Giovanna Fabio

Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers

The objective of this work was to develop and validate a set of clinical criteria for the classification of patients affected by periodic fevers. Patients with inherited periodic fevers (familial Mediterranean fever (FMF); mevalonate kinase deficiency (MKD); tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS); cryopyrin-associated periodic syndromes (CAPS)) enrolled in the Eurofever Registry up until March 2013 were evaluated. Patients with periodic fever, aphthosis, pharyngitis and adenitis (PFAPA) syndrome were used as negative controls. For each genetic disease, patients were considered to be ‘gold standard’ on the basis of the presence of a confirmatory genetic analysis. Clinical criteria were formulated on the basis of univariate and multivariate analysis in an initial group of patients (training set) and validated in an independent set of patients (validation set). A total of 1215 consecutive patients with periodic fevers were identified, and 518 gold standard patients (291 FMF, 74 MKD, 86 TRAPS, 67 CAPS) and 199 patients with PFAPA as disease controls were evaluated. The univariate and multivariate analyses identified a number of clinical variables that correlated independently with each disease, and four provisional classification scores were created. Cut-off values of the classification scores were chosen using receiver operating characteristic curve analysis as those giving the highest sensitivity and specificity. The classification scores were then tested in an independent set of patients (validation set) with an area under the curve of 0.98 for FMF, 0.95 for TRAPS, 0.96 for MKD, and 0.99 for CAPS. In conclusion, evidence-based provisional clinical criteria with high sensitivity and specificity for the clinical classification of patients with inherited periodic fevers have been developed.

HLA-ASSOCIATED SUSCEPTIBILITY TO ACQUIRED IMMUNODEFICIENCY SYNDROME IN ITALIAN PATIENTS WITH HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION

To investigate the contribution of genetic susceptibility to infection with human immunodeficiency virus, 50 subjects with lymphadenopathy syndrome (LAS) and 7 subjects with acquired immunodeficiency syndrome (AIDS) and Kaposis sarcoma were typed for HLA A, B, C, and DR antigens. The frequency of B35 was significantly higher in LAS patients who progressed to AIDS than in those who did not or in healthy controls. The association between DR5 and AIDS/Kaposis sarcoma was also confirmed in these patients.

Results from a multicentre international registry of familial Mediterranean fever: impact of environment on the expression of a monogenic disease in children

Background and aim Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by mutations of the MEFV gene. We analyse the impact of ethnic, environmental and genetic factors on the severity of disease presentation in a large international registry. Methods Demographic, genetic and clinical data from validated paediatric FMF patients enrolled in the Eurofever registry were analysed. Three subgroups were considered: (i) patients living in the eastern Mediterranean countries; (ii) patients with an eastern Mediterranean ancestry living in western Europe; (iii) Caucasian patients living in western European countries. A score for disease severity at presentation was elaborated. Results Since November 2009, 346 FMF paediatric patients were enrolled in the Eurofever registry. The genetic and demographic features (ethnicity, age of onset, age at diagnosis) were similar among eastern Mediterranean patients whether they lived in their countries or western European countries. European patients had a lower frequency of the high penetrance M694V mutation and a significant delay of diagnosis (p<0.002). Patients living in eastern Mediterranean countries had a higher frequency of fever episodes/year and more frequent arthritis, pericarditis, chest pain, abdominal pain and vomiting compared to the other two groups. Multivariate analysis showed that the variables independently associated with severity of disease presentation were country of residence, presence of M694V mutation and positive family history. Conclusions Eastern Mediterranean FMF patients have a milder disease phenotype once they migrate to Europe, reflecting the effect of environment on the expression of a monogenic disease.

HLA-Associated susceptibility to AIDS: HLA B35 is a major risk factor for Italian HIV-infected intravenous drug addicts

Thirty-one AIDS patients were typed for HLA A, B, C, and DR antigens. We confirmed that frequency of B35 is significantly higher in patients than in controls. No significant frequency differences in other HLA antigens were found. The analysis of HLA distribution in AIDS patients by risk categories suggests that B35 is a major risk factor, primarily mainly for patients belonging to the category of intravenous (IV) drug addicts.

