How We Treat Drug-Susceptible Pulmonary Tuberculosis: A Practical Guide for Clinicians.

Tuberculosis (TB) remains one of the leading causes of morbidity and mortality worldwide and pulmonary TB (PTB) is the main variant responsible for fueling transmission of the infection. Effective treatment of drug-susceptible (DS) TB is crucial to avoid the emergence of Mycobacterium tuberculosis-resistant strains. In this narrative review, through a fictional suggestive case of DS PTB, we guide the reader in a step-by-step commentary to provide an updated review of current evidence in the management of TB, from diagnosis to post-treatment follow-up. World Health Organization and Centre for Diseases Control (CDC) guidelines for TB, as well as the updated literature, were used to support this manuscript.

Scientific literature on neglected tropical diseases: a bibliometric analysis.

Neglected tropical diseases (NTDs) are a group of diseases mainly affecting people in low- and middle-income Countries. The aim of this study was to perform a bibliometric analysis of the scientific literature on NTDs. Using the MeSH database, we quantified the number of publications on MEDLINE targeting each NTD, which were published from 1 January 1999 to 31 January 2019. In order to weight the number of publications targeting a given NTD according to the total number of publications/year, we calculated a Yearly Publication Index (YPI) for each NTD/year. Linear regression was used to determine if there was a significant increase or decrease of YPI over time. In order to weight the number of publications according to disease burden (expressed in Disability-adjusted life years - DALYs) we calculated a DALYs-weighted Publication Index (DWPI) for each NTD. The highest absolute number of publications focused on leishmaniasis, dengue and Chagas disease; the lowest on tungiasis, dracunculiasis, chromoblastomycosis and yaws. The number of publications significantly increased for chikungunya, chromoblastomycosis, dengue, leishmaniasis, snakebite envenoming, and yaws. It significantly decreased for ascariasis, cysticercosis, echinococcosis, leprosy, lymphatic filariasis, mycetoma, onchocerciasis. Leprosy had the highest DWPI (i.e. the highest number of publication considering the burden of disease), followed by Chagas disease; lymphatic filariasis had the lowest, followed by onchocerciasis. Overall, lymphatic filariasis, onchocerciasis and ascariasis presented the worst scenario, with both very few publications compared with their disease burden and a decreasing number of publications.

Update of drug-resistant tuberculosis treatment guidelines: A turning point.

In December 2022 World Health Organization released a new treatment for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) guideline. The main novelty of this update is two new recommendations (i) a 6-month treatment regimen composed of bedaquiline, pretomanid, linezolid (600 mg), and moxifloxacin (BPaLM) is recommended in place of the 9-month or longer (18-month) regimens in MDR/RR-TB patients, now including extensive pulmonary TB and extrapulmonary TB (except TB involving central nervous system, miliary TB and osteoarticular TB); (ii) the use of the 9-month all-oral regimen rather than longer (18-months) regimen is suggested in patients with MDR/RR-TB and in whom resistance to fluoroquinolones has been excluded. Longer (18-month) treatments remain a valid option in all cases in which shorter regimens cannot be implemented due to intolerance, drug-drug interactions, extensively drug-resistant tuberculosis, extensive forms of extrapulmonary TB, or previous failure. The new guidelines represent a milestone in MDR/RR-TB treatment landscape, setting the basis for a shorter, all-oral, more acceptable, equitable, and patient-centered model for MDR/RR-TB management. However, some challenges remain to be addressed to allow full implementation of the new recommendations.

Risk Factors for Nontuberculous Mycobacteria Infections in Solid Organ Transplant Recipients: A Multinational Case-Control Study.

