Drug-induced interstitial lung disease during cancer therapies: expert opinion on diagnosis and treatment.

BACKGROUND: Drug-induced interstitial lung disease (DIILD) is a form of interstitial lung disease resulting from exposure to drugs causing inflammation and possibly interstitial fibrosis. Antineoplastic drugs are the primary cause of DIILD, accounting for 23%-51% of cases, with bleomycin, everolimus, erlotinib, trastuzumab-deruxtecan and immune checkpoint inhibitors being the most common causative agents. DIILD can be difficult to identify and manage, and there are currently no specific guidelines on the diagnosis and treatment of DIILD caused by anticancer drugs. OBJECTIVE: To develop recommendations for the diagnosis and management of DIILD in cancer patients. METHODS: Based on the published literature and their clinical expertise, a multidisciplinary group of experts in Italy developed recommendations stratified by DIILD severity, based on the Common Terminology Criteria for Adverse Events. RESULTS: The recommendations highlight the importance of multidisciplinary interaction in the diagnosis and management of DIILD. Important components of the diagnostic process are physical examination and careful patient history-taking, measurement of vital signs (particularly respiratory rate and arterial oxygen saturation), relevant laboratory tests, respiratory function testing with spirometry and diffusing capacity of the lung for carbon monoxide and computed tomography/imaging. Because the clinical and radiological signs of DIILD are often similar to those of pneumonias or interstitial lung diseases, differential diagnosis is important, including microbial and serological testing to exclude or confirm infectious causes. In most cases, management of DIILD requires the discontinuation of the antineoplastic agent and the administration of short-term steroids. Steroid tapering must be undertaken slowly to prevent reactivation of DIILD. Patients with severe and very severe (grade 3 and 4) DIILD will require hospitalisation and often need oxygen and non-invasive ventilation. Decisions about invasive ventilation should take into account the patient's cancer prognosis. CONCLUSIONS: These recommendations provide a structured step-by-step diagnostic and therapeutic approach for each grade of suspected cancer-related DIILD.

Cutaneous manifestations in a series of 417 patients with SARS-CoV-2 infection: epidemiological and clinical correlates of chilblain like lesions.

A variety of dermatological lesions have been described in COVID-19, although the prevalence and pathogenic relationship remain unclear particularly for chilblain-like lesions. Dermatological examination was performed in a prospective cohort of consecutive patients seen at the service for SARS-CoV-2 infection. Out of 417 patients with confirmed SARS-CoV-2 infection [median age 29.5 years (range 15-65); 62.5% males], dermatological lesions were detected in 7 (1.7%). Three patients had acral lesions; their age (range) was 15-29 years; all had a negative nasopharyngeal swab and developed IgG and/or IgM-specific antibodies; all presented none or mild symptoms. A fourth patient remained negative at repeated testing; mother, father and sister had a documented mild COVID-19. Non-acral lesions were observed in four older patients, with severe COVID-19. Chilblain-like lesions may be the sole manifestation of SARS-CoV-2 infection; their presence in asymptomatic school children and adolescents should be considered a potential signal of familial or community spread of the virus.

The increasing burden and complexity of multi-morbidity and polypharmacy in geriatric HIV patients: a cross sectional study of people aged 65 - 74 years and more than 75 years.

BACKGROUND: Geriatric Patients Living with HIV/AIDS (GEPPO) is a new prospective observational multicentre cohort consisting of all the HIV-positive geriatric patients being treated at 10 clinics in Italy, and HIV-negative controls attending a single geriatric clinic. The aim of this analysis of the GEPPO cohort was to compare prevalence and risk factors of individual non-communicable diseases (NCD), multi-morbidity (MM) and polypharmacy (PP) amongst HIV positive and HIV negative controls at enrolment into the GEPPO cohort. METHODS: This cross-sectional study was conducted between June 2015 and May 2016. The duration of HIV infection was subdivided into three intervals: < 10, 10-20 and > 20 years. The NCD diagnoses were based on guidelines defined criteria, including cardiovascular disease, hypertension, type 2 diabetes, chronic kidney disease, dyslipidaemia, chronic obstructive pulmonary disease. MM was classified as the presence of two or more co-morbidities. The medications prescribed for the treatment of comorbidities were collected in both HIV positive and HIV negative group from patient files and were categorized using the Anatomical Therapeutic Chemical (ATC) classification. PP was defined as the presence of five or more drug components other than anti-retroviral agents. RESULTS: The study involved a total of 1573 patient: 1258 HIV positive and 315 HIV negative). The prevalence of individual comorbidities was similar in the two groups with the exception of dyslipidaemia, which was more frequent in the HIV-positive patients (p <  0.01). When the HIV-positive group was stratified based on the duration of HIV infection, most of the co-morbidities were significantly more frequent than in control patients, except for hypertension and cardiovascular disease, while COPD was more prevalent in the control group. MM and PP were both more prevalent in the HIV-positive group, respectively 64% and 37%. CONCLUSIONS: MM and PP burden in geriatric HIV positive patients are related to longer duration of HIV-infection rather than older age per se.

