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Background The coronavirus disease 2019 (COVID-19) can result in severe pneumonia, leading to acute respiratory distress syndrome, which are treated using continuous positive airway pressure (CPAP). Patients must be evaluated quickly to commence early CPAP if required. Aim To identify patients with COVID-19 in the emergency department (ED) who require early CPAP, using vital signs measurements during triage. Method This was a retrospective, observational, single-centre cohort study of patients with COVID-19 admitted to the ED of a university hospital in Lombardy, Italy, between 21 February 2020 and 30 April 2020. These patients were divided into two groups: those who required CPAP and those did not require CPAP. Recordings of their vital signs were retrieved from triage medical records. The vital signs values recorded in the two groups on their arrival at the ED were compared. Results Of 601 patients, 120 (20%) required CPAP. It was identified that the typical characteristics of patients requiring early CPAP were: male (P=.013) with a median age of 68 years (P=.000), oxygen saturation of 92% (P=.000), temperature ≥38°C (P=.008), respiratory rate of 26 breaths per minute (P=.000) and had received pre-hospital oxygen therapy before arriving at the ED (P=.000). The CPAP group was divided into two subgroups: patients who had received pre-hospital oxygen therapy and those who had not. The median respiratory rate values between the two subgroups presented a statistically significant difference (P=.004). Conclusion This study identified the characteristics of a typical patient with COVID-19 who requires early CPAP. Based on the results, the authors have devised a triage flow chart that uses selected vital signs measurements (oxygen saturation, respiratory rate and receipt of pre-hospital oxygen therapy) to identify patients requiring early CPAP. This flow chart should be trialled in a prospective study before it is used to inform clinical decision-making.

Human monkeypox (MPX) is a neglected zoonotic disease caused by the MPX virus a double-stranded DNA virus which belongs to the Poxviridae family genus Orthopoxvirus. It is endemic in the rural rainforests of Central and Western Africa where it is responsible of human sporadic cases and outbreaks since 1970. Outside Africa MPXV caused an outbreak in 2003 in the United States linked to importation of infected rodents from Ghana and a few travel-related cases in the USA, United Kingdom, Israel and Singapore. Actually, a worldwide outbreak with more than 1200 confirmed cases mainly concentrated among men who have sex with men is ongoing.We present the case of an Italian man living in Portugal that was diagnosed with MPX at our clinic in Milan, Italy. Monkeypox virus infection was confirmed by a specific homemade Real-Time PCR. Samples obtained from different sites (pharynx, skin lesions, anal ulcer, seminal fluid) turned all positive with different viral load.Our report illustrates the challenge of a disease that seems to present in a different way from classic description with possible human-to-human transmission through sexual contact.

In Italy, SARS-CoV-2 vaccination campaign prioritized healthcare workers (HCWs) to receive two doses of BNT162b2 vaccine, irrespective of a previous SARS-CoV-2 infection. In this real-life study, we compared the humoral response to BNT162b2 vaccine in HCWs with and without a previous SARS-CoV-2 infection. Of the 407 HCWs enrolled, 334 (82.1%) were SARS-CoV-2-naive and 73 (17.9%) SARS-CoV-2-experienced. Post-vaccine humoral response was detectable in more than 98% of HCWs. Overall, the median level of anti-S IgG in SARS-COV-2-experienced HCWs was twice as high as those of SARS-CoV-2-naive subjects (24641.0 AU/mL [IQR: 15273.0-40000.0] versus 13053.8 [IQR: 7303.3-20105.8]

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by SARS-CoV-2 primarily affecting the respiratory system which can damage vessels walls virtually in any body district. Changes affecting retinal vessels are a good marker for systemic vascular alterations. This study investigated retinal vessels during the acute phase of COVID-19 and after patients recovery. Fifty-nine eyes from 32 COVID-19 patients and 80 eyes from 53 unexposed subjects were included. Mean arteries diameter (MAD) and mean veins diameter (MVD) were assessed through semi-automatic analysis on fundus color photos at baseline and 6 months later in patients and subjects unexposed to the virus. At baseline MAD and MVD were significantly higher in COVID-19 patients compared to unexposed subjects (p

Objectives: The recent introduction of direct-acting antiviral agents (DAAs) which can eliminate Hepatitis C virus (HCV) had revolutionized the treatment of HCV infections also in a complex clinical setting such as the patients with rheumatoid arthritis (RA). HCV elimination is also opportune due to the availability of more efficient immunosuppressive drugs, whose effect on the course of HCV infection is largely unknown. Methods: Consensus process was endorsed by the Italian Society of Rheumatology (SIR) and the Italian Society of Infectious and Tropical Diseases (SIMIT) to review the available evidence and produce practical, hospital-wide recommendations. The consensus panel consisted of 18 infectious diseases consultants, 20 rheumatologists and one clinical epidemiologist, who used the criteria of the Oxford Centre for Evidence-based Medicine to assess the quality of the evidence and the strength of their recommendations. Results: A core-set of statements about management of patients with RA and infection by HCV have been developed to help clinicians in their clinical practice. Conclusions: A screening for HCV should be performed in all RA patients and it is mandatory before starting an immunosuppressive therapy. Finally, a DAA treatment should be considered in all HCV-infected patients.Significance and Innovations HCV antibodies should be investigated at the time of diagnosis of RA and, in any case, before starting immunosuppressive therapy with disease-modifying antirheumatic drugs (DMARDs). HCV eradication with DAA should be attempted as soon as possible, depending on patient conditions allowing a continuous oral treatment lasting 8–12 weeks Conventional and biological DMARDs are allowed in patients with HCV infection, but they should be used cautiously in presence of advanced liver disease.

