Tiziana Tieghi

Changes in inflammatory biomarkers in HCV-infected patients undergoing direct acting antiviral-containing regimens with or without interferon

Background and aims Increased levels of chemokine interferon-gamma (IFN-γ)-inducible protein-10 (CXCL10), soluble CD163 (sCD163) and soluble CD14 (sCD14) have been reported in HCV infection. The aim of this study was to compare, sCD163 and sCD14 levels in HCV-infected patients undergoing direct acting antiviral (DAA)-containing regimens with or without interferon (IFN). Methods sCD163, sCD14 and CXCL10 were longitudinally measured by ELISA in 159 plasma samples from 25 HCV-infected patients undergoing IFN-based treatment plus telaprevir or boceprevir and 28 HCV infected subjects treated with DAA IFN-free regimens. Twenty-five healthy donors (HD) were included as controls. Results At baseline CXCL10, sCD163 and sCD14 levels were higher in HCV-infected patients than in HD. CXCL10 and sCD163 levels were significantly decreased in responder (R) patients who achieved sustained virological response (SVR), with both IFN-based and IFN-free regimens, while they were persistently elevated in non-responders (NR) patients who stopped IFN-based treatments because of failure or adverse events. Conversely, sCD14 levels were apparently unchanged during therapy, but at the end of treatment the levels reached normal ranges. Comparing the two regimens, the extent of CXCL10 reduction was more pronounced in patients undergoing DAA IFN-free therapies, whereas sCD163 and sCD14 reduction was similar in the two groups. Interestingly, only in IFN-based regimens baseline sCD163 levels were significantly higher in NR than in R patients, while in the IFN-free treatment group also patients with high sCD163 plasma levels obtained SVR. At the end of therapy, even if the biomarkers were largely decreased, their levels remained significantly higher compared to HD. Only in the early fibrosis stages, sCD163 values tended to normalize. Conclusions These results indicate that IFN-free regimens including newer DAA induce an early and marked decrease in circulating inflammatory biomarkers. However, the full normalization of biomarkers was not obtained, especially in patients with advanced fibrosis, thus underlying the need for a treatment in the early stages of HCV infection.

Liver Fibrosis in HCV Monoinfected and HIV/HCV Coinfected Patients: Dysregulation of Matrix Metalloproteinases (MMPs) and Their Tissue Inhibitors TIMPs and Effect of HCV Protease Inhibitors

An imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) may contribute to liver fibrosis in patients with hepatitis C (HCV) infection. We measured the circulating levels of different MMPs and TIMPs in HCV monoinfected and HIV/HCV coinfected patients and evaluated the potential for anti-HCV therapy to modulate MMP and TIMP levels in HCV subjects. We analyzed 83 plasma samples from 16 HCV monoinfected patients undergoing dual or triple anti-HCV therapy, 15 HIV/HCV coinfected patients with undetectable HIV load, and 10 healthy donors (HD). Levels of MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10, TIMP-1, and TIMP-2 were measured by a SearchLight Multiplex Immunoassay Kit. MMP-2 and MMP-9 were the highest expressed MMPs among all the analyzed samples and their levels significantly increased in HCV monoinfected and HIV/HCV coinfected subjects compared to HD. TIMP-1 levels were significantly higher in HCV and HIV/HCV subjects compared to HD and were correlated with liver stiffness. These findings raise the possibility of using circulating TIMP-1 as a non-invasive marker of liver fibrosis in HCV infection. A longitudinal study demonstrated that MMP-9 levels significantly decreased (40% reduction from baseline) in patients receiving dual as well as triple direct-acting antivirals (DAA) anti-HCV therapy, which had no effect on MMP-2, TIMP-1, and TIMP-2. As the dysregulation of MMP-2 and MMP-9 may reflect inflammatory processes in the liver, the decrease of MMP-9 following HCV protease inhibitor treatment suggests a positive effect on the reduction of liver inflammation.