Ageing with HIV: a multidisciplinary review.

INTRODUCTION: After the introduction of highly active antiretroviral treatment, the course of HIV infection turned into a chronic disease and most of HIV-positive patients will soon be over 50 years old. MATERIAL AND METHODS: This paper reviews the multiple aspects that physicians have to face while taking care of HIV-positive ageing patients including the definitions of frailty and the prevalence and risk factors of concomitant diseases. From a therapeutic point of view pharmacokinetic changes and antiretroviral-specific toxicities associated with ageing are discussed; finally therapeutic approaches to frailty are reviewed both in HIV-positive and negative patients. CONCLUSION AND DISCUSSION: We conclude by suggesting that the combined use of drugs with the least toxicity potential and the promotion of healthy behaviours (including appropriate nutrition and exercise) might be the best practice for ageing HIV-positive subjects.

Metformin improves putative longevity effectors in peripheral mononuclear cells from subjects with prediabetes. A randomized controlled trial.

BACKGROUND AND AIMS: Prediabetes increases cardiovascular risk and is associated with excess mortality. In preclinical models, metformin has been shown to exert anti-ageing effects. In this study, we sought to assess whether metformin modulates putative effector longevity programs in prediabetic subjects. METHODS AND RESULTS: In a randomized, single-blind, placebo-controlled trial, 38 prediabetic subjects received metformin (1500 mg/day) or placebo for 2 months. At baseline and after treatment, we collected anthropometric and metabolic parameters. Gene and protein levels of SIRT1, mTOR, p53, p66Shc, SIRT1 activity, AMPK activation, telomere length, and SIRT1 promoter chromatin accessibility were determined in peripheral blood mononuclear cells (PBMCs). Plasma N-glycans, non-invasive surrogate markers of ageing, were also analysed. Compared to baseline, metformin significantly improved metabolic parameters and insulin sensitivity, increased SIRT1 gene/protein expression and SIRT1 promoter chromatin accessibility, elevated mTOR gene expression with concomitant reduction in p70S6K phosphorylation in subjects' PBMCs, and modified the plasma N-glycan profile. Compared to placebo, metformin increased SIRT1 protein expression and reduced p70S6K phosphorylation (a proxy of mTOR activity). Plasma N-glycans were also favourably modified by metformin compared to placebo. CONCLUSION: In individuals with prediabetes, metformin ameliorated effector pathways that have been shown to regulate longevity in animal models. ClinicalTrials. gov identifier: NCT01765946 - January 2013.

Induced first abortion rates before and after HIV diagnosis: results of an Italian self-administered questionnaire survey carried out in 585 women living with HIV.

