Petri S. Mattila

Fecal Transplantation, Through Colonoscopy, Is Effective Therapy for Recurrent Clostridium difficile Infection

BACKGROUND & AIMS Treatment of recurrent Clostridium difficile infection (CDI) with antibiotics leads to recurrences in up to 50% of patients. We investigated the efficacy of fecal transplantation in treatment of recurrent CDI. METHODS We reviewed records from 70 patients with recurrent CDI who had undergone fecal transplantation. Fecal transplantation was performed at colonoscopy by infusing fresh donor feces into cecum. Before transplantation, the patients had whole-bowel lavage with polyethylene glycol solution. Clinical failure was defined as persistent or recurrent symptoms and signs, and a need for new therapy. RESULTS During the first 12 weeks after fecal transplantation, symptoms resolved in all patients who did not have strain 027 C difficile infections. Of 36 patients with 027 C difficile infection, 32 (89%) had a favorable response; all 4 nonresponders had a pre-existing serious condition, caused by a long-lasting diarrheal disease or comorbidity and subsequently died of colitis. During the first year after transplantation, 4 patients with an initial favorable response had a relapse after receiving antibiotics for unrelated causes; 2 were treated successfully with another fecal transplantation and 2 with antibiotics for CDI. Ten patients died of unrelated illnesses within 1 year after transplantation. No immediate complications of fecal transplantation were observed. CONCLUSIONS Fecal transplantation through colonoscopy seems to be an effective treatment for recurrent CDI and also for recurrent CDI caused by the virulent C difficile 027 strain.

Serological evidence of Merkel cell polyomavirus primary infections in childhood

BACKGROUND Merkel cell polyomavirus (MCPyV) was identified newly (2008) and is believed to be an etiologic factor of Merkel cell carcinoma (MCC). Recent molecular and serological data suggest that MCPyV infection is common in the general population. OBJECTIVES The aim of this study was to investigate the age of primary exposure to MCPyV. STUDY DESIGN A MCPyV-IgG EIA was developed using the MCPyV major capsid protein VP1 expressed and self-assembled into virus-like particles (VLPs) in insect cells. The assay was used to detect serum IgG antibodies in two groups of children. Group 1 comprised paired and 5-8 year follow-up sera from 217 children (3-13 years) with acute lower respiratory tract infection. Group 2 comprised sera from 158 children (1-4 years) with otitis media; 86 children underwent adenoidectomy and 72 did not, whereafter follow-up sera were obtained 3 years later. RESULT The prevalence of MCPyV-IgG was 9% at 1-4 years, and increased to 35% at 4-13 years among subjects from Group 1, with a 33% seroconversion rate during 5-8 years. Among Group 2, the seroconversion rate was 16% during 3 years. The IgG prevalence at 4-7 years as well as the IgG levels showed an apparent gender difference, with male preponderance prevailing among the children without adenoidectomy. CONCLUSION MCPyV primary infections occur ubiquitously in childhood, and the first exposure takes place at young age. The serology showed no evidence for a causative role of MCPyV in lower respiratory tract infection manifesting as acute wheezing, but was compatible with the notion of MCPyV persistence in tonsils.

TNFa‐Induced Expression of Endothelial Adhesion Molecules, ICAM‐1 and VCAM‐1, is Linked to Protein Kinase C Activation

The role of protein kinase C (PKC) in TNFα‐induced activation of endothelial adhesion molecules ICAM‐1 and VCAM‐1 was analysed. Phorbol myristate acetate, which is known to activate PKC, was able lo mimic TNFα‐induced up‐regulation of ICAM‐1 and partly also VCAM‐1 expression. Similarly a PKC inhibitor, H7, but not another kinase inhibitor. HA1004, inhibited TNFα‐induced enhancement of ICAM‐1 expression at both the mRNA and the protein level. Moreover we were able to measure a transient PKC activation peak at 16 min after TNFα induction in endothelial cells analysed by phorbol‐dibutyrate binding. These results indicate that the TNFα‐induced effect on the regulation of endothelial adhesion molecule expression is at least partly mediated by PKC activation.