Postpartum fever in the presence of a fibroid: Sphingomonas paucimobilis sepsis associated with pyomyoma

BackgroundPyomyoma is a life-threatening complication of uterine leiomyoma. It may occur in post- menopausal women, during pregnancy and in the postpartum period. Fever may be the only manifestation during the early stages of the disease. We detail the first reported case of postpartum pyomyoma-related sepsis due to Sphingomonas paucimobilis, a Gram-negative bacillus that is gaining recognition as an important human pathogen.Case presentationA woman presented with an asymptomatic uterine fibroid and a two-week history of fever during the postpartum period. Suppurative uterine leiomyoma was diagnosed, and blood cultures grew Sphingomonas paucimobilis. The myoma was surgically removed from the uterus without hysterectomy. Intravenous antimicrobial therapy was given for fifteen days, and the patient was discharged from hospital in good condition.ConclusionPyomyoma should be considered in broad differential diagnosis of postpartum fever. This case highlights a unique disease manifestation of S. paucimobilis, an emerging opportunistic pathogen with increasing significance in the nosocomial setting.

Active HCV infection is associated with increased circulating levels of interferon-gamma (IFN-γ)-inducible protein-10 (IP-10), soluble CD163 and inflammatory monocytes regardless of liver fibrosis and HIV coinfection

BACKGROUND AND OBJECTIVE Interferon-gamma (IFN-γ)-inducible protein-10 (IP-10), soluble (s) CD163 and sCD14 play an important role in the pathogenesis of HCV and HIV infection and are involved in inflammation and liver fibrosis. The aim of the present study was to evaluate at a single time point, plasma soluble biomarkers and inflammatory monocytes subsets in different groups of subjects: (i) HIV monoinfected patients on suppressive ART; (ii) HIV/HCV coinfected patients on ART, with undetectable HIV viremia (including either subjects who had active HCV replication or those who cleared HCV); (iii) HCV monoinfected individual with active viral replication. METHODS Hundred and twenty-nine plasma samples were analyzed including HCV and HIV monoinfected patients, HIV/HCV coinfected patients, with active HCV infection (AHI) or with HCV viral clearance (VHC) and healthy donors (HD). Levels of IP-10, sCD163 and sCD14 were measured by ELISA. Absolute cell counts of monocyte subpopulations were enumerated in whole blood by using flow cytometric analyses. RESULTS IP-10 and sCD163 plasma levels were higher in HCV monoinfected and in AHI coinfected pts compared to HIV monoinfected and HD, whereas sCD14 levels were higher only in HIV monoinfected patients. Considering the degree of fibrosis, sCD163 and sCD14 levels positively correlated with kPa values (as assessed by fibroscan) and FIB-4 in HCV monoinfected group. On the other hand, IP-10 did not correlate with the fibrosis stage and it was found increased also in patients with low fibrosis. Moreover, we found an increase of the inflammatory NCM subset, in non-cirrhotic HCV subjects, while no alterations were observed in HIV, AHI and VHC. CONCLUSIONS Our study suggests a scenario in which active HCV infection is associated with a strong pro-inflammatory state, even in the initial stage of liver fibrosis, regardless the presence of HIV coinfection, thus underlying the need of an early anti-HCV treatment.

Atypical presentation of crusted (Norwegian) scabies

cognitive and motor deficits. HIV seropositivity was discovered in 1998 (CDC Stage C3). The patient had undetectable HIV load and CD4 count = 166/mmc load, following a PI-based therapy. Differential diagnosis included exacerbation of psoriasis, atopic eczema, paraneoplastic syndrome or mycotic infection. Examination of skin scrapings from crusted plaques revealed the presence of mites. Localized crusted (Norwegian) scabies was diagnosed. The patient was treated with A 67-year-old HIV-infected man presented with hyperkeratotic lesions on the hands and nails (Fig. 1a, b). He had a history of HIV-associated encephalopathy with persistent

Late onset invasive pneumococcal disease in a liver transplanted patient: beyond the Austrian syndrome

Invasive disease caused by Streptococcus pneumoniae is a major cause of morbidity and mortality in high‐risk individuals with severe comorbidities, including asplenia, chronic alcoholism, and altered immune status. The risk of invasive pneumococcal disease has been significantly higher in transplant patients compared with the general population. Here, we report an unusual case of a disseminated pneumococcal infection with meningitis, endocarditis, spondylodiscitis, and muscle abscess in an asplenic patient on chronic immunosuppressive therapy for liver transplantation performed 17 years before.