OBJECTIVES: The aim of the study was to investigate whether HIV diagnosis affected reproductive planning over time and to assess independent predictors of abortion overall and following HIV diagnosis. METHODS: Donne con Infezione da HIV (DIDI) is an Italian multicentre study based on a questionnaire survey carried out in 585 HIV-positive women between November 2010 and February 2011. The incidence and predictors of abortion were measured by person-years analysis and Poisson regression. RESULTS: The crude incidence rate of abortion was 18.8 [95% confidence interval (CI) 16.5-21.4] per 1000 person-years of follow-up (PYFU). Compared with women who terminated their pregnancy before HIV diagnosis, women who terminated their pregnancy after HIV diagnosis but before 1990 showed a 2.56-fold (95% CI 1.41-4.65) higher risk. During 1990-1999 and 2000-2010, HIV diagnosis was not significantly associated with outcome [adjusted rate ratio (ARR) 0.93 (95% CI 0.55-1.59) and ARR 0.69 (95% CI 0.32-1.48), respectively]. Age [ARR 0.96 (95% CI 0.94-0.99) per 1 year older] and injecting drug use [ARR 1.38 (95% CI 0.98-1.94)] were found to be predictors of abortion overall. After HIV diagnosis, being on combination antiretroviral therapy [ARR 0.54 (95% CI 0.28-1.02)], monthly income < €800 [ARR 1.76 (95% CI 0.99-3.12)], younger age [ARR 0.95 (95% CI 0.91-1.00) per 1 year older] and fear of vertical transmission [ARR 1.95 (95% CI 1.04-3.67)] were found to be independently associated with abortion. CONCLUSIONS: We observed a higher incidence of abortion compared with data available for the general Italian population. Awareness of HIV diagnosis was predictive of abortion only in the 1980s. Women with HIV infection are still worried about vertical HIV transmission. Interventions promoting HIV screening among women who plan to have an abortion and informative counselling on motherhood planning in the setting of HIV care are needed.

Where is West Nile fever? Lessons learnt from recent human cases in northern Italy.

West Nile disease in humans has been detected for the first time in Italy in two regions, Emilia-Romagna and Veneto. We conclude that also West Nile fever cases should be specifically targeted by surveillance.

The societal burden of HIV/AIDS in Northern Italy: an analysis of costs and quality of life.

This study aims to measure the direct and indirect costs of HIV/AIDS care and quality of life (QoL) of HIV-infected patients in Northern Italy. We conducted a prospective cohort study over 12 months, enrolling a sample of 121 patients with HIV infection from two cities in Northern Italy. Patients were surveyed at baseline and were followed-up at 6 and 12 months. To assess the relationship between costs and stage of disease, patients were categorized into three groups at baseline: "No HAART" (asymptomatic and never before on highly active antiretroviral therapy (HAART)), "Stable HAART" (HAART with mild HIV infection and no prior opportunistic infections) and "HAART failure" (primary HAART regimen was altered because of severe side effects or immunological failure). Direct medical costs were based on utilization of (day) hospital admissions, diagnostic procedures, laboratory tests, clinic visits, consultations and antiretroviral drug use. Indirect costs included production losses due to absence from work, reduced productivity at work and reduced unpaid labour participation. QoL was assessed by visual analogue scale. Parametric regression was used to estimate the expected value and the standard deviation of annual costs per patient. The expected value of total annual costs was 1818 euros and 9820 euros and 12,332 euros, for groups "No HAART", "Stable HAART" and "HAART failure" respectively. We estimated annual expected earnings as 14,994 euros and 10,811 euros and 9820 euros for the same respective groups. The expected value of QoL on a scale of 0-1 in these same patient groups was 0.80, 0.78 and 0.64. We conclude that indirect costs contribute substantially to total costs and are comparable in magnitude to the direct costs excluding antiretroviral drugs. The costs of inpatient care in our cohort were almost negligible compared to total costs. Despite being in treatment, many patients were still gainfully employed and generated substantial expected annual earnings.

A randomized study investigating the efficacy and safety of amprenavir in combination with low-dose ritonavir in protease inhibitor-experienced HIV-infected adults.

OBJECTIVES: To compare the safety and efficacy of amprenavir [APV/j Agenerase trade mark; GlaxoSmithKline, [Ware, UK; 600 mg twice a day (bid)] boosted with low-dose ritonavir (RTV, 100 mg bid) with those of other protease inhibitors (PIs) in PI-experienced HIV-infected patients. STUDY DESIGN: Parallel-group, randomized, open-label, multicentre study. METHODS: One hundred and sixty-three patients with HIV predicted to be sensitive to APV, another PI and a nucleoside reverse transcriptase inhibitor (NRTI) were randomly assigned to receive either APV boosted with low-dose RTV (APV/r) or a standard of care (SOC) PI with or without low-dose RTV. The non-inferiority of APV/r to the SOC PIs was assessed by time-weighted average change from baseline (AAUCMB) in plasma viral load (vRNA) at week 16. RESULTS: The antiviral response for APV/r bid was non-inferior to that for the SOC PI group: the vRNA AAUCMB mean treatment difference was 0.043 log(10) HIV-1 RNA copies/mL [95% confidence interval (CI)-0.250, 0.335]. APV/r bid was generally well tolerated. CONCLUSIONS: Results confirm the antiviral activity, short-term safety and tolerability of APV/r bid in PI-experienced patients.