Background Hypoalbuminemia is frequently observed in patients with SARS‐CoV‐2 infection although its underlying mechanism and relationship with the clinical outcome still need to be clarified. Methods We retrospectively evaluated in patients with COVID‐19 hospitalised at the Fatebenefratelli‐Sacco Hospital in Milan, the prevalence of hypoalbuminemia, its association with the severity of COVID‐19, with the levels of C‐reactive protein, d‐dimer and interleukin‐6 and with clinical outcome over a follow‐up period of 30 days. Urinalysis was evaluated in a subgroup of patients. Results Serum albumin levels

BackgroundItaly was the first European country hit by the COVID-19 pandemic and has the highest number of recorded COVID-19 deaths in Europe.MethodsThis prospective cohort study of the correlates of the risk of death in COVID-19 patients was conducted at the Infectious Diseases and Intensive Care units of Luigi Sacco Hospital, Milan, Italy. The clinical characteristics of all the COVID-19 patients hospitalised in the early days of the epidemic (21 February -19 March 2020) were recorded upon admission, and the time-dependent probability of death was evaluated using the Kaplan-Meier method (censored as of 20 April 2020). Cox proportional hazard models were used to assess the factors independently associated with the risk of death.ResultsForty-eight (20.6%) of the 233 patients followed up for a median of 40 days (interquartile range 33-47) died during the follow-up. Most were males (69.1%) and their median age was 61 years (IQR 50-72). The time-dependent probability of death was 19.7% (95% CI 14.6-24.9%) 30 days after hospital admission. Age (adjusted hazard ratio [aHR] 2.08, 95% CI 1.48-2.92 per ten years more) and obesity (aHR 3.04, 95% CI 1.42-6.49) were independently associated with an increased risk of death, which was also associated with critical disease (aHR 8.26, 95% CI 1.41-48.29), C-reactive protein levels (aHR 1.17, 95% CI 1.02-1.35 per 50 mg/L more) and creatinine kinase levels above 185 U/L (aHR 2.58, 95% CI 1.37-4.87) upon admission.ConclusionsCase-fatality rate of patients hospitalized with COVID-19 in the early days of the Italian epidemic was about 20%. Our study adds evidence to the notion that older age, obesity and more advanced illness are factors associated to an increased risk of death among patients hospitalized with COVID-19.

Graphical abstract, Highlights • During COVID-19 pandemic cancer patients are a vulnerable category. • Few data about control infection strategy to ensure a COVID-19 free Oncology ward. • The essence of our protocol: triage, risk zones, traffic control and surveillance. • This strategy could be a practical contribution to control nosocomial COVID-19., The Coronavirus Disease-2019 (COVID-19) pandemic is spreading in Italy and Lombardy is one of the most affected region. Cancer patients are higher risk of complication from COVID-19 complications; therefore they should be protected from contagion while still ensuring access to cancer care. The aim of this article is to suggest a strategy to reorganize hospital spaces and Healthcare Professionals (HCPs) staff in order to avoid COVID-19 nosocomial infection in an Oncology ward. SARS-CoV-2 is primarily transmitted through respiratory droplets and by contact. We speculated that precautions against droplet and contact transmission should be the proper way to preserve ward from COVID-19. The essence of our protocol involves: triage outside of the ward, identification of risk zones, traffic control, surveillance of all the involved subjects. Whoever attends the ward must follow the general risk prevention and mitigation measures. The application of this practical strategy can contribute to breaking the cycle of community-hospital-community transmission.

Graphical abstract Figure 4 modified: A curves showing survival of participants with severe COVID-19 pneumonia treated with tocilizumab: B. Kaplan-meier survival curves in patients with severe COVID-19 stratified according to ventilation ststus at baseline. B. Incidence of bloodstream infections over the study period.Image, graphical abstract, Background Tocilizumab, a humanized monoclonal antibody, targets IL-6 receptors blocking downstream pro-inflammatory effects of IL-6. In preliminary reports it was suggested to be beneficial in patients with severe COVID-19. Methods In this open-label prospective study we describe clinical characteristics and outcome of 51 patients hospitalized with confirmed and severe COVID-19 pneumonia treated with tocilizumab intravenously. All patients had elevated IL-6 plasma level (>40 pg/mL) and oxygen saturation

Graphical abstract, SARS-CoV-2 is causing an increasing number of deaths worldwide because no effective treatment is currently available. Remdesivir has shown in vitro activity against coronaviruses and is a possible antiviral treatment for SARS-CoV-2 infection. This prospective (compassionate), open-label study of remdesivir, which was conducted at Luigi Sacco Hospital, Milan, Italy, between February 23 and March 20, 2020, involved patients with SARS-CoV-2 pneumonia aged ≥18 years undergoing mechanical ventilation or with an oxygen saturation level of ≤94% in air or a National Early Warning Score 2 of ≥4. The primary outcome was the change in clinical status based on a 7-category ordinal scale (1 = not hospitalised, resuming normal daily activities; 7 = deceased). The 35 patients enrolled from February 23 to March 20, 2020, included 18 in intensive care unit (ICU), and 17 in our infectious diseases ward (IDW). The 10-day course of remdesivir was completed by 22 patients (63%) and discontinued by 13, of whom eight (22.8%) discontinued because of adverse events. The median follow-up was 39 days (IQR 25-44). At day 28, 14 (82.3%) patients from IDW were discharged, two were still hospitalized and one died (5.9%), whereas in ICU 6 (33.3%) were discharged, 8 (44.4%) patients died, three (16.7%) were still mechanically ventilated and one (5.6%) was improved but still hospitalized. Hypertransaminasemia and acute kidney injury were the most frequent severe adverse events observed (42.8% and 22.8% of the cases, respectively). Our data suggest that remdesivir can benefit patients with SARS-CoV-2 pneumonia hospitalised outside ICU where clinical outcome was better and adverse events are less frequently observed. Ongoing randomised controlled trials will clarify its real efficacy and safety, who to treat, and when.

This report describes the isolation, molecular characterization, and phylogenetic analysis of the first three complete genomes of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) isolated from three patients involved in the first outbreak of COVID‐19 in Lombardy, Italy. Early molecular epidemiological tracing suggests that SARS‐CoV‐2 was present in Italy weeks before the first reported cases of infection.

This report describes the isolation, the molecular characterization and the phylogenetic analysis of the first three complete genomes of SARS-CoV-2 isolated from three patients involved in the first outbreak of COVID-19 in Lombardy, Italy. Early molecular epidemiological tracing suggests that SARS-CoV-2 was present in Italy weeks before the first reported cases of infection.