Susceptibility to HIV infection and AIDS in Italian haemophiliacs is HLA associated

Summary. We compared the frequencies of HLA antigens in two matched groups of 31 HIV‐seronegative and 31 HIV‐seropositive haemophiliacs, exposed during the years 1981–85 to comparable amounts and batches of presumably infectious clotting factor concentrates. The frequency of A2 was significantly higher in HIV‐seropositive than in seronegative haemophiliacs, with a relative risk (RR) of seroconversion of 3–92, whereas both Bw52 and DR4 were negatively associated with it. We also studied the distribution of HLA antigens in a larger group of 76 HIV‐seropositive haemophiliacs, who were at different clinical stages of HIV infection (CDC classes II‐IV) but were comparable for age and time elapsed since seroconversion. DR3 and DQw2 antigens were, particularly when concomitantly present, associated with a high risk of developing symptomatic HIV infection (RR = 11.79 and 25.33). Our data suggest that the HLA region controls susceptibility to infection with HIV and its progression to symptomatic disease in Italian haemophiliacs.

HLA-associated susceptibility to HIV-1 infection

We studied HLA antigen distribution of 50 heterosexual partners of HIV+ drug abusers with more than I year of sexual exposure to HIV, 36 children born to seropositive mothers and 61 haemophiliac patients exposed to presumably infectious clotting factor concentrates. B52 and B44 antigens were associated with HIV resistance while B51 was associated with HIV susceptibility. Forty‐nine HIV+ drug abusers, spouses of heterosexual partners studied and 25 HIV+ mothers of the children were also typed. DR11 phenotype was associated with infectiousness of HIV+ subjects. Our data suggest that the HLA region controls susceptibility to infection with HIV and infectiousness of HIV+ subjects in different risk groups.

Severity assessment of healthcare-associated pneumonia and pneumonia in immunosuppression

The study compares the ability of the PSI (pneumonia severity index), CURB-65 (confusion, urea >7 mol·L−1, respiratory rate ≥30 breaths·min−1, blood pressure <90 mmHg systolic or ≤60 mmHg diastolic, and age ≥65 yrs), CURB and CRB-65 scales and the Severe Community-Acquired Pneumonia (SCAP) score to predict 30-day mortality in healthcare-associated pneumonia (HCAP) patients, and analyses differences in the demographics, aetiology and outcomes of community-acquired pneumonia (CAP), HCAP and pneumonia in immunocompromised patients. 629 consecutive patients admitted to a tertiary care university hospital were prospectively categorised as having CAP (n=322) or HCAP (n=307), and the HCAP patients were further sub-divided into those who were immunocompromised (n=219) or immunocompetent (n=88). The 30-day mortality rate was 9.0% in the CAP group and 24.1% in the HCAP group. In the HCAP group, the PSI and SCAP scores had similar prognostic power (area under the curve (AUC) of 0.68 and 0.67, respectively) and performed better than the CURB-65 score (AUC ≤0.62). Among the immunocompetent HCAP patients, the PSI and CURB-65 scores were more sensitive than the others at every threshold, whereas SCAP was more specific than both of these. In the immunocompromised group, the PSI was highly sensitive but poorly specific at all thresholds. Our results suggest that prognostic tools should be designed for subsets of HCAP patients.

Immunogenetics of the Lennox-Gastaut syndrome: frequency of HL-A antigens and haplotypes in patients and first-degree relatives.

Twenty‐two patients with the Lennox‐Gastaut syndrome and their families were examined for HL‐A antigens by the micro‐lymphocytotoxicity test. The antigen HL‐A7 belonging to the HL‐A locus showed a significantly increased frequency (p < 0.0005) both in parents and in patients. The same antigen showed a significantly altered segregation in patients but a normal one in healthy siblings. Another antigen of the second HL‐A locus, HL‐A12, did not display a normal segregation in our patients, in whom it was nearly not represented.

