor subclass expressed by immune cells such as natural killer cells, neutrophils, macrophages and bone marrow and Thymus derived lymphocytes. Exposure of cluster of differentiation 4+ T cells to β2 agonists may induce their switch towards a pro-inflammatory (Th17) phenotype, possibly via inhibition of calcineurin activity.5 While we can not exclude a concurrent role of beclomethasone in the haemorrhagic cystitis, this seems unlikely as the drug was not taken by the patient at the time of the first haemorrhagic episode. More studies are needed to confirm the association between this specific ADR and salbutamol (and beclomethasone); this case report, however, suggests that attention to this issue has to be paid when these drugs are prescribed as inhaled preparations in paediatric patients. Acknowledgements: The financial support by Regione Lombardia (Monitoraggio degli Eventi Avversi in Pediatria project) is gratefully acknowledged.