Background: Coronavirus disease 2019 (COVID-19) has been associated to microvascular alterations. We screened the fundus of patients with COVID-19 to detect alterations of the retina and its vasculature and to assess possible correlations with clinical parameters. Methods: Cross-sectional study. The presence of retinal alterations in patients with COVID-19 and subjects unexposed to the virus was assessed using fundus photographs and their prevalence was compared. Mean arteries diameter (MAD) and mean veins diameter (MVD) were compared between patients and unexposed subjects with multiple linear regression including age, sex, ethnicity, body mass index, smoking/alcohol consumption, hypertension, hyperlipidaemia, diabetes as covariates. The influence of clinical/lab parameters on retinal findings was tested in COVID-19 patients. Findings: 54 patients and 133 unexposed subjects were enrolled. Retinal findings in COVID-19 included: haemorrhages (9·25%), cotton wools spots (7·4%), dilated veins (27·7%), tortuous vessels (12·9%). Both MAD and MVD were higher in COVID-19 patients compared to unexposed subjects (98·3 ± 15·3 µm vs 91·9 ± 11·7 µm, p = 0.006 and 138·5 ± 21·5 µm vs 123·2 ± 13·0 µm, p

The risk of infection associated with immunomodulatory or immunosuppressive disease-modifying drugs (DMDs) in patients with multiple sclerosis (MS) has been increasingly addressed in recent scientific literature. A modified Delphi consensus process was conducted to develop clinically relevant, evidence-based recommendations to assist physicians with decision-making in relation to the risks of a wide range of infections associated with different DMDs in patients with MS. The current consensus statements, developed by a panel of experts (neurologists, infectious disease specialists, a gynaecologist and a neuroradiologist), address the risk of iatrogenic infections (opportunistic infections, including herpes and cryptococcal infections, candidiasis and listeria; progressive multifocal leukoencephalopathy; human papillomavirus and urinary tract infections; respiratory tract infections and tuberculosis; hepatitis and gastrointestinal infections) in patients with MS treated with different DMDs, as well as prevention strategies and surveillance strategies for the early identification of infections. In the discussion, more recent data emerged in the literature were taken into consideration. Recommended risk reduction and management strategies for infections include screening at diagnosis and before starting a new DMD, prophylaxis where appropriate, monitoring and early diagnosis.

Background Plasmodium malariae is the most neglected of the six human malaria species and it is still unknown which is the mechanism underlying the long latency of this Plasmodium. Case presentation A case of PCR-confirmed P. malariae recurrence in a 52-year old Italian man was observed 5 months after a primary attack. In the interval between the two observed episodes of malaria the patient denied any further stay in endemic areas except for a visit to Libya, a country considered malaria-free. Genomic DNA of the P. malariae strain using five microsatellites (PM2, PM9, PM11, PM25, PM34) and the antigen marker of circumsporozoite (csp) was amplified and sequenced. Analysis of polymorphisms of the P. malariae csp central repeat region showed differences between the strains responsible of the first and second episode of malaria. A difference in the allele size was also observed for the sequence analysis of PM2 microsatellites. Conclusions Plasmodium malariae is a challenging human malaria parasite and even with the use of molecular techniques the pathogenesis of recurrent episodes cannot be precisely explained. Electronic supplementary material The online version of this article (10.1186/s12936-019-2806-y) contains supplementary material, which is available to authorized users.

Resume L’infection par le virus de l’hepatite B (VHB), est largement repandue dans le monde et frequemment retrouvee chez les patients souffrant de polyarthrite rhumatoide (PR). La Societe italienne de rhumatologie (SIR) et la Societe italienne des maladies infectieuses et tropicales (SIMIT) ont approuve un processus de consensus national visant a passer en revue les donnees probantes disponibles sur la prise en charge du VHB chez les patients atteints de PR et a formuler des recommandations pratiques destinees a l’ensemble des hopitaux. Le groupe de consensus etait compose de specialistes des maladies infectieuses, de rhumatologues et d’epidemiologistes et s’appuyait sur les criteres du Centre for Evidence-Based Medicine (medecine fondee sur les preuves) d’Oxford pour evaluer la qualite des donnees probantes et la validite des recommandations edictees. Un ensemble d’enonces ont ete developpes pour aider les medecins dans la prise en charge des patients atteints de PR et souffrant d’une infection au VHB. La vaccination et la prophylaxie des patients PR traites par biotherapies ont egalement ete examinees. L’infection par le VHB n’est pas rare en pratique clinique ; le depistage du VHB chez tous les patients souffrant d’arthrite precoce n’est toutefois pas universellement reconnu alors qu’il est considere comme obligatoire avant l’introduction de tout traitement immunosuppresseur ou hepatotoxique. En fait, il existe un risque specifique associe a l’utilisation des biotherapies chez les patients ayant une infection par le VHB et ce malgre les conclusions generalement rassurantes des etudes longitudinales sur la reactivation virale. Les patients atteints de PR et infectes par le VHB doivent etre orientes vers un hepatologue et correctement identifies comme porteurs actifs ou inactifs. Chez les porteurs actifs du VHB, un traitement antiviral doit etre instaure avant l’introduction des immunosuppresseurs. Les porteurs occultes du VHB doivent faire l’objet d’une surveillance appropriee ou recevoir une prophylaxie en raison du risque de reactivation associe au traitement administre.