Adenoidectomy Does Not Significantly Reduce the Incidence of Otitis Media in Conjunction With the Insertion of Tympanostomy Tubes in Children Who Are Younger Than 4 Years: A Randomized Trial

Objective. To evaluate the efficacy of adenoidectomy in reducing the incidence of otitis media among children who are younger than 4 years and receive tympanostomy tubes. Methods. A randomized trial was conducted at a tertiary center clinic. A total of 217 children who were aged 12 to 48 months and had recurrent acute otitis media (>3 episodes during the past 6 months) or chronic otitis media with effusion, no obstructive symptoms as a result of adenoid enlargement, and no previous surgical intervention were enrolled in the study. Adenoidectomy in conjunction with the insertion of tympanostomy tubes or insertion of tympanostomy tubes without adenoidectomy was studied. The number of otitis media episodes during the follow-up period of 12 months was measured. Results. During the follow-up, the mean number of otitis media episodes was 1.7 among children who underwent adenoidectomy with concurrent insertion of tympanostomy tubes and 1.4 among children who received tympanostomy tubes only. The risk for recurrent otitis media (≥3 episodes) could not be reduced by adenoidectomy (odds ratio: 1.66; 95% confidence interval: 0.80–3.46). Conclusion. Adenoidectomy does not significantly reduce the incidence of acute otitis media in otitis prone children who are younger than 4 years and receive tympanostomy tubes.

High incidence of PTLD after non-T-cell-depleted allogeneic haematopoietic stem cell transplantation as a consequence of intensive immunosuppressive treatment

Summary:The occurrence of post-transplant lymphoproliferative disorder (PTLD) in relation to immunosuppressive treatment was determined in 257 patients treated with non-T-cell-depleted allogeneic stem cell transplantation from an HLA-matched sibling (173 patients) or unrelated donor (84 patients). The conditioning consisted of total body irradiation and cyclophosphamide (myeloablative conditioning, 250 patients), or fludarabine combined with cyclophosphamide or a single 2 Gy dose of TBI (nonmyeloablative conditioning, seven patients). In transplantations from an unrelated donor, the patients also received antithymocyte globulin (ATG). The prophylaxis against graft-versus-host disease (GVHD) consisted of cyclosporine A, methotrexate, and methylprednisolone. The autopsy reports of deceased patients were systematically reviewed, and the autopsy materials of cases suggestive of PTLD were re-examined histologically for Epstein–Barr virus (EBV). Nineteen patients with EBV-positive PTLD were identified, of whom six had been transplanted from a sibling donor and 13 from an unrelated donor. All the patients who developed PTLD had been given ATG either for the treatment of steroid-resistant acute GVHD (all PTLD patients with a sibling donor and one with an unrelated donor), or as part of the conditioning (all patients with an unrelated donor). In conclusion, in transplantations from an HLA-identical donor with a non-T-cell-depleted graft, the risk of PTLD correlated strongly with the intensity of the immunosuppressive treatment.

Seroepidemiology of the Newly Found Trichodysplasia Spinulosa–Associated Polyomavirus

Trichodysplasia spinulosa (TS)-associated polyomavirus (TSV) was recently (in 2010) discovered in TS lesions. To investigate the seroprevalence and primary exposure time of this virus, we set up a virus protein (VP1) viruslike particle (VLP)-based immunoglobulin G enzyme immunoassay. The seroprevalence of TSV was 5%, among children aged 1-4 years, rising to 48% at 6-10 years, and 70% among 149 adults. The TSV antibodies did not cross-react with corresponding Merkel cell polyomavirus VLPs, and their reactivity appeared conformational. TSV circulates widely in the human population and primary exposure is extensive in childhood, beginning at age 1-2 years.

Exercise‐induced changes in respiratory impedance in young wheezy children and nonatopic controls

Exercise‐induced bronchoconstriction (EIB) is a specific sign of active asthma, but its assessment in young children may be difficult with lung function techniques requiring active cooperation. The aim of the study was to assess the normal pattern of exercise‐induced responses of respiratory impedance by using impulse oscillometry (IOS), and to investigate how these responses discriminate wheezy children from control subjects. IOS measurements were performed in a consecutive sample of wheezy children aged 3–7 years (n = 130) and in an aged matched control group of nonatopic children without respiratory symptoms (n = 79) before and after a free running test. After exercise, wheezy children showed significantly larger responses in respiratory resistance (Rrs5), reactance (Xrs5), and the resonance frequency (Fr) than the control subjects. In the control group, the upper 95% confidence limit of the maximal change was 32.5% for Rrs5, 85.7% for Xrs5, and 53.1% for Fr. By using analysis of receiver operating characteristics, the change in Rrs5 distinguished the wheezy children from the control subjects more effectively than change in Xrs5 or Fr. In wheezy children, the response was significantly effected by the outdoor temperature and exercise intensity in terms of maximum heart rate. In conclusion, an increase of 35% in Rrs5 after a free running test can be regarded as an abnormal response. Wheezy children show an enhanced airway response, which is clearly distinguishable from the control subjects. IOS is a feasible method to detect EIB in young children. Pediatr Pulmonol. 2008; 43:538–544.