Sarcoidosis and HIV infection: a case report and a review of the literature.

Sarcoidosis occurring in patients with AIDS is rare. This infrequent association has been attributed to the impairment of the immune system that may interfere with the granuloma formation in HIV infected patients. However, the introduction of highly active antiretroviral therapy (HAART) has brought about a substantial and sustained increase in CD4+ T lymphocyte cells, and has consequently led to the development of the so called "immune restoration disease". The case of an HIV infected man who developed sarcoidosis after the initiation of HAART is described. Skin nodule images and histological specimens are reported. The association between sarcoidosis and HIV infection is also reviewed.

Mediastinitis due to cryptococcal infection: a new clinical entity in the HAART era.

OBJECTIVES: Highly active antiretroviral therapy (HAART) produces a rapid decline in plasma HIV-1 RNA levels with concomitant immune reconstitution. Probably due to the enhanced immune function, shortly after starting HAART, some latent opportunistic infections precipitated. The aim of this study was to illustrate the results of a survey on Cryptococcus associated mediastinitis occurring after HAART introduction, carried out at a referral centre of Infectious Diseases in the north-east of Italy, between October 1999 and October 2000. METHODS: All consecutive HIV-positive patients, naive to HIV-protease inhibitor therapy, and diagnosed with culture-proven cryptococcal infection were included in the study. Clinical and immuno-virological parameters before HAART and subsequently for 12 months were evaluated. RESULTS: Three of five patients were diagnosed with cryptococcal mediastinitis within a median time of 90 days (range, 60-150) after commencing HAART and fluconazole prophylaxis. Diagnosis was established by lymph node biopsy alone. Clinical improvement was documented when systemic anti-fungal therapy was combined with surgical drainage of the suppurative lesions. The role of immune restoration was confirmed by the significant increase in CD4 cell count, the reduction of HIV-RNA to undetectable levels and the prominent inflammatory reactions of lymph nodes. CONCLUSIONS: Our report suggests that HIV-positive patients with prior cryptococcal systemic infection may present a re-exacerbation of atypical cryptococcosis as a manifestation of immune restoration, even when fluconazole prophylaxis is ongoing.

Splenic infarct during infectious mononucleosis.

We present a case of splenic infarct during infectious mononucleosis in a 17-y-old boy. The patient's condition improved without the need for surgery.

Antiapoptotic effects of IL-15 on pulmonary Tc1 cells of patients with human immunodeficiency virus infection.

In the early phases of human immunodeficiency virus (HIV) disease a T-cell alveolitis sustained by cytotoxic T lymphocytes (CTL) with anti-HIV activity occurs in the lung. With the progression of HIV disease, pulmonary CTL become infected and their cytotoxic activity declines. To investigate the potential causes leading to this phenomenon, we evaluated T cells obtained from the bronchoalveolar lavage (BAL) of 18 HIV-infected patients with T-cell alveolitis. BAL T cells were CD45R0+/CD8+ defined as Tc1 cells because they expressed cytoplasmic interferon gamma (IFN-gamma) and were CXCR3+/IL-12Rbeta2+. Furthermore, they bore the interleukin (IL)- 15 receptor, Fas antigen, and tumor necrosis factor receptor (TNFR) type II. When cultured for 24 h highly purified BAL T cells showed an excessive spontaneous apoptosis; after activation with anti-CD3 or ionomycin, the proportion of T cells undergoing cell death increased. Interestingly, we found a direct relationship between the predisposition to undergo spontaneous apoptosis and the levels of Fas expression by BAL T cells. Alveolar macrophages (AMs) expressed high levels of IL-15 which paralleled the intensity of T-cell infiltration in most patients. The predisposition of CD8 T cells to undergo cell death was downregulated by the incubation with IL-15; the protective effect of the cytokine was dose-dependent. Nonetheless, AMs also expressed proapoptotic molecules, including membrane TNF-alpha (mTNF-alpha). Based on these observations it may be suggested that an excessive, spontaneous, and activation-induced apoptosis of pulmonary lymphocytes may be observed in HIV lung and that AMs are major regulators of T-cell homeostasis.