Objectives Hepatitis B (HBV) infection, which is prevalent worldwide, is also frequently seen in patients with rheumatoid arthritis (RA). The Italian Society of Rheumatology (SIR) and the Italian Society of Infectious and Tropical Diseases (SIMIT) endorsed a national consensus process to review the available evidence on HBV management in RA patients and to produce practical, hospital-wide recommendations. Methods The consensus panel consisted of infectious disease consultants, rheumatologists and epidemiologists and used the criteria of the Oxford Center for Evidence-based Medicine to assess the quality of the evidence and the strength of their recommendations. Results A core-set of statements has been developed to help clinicians in the management of patients with RA and HBV infection. Vaccination and prophylaxis of RA patients treated with biological drugs have been also discussed. Conclusions HBV infection is not rare in clinical practice; a screening for HBV in all patients with early arthritis is not universally accepted, while it is considered mandatory before starting any immunosuppressive or hepatotoxic treatment. In fact, a specific risk, associated with the use of biologic treatments, exists for patients with HBV infection, although longitudinal studies of viral reactivation are generally reassuring. RA patients with HBV infection should be referred to the hepatologist and correctly classified into active or inactive carriers. Patients with active hepatitis B should undergo antiviral treatment before starting immunosuppressive treatments. Occult HBV carriers should be monitored or receive prophylaxis on the basis of the risk of reactivation associated with the administered treatment.

Summary Objectives To describe the pathogenesis, clinical presentation, cerebrospinal fluid findings and outcome of Aspergillus meningitis, meningoencephalitis and arachnoiditis. Methods A case of Aspergillus meningitis is described. A comprehensive review of the English-language literature was conducted to identify all reported cases of Aspergillus meningitis described between January 1973 and December 2011. Results Ninety-three cases (including the one described herein) of Aspergillus meningitis were identified. Fifty-two (55.9%) were in individuals without any predisposing factor or known causes of immunosuppression. Acute and chronic meningitis was diagnosed in 65.6% of patients and meningoencephalitis in 24.7% of them with the remaining presenting with spinal arachnoiditis and ventriculitis. Cerebrospinal fluid cultures for Aspergillus spp. were positive in about 31% of cases and the galactomannan antigen test in 87%. Diagnosis during life was achieved in 52 patients (55.9%) with a case fatality rate of 50%. The overall case fatality rate was 72.1%. Conclusions Aspergillus meningitis may occur in both immunocompetent and immunocompromised patients and run an acute or chronic course. The findings of this systematic review extend the information on this life-threatening infection and could assist physicians in achieving an improved outcome.

OBJECTIVE: Analysis of functionally defined T-cell differentiation in HIV-infected patients with low CD4(+) on virologically suppressive HAART is crucial to design clinically efficacious treatments. METHODS: We cross-sectionally investigated the maturation (CD45RA/CCR7, CD7) and function [antigen-specific enzyme-linked immunosorbent spot assay (ELISPOT), interleukin-2 (IL-2)/interferon-gamma-producing cells] of CD4(+) and CD8(+) T cells in 34 HIV-infected immunological nonresponders (INRs): CD4(+) cell count less than or equal to 200 cells/microl, HIV-RNA 50 copies/ml or less, as compared to 20 full responders (CD4(+) > 500 cells/microl, HIV-RNA < 50 copies/ml). RESULTS: We describe skewed T-cell maturation in INRs with outgrowth of effector memory CD45RA(-)CCR7(-) CD4(+)/CD8(+) and Th2-committed CD7(-)CD4(+), and reduced unprimed-naive T cells (P = 0.001). Functionally, INRs display reduced Gag-specific ELISPOT (P = 0.04) and IL-2-secreting CD8(+) (P = 0.08) while showing CMV-specific responses comparable to full responders. CONCLUSION: CD4 lymphopenia on HAART results in skewed, senescent T-cell maturation profile, inefficient T-helper function and poor HIV-specific CD8(+) response. This delineates a functional/phenotypic T-cell pattern that correlates to unfavourable clinical outcome.

OBJECTIVES Tumor necrosis factor (TNF)-alpha is elevated in chronic heart failure (CHF). The cause of this increase is not well known. Several hypotheses have been investigated. Previous experimental and clinical studies detected changes in TNF circulating levels related to arterial oxygen (O2) saturation. The aim of the present study was to evaluate whether standard O2 hospital therapy affects plasma concentration of TNF-alpha in stable CHF patients. METHODS A total of 18 patients (New York Heart Association class II and III) were enrolled and randomly assigned to two different orders of treatment: nine patients underwent a first night of O2 applied by nasal prongs and a second night of air delivered by nasal prongs, whereas the other nine patients were assigned to the contrary order of treatments (i.e. first night with air and second night with O2) in a crossover design. RESULTS Ten patients out of 18 had O2 saturation above 95% for at least 360 min. In these ten patients, the TNF-alpha plasma level increased after O2 compared to the basal condition (delta 5.47 +/- 1.72 pg/ml; P < 0.05) whereas, in the same patients, the TNF-alpha plasma level did not change after the night with air (delta -0.05 +/- 3.03 pg/ml). A linear positive correlation (r = 0.62, P < 0.01) between minutes of O2 saturation above 95% and TNF-alpha circulating differences from basal to post-O2 therapy was found. CONCLUSIONS Effective nocturnal hospital O2 therapy affects TNF-alpha plasma levels and the increase of TNF-alpha appears to be linearly related to the time of blood O2 saturation above 95%.

Post-kala-azar dermal leishmaniasis (PKDL) is a complication of visceral leishmaniasis (VL) observed mainly in Sudan and India where it follows treated VL in 50% and 10% of cases, respectively. We report a 46-year-old patient with acquired immune deficiency syndrome who, 7 months after diagnosis of VL, developed PKDL and uveal leishmaniasis following HAART-induced immune recovery. In southern Europe PKDL seems to be an emerging clinical presentation among human immunodeficiency virus (HIV)-infected patients experiencing HAART-induced immune recovery after a previous diagnosis of VL. The best treatment among HIV-infected patients remains to be determined.

Recent reports document resolution of human parvovirus B19-related pure red blood cell aplasia (PB19-PRCA) in HIV-infected patients upon commencement of highly active antiretroviral therapy (HAART). This article describes a patient with PB19-PRCA who, despite fully suppressive HAART, required cyclic administration of intravenous human immunoglobulin over a period of 17 months before PB19 seroconversion and subsequent resolution of relapsing severe anemia. All reports in the English literature describing PB19-related hematologic abnormalities in the post-HAART era are also described herein.

In 2 patients infected with human immunodeficiency virus (HIV), highly active antiretroviral therapy was unable to suppress HIV replication as a result of the emergence of drug-resistant HIV variants. Human cytomegalovirus (HCMV) retinitis developed in both patients, and an unusually complex mixture of drug-resistant HCMV variants was detected in both patients.

