Varied spectrum of clinical presentation and mortality in a prospective registry of visceral leishmaniasis in a low endemicity area of Northern Italy.

BACKGROUND: Visceral Leishmaniasis (VL) is endemic in 88 countries, in areas of relatively low incidence with a relevant proportion of immune suppressed patients clinical presentation, diagnosis and management may present difficulties and pitfalls. METHODS: Demographic data, clinical, laboratory features and therapeutic findings were recorded in patients identified by a regional VL disease registry from January 2007 to December 2010. RESULTS: A total of 55 patients (36 adults mean age 48.7 years, 19 children median age 37.5 months) were observed presenting with 65 episodes. All childen were immunocompetent, whereas adults affected by VL included both immunocompetent (n°17) and immunesuppressed (n°19) patients. The clinical presentation was homogeneous in children with predominance of fever and hepato-splenomegaly. A wider spectrum of clinical presentations was observed in immunocompromised adults. Bone marrow detection of intracellular parasites (Giemsa staining) and serology (IFAT) were the most frequently used diagnostic tools. In addition, detection of urinary antigen was used in adult patients with good specificity (90%). Liposomal amphotericin B was the most frequently prescribed first line drug (98.2% of cases) with 100% clinical cure. VL relapses (n°10) represented a crucial finding: they occurred only in adult patients, mainly in immunocompromised patients (40% of HIV, 22% of non-HIV immunocompromised patients, 5,9% of immunocompetent patients). Furthermore, three deaths with VL were reported, all occurring in relapsing immunocompromised patients accounting for a still high overall mortality in this group (15.8%). CONCLUSIONS: The wide spectrum of clinical presentation in immunesuppresed patients and high recurrence rates still represent a clinical challenge accounting for high mortality. Early clinical identification and satisfactory treatment performance with liposomal amphotericin B are confirmed in areas with low-level endemicity and good clinical standards. VL needs continuing attention in endemic areas where increasing numbers of immunocompromised patients at risk are dwelling.

Clinical and socioeconomic impact of different types and subtypes of seasonal influenza viruses in children during influenza seasons 2007/2008 and 2008/2009.

BACKGROUND: There are few and debated data regarding possible differences in the clinical presentations of influenza A/H1N1, A/H3N2 and B viruses in children. This study evaluates the clinical presentation and socio-economic impact of laboratory-confirmed influenza A/H1N1, A/H3N2 or B infection in children attending an Emergency Room because of influenza-like illness. METHODS: Among the 4,726 children involved, 662 had influenza A (143 A/H1N1 and 519 A/H3N2) and 239 influenza B infection detected by means of real-time polymerase chain reaction. Upon enrollment, systematic recordings were made of the patients' demographic characteristics and medical history using standardised written questionnaires. The medical history of the children was re-evaluated 5-7 days after enrollment and until the resolution of their illness by means of interviews and a clinical examination by trained investigators using standardised questionnaires. During this evaluation, information was also obtained regarding illnesses and related morbidity among households. RESULTS: Children infected with influenza A/H1N1 were significantly younger (mean age, 2.3 yrs) than children infected with influenza A/H3N2 (mean age, 4.7 yrs; p < 0.05)) or with influenza B (mean age, 5.2 yrs; p < 0.05). Adjusted for age and sex, children with influenza A/H3N2 in comparison with those infected by either A/H1N1 or with B influenza virus were more frequently affected by fever (p < 0.05) and lower respiratory tract involvement (p < 0.05), showed a worse clinical outcome (p < 0.05), required greater drug use (p < 0.05), and suffered a worse socio-economic impact (p < 0.05). Adjusted for age and sex, children with influenza B in comparison with those infected by A/H1N1 influenza virus had significantly higher hospitalization rates (p < 0.05), the households with a disease similar to that of the infected child (p < 0.05) and the need for additional household medical visits (p < 0.05). CONCLUSIONS: Disease due to influenza A/H3N2 viral subtype is significantly more severe than that due to influenza A/H1N1 subtype and influenza B virus, which indicates that the characteristics of the different viral types and subtypes should be adequately considered by health authorities when planning preventive and therapeutic measures.

Management of chronic hepatitis C in childhood: the impact of therapy in the clinical practice during the first 2 decades.