BACKGROUND: Risk factors for nontuberculous mycobacteria (NTM) infections after solid organ transplant (SOT) are not well characterized. Here we aimed to describe these factors. METHODS: Retrospective, multinational, 1:2 matched case-control study that included SOT recipients ≥12 years old diagnosed with NTM infection from 1 January 2008 to 31 December 2018. Controls were matched on transplanted organ, NTM treatment center, and post-transplant survival greater than or equal to the time to NTM diagnosis. Logistic regression on matched pairs was used to assess associations between risk factors and NTM infections. RESULTS: Analyses included 85 cases and 169 controls (59% male, 88% White, median age at time of SOT of 54 years [interquartile range {IQR} 40-62]). NTM infection occurred in kidney (42%), lung (35%), heart and liver (11% each), and pancreas transplant recipients (1%). Median time from transplant to infection was 21.6 months (IQR 5.3-55.2). Most underlying comorbidities were evenly distributed between groups; however, cases were older at the time of NTM diagnosis, more frequently on systemic corticosteroids and had a lower lymphocyte count (all P < .05). In the multivariable model, older age at transplant (adjusted odds ratio [aOR] 1.04; 95 confidence interval [CI], 1.01-1.07), hospital admission within 90 days (aOR, 3.14; 95% CI, 1.41-6.98), receipt of antifungals (aOR, 5.35; 95% CI, 1.7-16.91), and lymphocyte-specific antibodies (aOR, 7.73; 95% CI, 1.07-56.14), were associated with NTM infection. CONCLUSIONS: Risk of NTM infection in SOT recipients was associated with older age at SOT, prior hospital admission, receipt of antifungals or lymphocyte-specific antibodies. NTM infection should be considered in SOT patients with these risk factors.

Schistosomiasis, strongyloidiasis and Chagas disease: the leading imported neglected tropical diseases in Italy.

BACKGROUND: In recent years, an increasing number of individuals affected by neglected tropical diseases (NTDs) have been observed in Italy, due to migration, international travels and climate changes. Reliable data on the current NTD epidemiology in Italy and the health system preparedness on this issue are not available. METHODS: We report the results of a survey on selected NTDs (schistosomiasis, strongyloidiasis, echinococcosis, Chagas disease, leishmaniasis, cysticercosis, filariasis and scabies) in nine Italian sentinel centres, in order to investigate their occurrence throughout the country and identify which ones are a priority for public health interventions, development of protocols for case management, and training activities. To explore the preparedness of the centres, we investigate the availability of specific diagnostic tools and drugs, needed for the management of the most common NTDs. We also reviewed and summarized the available national policies, recommendations and guidelines on NTDs in Italy. RESULTS: Overall, 4123 NTDs cases were diagnosed in nine Italian centres within a 7-year period (2011-2017). Schistosomiasis and strongyloidiasis were the most common NTDs, accounting for about one-third each of all the diagnosed cases, followed by Chagas disease. The number of cases showed a significant trend to increase over time, mainly due to foreign-born subjects. Serology for Schistosoma spp. and Strongyloides stercoralis was available in seven and five centres, respectively. Agar plate stool culture for S. stercoralis was available in three sites. Ivermectin and praziquantel were always available in six centres. Six national policies, recommendations and guidelines documents were available, but for the most part, they are not fully implemented yet. CONCLUSIONS: This survey showed how some NTDs, such as schistosomiasis and strongyloidiasis, are becoming more common in Italy, due to multiple components. A list of seven key actions was proposed, in order to improve diagnosis, management and control of NTDs in Italy.

Predictors of time to sputum smear conversion in patients with pulmonary tuberculosis under treatment.

Sputum acid-fast bacilli smear conversion is a fundamental index of treatment response and reduced infectivity in patients with pulmonary tuberculosis (P-TB). To date, there are no models to predict the time to sputum conversion based on patient characteristics. This study aims to ascertain the time to sputum conversion in patients with smear-positive P-TB under treatment, and the variables associated with time to smear conversion. We retrospectively evaluated the time to sputum smear conversion of 89 patients with smear-positive P-TB undergoing treatment at the S. Orsola-Malpighi University Hospital, Bologna (Italy), a referral centre for the diagnosis of TB. Multivariate Cox regression analysis was performed to document variables independently associated with time to conversion. Median time to sputum smear conversion was 24 days (IQR 12-54); the sputum smear converted within the first 2 months of treatment in 78.7% patients. Multivariate Cox regression analysis showed that older age, high baseline mycobacterial load detected by Xpert MTB/RIF, and severity of lung involvement are predictors of persistent smear positivity. The identification of risk factors delaying smear conversion allowed us to develop predictive models that may greatly facilitate the management of smear-positive patients in terms of the duration of respiratory isolation and treatment.