Purpose To describe a case of optic nerve head tubercular granuloma, unresponsive to conventional therapy (antitubercular drugs and systemic steroids), successfully treated with anti–vascular endothelial growth factor (VEGF) intravitreal injections in addition to systemic drugs. Methods Case report. Results A 44-year-old patient was referred to our clinic for progressive vision decrease in his left eye during the preceding 4 months. A large granuloma infiltrating optic nerve head was visible at funduscopic examination along with diffuse intraocular inflammation. Workup for granulomatous uveitis supported the diagnosis of presumed intraocular tuberculosis. However, the large granulomatous lesion did not show a good response to conventional therapy for tubercular uveitis (antitubercular drugs and systemic steroids). Anti-VEGF (bevacizumab) intravitreal injections were performed as an adjunct to the ongoing therapy. After 2 injections, the patient showed an almost complete regression of the lesion (demonstrated by optical coherence tomography) and a restoration of vision. Conclusions Anti-VEGF intravitreal injections should be considered in the treatment of large tubercular granulomatous lesions in addition to conventional systemic therapy. Optical coherence tomography could be a suitable tool for studying and following optic nerve head granulomas.

The cancer chemopreventive synthetic retinoid N-(4-hydroxyphenyl)retinamide (HPR) possesses antiproliferative and apoptotic activity at pharmacological doses. In this study we show that addition of antioxidants to HL-60 cells cultured in the presence of 3 microM HPR, markedly suppresses the apoptopic effect of the retinoid and significantly prolongs cell survival (48-96 h). We also show, by the use of the oxidation-sensitive probe 2',7'-dichlorofluorescin diacetate (DCF-DA) and in combination with flow cytometric and spectrofluorimetric analysis, that treatment of cells with 3 microM HPR results in an immediate and sustained production of intracellular free radicals, most likely hydroperoxides. Interestingly, the formation of these HPR-induced free radicals is effectively blocked by the water soluble antioxidants L-ascorbic acid and N-acetyl-L-cysteine. Neither 3-15 microM N-(4-methoxyphenyl) retinamide (MPR), the structurally similar but biologically inert analog of HPR, nor 3 microM doses of the retinoids all-trans retinoic acid, 9-cis-retinoic acid, TTNPB and SR11237 induce intracellular free radicals, thus indicating that the specificity of this phenomenon is restricted to HPR. Altogether, we provide the first direct evidence that HPR stimulates the generation of intracellular free radicals, which appear to have a causative role in the induction of apoptosis in vitro. Our findings raise the possibility that the therapeutic efficacy of HPR may, at least in part, depend on these apoptosis-inducing oxidative phenomena.

We studied the prevalence of anti-HTLV-I/II antibodies in 22 patients with AIDS-related non-Hodgkin lymphoma (NHL), 453 HIV-1-infected patients without lymphoma (194 of whom were diagnosed as having AIDS), and 6 HIV-1-positive and 75 HIV-1-negative patients with Hodgkin lymphoma. The frequency of serological reactivity against HTLV antigens was significantly higher in the AIDS patients with lymphoma than in those without (8 of 22, 36.4% vs. 20 of 194, 10.3%-p = 0.0027). One of the HIV-1-positive and none of the HIV-1-negative patients with Hodgkin lymphoma showed anti-HTLV-I/II reactivity. Four of the eight seropositive NHL patients showed antibodies directed against HTLV-II recombinant antigens when tested for serological discrimination in a Western blot assay. A PCR study of PBMCs from the only patient with NHL still alive at the time of the study showed HTLV-II-specific sequences in the genomic DNA. These data suggest that HTLV-II or a closely homologous retrovirus infects a high proportion of patients with AIDS-associated NHL.

Background The bone marrow (BM) cytokine milieu might substantially affect T-lymphocyte homeostasis in HIV-positive individuals. Interleukin-7 (IL-7) is a bone marrow-derived cytokine regulating T-cell homeostasis through a CD4+-driven feedback loop. CD4+ T-lymphopenia is associated with increased free IL-7 levels and reduced IL-7R expression/function, which are only partially reverted by highly active antiretroviral therapy (HAART). We investigated the BM production, peripheral expression and signaling (pStat5+ and Bcl-2+ CD4+/CD8+ T cells) of IL-7/IL-7Rα in 30 HAART-treated HIV-positive patients who did not experience CD4+ recovery (CD4+ ≤200/µl) and who had different levels of HIV viremia; these patients included 18 immunological nonresponders (INRs; HIV-RNA≤50), 12 complete failures (CFs; HIV-RNA>1000), and 23 HIV-seronegative subjects. Methods We studied plasma IL-7 levels, IL-7Rα+CD4+/CD8+ T-cell proportions, IL-7Rα mRNA expression in PBMCs, spontaneous IL-7 production by BM mononuclear cells (BMMCs), and IL-7 mRNA/IL-7Rα mRNA in BMMC-derived stromal cells (SCs). We also studied T-cell responsiveness to IL-7 by measuring the proportions of pStat5+ and Bcl-2+ CD4+/CD8+ T cells. Results Compared to HIV-seronegative controls, CFs and INRs presented elevated plasma IL-7 levels and lower IL-7Rα CD4+/CD8+ cell-surface expression and peripheral blood production, confirming the most relevant IL-7/IL-7R disruption. Interestingly, BM investigation revealed a trend of higher spontaneous IL-7 production in INRs (p = .09 vs. CFs) with a nonsignificant trend toward higher IL-7-Rα mRNA levels in BMMC-derived stromal cells. However, upon IL-7 stimulation, the proportion of pStat5+CD4+ T cells did not increase in INRs despite higher constitutive levels (p = .06); INRs also displayed lower Bcl-2+CD8+ T-cell proportions than controls (p = .04). Conclusions Despite severe CD4+ T-lymphopenia and a disrupted IL-7/IL-7R profile in the periphery, INRs display elevated BM IL-7/IL-7Rα expression but impaired T-cell responsiveness to IL-7, suggesting the activity of a central compensatory pathway targeted to replenish the CD4+ compartment, which is nevertheless inappropriate to compensate the dysfunctional signaling through IL-7 receptor.