BACKGROUND AND AIM: Treatment of chronic hepatitis C in children is controversial and its role in the clinical practice is unknown. We retrospectively investigated the impact of treatment in a large cohort of children with chronic hepatitis C over the past 20 years. METHODS: 376 hepatitis C virus RNA positive children were recruited consecutively in five Italian centres since 1990 and followed for 1-17 years. RESULTS: 86 (23%) subjects were treated: 73 with recombinant interferon alone and 13 with pegylated-interferon and ribavirin. Sustained clearance of hepatitis C virus RNA was observed in 25% of the former, in 92% of the latter and in 9% of untreated cases (p < 0.001). Loss of viraemia was recorded in all children with genotype 2-3 and in 6 of 7 with hepatitis C virus genotype 1 treated with combination therapy. At last evaluation 45% of patients were young adults and 15% had cleared viraemia. Overall, 152 (40%) were putative candidates to therapy. CONCLUSIONS: Few Italian children with chronic hepatitis C have been treated in the past 20 years. The poor propensity to spontaneous clearance of viraemia and the efficacy of combination therapy should encourage to consider treatment in attempt to shorten the duration of viral replication.

Clinical importance and impact on the households of oseltamivir-resistant seasonal A/H1N1 influenza virus in healthy children in Italy.

A resistance of A/H1N1 influenza viruses to oseltamivir has recently emerged in a number of countries. However, the clinical and socioeconomic importance of this resistance has not been precisely defined. As children have the highest incidence of influenza infection and are at high risk of severe disease, the aim of this study was to evaluate the clinical importance and the impact on the households of oseltamivir-resistant seasonal A/H1N1 influenza virus in an otherwise healthy pediatric population. A total of 4,726 healthy children younger than 15 years with influenza-like illness were tested for influenza viruses by real-time polymerase chain reaction in the winters of 2007-2008 and 2008-2009 in Italy. The influenza A virus-positive samples underwent neuraminidase gene analysis using pyrosequencing to identify mutations H275Y and N294 S in A/H1N1, and E119V, R292K, and N294 S in A/H3N2. Among the A/H1N1 subtypes, the H275Y mutation was found in 2/126 samples taken in 2007-2008 (1.6%) and in all 17 samples (100%; p < 0.0001) taken in 2008-2009. No other mutation was identified in any of the A/H1N1 or A/H3N2 influenza viruses. No significant differences were found in terms of clinical importance or impact on the households between the children with oseltamivir-resistant seasonal A/H1N1 influenza virus and those with the wild-type. The spread of H275Y-mutated A/H1N1 seasonal influenza virus is a common phenomenon and the clinical importance and impact on the households of the mutated virus is similar to that of the wild-type in an otherwise healthy pediatric population.

Treatment of viral hepatitis B in children.

IMPORTANCE OF THE FIELD: Treatment of chronic hepatitis B (CHB) in children is aimed at reducing viral replication and at minimizing liver injury and related consequences in children with chronic active viral liver infection. AREAS COVERED IN THIS REVIEW: In this review, treatment options available for both adults and children are summarized, together with suggestions from our own experience. The most relevant works published between 1982 and 2009 on PubMed/Medline database search were used. WHAT THE READER WILL GAIN: At present, standardized treatment is available in only a few therapeutic options, such as IFN-alpha and lamivudine; it is hoped that these will be complemented in the future by new, encouraging drugs still under study in pediatric age patients. Moreover, current treatment approaches have their limitations: although IFN-alpha has been shown to be effective in patients with non-vertically-transmitted infection, HBeAg clearance while on treatment is similar to spontaneous seroconversion after long-term follow-up. IFN-alpha-induced side effects are frequent rarely severe in children. Lamivudine achieves similar results in children with active viral replication. However, despite good compliance to oral administration, this treatment can lead to the development of drug-resistant mutations. TAKE HOME MESSAGE: In conclusion, the decision to treat CHB in children demands that the possibility of favorable spontaneous viral clearance has been considered and must be made on the bases of the extent of liver damage.

Natural course of HCV infection in childhood cancer survivors.

