Evangelia Farmaki

Clinical picture and treatment of 2212 patients with common variable immunodeficiency

BACKGROUND Common variable immunodeficiency (CVID) is an antibody deficiency with an equal sex distribution and a high variability in clinical presentation. The main features include respiratory tract infections and their associated complications, enteropathy, autoimmunity, and lymphoproliferative disorders. OBJECTIVE This study analyzes the clinical presentation, association between clinical features, and differences and effects of immunoglobulin treatment in Europe. METHODS Data on 2212 patients with CVID from 28 medical centers contributing to the European Society for Immunodeficiencies Database were analyzed retrospectively. RESULTS Early disease onset (<10 years) was very frequent in our cohort (33.7%), especially in male subjects (39.8%). Male subjects with early-onset CVID were more prone to pneumonia and less prone to other complications suggesting a distinct disease entity. The diagnostic delay of CVID ranges between 4 and 5 years in many countries and is particularly high in subjects with early-onset CVID. Enteropathy, autoimmunity, granulomas, and splenomegaly formed a set of interrelated features, whereas bronchiectasis was not associated with any other clinical feature. Patient survival in this cohort was associated with age at onset and age at diagnosis only. There were different treatment strategies in Europe, with considerable differences in immunoglobulin dosing, ranging from 130 up to 750 mg/kg/mo. Patients with very low trough levels of less than 4 g/L had poor clinical outcomes, whereas higher trough levels were associated with a reduced frequency of serious bacterial infections. CONCLUSION Patients with CVID are being managed differently throughout Europe, affecting various outcome measures. Clinically, CVID is a truly variable antibody deficiency syndrome.

Candida tropicalis in a Neonatal Intensive Care Unit: Epidemiologic and Molecular Analysis of an Outbreak of Infection with an Uncommon Neonatal Pathogen

ABSTRACT From June to July 1998, two episodes of Candida tropicalis fungemia occurred in the Aristotle University neonatal intensive care unit (ICU). To investigate this uncommon event, a prospective study of fungal colonization and infection was conducted. From December 1998 to December 1999, surveillance cultures of the oral cavities and perinea of the 593 of the 781 neonates admitted to the neonatal ICU who were expected to stay for >7 days were performed. Potential environmental reservoirs and possible risk factors for acquisition of C. tropicalis were searched for. Molecular epidemiologic studies by two methods of restriction fragment length polymorphism analysis and two methods of random amplified polymorphic DNA analysis were performed. Seventy-two neonates were colonized by yeasts (12.1%), of which 30 were colonized by Candida albicans, 17 were colonized by C. tropicalis, and 5 were colonized by Candida parapsilosis. From December 1998 to December 1999, 10 cases of fungemia occurred; 6 were due to C. parapsilosis, 2 were due to C. tropicalis, 1 was due to Candida glabrata, and 1 was due to Trichosporon asahii (12.8/1,000 admissions). Fungemia occurred more frequently in colonized than in noncolonized neonates (P < 0.0001). Genetic analysis of 11 colonization isolates and the two late blood isolates of C. tropicalis demonstrated two genotypes. One blood isolate and nine colonization isolates belonged to a single type. The fungemia/colonization ratio of C. parapsilosis (3/5) was greater than that of C. tropicalis (2/17, P = 0.05), other non-C. albicans Candida spp. (1/11, P = 0.02), or C. albicans (0/27, P = 0.05). Extensive environmental cultures revealed no common source of C. tropicalis or C. parapsilosis. There was neither prophylactic use of azoles nor other risk factors found for acquisition of C. tropicalis except for total parenteral nutrition. A substantial risk of colonization by non-C. albicans Candida spp. in the neonatal ICU may lead to a preponderance of C. tropicalis as a significant cause of neonatal fungemia.

Thrombocytopenic purpura after measles-mumps-rubella vaccination: a systematic review of the literature and guidance for management.

OBJECTIVE To determine the incidence of immune thrombocytopenic purpura (ITP) after measles-mumps-rubella (MMR) immunization compared with natural measles and rubella, its clinical course and outcome, and the risk of recurrence after repeat MMR vaccination. STUDY DESIGN We performed a systematic review of the Ovid MEDLINE (1950 to present) bibliographic database. We selected studies that reported cases of thrombocytopenia in a known number of children who were immunized with MMR vaccine before development of ITP. We also extracted data from the same and other studies regarding bleeding manifestations and the resolution of MMR-associated thrombocytopenia or thrombocytopenic purpura within 6 months. Finally, we studied the risk of ITP recurrence after MMR immunization or reimmunization. RESULTS On the basis of 12 studies, the incidence of MMR-associated ITP ranged from 0.087 to 4 (median 2.6) cases per 100,000 vaccine doses. Severe bleeding manifestations were rare, and MMR-associated thrombocytopenia resolved within 6 months from diagnosis in 93% of the children. MMR vaccination of unimmunized patients with ITP and revaccination of patients with prior ITP did not lead to recurrence of thrombocytopenia. CONCLUSIONS MMR-associated ITP is rare, self-limited, and non-life threatening, and susceptible children with ITP should be immunized with MMR at the recommended ages.