18F-FDG PET/CT in visceral leishmaniasis: uptake patterns in the context of a multiannual outbreak in Northern Italy.

OBJECTIVES: Visceral leishmaniasis (VL) is the most severe manifestation of the infection caused by the protozoan Leishmania, recently on increase in Italy and Spain. The aim of the study was to describe FDG uptake patterns in VL patients (pts) who underwent 18F-FDG PET/CT. METHODS: A retrospective monocentric study of pts who underwent FDG PET/CT between 2008 and 2017 and later diagnosed with VL was performed. Semi-quantitative parameters were calculated in FDG-positive lesions: SUVmax, SUVmax spleen/SUVmax liver ratio (SLR), SUVmax focal/diffuse spleen ratio (FDR). RESULTS: Overall, 23 pts were included. PET/CT was negative in 2 immunocompromised pts, positive in 21/23 (91%) [6 spleen only, 2 spleen + nodes, 7 spleen + bone marrow (BM), 4 spleen + BM + nodes, 1 spleen + BM + lung, 1 BM only + nodes, 2 nodes only]. Splenic involvement was demonstrated in 20/23 (87%) pts. Two different splenic patterns were observed: diffuse (13/20 pts, mean spleen SUVmax = 7.3 ± 4.2 [4.0-14.1], mean SLR = 2.2 ± 1.6 [1.3-6.7]) and focal over diffuse (7/20 pts, mean SUVmax = 12.6 ± 4.5 [9.5-20.5], mean SLR = 2.8 ± 0.8 [2.1-4.4], mean FDR = 2.1 ± 0.8 [1.2-3.6]). Extra-splenic FDG-avid findings were detected in 15/21 pts (65%): bone marrow in 13/15 (mean SUVmax = 4.0 ± 1.3 [2.8-6.0]), nodes in 67/15 and lung in 1/15. CONCLUSIONS: PET/CT demonstrated splenic FDG uptake in all immunocompetent VL pts; two splenic patterns (diffuse/focal over diffuse) were observed and indistinguishable from splenic involvement by other disorders. The most frequent extra-splenic FDG-positive sites were BM and lymph nodes. Considering the potential disease aggressiveness and recent outbreaks in north-eastern Italy, VL should be considered in the differential diagnosis of FDG-positive splenic findings in pts from endemic areas or reporting travels to endemic countries.

Systematic Tuberculosis Screening in Asylum Seekers in Italy.

The preliminary findings of a tuberculosis (TB) screening of asylum seekers performed in a reception center located in northern Italy reveal a post-entry screening prevalence rate of 535 per 100000 individuals screened. This result shows that systematic use of chest radiography is a useful tool for active TB screening among asylum seekers in Italy.

Serological and molecular tools to diagnose visceral leishmaniasis: 2-years' experience of a single center in Northern Italy.

The diagnosis of visceral leishmaniasis (VL) remains challenging, due to the limited sensitivity of microscopy, the poor performance of serological methods in immunocompromised patients and the lack of standardization of molecular tests. The aim of this study was to implement a combined diagnostic workflow by integrating serological and molecular tests with standardized clinical criteria. Between July 2013 and June 2015, the proposed workflow was applied to specimens obtained from 94 in-patients with clinical suspicion of VL in the Emilia-Romagna region, Northern Italy. Serological tests and molecular techniques were employed. Twenty-one adult patients (22%) had a confirmed diagnosis of VL by clinical criteria, serology and/or real-time polymerase chain reaction; 4 of these patients were HIV-positive. Molecular tests exhibited higher sensitivity than serological tests for the diagnosis of VL. In our experience, the rK39 immunochromatographic test was insufficiently sensitive for use as a screening test for the diagnosis of VL caused by L. infantum in Italy. However, as molecular tests are yet not standardized, further studies are required to identify an optimal screening test for Mediterranean VL.

Febrile rhabdomyolysis of unknown origin in refugees coming from West Africa through the Mediterranean.