GOALS OF WORK: To describe the course of hepatitis C in a cohort of 105 survivors after childhood cancer. PATIENTS AND METHODS: Data on chemo/radiotherapy, clinical status, serial alanine aminotransferase (ALT) evaluation, and virological parameters after the end of treatment were collected for each patient. Liver biopsies, when performed, were centrally evaluated by a pathologist. MAIN RESULTS: All patients were alive at the end of follow-up and did not show hepatic insufficiency. ALT evaluation along the entire follow-up showed a moderate (87%) or a remarkable (13%) cytolytic pattern. Young age at diagnosis, hematopoietic stem cell transplantation, and duration of infection significantly correlate with a worse hepatic activity. Type of tumor and chemo and/or radiotherapy regimens did not influence the pattern of hepatic cytolysis. Liver biopsy, centrally reviewed in 30% of the cohort, showed one case of cirrhosis and mild fibrosis in 71% of the group. Higher degrees of fibrosis did not seem to be related to any exposition to chemo/radiotherapy but correlated significantly with the more remarkable cytolytic course. CONCLUSIONS: The outcome of hepatitis C in our patients is comparable to the one described in European cohorts of adult cancer survivors and perinatally infected subjects. Nevertheless, progression to high degrees of hepatic damage has to be monitored by a careful follow-up.

Universal childhood immunisation against Streptococcus pneumoniae: the five-year experience of Liguria Region, Italy.

Liguria was the first Italian Administrative Region, since 2003, to actively recommend free-of-charge immunisation, of all infants, with heptavalent Pneumococcal Conjugate Vaccine (PCV-7), within a research pilot-project. Vaccination coverage among infants rapidly increased from 42.8% in 2003 to 83.3% in 2004, progressively reaching levels of 93.4% in 2007. Two scientific projects have been carried out, aimed: (i) to assess the immunogenicity of PCV-7 and of a hexavalent vaccine Diphtheria-Tetanus-Trivalent Acellular Pertussis-Hepatitis B-Inactivated Polio Virus-Haemophilus influenzae type B (DTaP-HBV-IPV-Hib) when co-administered to healthy infants at 3, 5 and 11-12 months of age (routine schedule), and (ii) to evaluate the effect of the immunisation campaign in preventing pneumococcal-associated hospitalisations. Results in 151 infants showed the high immunogenicity of the vaccines, seroprotection rates, measured 1 month after the third dose, ranging between 97.3% (serotype 6 B) and 100% (serotypes 4 and 9 V) for PCV-7 and between 99.3% and 100% against common antigens of hexavalent vaccine. Monitoring nearly 70,000 children, aged 0-24 months, during the period 2000-2007, and comparing hospitalisation rates occurred in subjects belonging to birth cohorts before and after the introduction of widespread immunisation, a significant decline for all-cause and pneumococcal pneumonia and for acute otitis media was observed, with preventive fractions of 15.2%, 70.5% and 36.4%, respectively.

Etanercept as a salvage treatment for refractory aplastic anemia.

About 10-15% of patients with acquired aplastic anemia (AAA) have resistant/recurrent disease not eligible for standard treatment like hematopoietic stem cell transplantation and/or combined immunosuppression. We report a 17-year-old male with an 11 years history of AAA who, after two courses of immunosuppression, was red cell transfusion-dependent, severely thrombocytopenic, refractory to platelet transfusion, had iron overload and post-transfusion HCV infection. This patient achieved transfusion independence from platelets and normalized Hb after treatment with the anti-TNF agent Etanercept. Over a 12 months follow-up he experienced only transient increase of liver transaminases.

Epidemiology and clinical features of Mycoplasma pneumoniae infection in children.

Mycoplasma pneumoniae (MP) is, considered to affect rarely children less than 5 yrs of age. This study was performed to describe the epidemiology and the clinical features of MP lower respiratory tract infection (LRTI) in children, presenting to a tertiary children hospital. Eleven month-longitudinal study of LRTI due to MP, diagnosed by polymerase chain reaction (PCR) on throat swab specimen, was performed. Out of 866 children with LRTI admitted to the Gaslini Pediatric Institute in Genoa, 102 had a positive PCR for MP. We found 39 preschool-aged children, 42 school-aged children and 21 young adolescent [6.20 (3.81) yrs old]. Interestingly, eight MP+ infants had <8 months of age. The commonest presentations were cough and/or fever (76.5%). Tachypnoea, upper respiratory tract involvement, diarrhoea and vomiting were more common in the <5 yr Gr as compared to the other groups. Chest X-ray was found abnormal in 76 children: consolidations were the commonest finding. Laboratory test showed that the preschool-aged children had a higher number of lymphocytes (p<0.0001) and monocytes (p=0.009). Thrombocytosis was found in 35.7% of children and was more frequent in the preschool-aged children (p=0.013). MP infection is common in preschool-aged children, including young infants, and may have different clinical presentation, as compared to older children.

Long-term course of chronic hepatitis C in children: from viral clearance to end-stage liver disease.