Summary. Fluvastatin showed anti-hepatitis C virus (HCV) activity in vitro, through the inhibition of geranylgeranylation of cellular proteins, and a synergistic effect with interferon (IFN)-α. Nevertheless statins up-regulate low-density lipoprotein (LDL) receptor, required for HCV cell entry, and the closely related scavenger receptors SRBI and CD36; moreover they reduce class II major histocompatibility complex expression on antigen presenting cell, modulating T-cell activation. In vivo LDL levels have been identified as prognostic indicator of sustained viral response to IFN in patients with HCV infection, suggesting that lipid-lowering agents might conversely favour HCV entry into the hepatocytes and translate into higher viral replication. We evaluated the effect of fluvastatin on HCV-RNA levels, CD36 expression and T-cell homeostasis in HCV-RNA positive patients. HCV-RNA was measured at baseline and after 4 weeks in 42 HCV/HIV-1 co-infected patients, randomized to receive either fluvastatin 80 mg qd or no treatment. CD36 expression and markers of T-cell activation were evaluated by means of flow cytometry. Plasma interleukin (IL)-10, IFN-γ and IL-7 were measured by ELISA. Serum cholesterol and LDL decreased significantly in the treatment group (P = 0.0001 and 0.01, respectively). Surprisingly a significant increase of HCV-RNA levels was seen after 4 weeks of fluvastatin (P = 0.03). The percentages of naive/activated/apoptotic cells and CD36 expression remained unchanged. Fluvastatin did not inhibit HCV-RNA replication in vivo; conversely we observed a significant increase of HCV-RNA levels. CD36 expression on monocytes were not up-regulated by statins as previously reported in vitro. The correlation between HCV infectivity, oxidized-LDL receptor and statins in HCV infection need further evaluation.

A 41-year-old heterosexual man with a recently diagnosed HIV infection was admitted to our department complaining of a 5-month history of malaise, non-productive cough and a weight loss of 8 kg. He was a non-intravenous drug user. On physical examination he had a generalised maculopapular rash which was more …

Human parvovirus 4 (PARV4) is a recently discovered member of the Parvoviridae. We investigated the presence of this virus in bone-marrow aspirates of 35 Italian patients with AIDS. Viral DNA was detected by polymerase chain reaction in over 40% of patients (16/35). The infection was most prevalent in injection drug users (IDU; 12/18; 66.7%) as opposed to non-IDU (4/17; 23.5%). PARV4 infection is widespread in Italian patients with AIDS.

SummaryCD81 is a member of the tetraspan superfamily and plays a role in immune responses and in hepatitis C virus (HCV) pathogenesis. We analysed CD81 cell surface and mRNA expression in different lymphocytic subpopulations in human immunodeficiency virus (HIV)-1, HCV and dually infected subjects. CD81 cell surface expression was evaluated with fluorescence activated cell sorter (FACS) analysis; mRNA quantification was performed with semiquantitative polymerase chain reaction (PCR). CD81 cell surface expression on CD4+ T lymphocytes was significantly different by analysis of variance (anova) test (P

Background The availability of several therapeutic regimens has transformed HIV infection from a life-threatening disease into a chronic condition. Older patients (>50 years old) with HIV infection constitute a new treatment challenge in terms of the cumulative effects of ageing and antiretroviral therapy (ART). Methods The immunovirological effects and metabolic interactions of 48 weeks of ART in older patients followed up in three Infectious Diseases Units in Milan, Italy since 1994 were compared with those in younger controls aged 25–35 years. Results The 159 older patients and 118 controls enrolled in the study were comparable for HIV stage, baseline CD4 cell count and viral load but differed for mode of HIV transmission, comorbid conditions and related chronic treatments. Mean viral load decreased after 48 weeks of treatment by 2.6 log10 HIV RNA copies/mL and CD4 count increased by 137.5 cells/μL in older patients, and similar values for immunovirological effects were obtained in the young controls. The relative risk (RR) of an abnormal test in older patients was 7.33 [95% confidence interval (CI) 4.36–12.36] for glucose, 1.73 (95% CI 1.45–2.07) for total cholesterol, 1.56 (95% CI 1.22–2.0) for high-density lipoprotein cholesterol, 1.26 (95% CI 1.02–1.56) for triglycerides, 6.48 (95% CI 4.36–9.66) for serum creatinine, and 0.45 (95% CI 0.35–0.58) for ALT. Moderate/severe liver and renal toxicities were recorded in the older patients but not in the controls. The tolerability of ART did not differ between the older patients and the controls. Thirty-nine new cardiovascular, endocrine-metabolic and neuralgic disorders (24.52 per 100 person-years) were diagnosed in the older patients and four (3.39 per 100 person-years) in the controls (P

Inadequate CD4 cell count recovery despite full HIV RNA control occurs in 30% of HAART-treated HIV-infected patients. A better understanding of the relationship between T-cell dynamics and the HIV intracellular reservoir in HIV-infected patients failing to recover CD4 cell count following long-term HAART, is required.In a cross-sectional study T-cell turnover and homeostatic parameters featuring discordant responses were investigated in 27 immunologic non-responders (INR; CD4 count,or = 200 cells/microl; HIV RNA,or = 50 copies/ml), 15 virological non-responders (VNR; CD4 count,or = 350 cells/microl; HIV RNA,or = 10 000) and 22 full responders (FR; CD4 count,or = 500 cells/microl; HIV RNA,or = 50 copies/ml).INR displayed significantly higher activated CD38CD8 than FR (P0.05) and was comparable to VNR (P0.05). As compared with VNR and FR, INR displayed the highest level of proliferating Ki67CD4 and apoptotic CD4 cells (P0.05). VNR presented lower proliferation and apoptosis than FR and INR. INR displayed the lowest levels of naive T cells (P0.05) and a predominant memory pattern. Despite the memory/activated/apoptotic phenotype, INR showed a statistically non-significant reduction in T-cell receptor excision circles (TREC) compared to FR (P0.05), and substantially heightened interleukin (IL)-7 (P0.05), while VNR showed higher naive T-cell counts and TREC. Moreover, the reservoir of infected CD4 cells was increased in INR, with a trend toward highest intracellular HIV DNA within total, naive and memory CD4 cells.The lack of CD4 cell count recovery in INR seems to reflect a highly activated apoptotic T-cell compartment, with elevated IL-7 and thymic impairment. High levels of intracellular HIV-DNA in INR could be strictly involved in the lack of T-cell reconstitution. Immune correlates of an ultimate direction of the response to HAART, could be exploited in clinical practice for the most effective management of discordant patients, to amend immune imbalances and to improve clinical outcome.