The effect of anti-TNF treatment on the immunogenicity and safety of the 7-valent conjugate pneumococcal vaccine in children with juvenile idiopathic arthritis.

Our aim was to study the effect of anti-TNF treatment on immunogenicity and safety of the 7-valent conjugate pneumococcal vaccine in children with juvenile idiopathic arthritis. Thirty-one children (mean age:12.9+/-4.6 years) treated with anti-TNFs plus Disease Modifying Anti-Rheumatic Drugs (DMARDs) and 32 age-matched children treated only with DMARDs were vaccinated with two doses of PCV7. After the first vaccine dose geometric mean titers (GMTs) were significantly increased for all vaccine serotypes (p<0.0001) in both groups and were found to be protective (>0.35microg/ml) in 87-100% of all children, depending on the serotype. Children receiving anti-TNFs achieved a significantly lower GMTs against serotypes 4, 14 and 23F (p<0.05). A >or=4-fold increase of the baseline titers to >or=5 vaccine serotypes was observed in 50% and 75% of the anti-TNF and control patients, respectively (p=0.0697). No patient developed vaccine-associated serious adverse events or disease flares.

Filamentous Fungi in a Tertiary Care Hospital: Environmental Surveillance and Susceptibility to Antifungal Drugs

OBJECTIVE To evaluate filamentous fungi with respect to environmental load and potential drug resistance in a tertiary care teaching hospital. DESIGN Monthly survey in 2 buildings of the hospital during a 12-month period. SETTING Hippokration Hospital in Thessaloniki, Greece. METHODS Air, surface, and tap water sampling was performed in 4 departments with high-risk patients. As sampling sites, the solid-organ transplantation department and the hematology department (in the older building) and the pediatric oncology department and the pediatric intensive care unit (in the newer building) were selected. RESULTS From January to May of 2000, the fungal load in air (FLA) was low, ranging from 0 to 12 colony-forming units (cfu) per m(3) in both buildings. During the summer months, when high temperature and humidity predominate, the FLA increased to 4-56 cfu/m(3). The fungi commonly recovered from culture of air specimens were Aspergillus niger (25.9%), Aspergillus flavus (17.7%), and Aspergillus fumigatus (12.4%). Non-Aspergillus filamentous fungi, such as Zygomycetes and Dematiaceous species, were also recovered. The pediatric intensive care unit had the lowest mean FLA (7.7 cfu/m(3)), compared with the pediatric oncology department (8.7 cfu/m(3)), the solid-organ transplantation department (16.1 cfu/m(3)), and the hematology department (22.6 cfu/m(3)). Environmental surfaces were swabbed, and 62.7% of the swab samples cultured yielded filamentous fungi similar to the fungi recovered from air but with low numbers of colony-forming units. Despite vigorous sampling, culture of tap water yielded no fungi. The increase in FLA observed during the summer coincided with renovation in the building that housed the solid-organ transplantation and hematology departments. All 54 Aspergillus air isolates randomly selected exhibited relatively low minimum inhibitory or effective concentrations for amphotericin B, itraconazole, voriconazole, posaconazole, micafungin, and anidulafungin. CONCLUSION Air and surface fungal loads may vary in different departments of the same hospital, especially during months when the temperature and humidity are high. Environmental Aspergillus isolates are characterized by lack of resistance to clinically important antifungal agents.

Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation

Background: X‐linked hyper‐IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients. Objectives: We sought to collect data on the clinical presentation, treatment, and follow‐up of a large sample of patients with XHIGM to (1) compare long‐term overall survival and general well‐being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT. Methods: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan‐Meier method compared with log‐rank tests and modeled by using proportional hazards regression. Results: Twenty‐eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow‐up and vital status information. Sixty‐seven (38%) patients received HCT. The average follow‐up time was 8.5 ± 7.2 years (range, 0.1‐36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987‐1995; the hazard ratio was significantly less than 1 for diagnosis years 1995‐1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2‐10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft‐versus‐host disease, and most deaths occurred within 1 year of transplantation. Conclusion: No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964‐2013). However, survivors treated with HCT experienced somewhat greater well‐being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates.