Rifaximin in the treatment of recurrent Clostridium difficile infection

Clostridium difficile can cause severe antibiotic‐associated colitis. Conventional treatments with metronidazole and vancomycin improve symptoms, but after discontinuation of treatment, C. difficile infection (CDI) recurs in a number of patients. Rifaximin is a rifamycin‐based non‐systemic antibiotic that has effect against C. difficile.

Lymphoproliferative disease after allogeneic stem cell transplantation—pre-emptive diagnosis by quantification of Epstein–Barr virus DNA in serum

BACKGROUND Lymphoproliferative disease (PTLD) is a life-threatening complication of organ transplantation. In matched, allogeneic, non-T-cell-depleted stem-cell transplantations (SCT) the disease develops early but has been thought to be rare. OBJECTIVES We determined by strict histopathological criteria the incidence of fatal Epstein-Barr-virus (EBV)-related PTLD in a large number of SCT, and assessed the diagnostic value of a real-time quantitative polymerase chain reaction (qPCR) for EBV-DNA in serum specimens. STUDY DESIGN Of the 257 SCT performed in Helsinki during 1994-1999, 132 (51%) recipients were alive and 125 (49%) had succumbed by June 2001. The necropsies were analyzed for EBV-related PTLD as evidenced by disseminated lymphocytic infiltrates labeled histochemically for antigens and RNA (EBER 1 and 2) detectable by in situ technology. From a subset of the PTLD cases (N=12) and a series of corresponding stem-cell recipient controls (N=36), consecutive samples of serum (N=103 and 364, respectively) were studied by qPCR for EBV-DNA, and the clinical data were reviewed. RESULTS The post-mortem analysis revealed 18 cases of PTLD (14% of the deceased), all of whom had received intensive immunosuppressive treatment including anti-thymocyte globulin for treatment or prophylaxis of graft versus host disease (GVHD). By using qPCR all the PTLD patients became EBV-DNA positive, in progressively rising copy numbers. EBV-DNA was first detectable 70 (median; range 24-154) days after SCT or 23 (4-86) days before death; i.e. earlier than the symptoms which appeared 15 (2-85) days before death. Among the SCT controls, EBV-DNA occurred sporadically (in only 3.9% sera). CONCLUSIONS qPCR for EBV-DNA in serum is a highly sensitive (100%) and specific (96%) diagnostic approach. Intensely immunosuppressed stem-cell recipients are at a great risk of developing PTLD, and should be carefully monitored for EBV-DNA, for pre-emptive treatment of this life-threatening disorder.

Factor H Binding as a Complement Evasion Mechanism for an Anaerobic Pathogen, Fusobacterium necrophorum

Fusobacterium necrophorum subspecies funduliforme is an obligate anaerobic Gram-negative rod causing invasive infections such as the life-threatening Lemierre’s syndrome (sore throat, septicemia, jugular vein thrombosis, and disseminated infection). The aim of our study was to understand if and how F. necrophorum avoids C activation. We studied 12 F. necrophorum subsp. funduliforme strains isolated from patients with sepsis. All strains were resistant to serum killing after a 1-h incubation in 20% serum. The bacteria bound, at different levels, the C inhibitor factor H (fH). Binding was ionic and specific in nature and occurred via sites on both the N terminus and the C terminus of fH. Bound fH remained functionally active as a cofactor for factor I in the cleavage of C3b. Interestingly, patients with the most severe symptoms carried strains with the strongest ability to bind fH. An increased C3b deposition and membrane attack complex formation on the surface of a weakly fH-binding strain was observed and its survival in serum at 3.5 h was impaired. This strain had not caused a typical Lemierre’s syndrome. These data, and the fact that fH-binding correlated with the severity of disease, suggest that the binding of fH contributes to virulence and survival of F. necrophorum subsp. funduliforme in the human host. Our data show, for the first time, that an anaerobic bacterium is able to bind the C inhibitor fH to evade C attack.