Topical tacrolimus in atopic dermatitis : Effects of long-term treatment on skin and respiratory symptoms

Objective: Patients with atopic dermatitis often have a poor long-term response to conventional topical or systemic treatments. Staphylococcal superinfections, skin atrophy due to corticosteroid use, and asthma and allergic rhinitis are common. Only a few, usually short-term, studies have addressed the effects of different treatments on these problems. Tacrolimus ointment is the first topical compound suitable for long-term treatment. The aim of this thesis was to evaluate the effects of long-term topical tacrolimus treatment on cutaneous staphylococcal colonization, collagen synthesis, and symptoms and signs of asthma and allergic rhinitis. Methods: Patients with moderate-to-severe atopic dermatitis were treated with intermittent 0.1% tacrolimus ointment in prospective, open studies lasting for 6 to 48 months. In Study I, cutaneous staphylococcal colonization was followed for 6 to 12 months. In Study II, skin thickness and collagen synthesis were followed by skin ultrasound and procollagen I and III propeptide concentrations of suction blister fluid samples for 12 to 24 months and compared with a group of corticosteroid-treated atopic dermatitis patients and with a group of healthy subjects. Study III was a cross-sectional study of the occurrence of respiratory symptoms, bronchial hyper-responsiveness, and sputum eosinophilia in atopic dermatitis patients and healthy controls. In Study V, the same parameters as in Study III were assessed in atopic dermatitis patients before and after 12 to 48 months of topical tacrolimus treatment. Study IV was a retrospective follow-up of the effect of tacrolimus 0.03% ointment on severe atopic blepharoconjunctivitis and conjunctival cytology. Results: The clinical response to topical tacrolimus was very good in all studies (p≤0.008). Staphylococcal colonization decreased significantly, and the effect was sustained throughout the study (p=0.01). Skin thickness (p<0.001) and markers of collagen synthesis (p<0.001) increased in the tacrolimus-treated patients significantly, whereas they decreased or remained unchanged in the corticosteroid-treated controls. Symptoms of asthma and allergic rhinitis (p<0.0001), bronchial hyper-responsiveness (p<0.0001), and sputum eosinophilia (p<0.0001) were significantly more common in patients with atopic dermatitis than in healthy controls, especially in subjects with positive skin prick tests or elevated serum immunoglobulin E. During topical tacrolimus treatment the asthma and rhinitis (p=0.005 and p=0.002) symptoms and bronchial hyper-responsiveness (p=0.02) decreased significantly, and serum immunoglobulin E and sputum eosinophils showed a decreasing trend in patients with the best treatment response. Treatment of atopic blepharoconjunctivitis resulted in a marked clinical response and a significant decrease in eosinophils, lymphocytes, and neutrophils in the conjunctival cytology samples. No significant adverse effects or increase in skin infections occurred in any study. Conclusions: The studies included in this thesis, except the study showing an increase in skin collagen synthesis in tacrolimus-treated patients, were uncontrolled, warranting certain reservations. The results suggest, however, that tacrolimus ointment has several beneficial effects in the long-term intermittent treatment of atopic dermatitis. Tacrolimus ointment efficiently suppresses the T cell-induced inflammation of atopic dermatitis. It has a normalizing effect on the function of the skin measured by the decrease in staphylococcal colonization. It does not cause skin atrophy as do corticosteroids but restores the skin collagen synthesis in patients who have used corticosteroids. Tacrolimus ointment has no marked systemic effect, as the absorption of the drug is minimal and decreases along with skin improvement. The effects on the airway: decrease in bronchial hyper-responsiveness and respiratory symptoms, can be speculated to be caused by the decrease in T cell trafficking from the skin to the respiratory tissues as the skin inflammation resolves, as well as inhibition of epicutaneous invasion of various antigens causing systemic sensitization when the skin barrier is disrupted as in atopic dermatitis. Patients with moderate-to-severe atopic dermatitis seem to benefit from efficient long-term treatment with topical tacrolimus.

Healthcare-Associated Infections in Pediatrics

Healthcare-associated infections (HAIs) are known to increase the risk for patient morbidity and mortality in different healthcare settings and thereby to cause additional costs. HAIs typically affect patients with severe underlying conditions. HAIs are prevalent also among pediatric patients, but the distribution of the types of infection and the causative agents differ from those detected in adults. The aim of this study was to obtain information on pediatric HAIs in Finland through an assessment of the surveillance of bloodstream infections (BSIs), through two outbreak investigations in a neonatal intensive care unit (NICU), and through a study of postoperative HAIs after open-heart surgery. The studies were carried out at the Hospital for Children and Adolescents of Helsinki University Central Hospital. Epidemiological features of pediatric BSIs were assessed. For the outbreak investigations, case definitions were set and data collected from microbiological and clinical records. The antimicrobial susceptibilities of the Serratia marcescens and the Candida parapsilosis isolates were determined and they were genotyped. Patient charts were reviewed for the case-control and cohort studies during the outbreak investigations, as well as for the patients who acquired surgical site infections (SSIs) after having undergone open-heart surgery. Also a prospective postdischarge study was conducted to detect postoperative HAIs in these patients. During 1999-2006, the overall annual BSI rate was 1.6/1,000 patient days (range by year, 1.2–2.1). High rates (average, 4.9 and 3.2 BSIs/1,000 patient days) were detected in hematology and neonatology units. Coagulase-negative staphylococci were the most common pathogens both hospital-wide and in each patient group. The overall mortality was 5%. The genotyping of the 15 S. marcescens isolates revealed three independent clusters. All of the 26 C. parapsilosis isolates studied proved to be indistinguishable. The NICU was overcrowded during the S. marcescens clusters. A negative correlation between C. parapsilosis BSIs and fluconazole use in the NICU was detected, and the isolates derived from a single initially susceptible strain became less susceptible to fluconazole over time. Eighty postoperative HAIs, including all severe infections, were detected during hospitalization after open-heart surgery; 34% of those HAIs were SSIs and 25% were BSIs. The postdischarge study found 65 infections that were likely to be associated with hospitalization. The majority (89%) of them were viral respiratory or gastrointestinal infections, and these often led to rehospitalizations. The annual hospital-wide BSI rates were stable, and the significant variation detected in some units could not be seen in overall rates. Further studies with data adequately adjusted for risk factors are needed to assess BSI rates in the patient groups with the highest rates (hematology, neonatology). The outbreak investigations showed that horizontal transmission was common in the NICU. Overcrowding and lapses in hand hygiene probably contributed to the spreading of the pathogens. Following long-term use of fluconazole in the NICU, resistance to fluconazole developed in C. parapsilosis. Almost one-fourth of the patients who underwent open-heart surgery acquired at least one HAI. All severe HAIs were detected during hospitalization. The postdischarge study found numerous viral infections, which often caused rehospitalization.