Metabolic alterations and abnormalities of fat distribution are common findings in antiretroviral-treated HIV-1-infected patients. CD36 is a multifunctional receptor with a wide tissue distribution that plays a crucial role in the cellular uptake and metabolism of lipids.To define the level of CD36 expression on circulating monocytes from HIV-1-infected patients and healthy controls (HCs) and to correlate CD36 expression levels with metabolic and immunovirologic parameters.CD36 expression on peripheral blood monocytes was measured by means of flow cytometry in 165 HIV-1-infected patients and in 35 HCs. Statistical analysis was performed by means of univariate and multivariate analysis of variance models.CD36 expression was significantly higher in HIV-1-infected patients compared with HCs (P0.0001). HIV-1 infection was the only variable associated with CD36 expression on multivariate analysis, whereas no correlation was found between CD36 level and age, sex, body mass index, lipid serum levels, HIV RNA levels, time on antiretroviral therapy, or kind of antiretroviral regimen.HIV-1 infection is associated with increased expression of CD36 on circulating monocytes, and antiretroviral drugs play only a minor role in the complex homeostasis of this receptor. Given its role in the cellular uptake and accumulation of lipids, CD36 increased levels on monocytes could represent a proatherogenic condition in HIV-infected patients.

Emerging evidence indicates that CD4 and CD8 T cell recovery is differentially regulated during HIV infection. The hallmark of interleukin-2 (IL-2)-induced immune reconstitution is the selective outgrowth of CD4 through undefined mechanisms.To delineate the effect of IL-2 on T cell homeostasis by analysing the differential impact of IL-2 immunotherapy on CD4 and CD8 dynamics.A randomized trial of 15 HIV-positive patients, eight receiving IL-2 immunotherapy with highly active antiretroviral therapy (HAART) and seven with HAART alone. Patients were followed for a 48-week period following three IL-2 cycles (overall, 10 weeks in duration).CD4 and CD8 count, naive and memory immunophenotype, proliferation by Ki67, and CD8+CD38+ activated pattern were measured longitudinally by flow cytometry. Thymic output contribution to both CD4 and CD8 was evaluated by measurement of T cell receptor excision circles (TREC). Wilcoxon test was used to compare results.Compared with changes seen with HAART alone, IL-2 induced a more significant rise in CD4 than CD8 T cell count (P0.01), associated with a significant increase in Ki67-proliferating CD4 (P0.05), whereas no changes were seen in CD8+Ki67+ (P0.05). Furthermore, IL-2 administration was associated with CD4 TREC increase, whereas CD8 TREC remained stable (P0.05). Modifications in CD4 and CD8 T cells seen in patients taking only HAART were not associated with changes in CD4 and CD8 TREC.By showing a differential impact on CD4 and CD8 homeostasis, the study suggests that IL-2-associated immune reconstitution results from protean interactions between T cell compartments; this has significant implications for the correct planning of immunotherapeutic strategies.

Presented here are the results of a cohort study conducted on 3,483 consecutive HIV/AIDS patients between January 1993 and December 2000 to determine trends in AIDS incidence and presentation. The incidence of AIDS was calculated in the general population and examined further according to gender, age (or = or49 years), and heterosexual behaviour as a risk factor for HIV. Multivariate analysis was used to identify variables associated with AIDS presenters (defined as patients diagnosed with AIDS within 1 month of the first HIV-positive test). The numbers of patients with AIDS classified as (i) AIDS presenters, (ii) known HIV-positive patients on antiretroviral treatment, and (iii) known HIV-positive patients not receiving antiretroviral treatment were calculated. The overall incidence of AIDS decreased over time, mainly due to the lower number of patients on antiretroviral treatment developing AIDS. Factors associated with a higher risk of being an AIDS presenter were male gender and year of HIV diagnosis. Among patients with AIDS, the proportion of AIDS presenters increased from 13.8% prior to 1997 (when protease inhibitors were introduced in Italy) to 32.5% after 1997. Variables predictive of being an AIDS presenter were male gender, age at diagnosis, and AIDS diagnosis in the years 1997-2000. Heterosexuals had a higher risk of being AIDS presenters and a lower risk of being HIV-positive and not receiving antiretroviral treatment than intravenous drug users. In Italy, AIDS occurs mainly in subjects unaware of their HIV status (especially males, the elderly, and those infected heterosexually) or in patients refusing antiretroviral therapy (mainly intravenous drug users who do not refer to specialised centres).

n p 12 n p 10 IL-2-related serious adverse events and no significant differences in plasma human immu- nodeficiency virus (HIV) RNA level were observed in the 2 groups. A higher incidence of HIV-related clinical events was observed among patients receiving HAART alone (3/10) than among subjects receiving HAART plus IL-2 (0/12). Significant increases in CD4 + , naive, and CD4 + CD7 + cells and plasma levels of IL-7 were observed in patients receiving IL-2 versus patients receiving HAART alone. A significant increase in cell turnover did not lead to a decrease in the frequency of T cell receptor excision circles, which remained stable. Rather, increased numbers of T cell receptor excision circles per microliter of blood were observed (not statistically significant). Thus, adjuvant IL-2 therapy in immunologic nonresponders resulted in a clinical benefit, suggesting that the quantitative cell recovery involves functionally competent immune cells. Although highly active antiretroviral therapy (HAART) can provide sustained control of human immunodeficiency virus (HIV) replication, it allows for only a partial immune reconsti- tution (1-3). Moreover, up to 27% of HIV-positive patients un- dergoing HAART fail to restore the circulating CD4 T cell compartment, despite good control of HIV plasma viremia ("im- munologic nonresponders" (INRs)) (4-7). Even if several varia- bles have been identified that correlate with the degree of CD4 T cell restoration during HAART (6, 8-10), the actual underlying factors responsible for the inappropriate immune recovery ob- served in INRs have not been completely understood thus far.