Acquired immunodeficiency syndrome-related Kaposi's sarcoma regression after highly active antiretroviral therapy: biologic correlates of clinical outcome.

BACKGROUND: Kaposi's sarcoma (KS) is the most common cancer seen in subjects with acquired immunodeficiency syndrome (AIDS). KS etiology and pathogenesis are still ill defined, and no definite improvement in survival has been obtained with current chemotherapeutic regimens. This open prospective study was aimed at evaluating the clinical response of AIDS-related KS to highly active antiretroviral therapy (HAART), a combination of protease and reverse transcriptase inhibitors, as well as the relationship between clinical response, human immunodeficiency virus type 1 (HIV-1) burden, and antibody titer against human herpesvirus 8 (HHV8) proteins. PATIENTS AND METHODS: Fourteen KS patients were studied; 12 were in the poor-risk group. At given intervals, the patients underwent clinical examination, and their CD4(+) cell counts, plasma HIV-1 RNA levels, and antibody titers to lytic-phase ORF65 and latent-phase HHV8 proteins were determined. RESULTS: When last seen, the overall clinical response rate was 86% (median follow-up, 22 months); 10 complete and two partial responses were achieved, and two patients showed disease progression. All patients with complete or partial response showed a consistent decrease in HIV-1 RNA levels, with a corresponding increase in CD4(+) cell counts; HIV-1 RNA levels in the two progressors remained persistently high, despite a change in HAART. HHV8 ORF65 antibody titers were generally higher in patients with extensive skin or mucosal/visceral involvement versus patients with limited disease; no differences in latent-phase HHV8 antibody titers were observed in relation to tumor burden. CONCLUSION: The findings indicate that antiretroviral therapy with protease inhibitors is effective for AIDS-related KS; the clinical response was correlated with a decrease in plasma HIV-1 RNA levels and an increase in CD4(+) lymphocytes, whereas antibody levels to the lytic-phase HHV8 protein were influenced by the extent of tumor involvement.

Human immunodeficiency virus type 1 modulates telomerase activity in peripheral blood lymphocytes.

The effect of human immunodeficiency virus type 1 (HIV-1) on telomerase activity in peripheral blood lymphocytes (PBL) was examined. Telomerase is an enzyme that is involved in mechanisms that control cell life span and replicative potential. HIV-1 reduced telomerase activity in in vitro-infected PBL and impaired enzyme activation upon cell stimulation. Telomerase activity was significantly lower in PBL from 23 HIV-1-infected patients than in PBL from healthy donors and significantly increased during highly active antiretroviral therapy (HAART) in 10 patients who had both a virological and an immunological response and in 5 and 8 patients with a virological or an immunological response, respectively. Further analyses of fractionated cells revealed that telomerase activity increased mainly in CD4(+) lymphocytes. Overall, these findings demonstrate that HIV-1 infection down-modulates telomerase activity and suggest that both the HIV-1 decline and immunorestoration in response to HAART contribute to increased telomerase activity in CD4(+) lymphocytes.

Genital human papillomavirus types in immunocompetent and immunodepressed women in northeast Italy: prevalence and cytomorphological correlations.

OBJECTIVE: We evaluated the prevalence of genital human papillomavirus (HPV) types in correlation with cytomorphological findings in patients at different risk for cervical intraepithelial neoplasia living in northeast Italy. METHODS: Exfoliated cervicovaginal cells from 943 women, who were divided into three groups, were analyzed by polymerase chain reaction. RESULTS: Overall, HPV prevalence rates were 7%, 38%, and 52%, respectively. The single most frequent type was HPV 16 (18%), followed by types 6, 31, 53, 58, 61, and novel/unidentified (5-7%); other types had a frequency <5%. Infection with multiple types was present in 12%. In HIV-infected women, HPV infection was correlated with lower CD4 level and higher viral load; HGSILs were correlated only with a lower CD4 count, and no correlations were found for LGSILs. CONCLUSIONS: HGSILs were associated with high-risk types, mainly HPV 16 (40%). LGSILs, instead, were associated with a broad spectrum of low-risk and high-risk types.