Peripheral lymphocytes and intracellular cytokines in C282Y homozygous hemochromatosis patients

BACKGROUND/AIMS Several abnormalities in the immune status of hereditary hemochromatosis patients have been reported. We evaluated the peripheral blood lymphocytes phenotype and cytokine profile of CD8(+) and CD4(+) T cells in C282Y homozygous hereditary hemochromatosis patients compared to control subjects. METHODS Peripheral blood lymphocytes from 17 asymptomatic patients and 14 control subjects were analyzed. We determined the distribution of lymphocyte subsets and investigated at single-cell level by flow-cytometry the potential of cytokines production. The frequency of cytokine (interferon gamma, tumor necrosis factor alpha, interleukin 2 (IL-2), IL-4, IL-5, IL-10 and IL-13) producing cells was assessed in total T-lymphocytes, CD3(+)CD8(+) and CD3(+)CD4(+) subsets. RESULTS The patients studied showed a significant decrease of total lymphocyte count, T CD4(+)CD3(+), CD28(+), CD8(+)CD28(+) lymphocytes and natural killer (NK) CD56(+)CD16(+)CD3(-) cells. The reduction of CD28(+) and CD8(+)CD28(+) lymphocyte count was inversely related to transferrin saturation index. An increase in the ability of T-cells to produce all the cytokines studied and a major increase in IL-4 and IL-10 production in the CD3(+)CD8(+) subset was found. Our results demonstrate that activated Th1 and Th2 lymphocytes coexist in the peripheral blood of hereditary hemochromatosis patients and that T-cytotoxic (Tc) 2 subset is more expanded than in control population. CONCLUSIONS The association of a decreased number of T CD8(+) cytotoxic lymphocytes and NK cells, and the development of Tc2 cells in asymptomatic C282Y homozygous patients represents an imbalance in their immune function that might contribute to the high incidence of hepatocarcinoma.

Dasatinib-related alveolar pneumonia responsive to corticosteroids

Imatinib mesylate (Gleevec), an inhibitor of BCR/ ABL tyrosine kinase, has changed the approach to the treatment of chronic myeloid leukemia (CML). Complete cytogenetic responses have been observed in 75 – 90% of the patients receiving imatinib as firstline therapy [1,2] and in 50 – 60% of those treated after failing on IFN-a [3 – 5]. However, although imatinib is usually well tolerated, there have been reports of adverse reactions such as superficial edema, nausea, diarrhea, muscle cramps and skin rash [3,4] and some patients may develop resistant disease and/or drug intolerance. Dasatinib (BMS 354825) is a new, orally bioavailable ABL kinase inhibitor that is two log more potent than imatinib and active against 14 of the 15 imatinib-resistant BCR-ABL mutants [6] and may, therefore, be a good alternative in imatinib-resistant or intolerant CML patients [7]. We here describe a case of dasatinib-related alveolar pneumonia that resolved after treatment with corticosteroids. A 60-year-old European man with no history of pulmonary disease was diagnosed as having chronic phase Phþ CML with a low Sokal risk score in November 1994. After debulking with hydroxyurea, treatment with high-dose IFN-a and low-dose ARA-C led to a good hematological response, but periodic bone marrow examinations during follow-up did not reveal any signs of a cytogenetic response. The IFN-a therapy was well tolerated except for the onset of iatrogenic transient eczema after *1 year. Given the absence of a cytogenetic response, the patient continued hydroxyurea treatment to maintain hematological remission until January 2002, when imatinib mesylate was started. After 2 years of therapy with imatinib (400 mg per day), he achieved only a minimal cytogenetic response; the dose was increased to 600 mg per day until May 2005, but was then discontinued because of the onset of grade 3 non-hematological toxicity characterized by intense muscle pain. For this reason, together with the appearance of additional cytogenetic anomalies and a punctiform mutation (M351T), the patient consented to start oral dasatinib treatment at a dose of 70 mg b.i.d. on 12 May 2005, when he was taking no other medications. The treatment was well tolerated until day 27, when hyperpyrexia appeared: chest X-rays revealed slight bibasilar pleural effusion without any significant changes in gas exchange or any impairment in the patient’s general clinical condition. Twelve hours after hospitalization, there was a marked and rapid worsening in his clinical picture, with persistent hyperpyrexia (38.58C), acute episodes of bronchospasm responsive to aerosol and intravenous hydrocortisone (200 mg) and impaired gas exchange requiring oxygen treatment (10 L min with a Venturi mask). Furthermore, roundish papules of a probably vasculitic nature, with a reddish center and lighter margins, appeared bilaterally during the following hours at the level of the lower third of the tibia and the heel, more markedly on the left leg. There were also signs of arthritis of the interphalangeal joint of the second finger of the left hand. Additional chest X-rays revealed worsening bilateral pleural effusion. Given this grade 3 pulmonary toxicity, dasatinib was discontinued on 8 June 2005 and the patient