OBJECTIVES: Cases of undiagnosed severe febrile rhabdomyolysis in refugees coming from West Africa, mainly from Nigeria, has been observed since May 2014. The aim of this study was to describe this phenomenon. METHODS: This was a multicentre retrospective observational study of cases of febrile rhabdomyolysis reported from May 2014 to December 2016 in 12 Italian centres. RESULTS: A total of 48 cases were observed, mainly in young males. The mean time interval between the day of departure from Libya and symptom onset was 26.2 days. An average 8.3 further days elapsed before medical care was sought. All patients were hospitalized with fever and very intense muscle aches. Creatine phosphokinase, aspartate aminotransferase, and lactate dehydrogenase values were abnormal in all cases. The rhabdomyolysis was ascribed to an infective agent in 16 (33.3%) cases. In the remaining cases, the aetiology was undefined. Four out of seven patients tested had sickle cell trait. No alcohol abuse or drug intake was reported, apart from a single reported case of khat ingestion. CONCLUSIONS: The long incubation period does not support a mechanical cause of rhabdomyolysis. Furthermore, viral infections such as those caused by coxsackievirus are rarely associated with such a severe clinical presentation. It is hypothesized that other predisposing conditions like genetic factors, unknown infections, or unreported non-conventional remedies may be involved. Targeted surveillance of rhabdomyolysis cases is warranted.

Multidetector CT urography in urogenital tuberculosis: use of reformatted images for the assessment of the radiological findings. A pictorial essay.

Urogenital tuberculosis (UGTB) is the most common form of extrapulmonary TB and is responsible for a destructive inflammation of the renal parenchyma and urinary tract often leading to the loss of kidney function. For these reasons, the early diagnosis of this disease, once considered disappeared in developed countries, is very important to establish a prompt and efficient treatment. However, the subtle and non-specific symptoms, often represented by recurrent and persistent lower urinary tract symptoms, can confound and delay the diagnosis. Therefore, an adequate and comprehensive imaging study is necessary in patients with persistent urinary tract infections not responding to the antibiotics and can suggest the hypothesis although bacteriological and/or histologic analysis is required for a definitive diagnosis. In the past years, intravenous urography (IVU) has allowed a comprehensive study of the urinary excretory tract, promoting the knowledge of the radiological findings of this disease. Nowadays, computed tomography urography (CTU), with the implementation of multidetector (MD) technology, has replaced IVU in all its indications; the MDCTU improves the assessment of renal and urinary tract lesions using reformatted images [such as multiplanar reconstruction (MPR) and maximum intensity projection (MIP)]. Therefore, our paper aims to provide a guide for radiologist for searching the classic signs of UGTB on MDCTU, encouraging the use of the MPR and MIP reformatted images.

First evaluation of QuantiFERON-TB Gold Plus performance in contact screening.

Identifying latently infected individuals is crucial for the elimination of tuberculosis (TB). We evaluated for the first time the performance of a new type of interferon-γ release assay, QuantiFERON-TB Plus (QFT-Plus), which includes an additional antigen tube (TB2), stimulating both CD4+ and CD8+ T-cells in contacts of TB patients.Contacts were screened for latent TB infection by tuberculin skin test, QFT-Plus and QuantiFERON-TB Gold in Tube (QFT-GIT).In 119 TB contacts, the overall agreement between QFT-Plus and QFT-GIT was high, with a Cohen's κ of 0.8. Discordant results were found in 12 subjects with negative QFT-GIT and positive QFT-Plus results. In analyses of markers of TB exposure and test results, the average time spent with the index case was the strongest risk factor for positivity in each of these tests. The difference in interferon-γ production between the two antigen tubes (TB2-TB1) was used as an estimate of CD8+ stimulation provided by the TB2. TB2-TB1 values >0.6 IU·mL-1 were significantly associated with proximity to the index case and European origin.QFT-Plus has a stronger association with surrogate measures of TB exposure than QFT-GIT in adults screened for latent TB infection. Interferon-γ response in the new antigen tube used an indirect estimate of specific CD8+ response correlates with increased Mycobacterium tuberculosis exposure, suggesting a possible role in identifying individuals with recent infection.

Tenofovir/emtricitabine/efavirenz plus rosuvastatin decrease serum levels of inflammatory markers more than antiretroviral drugs alone in antiretroviral therapy-naive HIV-infected patients.