BACKGROUND & AIMS: The natural course of chronic hepatitis C (CHC) in children is not well understood. The aim of this study was to assess the long-term course of CHC in a large sample of otherwise healthy children. METHODS: From 1990 to 2005, 504 consecutive antihepatitis C virus (HCV)-positive children were enrolled at 12 centers of a national observatory and were followed up retrospectively/prospectively. RESULTS: Putative exposure was perinatal in 283 (56.2%) cases, parenteral in 158 (31.3%), and unknown in 63 (12.5%). At baseline, 477 (94.6%) cases were HCV RNA seropositive, 118 (24.7%) of which were treated with standard interferon alpha. Ten years after putative exposure, the outcome in 359 HCV RNA-positive, untreated patients was (1) undetectable viremia in 27 (7.5%) (by Cox regression analysis, spontaneous viral clearance was independently predicted by genotype 3 [hazard ratio 6.44; 95% confidence interval: 2.7-15.5]) and (2) persistent viremia in 332 (92%) cases. Six of these 332 cases (1.8%) progressed to decompensated cirrhosis (mean age, 9.6 years). This latter group included 5 Italian children perinatally infected with genotype 1a (4 of the mothers were drug users). Thirty-three (27.9%) treated patients achieved a sustained virologic response. CONCLUSIONS: Over the course of a decade, few children with chronic HCV infection cleared viremia spontaneously, and those who did were more likely to have genotype 3. Persistent viral replication led to end-stage liver disease in a small subgroup characterized by perinatal exposure, maternal drug use, and infection with HCV genotype 1a. Children with such features should be considered for early treatment.

Twenty-four novel mutations in Wilson disease patients of predominantly Italian origin.

Herein we report the results of mutation analysis of the ATP7B gene in a group of 134 Wilson disease (WD) families (268 chromosomes) prevalently of Italian origin. Using the SSCP and sequencing methods we identified 71 disease-causing mutations. Twenty-four were novel, while 19 more mutations already described, were identified in new populations in this study. A known mutation G591D showed a regional distribution, since it was only detected in 38.5% of the analyzed chromosomes in WD patients originating from Apulia, a region of South Italy. Detection of new mutations in the ATP7B gene increases our capability of molecular analysis that is essential for early diagnosis and treatment of WD.

Epidemiological profile of 806 Italian children with hepatitis C virus infection over a 15-year period.

BACKGROUND/AIMS: To evaluate the epidemiological profile of Italian children with hepatitis C virus (HCV) infection over a 15-year period. METHODS: Fifteen tertiary care centers, belonging to a national Observatory established in 1998, retrospectively/prospectively recruited 806 consecutive HCV-infected, otherwise healthy, children seen from 1990 to 2004. RESULTS: Seven hundred and sixty four were Italian and 42 from foreign countries. Newly-diagnosed cases declined from 332 in 1995-1999 to 196 in 2000-2004, while the proportion of foreign children rose from 3% to 13%. Transfusion-transmitted infection disappeared after 1992. Maternal infection (with drug abuse in 63% of cases in the North) has become the most important mode of HCV diffusion throughout Italy and the exclusive source for all children infected in 2000-2004. The prevalence of HCV genotypes 3 and 4 increased and that of genotype 1b decreased significantly (p<0.02). Male/female ratio was significantly (p<0.001) lower among vertically infected (0.6) than in transfused children (1.3). CONCLUSIONS: The number of children with newly-diagnosed HCV infection is declining in Italy and most post-transfusion cases are now young adults. Thus foreign children could significantly contribute to the reservoir of pediatric infection in years to come. New infections result from maternal transmission and seem to privilege females and genotypes 3 and 4.

The canine copper toxicosis gene MURR1 is not implicated in the pathogenesis of Wilson disease.