Comparative study of dual energy X‐ray absorptiometry and quantitative ultrasonography with the use of biochemical markers of bone turnover in boys with haemophilia

Summary.  Our aim was to evaluate bone status in boys with haemophilia using dual energy X‐ray absorptiometry (DXA) and quantitative ultraSonography (QUS), and in addition, to compare these two methods with the use of biochemical markers of bone turnover. Twenty‐six boys with a mean decimal age of 12.08 ± 4.44 years were included in the study which included a DXA scan at lumbar spine and radial, as well as tibial QUS. Serum levels of soluble receptor activator of nuclear factor κB ligand (sRANK‐L), osteoprotegerin (OPG) and osteocalcin (OC) were measured and joint evaluation was performed using the Hemophilia Joint Health Score (HJHS). With regard to the study results, only 2 of 26 patients (7.7%) had bone mineral density (BMD) Z‐scores <−2, and 4 patients (15.4%) had BMD Z‐scores between −1 and −2. Only one patient had radial and other two had tibial QUS Z‐scores <−2. No agreement was recorded between QUS and DXA in identifying patients at risk for osteoporosis (k = 0.275, P = 0.063). Haemophiliacs had significantly higher serum levels of sRANK‐L (21.04 ± 4.78 vs. 18.58 ± 2.28 ng mL−1, P = 0.038) and of OC (5.35 ± 2.29 vs. 3.09 ± 0.61 ng mL−1, P = 0.002) and significantly decreased levels of OPG (15.78 ± 2.53 vs. 23.79 ± 4.39 pg mL−1, P < 0.001) compared with controls. QUS Z‐scores at tibia significantly correlated with HJH Scores (r = −0.450, P = 0.040), whereas lumbar BMD Z‐scores significantly correlated with body mass index Z‐scores (r = 0.500, P = 0.009). More studies are warranted to identify the most accurate densitometric method for assessing bone status in haemophiliacs.

Cytokines in immunodeficient patients with invasive fungal infections: an emerging therapy

Immune response is the major contributor to host defense against opportunistic fungal infections such as candidiasis, aspergillosis and other rare infections. A number of cytokines have been developed and studied in vitro for activity against fungal pathogens. The most studied among them in relation to fungal infections are granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF) and interferon-gamma (IFN-gamma). The fields where these cytokines have been predominantly studied or where they may need more study are primary immunodeficiencies of the phagocytic cells, neonatal age, human immunodeficiency virus infection and cancer-related conditions such as neutropenia and hemopoietic cell transplantation. In this review, the in vitro, experimental animal and clinical data of cytokines are summarized in relation to invasive candidiasis, aspergillosis and emerging fungal infections. Cytokine administration to patients together with antifungal agents, as well as transfusion of cytokine-upgraded phagocytes, are promising immunotherapeutic modalities for further research.

Gemella morbillorum endocarditis in a child.

Gemella morbillorum, formerly called Streptococcus morbillorum, is a catalase-negative, facultatively anaerobic Gram-positive coccus. It was transferred from the genus S. morbillorum in 1988 on the basis of DNA hybridization, physiologic properties and 16S ribosomal RNA gene sequence analysis. It is part of the commensal flora of the gastrointestinal and genitourinary tracts in humans and is a potential pathogen. Infections caused by this organism are uncommon. In adults endocarditis is the most frequent infection reported to be caused by G. morbillorum. Bacteremia and localized infections such as meningitis, 3 arthritis, 5 sinusitis and intracranial and other abscesses 7 also have been reported. Septic shock caused by this organism has been usually observed in immunocompromised patients. We describe a case of endocarditis caused by G. morbillorum in a child. We also review G. morbillorum infections in children.

Cerebral aspergillosis in an infant with corticosteroid-resistant nephrotic syndrome

Abstract.Cerebral aspergillosis is a devastating disease in patients with a compromised immune system. A unique case of a male infant with corticosteroid-resistant nephrotic syndrome complicated by pulmonary and cerebral aspergillosis is described. The patient rapidly developed coma and neurological symptoms and died soon thereafter. Central nervous system aspergillosis was diagnosed radiologically and by detection of Aspergillus DNA and antigen (galactomannan) in blood and cerebrospinal fluid. Moderate immunosuppressive therapy and antifungal phagocytic dysfunction due to nephrotic syndrome per se may have contributed to the occurrence of invasive aspergillosis in our patient. Awareness of this serious complication and early application of diagnostic procedures and antifungal therapy may improve the dismal outcome.