OBJECTIVES: Statins are lipid-lowering drugs that exhibit anti-Inflammatory and immune-modulatory properties, leading to a reduction of serum levels of C-reactive protein (CRP) in the general population. DESIGN: To assess the anti-inflammatory effects of statins in HIV-infected patients, because very limited data are available today. METHODS: Longitudinal, observational study of HIV-infected adult patients naive to antiretroviral therapy who started tenofovir/emtricitabine/efavirenz and were followed-up for 48 weeks. Patients with baseline normal cholesterol level and taking only antiretroviral drugs (group A) were compared to those with baseline hypercholesterolemia who received rosuvastatin (10 mg daily) in association with antiretroviral treatment (group B). The primary observation was change in serum markers of inflammation (high-sensitivity C-reactive protein [hsCRP], interleukin-6 [IL-6], interleukin-8 [IL-8]) and tumor necrosis factor-α [TNF- α]) in both groups, whereas secondary observations include variations in CD4 lymphocyte count, HIV viral load, and occurrence of adverse events. RESULTS: Eighty-six patients were enrolled into the study: 46 in group A and 40 in group B. After 48 weeks, patients treated with antiretroviral therapy plus rosuvastatin had significantly greater decreases in serum concentrations of all Inflammatory markers than those taking antiretroviral therapy only. Changes in mean levels of hsCRP and TNF-α were -35.1% and -22.4% in group B and -8.2% and 5.4% in group A, respectively (P < .001, for both parameters). No significant differences in immunovirological parameters and safety profile were reported across the compared groups. CONCLUSIONS: Our findings suggest that tenofovir/emtricitabine/efavirenz plus rosuvastatin has a greater antiInflammatory effect than antiretroviral drugs only.

Prevalence of sub-clinical vertebral fractures in HIV-infected patients.

Although the increased prevalence of low bone mineral density among HIV-infected patients has raised concern for increased fracture risk, few investigations have evaluated fracture rates. Increasing evidence indicates that HIV patients are at higher risk of osteoporotic fractures compared to the general population. This is a very important issue, because fragility fractures are complications with a significant prognostic value. Our study performed lateral spine X-ray to assess the prevalence of sub-clinical vertebral fractures in 202 HIV patients. Factors associated with vertebral fractures were also investigated. The prevalence of vertebral fractures was significantly high (23.3%): 14 subjects had SDI (spine deformity index)= 1, 22 SDI=2-3 and 11 SDI >4. Differences in the prevalence of vertebral fractures between naive and ART experienced patients was 18% vs. 24%, respectively. Furthermore, patients had a high prevalence of severe and multiple fractures; in 19 patients (40%) fractures involved multiple vertebrae. Patients with vertebral fractures were significantly older, with renal insufficiency and steroid use more frequently than subjects with no fractures. Our data suggest that the prevalence of vertebral fractures in HIV infection may be higher than expected, and lateral spine X-ray has a role in the screening of bone disease, at least in patients with a significant risk of fragility fractures.

Prevalence of renal disease within an urban HIV-infected cohort in northern Italy.

BACKGROUND: Renal disease is an increasingly recognized noninfectious comorbidity associated with human immunodeficiency virus (HIV) infection. METHODS: Our retrospective, cross-sectional study evaluated prevalence of nephropathy among HIV-infected patients followed up in our outpatient clinic during the year 2011. Renal dysfunction and chronic kidney disease (CKD) were defined as estimated glomerular filtration rate (eGFR) <90 ml/min per 1.73 m(2) and as renal damage or eGFR <60 ml/min per 1.73 m(2) over a 3-month or greater period, respectively. RESULTS: We enrolled 894 HIV-infected patients with a mean age of 44.2 years and a mean current CD4 lymphocyte count of 508 cells/mm(3). The prevalence of renal dysfunction and CKD was 27.4 and 21.3 %, respectively. Older age, male gender, hypertension, diabetes, proteinuria, hypertriglyceridemia, lower nadir CD4 cell count, current use of tenofovir or tenofovir plus a ritonavir-boosted protease inhibitor were independently associated with renal dysfunction. CONCLUSION: Renal dysfunction is a frequent comorbidity among HIV-infected persons and requires a careful clinical and laboratory monitoring of renal function.