Quantitative ultrasound (QUS) in HIV-infected patients: a reliable and low-cost technique for bone health assessment

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK

Legionella pneumophila pneumonia during telaprevir-based triple therapy for HCV chronic hepatitis.

The recent introduction in clinical practice of two directacting antiviral agents (DAAs), such as telaprevir and boceprevir, has dramatically improved the rate of virologic response in patients with chronic hepatitis C virus (HCV) genotype 1 [1]. However, challenges to the use of DAAs in combination with pegylated interferon alfa (PegIFN) ? ribavirin (RBV) include the potential for drug–drug interactions and a lower safety profile, especially in patients with compromised liver function. A high incidence of severe infections has been recently reported in a cohort of HCV cirrhotic patients receiving triple antiviral therapy [2]. Here, we report the case of a non-cirrhotic HCVinfected patient who developed severe Legionella pneumophila pneumonia during telaprevir-based triple therapy. A 65-year old man chronically infected with HCV genotype 1b who did not achieve a sustained virologic response after a prior course of PegIFN/RBV therapy was recruited to start triple anti-HCV therapy. He had a history of controlled diabetes mellitus and hypertension. The patient underwent three cycles of standard antiviral treatment before treatment initiation with DAAs, the last of which was started in July 2007 and consisted of PegIFNa2b 120 lg once a week ? RBV 1,200 mg daily. This treatment was stopped at week 12 because the drop in HCV-RNA levels was less than 2 log compared to the initial viremia. The patient was therefore considered to be a null responder to the previous standard of care therapy based on IFN and RBV. At the time of enrollment to triple therapy, the patient had increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (73 IU/ L and 124 IU/L, respectively). Haemoglobin was 14.8 g/ dL; white cell count, 6,140 cell/mmc; platelet count, 166,000/mmc. Albuminemia was 4.5 g/dL, and coagulation parameters and renal function were normal. Plasma HCV-RNA was 6.5 log10 IU/mL, and the IL28 polymorphism CT was detected. Liver ultrasound fibroelastography (fibroscan) documented a liver stiffness of 11.8 kPa (Metavir score F3). Screening for autoantibodies was negative; serology for immunodeficiency virus, hepatitis B, hepatitis A, and syphilis was negative. In March 2013, antiHCV triple therapy was started with a combination of PegIFNa2a (180 lg/weekly), weight-based dose of RBV (1,200 mg/daily), and the NS3-4A serine protease inhibitor telaprevir (2,250 mg daily). After 4 weeks of treatment, the plasma HCV-RNA dropped to undetectable levels and remained negative during subsequent evaluations. During treatment, the platelet count fell (65,000/mmc) and haemoglobin decreased to 11.2 g/dL. After 8 weeks of treatment a maculo-papular erythematous eruption involving the anterior surface of both legs was observed. No constitutional symptoms were present, visible mucous membranes were normal, and no lymphoadenopathy developed. Blood tests were stable and eosinophils were within normal range. Skin lesions fully resolved within 4 days with antihistamines and hydration. After 11 weeks of triple therapy, the patient was hospitalized because of abrupt onset of fever, cough, diarrhea, and dyspnea. On admission the patient was slightly confused. Physical examination revealed a pulse rate of 88 beats/min, a respiratory rate of T. Tieghi R. Marocco V. Belvisi C. Del Borgo S. Savinelli M. Lichtner C. M. Mastroianni Department of Public Health and Infectious Diseases, Fondazione Eleonora Lorillard Spencer Cenci, Sapienza University, Latina, Italy

Bartonella henselae infection presenting with ocular and hepatosplenic manifestations in an immunocompetent child.