BACKGROUND: It has recently been demonstrated that the Wilson disease (WD) protein directly interacts with the human homolog of the MURR1 protein in vitro and in vivo, and that this interaction is specific for the copper transporter. The aim of the present study was to clarify the role of MURR1 in the pathogenesis of WD as well as in other WD-like disorders of hepatic copper metabolism of unknown origin. METHODS: Using the single-strand conformation polymorphism (SSCP) method followed by sequencing, we analyzed the 5' untranslated region (UTR) and three exons of the MURR1 gene in three groups of patients: 19 WD: patients in whom no mutations were detected in the ATP7B gene, 53 WD: patients in whom only one mutation in the ATP7B gene was found, and 34 patients in whom clinical and laboratory data suggested a WD-like disorder of hepatic copper metabolism of unknown origin. RESULTS: We detected in these patients six rare nucleotide substitutions, namely one splice-site consensus sequence and one missense and four silent nucleotide substitutions. All substitutions except one were found in the heterozygous state. No difference in the frequencies of the various substitutions was observed between patients and controls. CONCLUSIONS: These data suggest that the MURR1 gene and its protein product are unlikely to play a primary role in the pathogenesis of Wilson disease. More extensive studies with larger numbers of clinically homogeneous patients should be carried out to establish whether nucleotide alterations in the MURR1 gene may have a role in causing WD or WD-like disorders or act as modifying factors in the phenotype variability in WD.

Cerebrovascular disease and varicella in children.

Varicella-associated stroke has been reported with increasing frequency in recent years. In many cases, diagnosis is difficult because of the late onset of manifestations after the acute infectious episode. Four cases of cerebrovascular disease after varicella infection were observed. Three children presented hemiparesis and one facial paresis. The neuroradiological findings comprised stenosis/occlusion of middle cerebral artery or nucleo capsular signal alteration. Because, several pathogenetic mechanisms have been proposed as the cause of stroke, the relationship between prothrombotic conditions, antipospholipid antibodies and stroke in these patients is discussed. The difficulty in defining the pathogenesis of the ischemic episode is related to problems in the choice of antithrombotic treatment, which is still not standardized and must be decided on individual basis. In the event of rapid onset of stroke after exanthem high dose antiviral therapy seems to be justified. On the basis of our experience and of literature data on varicella-associated stroke, we recommend that VZV infection be taken into account in every episode of stroke in children.

HCV infection in very-long-term survivors after cancer chemotherapy and bone marrow transplantation: a single-center experience.

The long-term evolution of hepatitis C virus (HCV) infection in oncologic and/or transplanted patients is still unknown. Patients treated for cancer are different from the general HCV-infected population because of the immunosuppression and the hepatotoxic treatments, which act as co-factors of liver damage. Recently it was observed that antimetabolites play a role in accelerating the process of hepatic fibrosis. The aims of this retrospective study were to describe the clinical course of chronic hepatitis C acquired during anticancer treatment in a group of patients referred to a single center, and to correlate the course of hepatic disease to the type of treatment they received. Among the 17 children who underwent very long follow-up (range 10-18.5 years), the authors identified a group with more active hepatic cytolysis through the serial observation of mean ALT values, HCV RNA determination, and histologic data when available. During follow-up, none of them developed hepatic failure, cirrhosis, or hepatocarcinoma. No single risk factor, such as exposure to antimetabolites, alkylating agents, or other chemotherapy, radiotherapy to the abdomen, exposure to other hepatotoxic drugs, appearance of vaso-occlusive disease, acute and/or chronic graft-versus-host disease, or length of immunosuppression, correlated with a worse course of hepatitis. No definitive conclusions can be drawn. However, multivariate analysis of hepatic risk factors in larger cohorts of patients will be able to provide us with more precise information about the clinical outcome of chronic hepatitis in survivors.

MVK mutations and associated clinical features in Italian patients affected with autoinflammatory disorders and recurrent fever.

Autosomal recessive autoinflammatory disorder caused by mutations of the mevalonate kinase gene (MVK), leading to mild, incomplete MK enzyme deficiency (MKD), has been known so far as Hyper-IgD and periodic fever syndrome (HIDS) and regarded as mostly occurring in Northern Europe. Here we report the results of the molecular characterization of the first Italian series of patients affected with autoinflammatory disorders and periodic fever. A total of 13 different mutations, scattered throughout the MVK coding region, were identified in either homozygous or compound heterozygous state in 15 patients. The mutation leading to the V377I amino-acid change, already described also in other series, resulted the most common with a frequency of 50% of all MKD alleles. Among the other mutations, eight had never been described before, including an interstitial deletion of 19 nucleotides in exon 2. In addition to these nucleotide changes, private and polymorphic MVK variants have been detected in the patients under analysis and checked also in a set of control individuals. Clinical features are reported for each of the 15 MKD patients, and life-threatening infections and systemic amyloidosis presented as unexpected MKD-related complications. Our study demonstrates that MKD is a common cause of recurrent fever also in the Italian population, where it is associated with both a wide spectrum of previously unreported MVK mutations and peculiar phenotypic features.