Kaposi sarcoma–associated herpesvirus (KSHV)–related multicentric Castleman disease (MCD) is potentially lethal. Growing evidence indicates that, as in Epstein-Barr virus–driven lymphoproliferative disorders after transplantation, KSHV DNA burden in peripheral blood mononuclear cells (PBMCs) may represent the most accurate marker of disease activity. This report describes a patient with human immunodeficiency virus who was followed up clinically and by quantitative polymerase chain reaction for KSHV DNA sequences in PBMCs for more than 3 years following the diagnosis of KSHV-related MCD. Therapy with the antiherpesvirus agent cidofovir, antihuman interleukin-6 antibody BE-8, antiblastic chemotherapy, and combination antiretroviral agents did not achieve durable clinical or virologic remission of the disease. By contrast, administration of the anti-CD20 monoclonal antibody rituximab was well tolerated and allowed a 14-month remission of clinical symptoms and KSHV viremia. Rituximab should be added to the therapeutic armamentarium for KSHV-related MCD.

The aim was to evaluate whether the three-month CD4 cell counts are a reliable predictor of the long-term clinical outcome of HAART-treated patients, by an observational study of 585 patients initiating HAART in a clinical setting. Clinical failure was defined as the occurrence of new or recurrent AIDS-defining events or death, and was analysed by means of intention-to-treat, univariate and multivariate analyses. An adjusted Cox regression model was used to evaluate the effect of three-month CD4+ counts on clinical outcome. Clinical failure occurred in 65 patients (11.1%) during a median follow-up of 31 months (1-65) as a result of new AIDS-defining events (ADEs) in 48 patients, ADE recurrence in six, and death in 11. The mean (median; range) CD4+ counts were 156/microL (155; 4--529) in patients with and 362/microL (326; 18--1162) in patients without clinical failure (P.0001). Moreover, the proportion of patients with mean CD4+ counts200 microL was higher in those experiencing subsequent clinical failure (chi2: 41.11; P.00001). Multivariate analysis showed that baseline CD4+ counts50 microL, HIV-RNA100,000 copies/mL and AIDS at baseline predicted failure; after adjusting for three-month CD4+ counts, this marker was the only one independently associated with clinical failure (HR 2.93; 95% Cl: 1.16--7.38). The three-month immunologic response is a reliable predictor of long-term clinical outcome.

The objective was to evaluate the influence of immunological and virological markers on clinical outcome in patients receiving their first highly active antiretroviral therapy (HAART) regimen. Observational study of 585 patients initiating HAART in a clinical setting. Clinical failure was defined as the occurrence of new or recurrent AIDS-defining events or death and was analysed by means of intention-to-treat univariate and multivariate analyses. An adjusted Cox regression model was used to evaluate the effect of 3-month CD4 cell counts on clinical outcome. Clinical failure occurred in 55 patients (9.4%) during a median follow-up of 483 days (range 33--1334 days): 45 new AIDS--defining events (ADEs) in 38 ADE recurrence in six and death in 11. Twenty-four of the 45 new ADEs (53.4%) occurred during the first 3 months of HAART and 11 of 45 (24.4%) in the presence of CD4 cell counts > 200 x 10/6 cells/l. The mean (median range) CD4 counts were 144 x 10/6 cells/l (128 4--529) in patients with and 322 x 10/6 cells/l (288 14--1162) in patients without clinical failure (P < 0.0001). Moreover the proportion of patients with mean CD4 cell counts < 200 x 10/6 cells/l was higher in those experiencing subsequent clinical failure (x/2 test: 26.75; P < 0.00001). Multivariate analysis showed that baseline CD4 cell counts < 50 x 10/6 cells/l and AIDS at enrolment predicted failure; after adjusting for 3-month CD4 cell counts this marker was the only one independently associated with clinical failure (hazard risk 4.79; 95% confidence interval 1.40--16.47). The 3-month immunological response is a reliable predictor of long-term clinical outcome. (authors)

Cytokine production, prevalence of viral isolation, and surface marker expression of peripheral blood mononuclear cells (PBMCs) were analyzed in HIV+ individuals with different patterns of disease progression to establish correlations between these parameters. Thus, mitogen-stimulated in vitro production of interferon gamma (IFN-gamma) and interleukin 2 (IL-2) (type 1 cytokines), and of IL-4 and IL-10 (type 2 cytokines) as well as prevalence of viral isolation were evaluated in 26 HIV+ long-term nonprogressors (LTNPs), in 28 HIV+ patients with progressive HIV infection (PI), and in 24 HIV-seronegative controls (HCs). Surface expression of activation and nonactivation markers was also analyzed in a group of these donors. We report that (1) IL-2 and IFN-gamma production is reduced and IL-4 and IL-10 production is increased in PI patients compared to HCs and LTNPs; (2) prevalence of HIV isolation is lower in LTNPs compared to PI, and the primary viral isolates in LTNPs show a slow/low (S/L) phenotype; and (3) the elevated production of type 2 cytokines is paralleled by an increase in CD57+CD4+CD7- lymphocytes. Thus, whereas a high IL-2, high IFN-gamma/low IL-4, low IL-10 cytokine production pattern is present in HC and in LTNP HIV+, progression of HIV infection is associated with a low IL-2 low IFN-gamma/high IL-4, high IL-10 cytokine profile; increased prevalence of HIV isolation; and an augmented percentage of CD57+CD4+CD7- lymphocytes. These findings further confirm that a dominant type 1 cytokine profile together with reduced prevalence of virus isolation is associated with lack of progression in HIV infection.