To the Editors: Disseminated Bartonella henselae infection is rarely described in immunocompetent subjects. Here, we report a case of an immunocompetent child who developed bartonellosis with hepatosplenic and ocular manifestations. A 10-year-old previously healthy boy was admitted to the Infectious Diseases Unit, Latina, Italy, because of a 2-week history of fever (T max 38.4°C) and recent onset of painless diminished visual acuity in the left eye. He had had no significant ocular problems in the past. There was no history of recent travel and trauma. He had no vomiting and did not complain of headache. The patient had been scratched on his left flank by a kitten 6 weeks before the onset of symptoms. On admission, his oral temperature was 38°C, heart rate 90 beats per minute, respiratory rate 22 breaths per minute and blood pressure 120/70 mm Hg. There was lymph node swelling in the left inguinal region and splenomegaly. A nearly healed lesion was present at site of scratch. The lungs and heart were normal as was the neurologic evaluation. The white blood cell count was normal and hemoglobin was 11 g/dL. Liver and kidney function tests were normal. C-reactive protein was 2.51 mg/dL (normal range 0–0.5 mg/dL), erythrocyte sedimentation rate was 42 mm/h. Cultures of blood samples and urine were sterile. Ophthalmologic evaluation showed mild conjunctival hyperemia without eye discharge and no signs of anterior uveitis. Fundus examination showed focal chorioretinitis on left eye with a circumscribed whitish retinal lesion due to a granuloma with serious retinal detachment along the inferotemporal arcade and small punctiform whitish lesions in the inferotemporal quadrant. The optic nerve appeared normal and the vitreous was clear. The right eye was normal. On the basis of fundoscopy, a diagnosis of left chorioretinitis was made. Ultrasound and magnetic resonance imaging of the abdomen demonstrated mild homogenous splenomegaly and multiple hypodense areas within the spleen and liver parenchyma. Serology was negative for Epstein-Barr virus, cytomegalovirus, hepatitis viruses, human immunodeficiency virus, syphilis, toxoplasma and Francisella. On the other hand, the serology for B. henselae (indirect immunofluorescence antibody IFA) was positive (IgG>1:256). Polymerase chain reaction for B. henselae DNA from peripheral blood sample was negative. Treatment with azythromicin (500 mg/daily) was started, and the patient was treated for 3 weeks. We observed a gradual resolution of the granuloma and flattening of the lesion that resulted in a chorioretinal scar with disappearance of the punctiform lesions. A complete resolution of clinical symptoms and hepatosplenic lesions was obtained within 3 weeks (Fig. 1). Cat-scratch disease is a benign, selflimiting zoonotic disease caused by the bacillus B. henselae. Typical cat-scratch disease presentations include fever, regional lymphadenopathy and a nontender papule in the scratch line. Other manifestations such as ocular involvement, encephalopathy, hepatosplenic infection, osteomyelitis and endocarditis are exceptional in immunocompetent subjects. We believe that this is the first report of a immunocompetent pediatric patient presenting with both chorioretinitis and hepatosplenic lesion as an initial manifestation of systemic bartonellosis.

Persistent high plasma levels of sCD163 and sCD14 in adult patients with measles virus infection

Background and aims Measles is an infectious disease that represents a serious public health problem worldwide, being associated with increased susceptibility to secondary infections, especially in the respiratory and gastrointestinal tracts. The aim of this study was to evaluate sCD163 and sCD14 levels in measles virus (MV) infected patients, as markers of immune activation, in order to better understand their role in the pathogenesis of the disease. TNF-α plasma levels were also evaluated. Methods sCD163, sCD14 and TNF-α were measured by ELISA in plasma samples of 27 MV infected patients and 27 healthy donors (HD) included as controls. Results At the time of hospital admission, sCD163 and sCD14 levels were significantly higher in MV infected patients than in HD, while a decrease in TNF-α levels were found even if without statistical significance. sCD163 and sCD14 levels were significantly decreased after two months from acute infection compared to hospital admission although they remained significantly higher compared to HD. TNF-α levels increased significantly during the follow-up period. Considering clinical parameters, sCD163 levels positively correlated with aspartate aminotransferase, white blood cell count and neutrophils rate, while negatively correlated with the lymphocyte percentage. sCD14 levels positively correlated with the neutrophil and lymphocyte percentages. Conclusions These results indicate that, despite the resolution of symptoms, an important macrophage/monocyte activation persists in measles patients, even after two months from infection.